COMMENTARIES PRIMARY RESEARCH 65 O Cannabis: What have we done by legalizing marijuana 6 Knowledge, practices, and attitudes of certified medical in pregnancy? marijuana consultants in Washington state Daniel B. Hardy Louise Kaplan, Tracy Klein, Marian Wilson, Janessa Graves 69 Freedom of expression litigation and the harms of cannabis 13 Knowledge, attitudes and current practices of Palestinian Melanie L. McPhail and Jacob J. Shelley internists toward aspirin prescription Iyad Ali, Hamzeh Al Zabadi, Nisreen R. Dayyeh 74 Cannabis and driving research: Lessons from an unlikely teacher 17 ‘Wrong treatment’: Doctors’ take on medical futility in a Liliana Alvarez low-resource ICU Tonia Chinyelu Onyeka, Ikem Okonkwo, Uzochukwu, 78 Growing up high: Understanding the impacts of Aniebie, Innocent Ugwa, Felix Chukwuneke, David Agom adolescent cannabis use on mental health and brain Development 23 Effect of weight loss diets on biochemical parameters Steven R. Laviolette and anthropometric measurements in prolactinoma patients Esen Yesil, Gül Kızıltan, Cüneyd Anıl, Mehtap Akçil Ok, Nilüfer Bayraktar PERSPECTIVES 83 Palliative care for homeless patients: A practical approach 29 Perioperative blood loss in South African primary hip for medical students arthroplasty patients Mithunan Ravindran, Nishwa Shah, Naheed Dosani Mohamed S. Khattab and Yoshan Moodley 85 A medical student’s comparison between pre-medical and pre-clinical education Yue Bo Yang REVIEWS 35 Current status and prospects for the application of cannabinoids in organ transplantation INTERVIEWS Brian Earl 87 Interview with Dr. Snead Happy Inibhunu and Annie Yu 41 Effectiveness of an educational intervention to increase human papillomavirus knowledge in high-risk populations: 91 Interview with Dr. Ruth Ross A systematic review Mana Modares and Jeff Park Edwin N. Mogaka, Ahmed A. Fadairo, Kristin L. Cannon, Olusola A. Sadiku 95 Interview with Dr. Alan Bell Nicholas Scrivens 48 Physicians in prehospital care: A review of the clinical and economic evidence Daniel Kapustin, Sparsh Shah

All articles are externally peer-reviewed with the exception of poetry, short stories and book reviews. All manuscripts are internally reviewed. Informed consent practices and any conflicts of interest are specified in the articles if applicable.

Front cover illustration by Li Mona

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Preface

Dear UTMJ Reader,

We are excited to present Volume 96, Issue 3 of the University of emerging research addresses many of the gaps that currently exist Toronto Medical Journal, which focuses on the important and timely on this topic. In this issue of the University of Toronto Medical Journal, topic of Cannabis. Research has identified several potentially we will highlight recent advances in cannabis research and discuss beneficial effects of cannabis and cannabis-based products, with the impact of legalization in Canada. promising applications for various diseases, including childhood This is the final issue of theUniversity of Toronto Medical Journal’s epilepsy, multiple sclerosis, mood disorders, palliative care and 96th volume. We are very proud of the issues that we have published chronic pain.1 In 2001, the Marihuana Medical Access Regulations over this past year and would like to sincerely thank members of were enacted in Canada which allowed individuals to legally the editorial team for all of the hard work that went into preparing possess and use medicinal cannabis. Since this time, the number each issue. We are also grateful to the patrons that continue to of individuals authorized to use medicinal cannabis has grown support the University of Toronto Medical Journal and the authors that exponentially.2 However, the level of clinical evidence available to have allowed us to showcase their important work. We hope that support cannabis and cannabinoids as pharmacotherapy remains you enjoy reading this issue as much as we enjoyed preparing it. limited for most disorders.1 Concerns have also been raised regarding the potential adverse effects of cannabis use, including Appreciatively, the effects of smoke inhalation on the respiratory system, the risk for developing cannabis use disorder, the neurodevelopmental effects Mazen El-Baba and Mark Lukewich of cannabis on the adolescent brain and safety issues surrounding the potential for impaired driving.3 Not surprisingly, the clinical utility of cannabis and cannabis-based products remains an active area of debate among physicians.4 On October 17, 2018, Canada became the second country to formally legalize recreational cannabis use on a national scale. It References 1. Hill KP. Medical use of cannabis in 2019. JAMA. 2019; doi: 10.1001/ was anticipated that legalization of cannabis, and regulation of its jama.2019.11868. [Epub ahead of print] production and sale, would decrease adolescent access and reduce 2. Health Canada. 2019. Market data under the Access to Cannabis for Medical Purposes Regulations. Retrieved August 1, 2019 from https://www.canada.ca/ the harms associated with illegal distribution. Concerns have been en/health-canada/services/drugs-medication/cannabis/licensed-producers/ raised about the need to better understand the short-term and market-data.html. long-term consequences of cannabis use. Now more than ever, 3. Memedovich KA, Dowsett LE, Spackman E, Noseworthy T, Clement F. The adverse health effects and harms related to marijuana use: an overview review. patients are looking to healthcare professionals to educate them CMAJ Open. 2018; 6:E339–E346. about the harms and benefits of cannabis use for recreational and 4. Fitzcharles MA, Shir Y, Häuser W. Medical cannabis: strengthening evidence in medicinal purposes. It is important that we remain informed as the face of hype and public pressure. CMAJ. 2019; 191:E907-E908.

UTMJ • Volume 96, Number 3, June 2019 3 A student-run scientific publication since 1923

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The University of Toronto Medical Journal (UTMJ) was established in 1923 and is Canada’s oldest student run medical journal. We strive to uphold the UTMJ’s legacy of excellence by publishing interesting and timely research articles for our esteemed readers. Medical trainees continue to be important contributors to many of the research articles published by the UTMJ. We recognize the value in student research and are proud to serve as an outlet for this work. The UTMJ recently established three awards to acknowledge outstanding submissions from medical trainees in each of our issues. We would like to congratulate the following award winners for the current issue on Artificial Intelligence in Healthcare:

First Prize Freedom of Expression Litigation and the Harms of Cannabis Melanie L. McPhail and Jacob J. Shelley

Second Prize Current Status and Prospects for the Application of Cannabinoids in Organ Transplantation Brian Earl

Third Prize Palliative Care for Homeless Patients: A Practical Approach for Medical Students Mithunan Ravindran, Nishwa Shah, Naheed Dosani

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UTMJ • Volume 96, Number 3, June 2019 5 Primary Research

Knowledge, practices, and attitudes of certified medical marijuana consultants in Washington state

Louise Kaplan (PhD)1; Tracy Klein (PhD)1; Marian Wilson (PhD)2; Janessa Graves(PhD)2

1Washington State University Vancouver College of Nursing, VLIB 210, 14264 NE Salmon Creek Ave, Vancouver, WA, USA 2Washington State University Spokane College of Nursing, 103 E. Spokane Falls Blvd, Spokane, WA, USA

Introduction Abstract egalization of marijuana use is changing globally. In Background: Washington is the only U.S. state to 2018, Canada joined Uruguay in legalizing recreational recognize and certify the medical marijuana consultant marijuana for adult use, 17 years after legalizing medical marijuanaL use.1 In 2018, a constitutional court in South Africa role. Medical marijuana customers have the option to use the services of a consultant for advice on the selection of ruled the private use of marijuana legal, while in the United States (U.S.), policies vary from state to state.2 Medical cannabis use is marijuana products that may benefit a qualifying terminal partially or fully legal in a total of 21 countries worldwide including or debilitating medical condition, the risks and benefits Australia, Chile, Israel, Mexico, and Turkey.2 Policy shifts of this of these products, and the risks and benefits of methods nature demand monitoring and evaluation to assure unintended of administration of these products. The purpose of this consequences do not occur. study was to investigate of the knowledge, practices, and In the U.S., Washington State’s original medical marijuana law attitudes regarding medical marijuana among certified was created by a ballot measure in 1998.3 Recreational marijuana medical marijuana consultants in Washington State, became legal in the state in 2012 through another ballot measure. and to identify sources of information used by medical However, retail marijuana stores did not open until July 2014.4 The marijuana consultants to advise patients regarding the Washington State Legislature merged the medical and recreational use of marijuana for medical conditions. marijuana systems in 2015 and concurrently created the medical Methods: A cross-sectional mixed-mode survey was marijuana consultant role.5 Washington is the first and only state administered to a random sample of 360 Washington in the U.S. to recognize and authorize this role. A consultant is State medical marijuana consultants selected from the a non-medical provider certified by the state who may provide state Department of Health’s list of 740 consultants with medical marijuana customers with information about marijuana 6 active certification as of December 2017. use. This article describes the knowledge, practices, and attitudes Results: Most respondents (84–100%) correctly of Washington State’s medical marijuana consultants. identified conditions that qualify a patient to receive Among the 34 states, the District of Columbia, Guam, and an authorization to use medical marijuana. Fewer Puerto Rico that have laws allowing medical marijuana and cannabis programs, only Minnesota, New York, and Connecticut respondents (8–31%) accurately identified conditions that require a pharmacist to dispense medical cannabis products.7 In do not qualify a patient to receive a medical marijuana Washington State, a medical marijuana patient has the option to authorization, such as depression and anxiety. Consultants obtain assistance from the medical marijuana consultant whose heartily endorsed marijuana for medical conditions and role is defined in state law. All medically endorsed marijuana retail believed it carries little risk. Many felt the required training stores are required to have a certified medical marijuana consultant for the consultant role did not sufficiently prepare them available to provide services to patients.8 The consultant may be to understand scientific information regarding marijuana the store owner, employee, or a volunteer.9 benefits and risks, although they expressed reliance on Certified consultants may assist a medical marijuana customer this course for counseling patients. in a retail store with the selection of products that may benefit a Conclusions: While consultants were generally qualifying terminal or debilitating medical condition, describe the knowledgeable regarding law and practice, additional risks and benefits of these products, and describe the risks and training is advised to clarify both current evidence and benefits of methods of administration of the products. Consultants current health implications of marijuana, especially for may not provide medical advice, diagnose conditions, recommend mental health conditions. State or national expansion of changing current treatment(s) in place of marijuana, or open and legal recognition of medical marijuana should include evidence-based training policies for those in positions to influence the public’s purchase and use of marijuana for health conditions. Corresponding Author: Louise Kaplan [email protected]

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Knowledge, practices, and attitudes of certified medical marijuana consultants in Washington state

use actual products to demonstrate their use.6 The role of the hosted online using the Qualtrics® survey software and was available medical marijuana consultant is delineated in state law and rule. in paper form for participants who preferred print medium. The A certified consultant must be age 21 years or older, complete researchers’ Institutional Review Board deemed the study exempt a 20 hour Department of Health approved training program, from human subjects review. and possess a cardio-pulmonary resuscitation certification.9 The Potential participants were mailed an introductory letter training program must include at least 6 topics such as information followed by an email message describing the study and inviting about the terminal or debilitating conditions that qualify a patient them to participate. Both invitations included a web link and access for a medical marijuana authorization, the short and long-term code unique to each participant to access the web version of the effects of cannabinoids, safe handling of marijuana products, and questionnaire. After 1 week, up to six additional contacts were the medical marijuana law.6 made to non-respondents (two postcards, three emails, and one Washington State law does not stipulate the Department of paper questionnaire with a prepaid return envelope). A crosswalk Health (DOH) or Liquor and Cannabis Board (LCB) evaluate file developed to send reminders to non-respondents was destroyed or oversee the consultants.6 Investigation of a consultant occurs at the conclusion of the survey. Participation in this study was only when a complaint is filed.9 Consultants are the primary anonymous and confidential. As an incentive, an external link person interfacing with cannabis consumers who have received an was available to provide contact information for entry in a random authorization. The consumer may interact with the consultant on a drawing for a $50 gift card. regular basis and consistently more often than with the health care professional who provided the medical marijuana authorization. Analysis The aims of this study were to describe the knowledge, practices, We performed statistical analysis using Stata/MP version 14.2 and attitudes regarding medical marijuana among certified medical to obtain descriptive statistics on the sample’s demographics and marijuana consultants in Washington State and to identify sources to summarize the responses to the closed-ended survey questions of information used by medical marijuana consultants to advise using frequencies and percentages. Open-ended items were patients regarding the use of marijuana for medical conditions. tabulated using content analysis to provide an understanding of the respondents’ perspectives.12 Words and phrases with common Methods meanings were grouped into major categories to define concepts A cross-sectional mixed-mode survey was administered to from participant perspectives using standard approaches for inter- a random sample of 360 Washington State medical marijuana coder reliability. consultants selected from the Department of Health’s list of 740 consultants with active certification as of December 2017. Results From the random sample of 360 medical marijuana consultants Questionnaire invited to participate in the study, 101 fully completed and 17 The study’s 16-item questionnaire based on Washington State partially completed the survey yielding an overall response rate law and prior well-validated survey instruments identified in the of 32.8%. The sample was almost evenly divided between males extant literature.3,10,11 Staff from the Washington State Department and females (43% and 42%, respectively, with a 15% non-response of Health’s medical marijuana program served as content experts rate for this question). The average age was 37.4 years (standard to review the questionnaire. The revised instrument contained 15 deviation (SD) 12.9 years) and the median was 33 years (interquartile closed-ended questions regarding knowledge of state law, attitudes range 27–45). All but 13 participants obtained their certification in about medical marijuana, and current practice as a medical 2016 and 2017. The majority (83%) identified as white and 78% marijuana consultant. For example, one question asked consultants of participants were working or volunteering in a Washington State to select from a list of conditions those that qualify an individual for retail store as a medical marijuana consultant. More than half a medical marijuana authorization. This required the respondent (58%) indicated that their medical marijuana consultant training to distinguish qualified conditions from conditions not approved. course prepared them well, very well, or extremely well for their Conditions not approved were selected based on a review of work, although their open-ended comments revealed additional medical marijuana laws in other states with qualifying conditions suggestions for the course improvement. other than those in Washington State law. In another question, the respondent was asked to use a Likert scale ranging from strongly Knowledge of qualified conditions agree to strongly disagree to express attitudes about medical Most respondents (84–100%) correctly identified conditions marijuana use. One open-ended question invited respondents to that qualify a patient to receive a medical marijuana authorization share anything they believed was important for the researchers to (Figure 1). Comparatively fewer respondents (8–31%) accurately know. The demographic data collected included the respondent’s identified conditions that do not qualify a patient to receive a sex, age, race/ethnicity, and which training course was completed medical marijuana authorization, such as depression and anxiety. and in what year. The entire questionnaire is available at https:// The proportion of respondents who indicated that they did not labs.wsu.edu/medicalmarijuanasurvey/. know whether a condition qualified for authorization ranged from 0–11% for qualified conditions, and 4–22% for non-qualified Survey administration conditions. The survey was administered between February 6, 2018 and March 30, 2018 with multiple contacts to non-responders through a university survey research center. The survey instrument was

UTMJ • Volume 96, Number 3, June 2019 7 Primary Research

Knowledge, practices, and attitudes of certified medical marijuana consultants in Washington state

Answered correctly

Answered incorrectly

Don’t know

Figure 1. Medical marijuana consultant knowledge regarding qualified conditions for medical marijuana in Washington State, 2018. Note: Horizontal axis indicates the percent of all respondents for each question (sample size indicated). Legally qualifying conditions for medical marijuana in Washington State are indicated with underlined text. Symbols denote the following: *Hepatitis C with debilitating nausea or intractable pain unrelieved by standard treatments or medications; **Crohn’s disease with debilitating symptoms unrelieved by standard treatments or medications; †glaucoma either acute or chronic, with increased intraocular pressure unrelieved by standard treatments and medications; ‡diseases, including anorexia, which result in nausea, vomiting, wasting, appetite loss, cramping, seizures, muscle spasms, or spasticity, when these symptoms are unrelieved by standard treatments or medications; §intractable pain unrelieved by standard medical treatments and medications.

Knowledge of laws about marijuana authorization that patients in the state’s database could possess more marijuana terms and consultant services than those not in the database. Most respondents correctly identified statements regarding Respondents reported that they obtained information about regulations related to possession of or growing marijuana (74– medical marijuana risks and benefits from training courses (85%), 89%) and health plan coverage for medical marijuana (84%) other consultants (72%), patients (68%), and websites (55%). A (Table 1). Regulations relating to criminal sanctions appeared similar pattern was observed for sources of information about to be less well known. For example, 37% correctly indicated which type of marijuana product a customer should select (Figure that healthcare professionals who can provide authorizations for 2). Scientific journals were identified as sources of information for medical marijuana cannot be arrested or prosecuted under state marijuana risks and benefits by only 14% of respondents and as law for advising patients about medical use of marijuana. Eighty- sources of information about which type of marijuana product seven percent of respondents knew that the statement “Employers a consumer should select by 19% of respondents. Licensed are required to provide an accommodation in the workplace for healthcare professionals served as sources of information for the medical use of marijuana,” was inaccurate. The majority of risks and benefits of medical marijuana and product selection by respondents exhibited accurate knowledge regarding authorized 34% and 50% of respondents, respectively. medical marijuana consultant services (Table 1). Attitudes toward medical marijuana Practices Respondents strongly endorsed statements that were Almost all respondents correctly identified the legally supportive of medical marijuana such as, “The FDA should authorized functions of the consultant role (Table 1). One reclassify marijuana so it is no longer a schedule I drug.” with exception is the 23% of respondents who did not know they may which 97% strongly agreed (Figure 3). Attitudes regarding the provide instruction and demonstrate to customers the proper use of potential deleterious health impacts of marijuana were supported marijuana products. A little more than half (58%) of respondents less frequently. For example, few respondents (9% and 10%, stated they use the knowledge gained from their training outside of respectively) strongly or somewhat agreed that using marijuana the retail setting, which is not allowed by law. Also notable was that poses serious mental or physical health risks. Twenty-eight percent 89% correctly selected the quantity a medical marijuana patient agreed that marijuana can be addictive. could possess, and 87% knew that a healthcare professional could authorize more than the standard amount allowed for possession Open-ended responses under Washington law. Over two-thirds (80%) correctly identified One open-ended survey item allowed participants to write in anything they believed was important for the researchers to know

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Knowledge, practices, and attitudes of certified medical marijuana consultants in Washington state

Medical marijuana consultant knowledge about authorizing the use of medical Table 1. Medical marijuana training course marijuana and services a medical marijuana consultant is permitted to provide at the retail outlet in Washington State, 2018 Other medical marijuana consultants Reports from patients

Authorization terms for medical Correct Answered Answered Don’t Websites marijuana use response correctly incorrectly know Licensed HC professionals Amount of marijuana a qualifying pa- Yes 92 (89.3) 7 (6.8) 4 (3.9) Family & friends tient entered into the state’s database Retail store employees may possess (n = 103) Marijuana industry magazines Additional amount a health care profes- Yes 90 (87.4) 5 (4.9) 8 (7.8) Scientific journals sional may recommend a qualifying Any other sources patient be allowed to grow and possess Books (n = 103)

Employers must provide workplace Yes 90 (86.5) 8 (7.7) 6 (5.8) Percent of respondents Information about which type of marijuana product a customer should select accommodation (n = 104) Information about medical marijuana risks and benefits Health plans are liable for reimburse- No 87 (83.7) 6 (5.8) 11 (10.6) Figure 2. Information sources used by medical marijuana consultants in ment (n = 104) Washington State, 2018. N = 101. HC, health care professionals. All qualifying patients may possess the No 82 (79.6) 17 (16.5) 4 (3.9) same amounts of marijuana products (n = 103)

Amount a qualifying patient or Yes 76 (73.8) 23 (22.3) 4 (3.9) designated provider entered into the state’s database may grow or possess (n = 103)

All children under age 18 must be in Yes 72 (70.6) 22 (21.6) 8 (7.8) the database (n = 102)

All adults must be in the database (n No 54 (52.4) 48 (46.6) 1 (1.0) = 103) Percent of respondents A person supervised for a criminal No 48 (46.6) 18 (17.5) 37 (35.9) conviction may never be a qualifying patient (n = 103) Marijuana The FDA Training Healthcare There are Healthcare There are Marijuana Using Using helps should about professionals significant professionals significant can be marijuana marijuana All health care professionals are not No 38 (36.9) 47 (45.6) 18 (17.5) patients who reclassify medical should have physical should mental addictive poses poses subject to criminal sanctions or civil suffer from marijuana marijuana continuing health recommend health (n=100) serious serious chronic, so that is should be education benefits marijuana benefits physical mental consequences for advising a patient debilitating no longer a incorporated about medical to using as a medical to using health risks health risks about medical marijuana (n = 103) medical schedule I into marijuana marijuana therapy marijuana (n=101) (n=100) condition drug healthcare prior to (n=99) (n=99) (n=99) (n=100) (n=101) professional authorizing Selling or donating topical products Yes 36 (35.0) 35 (34.0) 32 (31.1) education its use for with a THC concentration < 0.3% to (n=101) patients qualifying patients (n = 103) (n=100) Strongly or somewhat agree Neutral Strongly or somewhat disagree ICU Length of Stayb 2.03 ± 2.36 ± 5.33 ± 7.45 12.82 2.04 2.47 ±14.97 Figure 3. Medical marijuana consultant attitudes towards marijuana and medical marijuana, Washington State, 2018. Note: Respondents were asked Allowed medical marijuana consultant Correct Answered Answered Don’t to report their level of agreement for each of the listed questions. services response correctly incorrectly know

Offer to diagnose or cure any disease, No 101 0 (-) 0 (-) injury, pain, or health problem physical (100.0) or mental by the use of marijuana (n Discussion = 101) Medical marijuana consultants serve a legislatively determined Advise a customer about the safe Yes 100 0 (-) 0 (-) role in the dispensing of marijuana to qualified medical patients in handling and storage of marijuana (n (100.0) = 100) Washington State. Respondents in our sample were best informed about aspects of the law related to their work functions. However, Modify or eliminate treatment not No 98 (98.0) 1 (1.0) 1 (1.0) involving medical marijuana (n = 99) gaps were evident regarding consultants’ knowledge about the

Assist with the selection of products Yes 97 (97.0) 2 (2.0) 1 (1.0) relationship between Washington State’s medical marijuana (n = 100) law and available scientific evidence. Consultants expressed Describe risks and benefits of product Yes 94 (95.9) 2 (2.0) 2 (2.0) overwhelming support for medical marijuana and its legalization. administration (n = 98) They frequently relied upon information about medical marijuana Describe risks and benefits of products Yes 94 (93.1) 4 (4.0) 3 (3.0) obtained in the 20-hour certification course. Open-ended (n = 101) comments indicated that some questioned the quality and rigor of Instruct on and demonstrate proper use Yes 73 (73.0) 23 (23.0) 4 (4.0) of marijuana (n = 100) the course. One stated that “Much of the course I took seemed more geared toward business owners/managers...not necessarily geared toward the medical benefits/risks and how to be a medical Note: Values in columns indicate n (%). marijuana consultant.” about their experience as a marijuana consultant. Responses Knowledge centered around the following four general categories with Consultant knowledge varied regarding qualifying conditions, supporting comments: 1) the need for more marijuana research, 2) their certified role, and aspects of the law relevant to sales in the the need for improved marijuana education for health professionals retail stores where they work. Almost all respondents correctly and consultants, 3) systematic barriers in patient access to marijuana identified health conditions that qualify an individual for a medical products, and 4) endorsement of the benefits of marijuana. marijuana authorization. In contrast, two-thirds or more incorrectly

UTMJ • Volume 96, Number 3, June 2019 9 Primary Research

Knowledge, practices, and attitudes of certified medical marijuana consultants in Washington state identified or did not know the health conditions that do not qualify the quantity that can be sold to medical marijuana patients based an individual for an authorization, including anxiety, depression, on registration in the database, it is possible some consultants may Parkinson’s disease, and rheumatoid arthritis. Knowledge on sell more or less product than state law allows. qualifying conditions is important because consultants assist While 58% of respondents endorsed the required consultant medical marijuana patients with selection of products and advise certificate course as preparing them well for their role, the majority on their use. They also may interact with retail customers who (73%) chose the course as their primary source of knowledge for do not have an authorization card. However, several participants product selection and practices with medical marijuana patients. commented in the open-ended item that advice on the medical For most (85%), the information on marijuana risks and benefits benefits of marijuana is something they discuss frequently with came from the course and secondarily came from other consultants friends and family despite the law authorizing their services only and patients. Very little information was gleaned from scientific when acting as an owner, employee, or volunteer of a licensed retail journals or books. This may be related to a lack of access to outlet and only for medical marijuana patients. academic journals and books or a lack of familiarity with scientific While no comparable surveys of consultants exist, knowledge studies. One recommendation to strengthen the foundation of of surveyed consultants can be compared to a study of Minnesota the consultant role would be adding course content that explains pharmacists. Although the two roles are not professionally how to evaluate the strength and quality of marijuana research equivalent, in Minnesota, New York, and Connecticut, pharmacists and evidence. This could influence consultants’ attitudes regarding are the only authorized personnel who may dispense marijuana health risks. For example, adults using marijuana for medical to patients. Minnesota pharmacists were surveyed in 2015 prior purposes have reported adverse effects including nausea and to implementation of the state’s medical marijuana program. vomiting, confusion, and hallucinations.14 It is possible that patients Pharmacists had variable knowledge of qualifying conditions experiencing negative effects from marijuana do not recognize, and appeared to have an incomplete understanding about their attribute, and/or report them. They may simply stop purchasing role, the pharmacotherapy of marijuana, and many of the state’s marijuana products thereby skewing the information consultants regulations.13 In our study, as with the Minnesota pharmacists’ receive from patients regarding health effects. study, knowledge gaps have the potential to affect decisions of patients legally seeking medical marijuana. Pharmacists Attitudes in the Minnesota study expressed concerns regarding their Knowledge gaps have the potential to influence attitudes, knowledge of marijuana pharmacology, pharmacokinetics, and which may help explain consultants’ attitudes about marijuana’s pharmacodynamics as compared to their knowledge for other mental health benefits, physical risks, and risks of addiction. Many medications.13 For Washington’s consultants, it is important to consultants did not endorse the belief that marijuana has addictive consider if the consultant certification course adequately prepared qualities or risk for serious physical or mental side effects. Of note, them for their job. Almost half (42%) of respondents indicated two of the top conditions medical marijuana patients report using their certification course “not at all” or only “somewhat well” marijuana to manage are anxiety and depression.15 Findings from prepared them for their practice with patients. As one respondent animal studies indicate that activating the endocannabinoid system stated, “The course wasn’t about patient safety, patient care - it may help minimize stress and depression,16 yet the conclusions was strictly about getting products off the shelf and making sure from the National Academies of Sciences, Engineering, and you followed all of the laws and processed authorizations into the Medicine [NAS]17 suggest that the strength of the evidence is databank correctly.” variable regarding the benefits of marijuana use for mental health Knowledge of the law is essential for proper implementation. symptoms. Findings from this study suggest a potential need for improvements In their comprehensive review, the NAS determined to the medical marijuana consultant course and/or that required “substantial evidence” links marijuana use and the development of continuing education should be designed to correct the identified schizophrenia or other psychoses, and “moderate evidence” links deficits. It may be useful to involve practicing consultants in marijuana use to increased symptoms of mania and hypomania educational development decisions to target the knowledge in individuals diagnosed with bipolar disorders.17,18 Marijuana domains most critical to their interactions with medical marijuana use is also linked to a small increased risk for the development of patients. depressive disorders, and major depressive disorder is a risk factor for the development of problem marijuana use.17,19 Cannabis use Practices has more recently been linked to the development of opioid use State certification is required to practice in the consultant role, disorder20 and other substance use disorders, including cannabis and by law consultants may only use their knowledge to assist use disorder.21 Moderate evidence finds an increased incidence of qualifying patients even though recreational marijuana users suicidal ideation, suicide attempts, and suicide completion among purchase products in the same retail store.6 Within the retail setting, heavier marijuana users.17,22 Yet, 85% of our surveyed consultants the law specifies limitations to practice. One of the most explicit reported that there are significant mental health benefits to using is the consultant may not “offer to diagnose or cure any disease, marijuana, while only 9% indicated mental health risks exists, injury, pain, or health problem physical or mental by the use of suggesting an under-appreciation for potential adverse mental marijuana.” Consultants were generally knowledgeable regarding health effects. More than half of the consultants responded the constraints of their certified practice, as evidenced by more incorrectly that depression or anxiety are qualifying conditions than 90% correct responses on the items regarding allowable for legal use of medical marijuana and fewer than one-third of services. Nonetheless, with almost one-third not informed about respondents believed marijuana could be addictive. In 2010, the

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Knowledge, practices, and attitudes of certified medical marijuana consultants in Washington state

Washington State Medical Quality Commission denied a patient effective at a local or national level. Communication regarding use petition to include bipolar disorder, severe depression, and social of marijuana for medical or non-medical purposes impacts public anxiety as qualifying conditions for medical marijuana due to lack attitudes regarding harm reduction.31 A nationalized context may of scientific evidence supporting use as compared to available be more effective in communicating risk reduction in terms of therapies.23 consistency of message and delivery than the use of a role such as A large majority (90%) of respondents endorsed significant the consultant. Canadian legalization of marijuana was promoted physical health benefits to using marijuana, while 76% strongly as a strategy to protect public health and safety by preventing or somewhat disagreed that its use poses serious physical health access to youth and increasing public awareness of health risks.32 risks. Studies linking marijuana use to cancer are limited by The Canadian Medical Association (CMA), however, considers methodological challenges. However, there is some evidence linking the law an uncontrolled experiment that poses the potential marijuana smoking to testicular cancer.17,24 Substantial evidence to put industry profits and tax revenues ahead of the health of has found a statistical association between marijuana smoking and Canadians. The CMA has called for monitoring of marijuana worse respiratory symptoms and more frequent chronic bronchitis use and an amendment to the law if use increases whether among episodes.17,25 More high-quality research is needed regarding adults or youth.33 marijuana’s relationship to other types of cancer and lung diseases, along with more studies to specify other physical effects including Limitations heart attacks, strokes, and diabetes.17 Our study had several limitations. First, although we used a randomized sample of all marijuana consultants in Washington Attitudes regarding legality and use of marijuana State, the representativeness of our findings may be limited by Attitudes about the use of marijuana held by consultants most self-selection bias. It is possible those consultants who did not strongly supported the removal of marijuana as a schedule I drug choose to complete the survey had differing views from those who as well as its beneficial use for chronic and debilitating physical participated in our research. The survey did not request identifying or mental conditions. As stated by one respondent in the open or sensitive information, so non-respondents were unlikely to opt comments: “There is a huge demographic of senior citizens out based on a strong opinion about the topic or questions asked. who are discontinuing their opiate prescriptions and opting for Second, while all potential participants were recently licensed CBD heavy medical marijuana.” Strong positive endorsement marijuana consultants, it is possible that respondents were more of the benefits of marijuana aligned with the weak agreement enthusiastic about marijuana, resulting in response bias. The regarding statements about its addictive qualities or its risk for demographic characteristics of non-respondents and marijuana serious physical or mental side effects. Combined with a belief in consultants outside of the study sample are unknown. Therefore, its beneficial use, these attitudes endorse less restrictive regulation it is not possible to compare respondents to non-respondents or for access to medical marijuana. Complicating matters, there is the underlying marijuana consultant population. Third, this study current discordance in the existing Washington law that authorizes relied upon self-reported attitudes, knowledge, and practices. the use of medical marijuana for posttraumatic stress disorder, a While this approach was appropriate given our goal of presenting mental health condition, but does not authorize it for anxiety or marijuana consultants’ perspectives, self-reported information depression. These disorders can overlap in symptomatology and might be inaccurate or misleading and is subject to reporting bias. commonly occur in patients who have chronic and debilitating For example, attitudes about marijuana harms could be misreported physical conditions.26-28 Post-traumatic stress disorder was added as by respondents if they fear of additional regulations that could a qualifying condition by the Washington State legislature in 2015 interfere with one’s livelihood as a consultant. Finally, not all survey when it also added traumatic brain injury. questions have been tested for reliability and validity. Therefore, Similar to the attitudes of the consultants, a majority of the understanding of the items may have differed among respondents general public in the U.S. also supported the legality of marijuana and resulted in some inaccuracies from misinterpretations. and state distribution for some medical use. When asked if marijuana should be legal without questions regarding patient Conclusion access and distribution, there is a general trend upward which is The mission of the Washington State Department of Health bipartisan towards favoring legality. In 2017, 61% of surveyed (DOH) is to protect and improve the health of all people in the American adults were in support of legalization.29 The Brookings state.34 The attitudes and knowledge reported by certified medical Institute reported that more than 75% of Americans believe marijuana consultants in this study support the recommendation to marijuana has legitimate medical use.29 It is also clear that the the DOH to revise the current curriculum required for consultant public recognizes the incongruity between state and federal laws on certification. Consultants rely heavily on their required courses, marijuana, with 60% of Americans agreeing that in states where along with other consultants and patients for information. Including marijuana is legal, federal marijuana laws should not be enforced.29 the most current research-based evidence in coursework as well Eleven states and the District of Columbia have legalized as guidance on how to interpret research quality and sources of recreational marijuana for adults, all with variable laws regarding information might increase consultants’ ability to provide current, medical conditions and use.30 The current environment of state factual information to medical marijuana customers. based (U.S.) versus national legalization (Canada) of marijuana for The medical marijuana consultant role is new and has medical use offers an opportunity to analyze and compare how population health implications. Consequently, evaluation of the important public health messages are conveyed regarding use, role should occur. Regulators should appraise whether the role misuse, and harm reduction and whether such messages are more fulfills its intended purpose, if revisions to regulations are needed,

UTMJ • Volume 96, Number 3, June 2019 11 Primary Research

Knowledge, practices, and attitudes of certified medical marijuana consultants in Washington state and if the role has an effect on patient outcomes. Additionally, it is 17. National Academies of Sciences, Engineering, and Medicine, Health and Medi- cine Division, Board on Population Health and Public Health Practice, Com- important to determine consultant and customer satisfaction with mittee on the Health Effects of Marijuana: An Evidence Review and Research the role. As the first and only U.S. state with medical marijuana Agenda. The health effects of cannabis and cannabinoids: The current state of consultants, Washington has a responsibility to decide if the role evidence and recommendations for research [Internet]. Washington (DC): Na- tional Academies Press (US); 2017 [cited 2018 Oct 22]. (The National Academies provides a value and if it should be replicated by other states. The Collection: Reports funded by National Institutes of Health). Available from: efficacy of state/local based versus national messaging strategies http://www.ncbi.nlm.nih.gov/books/NBK423845/ could also be examined in conjunction with the implementation of 18. Gibbs M, Winsper C, Marwaha S, et al. Cannabis use and mania symptoms: A systematic review and meta-analysis. J Affect Disord. 2015;171:39–47. doi: Canada’s national marijuana law. Evaluation of the effectiveness 10.1016/j.jad.2014.09.016 of prevention strategies and harm reduction guidelines such as 19. Lev-Ran S, Roerecke M, Le Foll B, et al. The association between cannabis use and depression: A systematic review and meta-analysis of longitudinal studies. the Lower-Risk Cannabis Use Guidelines developed in Canada Psychol Med. 2014;44(4):797–810. doi: 10.1017/S0033291713001438 is imperative.35 Legalization of marijuana around the world for 20. Olfson M, Wall MM, Liu S-M, et al. Cannabis use and risk of prescription opi- medical and recreational use serves as a tacit endorsement of its oid use disorder in the United States. Am J Psychiatry. 2018;175(1):47–53. doi: 10.1176/appi.ajp.2017.17040413 use despite limited evidence of risks and benefits. 21. Blanco C, Hasin DS, Wall MM, et al. Cannabis use and risk of psychiatric disorders: Prospective evidence from a US national longitudinal study. JAMA Psychia- Acknowledgement try. 2016;73(4):388–95. doi: 10.1001/jamapsychiatry.2015.3229 22. Delforterie MJ, Lynskey MT, Huizink AC, et al. The relationship between can- This investigation was supported in part by funds provided by nabis involvement and suicidal thoughts and behaviors. Drug Alcohol Depend. the State of Washington Initiative Measure No. 502. 2015;150:98–104. doi: 10.1016/j.drugalcdep.2015.02.019 23. State of Washington Department of Health. Final order on petition for inclusion of bipolar disorder, severe depression and anxiety-related disorders (social phobia) References as terminal or debilitating conditions under rcw 69.51A.010(4) [Internet]. 2010 1. MacIver B. Cannabis legalization world map [Internet]. Cannabis Business [cited 2018 Oct 23]. Available from: https://www.doh.wa.gov/portals/1/Docu- Times; 2017 [cited 2019 June 4]. Available from: https://www.cannabisbusiness- ments/3000/FinalOrder.pdf times.com/article/cannabis-legalization-world-map/ 24. Gurney J, Shaw C, Stanley J, et al. Cannabis exposure and risk of testicular can- 2. Lemon J. Where is weed legal around the world? You can now officially smoke cer: A systematic review and meta-analysis. BMC Cancer [Internet]. 2015 [cited pot in Canada [Internet]. Newsweek; 2018 [cited 2019 June 4]. Available from: 2018 Oct 22]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/ https://www.newsweek.com/where-weed-legal-around-world-you-can-now-offi- PMC4642772/ cially-smoke-pot-canada-1173623 25. Tetrault JM, Crothers K, Moore BA, et al. Effects of marijuana smoking on pul- 3. Definitions. RCW 69.51A.010 [Internet] Washington State Legislature; 2018 monary function and respiratory complications: A systematic review. Arch Intern [cited 2018 Nov 15]. Available from: http://app.leg.wa.gov/RCW/default. Med. 2007;167(3):221–8. doi: .1001/archinte.167.3.221 aspx?cite=69.51A.010 26. Katon W, Lin EHB, Kroenke K. The association of depression and anxiety with 4. Washington State Institute for Public Policy. I-502 evaluation plan and prelimi- medical symptom burden in patients with chronic medical illness. Gen Hosp Psy- nary report on implementation [Internet]. 2015 [cited 2018 Nov 15]. Available chiatry. 2007;29(2):147–55. doi: 0.1016/j.genhosppsych.2006.11.005 from: https://www.wsipp.wa.gov/ReportFile/1616/Wsipp_I-502-Evaluation- 27. Thomas J, Jones G, Scarinci I, et al. A descriptive and comparative study of the Plan-and-Preliminary-Report-on-Implementation_Report.pdf prevalence of depressive and anxiety disorders in low-income adults with type 5. Senate Bill 5052. Establishing the cannabis patient protection act [Internet]. 2015 2 diabetes and other chronic illnesses. Diabetes Care. 2003;26(8):2311–7. doi: [cited 2018 Nov 15]. Available from: apps2.leg.wa.gov/billsummary?BillNumber 10.2337/diacare.26.8.2311 =5052&Year=2015&BillNumber=5052&Year=2015#documentSection 28. Cohen BE, Edmondson D, Kronish IM. State of the art review: Depression, 6. Medical Marijuana Consultant Certificate. RCW 69.51A.290 [Internet]. Wash- stress, anxiety, and cardiovascular disease. Am J Hypertens. 2015;28(11):1295– ington State Legislature; 2018 [cited 2018 Nov 15]. Available from: http://app. 302. doi: 10.1093/ajh/hpv047 leg.wa.gov/RCW/default.aspx?cite=69.51A.290 29. Pew Research Center. October 2017 Political report: Final topline [Internet]. 7. National Conference of State Legislators. State Medical Marijuana Laws [Inter- Pew Research Center; 2018 [cited 2018 Oct 22]. Available from: http://www. net]. National Conference of State Legislators; 2018 [cited 2018 Nov 15]. Avail- pewresearch.org/wp-content/uploads/2018/01/01-05-18-marijuana-topline- able from: http://www.ncsl.org/research/health/state-medical-marijuana-laws. for-release.pdf aspx 30. National Conference of State Legislators. State medical marijuana laws [Inter- 8. Washington State Department of Health. Medical marijuana: Certified con- net]. 2019 [cited 2019 Aug 22]. Available from: http://www.ncsl.org/research/ sultant [Internet]. 2019 [cited 2019 June 4]. Available from: https://www.doh. civil-and-criminal-justice/marijuana-overview.aspx wa.gov/YouandYourFamily/Marijuana/MedicalMarijuana/ConsultantCertifi- 31. Steiner, L, Nicol AM, Eykelbosh, A. How we talk about “Pot” matters: Strate- cationProgram gies for improved cannabis risk communication. Environmental Health Review. 9. Washington State WAC Chapter 246-72. Sect. Medical Marijuana Consultant 2019;62(1):8-13.32. An Act respecting cannabis and to amend the Controlled Certificate [Internet]. 2018 [cited 2018 Nov 15]. Available from: https://app.leg. Drugs and Substances Act, the Criminal Code and other Acts. 42nd Parliament, wa.gov/WAC/default.aspx?cite=246-72&full=true 1st sess [Internet]. 2018 [cited 2019 June 7]. Available from: www.parl.ca/Con- 10. Kondrad E, Reid A. Colorado family physicians’ attitudes toward medical tent/Bills/421/Government/C-45/C-45_4/C-45_4.PDF marijuana. J Am Board Fam Med JABFM. 2013;26(1):52–60. doi: 10.3122/ 33. Kelsell D. Watching Canada’s experiment with legal cannabis. CMAJ. jabfm.2013.01.120089 2018;190(41):E1218. doi: 10.1503/cmaj.181287 11. Chan MH, Knoepke CE, Cole ML, et al. Colorado medical students’ atti- 34. State of Washington Department of Health. Vision, mission and values. [Inter- tudes and beliefs about marijuana. J Gen Intern Med. 2017;32(4):458–63. doi: net]. 2019 [cited 2019 Jan 13]. Available from: https://ww.doh.wa.gov/Abou- 10.1007/s11606-016-3957-y tUs/VisionMissionandValues 12. Hsieh H-F, Shannon SE. Three approaches to qualitative content analysis. Qual 35. Fischer, B, Russell, C, Saboini, P, et al. Lower-risk cannabis use guidelines: A Health Res. 2005;15(9):1277–88. doi: 10.1177/1049732305276687 comprehensive update of evidence and recommendations. American Journal of 13. Hwang J, Arneson T, St Peter W. Minnesota pharmacists and medical cannabis: Public Health. 2017 Aug 1;107(8):E1. doi: 10.2105/AJPH.2017.303818 A survey of knowledge, concerns, and interest prior to program launch. PT Peer- Rev J Formul Manag. 2016;41(11):716–22. 14. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: A systematic review and meta-analysis. JAMA. 2015;313(24):2456–73. doi: 10.1001/ jama.2015.6358 15. Sexton M, Cuttler C, Finnell JS, et al. A cross-sectional survey of medical cannabis users: Patterns of use and perceived efficacy. Cannabis Cannabinoid Res. 2016;1(1):131–8. doi: 10.1089/can.2016.0007 16. Haj-Dahmane S, Shen R-Y. Chronic stress impairs α1-adrenoceptor-induced endocannabinoid-dependent synaptic plasticity in the dorsal raphe nucleus. J Neurosci. 2014;34(44):14560–70. doi: 10.1523/JNEUROSCI.1310-14.2014

12 UTMJ • Volume 96, Number 3, June 2019 Primary Research

Knowledge, attitudes and current practices of Palestinian internists toward aspirin prescription

Iyad Ali1; Hamzeh Al Zabadi2; Nisreen R. Dayyeh3

1Department of Biochemistry, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine 2Department of Public Health, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine 3Department of Medicine, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine

Introduction Abstract spirin is considered the most universal and cheap 1 Background and Aim: Long-term aspirin therapy is medication. Aspirin acts as an analgesic, anti-inflammatory, and antiplatelet drug and its effect is attributed to the crucial for patients at increased risk for cardiovascular inhibitionA of cyclooxygenase-dependent platelets.2,3 Aspirin is diseases. However, differing perceptions among healthcare used in preventing a multitude of cardiovascular diseases (CVD), providers profoundly shape the challenges observed in risk including myocardial infarction (MI), stroke, and peripheral assessment. This study assessed the knowledge, attitudes vascular diseases (PVDs). Furthermore, aspirin may reduce non- 2 and current practices of internists who prescribe aspirin vascular events such as cancer when used in regular doses. Aspirin has been increasingly used to treat fatal and nonfatal as a preventive measure for cardiovascular diseases. CVD, especially in the elderly population and among patients at Methods: A questionnaire was distributed to a total of high risk to develop CVD.4 Many trials confirmed that aspirin has 38 internists working at healthcare centres in Nablus, succeeded in preventing various vascular diseases. Meanwhile, Palestine. other studies concluded that a low daily dose of aspirin reduces Results: The majority of physicians (95%) reported that the risk for stroke and MI by up to 25%.5 Cryer and his team they prescribe aspirin for patients following a coronary concluded that the use of low to medium doses of aspirin improves CVD prophylaxis.6 In addition, a low daily dose of aspirin was artery bypass graft. About 92% of physicians prescribe also beneficial in reducing the risk of post-MI vascular events. On aspirin for patients with a peripheral vascular disease the other hand, a dose of 650-1300 mg/day was more beneficial or acute myocardial infarction, and 85% of physicians for patients with transient ischemic attacks (TIA) or strokes. prescribe aspirin if patients have a history of stroke Unfortunately, the high dose comes at the cost of more side effects.7 and congestive heart failure, or stable angina. The Therefore, aspirin therapy should always be an adjunct, rather than the primary therapy in management of CVD. prescribing of aspirin as prophylaxis for patients without Secondary prevention of CVD is considered a key element of cardiovascular disease, but with one or more risk factors, a cost-effective health strategy to help fight the increasing burden was reported by 61% to 79% of the physicians depending of these diseases.8 Many efforts have been undertaken by the World on the nature and number of risk factors. In some cases, Health Organization to reduce the mortality rates of CVD. Some the presence of additional diseases in association with of these efforts focused on the importance of aspirin for individuals 9 cardiovascular diseases tended to hinder physicians from at high risk to develop CVD. According to a retrospective study on diabetic hypertensive patients attending government clinics, there prescribing aspirin. had been an improvement in antiplatelet therapy when aspirin was Conclusions: The majority of Palestinian internal used as a primary prevention for CVD.10 physicians recommend the use of aspirin as a primary In Palestine, patients with CVD typically receive medical care prevention tool for cardiovascular disease in spite of its from general practice (GP) physicians rather than cardiologists. As potential negative side effects. Our results revealed that a result of cardiologists’ shortage, and the absence of guidelines for GPs, there is a necessity for improving the primary and secondary physicians in Palestine tend to prescribe aspirin with prevention services through short courses that teach and reinforce varying patterns and therefore a set of evidence-based the necessity for implementing health guidelines. This study recommendations should be implemented. assessed the knowledge, attitudes and current practices of internists who prescribe aspirin as a preventive procedure for cardiovascular diseases.

Corresponding Author: Iyad Ali [email protected]

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Knowledge, attitudes and current practices of Palestinian internists toward aspirin prescription

Materials and Methods prescription frequency decreased from 92% to 79% in cases Study population of MI and asthma or a hiatus hernia. About 89% of physicians The study’s population consisted of all internists in Nablus, prescribed aspirin if patients had a history of stroke and congestive Palestine. All physicians were visited and the response rate was heart failure. about 95%. A total of 38 physicians out of 40 agreed to complete The risk factors for MI encourage physicians to prescribe a self-administrated questionnaire and sign a consent form. aspirin. Aspirin was prescribed by 79% of physicians for smoking patients with a family history of acute MI and hypercholesterolemia; Study tool: Questionnaire 66% of physicians prescribed aspirin for patients with non-insulin A questionnaire was used to collect data from our study dependent diabetes mellitus (NIDDM). The prescribing of aspirin population. The questionnaire was obtained from Al Omari2 and as prophylaxis for patients without CVD, but with a family history was modified to match the local conditions. of MI, was reported by 61% of physicians (Table 3). Nonetheless, Participants working in different centres during a period of aspirin was prescribed by 63% of physicians for smoking patients three months (1st of November 2016 to 30th of January 2017) with a family history of acute MI and hypertension. Aspirin was were asked to fill out a questionnaire. These centres included prescribed by 76% of physicians to TIA and potential bleeding Najah National University Hospital (NNUH), Ministry of Health disorder patients, as well as for patients with past TIA and inactive (MOH), and private internal medicine clinics. The questionnaire’s duodenal ulcers (Table 3). structure was designed to assess the physicians’ awareness, attitudes, About 58% of physicians reported that they prescribe aspirin and practices of prescribing aspirin for the primary and secondary for all patients with vascular diseases. Most physicians who prevention of vascular diseases in eligible patients. consider aspirin for all patients with vascular diseases work at the The questionnaire was divided into two sections: the first MOH (73%). However, only 50% of physicians who are working section covered personal and professional characteristics of the in NNUH and in private healthcare consider aspirin for all patients participants such as, gender, age, experience, and place of work; with vascular diseases. Most of MOH physicians (82%) ensured the second section included 15 scenarios that had been mentioned that they recorded their advice about aspirin in the patient’s records. in a study by Welton et al.11 Some scenarios included patients About 55% of the physicians agreed that patients with ischemic with vascular diseases and those who were previously suffering heart disease should receive aspirin using the repeat prescribing from CVDs, whilst other scenarios included patients free from system. Around 91% of MOH physicians prescribe aspirin by vascular diseases, but with multiple risk factors. In addition, the using their repeat prescribing system. On the other hand, 50% questionnaire explored information about aspirin formulation, of NNUH physicians and only 37% of private sector physicians usage, recommended dose and co-prescribing. Data were analyzed using a statistical package for social sciences Table 1. Socio-demographic characteristics of the study participants (SPSS. Version 16). Chi-square testing was used to describe the Variable Frequency (%) percentages of results, and a p-value less than 0.05 was considered Gender statistically significant. Female 4 (10.5) Male 34 (89.5)

Years of experience Results 1 year 1 (2.5) A total of 38 internists (4 females and 34 males) completed the 2 years 3 (7.9) 3 years 4 (10.5) questionnaire. The mean age of physicians was 46 years (SD ±11.4 4 years or more 30 (78.9) years). Half of the physicians were working in private healthcare Place of work clinics; whereas 29% of physicians were working in MOH (Table NNUH* 8 (21.1) MOH** 11 (28.9) 1). The majority (78%) of the participants had at least four years of Private 19 (50) experience in the medical field. Age (years) In the context of CVD prevention, most physicians (66%) Less than 40 years 17 (44.7) 40-60 years 16 (42.1) prescribe 100 mg aspirin, 16% prescribe 75 mg aspirin, and 18% More than 60 years 5 (13.2) prescribe other doses (Table 2). Regarding the place of work, Mean± SD 46.16±11.4 results show that the majority of physicians who work in private *NNUH: Najah National University Hospital; **MOH: Ministry of Health healthcare (68%) prescribe 100 mg aspirin. Meanwhile, in NNUH there was a variation between all prescribed doses. Finally, results Table 2. Dosage of aspirin prescription in relation to the place of work revealed that about 82% of physicians in MOH prescribe 100 mg aspirin (Table 2). Dose (mg) Number of Physicians (%) The majority of physicians reported that they prescribe NNUH MOH Private Total aspirin for patients following coronary artery bypass grafting and 75 3 (38) 0 (0) 3 (16) 6 (15.7) PVDs – 95% and 92%, respectively. In addition, 84% and 92% 80 0 (0) 1 (0.09) 1 (0.05) 2 (0.05) of physicians prescribe aspirin for patients with stable angina and 100 3 (38) 9 (82) 13 (68) 25 (65.8) acute MI, respectively (Table 3). On the contrary, only 42% of 150 1 (13) 1 (0.09) 0 (0) 2 (0.05) physicians reported that they prescribe aspirin for patients with 300 0 (0) 0 (0) 2 (11) 2 (0.05) atrial fibrillation. The frequency of aspirin prescription was decreased when 325 1 (13) 0 (0) 0 (0) 1 (0.03) cardiovascular disease was present with another disorder. The *NNUH: Najah National University Hospital; **MOH: Ministry of Health

14 UTMJ • Volume 96, Number 3, June 2019 Primary Research

Knowledge, attitudes and current practices of Palestinian internists toward aspirin prescription

use their repeat prescribing system (Table 4). Approximately are aware of the role of aspirin in patients with vascular disease. 63% of physicians prescribe aspirin with prophylactic anti-ulcer In the Palestinian health system, nurse practitioners are not medication (Table 4). Out of these physicians, 68% belong to the authorized to prescribe any drugs for patients but may give CVD private sector and 50% belong to NNUH. patients aspirin at the time of admission. There were physicians Comparing the percentages of how physicians perceive the that opposed the prescription of aspirin alongside NSAID drugs; knowledge and awareness of nurse practitioners, our results this included 100% of NNUH physicians, and 73% and 89% from revealed that 73% of MOH physicians feel that nurse practitioners MOH and private physicians, respectively (Table 4). Regarding

Table 3. Patterns of aspirin prescription as reported by physicians according to diagnosis in relation to the place of work.

Number of Physicians (%)

Diagnosis/Risk for a Disease NNUH MOH Private Total P-value

Single cardiovascular disease Post-coronary artery bypass graft 7 (88) 10 (91) 19 (100) 36(95) 0.330 Peripheral vascular disease 6 (75) 11 (100) 18 (95) 35(92) 0.114 Stable angina 6 (75) 10 (91) 16 (84) 32(84) 0.640 Acute MI 7 (88) 10 (91) 18 (95) 35(92) 0.804 Stroke 6 (75) 11 (100) 15 (79) 22(58) 0.227 Atrial fibrillation 4 (50) 6 (55) 6 (69) 16(42) 0.597 Cardiovascular disease with another diagnosis Past acute MI and asthma 6 (75) 10 (91) 14 (74) 30(79) 0.512 Past acute MI and hiatus hernia 6 (75) 10 (91) 14 (74) 30(79) 0.512 Past stroke and congestive heart failure 7 (88) 11 (100) 16 (84) 34(89) 0.389 Past TIA and inactive duodenal ulcer 7 (88) 8 (73) 14 (74) 29(76) 0.703 TIA and potential bleeding disorder 7 (88) 10 (91) 12 (63) 29(76) 0.160

Risk factors for cardiovascular diseases Smoking, family history of acute MI, and HC 5 (61) 8 (73) 17 (90) 30(79) 0.244 Non-insulin dependent diabetes mellitus 4 (50) 7 (64) 14 (74) 25(66) 0.488 Strong family history of MI 4 (50) 7 (64) 12 (63) 23(61) 0.790 Smoking, HP, and family history of acute MI 7 (88) 10 (91) 17 (90) 24(63) 0.972 MOH: Ministry Of Health; NNUH: An-Najah National University; MI: Myocardial Infarction; HP: Hypertension; TIA: Transient Ischemic Attack; HC: Hypercholesterolemia.

Table 4. Physicians’ practices and attitudes towards aspirin prescription

Number of Physicians (%)

Practice and attitudes NNUH MOH Private Total P-value

I consider aspirin for all patients with vascular diseases. Agree 4 (50) 8 (73) 10 (53) 22 (58) 0.700 Disagree 3 (38) 2 (18) 8 (42) 13 (34) I record in the patient records whether I have advised them about aspirin. Agree 6 (75) 9 (82) 16 (84) 31 (82) 0.782 Disagree 1 (13) 2 (18) 2 (11) 5 (13) I prescribe aspirin to patients with ischemic heart disease by using my repeat prescribing system*. Agree 4 (50) 10 (91) 7 (37) 21 (55) 0.066 Disagree 2 (25) 1 (9) 5 (26) 8 (21) I often prescribe aspirin with prophylactic anti-ulcer medication. Agree 4 (50) 7 (64) 13 (68) 24 (63) 0.713 Disagree 4 (50) 3 (27) 5 (26) 12 (32) I feel that nurse practitioners are aware of the role of aspirin in the patient with vascular disease. Agree 3 (38) 8 (73) 11 (58) 22 (58) 0.597 Disagree 3 (38) 2 (18) 6 (32) 11 (29) I mainly prescribe aspirin with NSAIDs (over the counter). Agree 3 (38) 8 (73) 11 (58) 22 (58) 0.597 Disagree 3 (38) 2 (18) 6 (32) 11 (29) Most of my patients receive their aspirin on prescription. Agree 3 (38) 8 (73) 11 (58) 22 (58) 0.597 Disagree 3 (38) 2 (18) 6 (32) 11 (29) Patients without vascular disease ask me if they should be taking aspirin daily. Agree 3 (38) 8 (73) 11 (58) 22 (58) 0.597 Disagree 3 (38) 2 (18) 6 (32) 11 (29) *repeat prescribing system is a system that allows patients to get the medicines they need to take on a regular basis without needing to see the physician. NNUH: An-Najah National University; MOH: Ministry Of Health.

UTMJ • Volume 96, Number 3, June 2019 15 Primary Research

Knowledge, attitudes and current practices of Palestinian internists toward aspirin prescription aspirin prescription, 82% of MOH physicians agreed that patients Conclusions received their aspirin upon prescription. Although aspirin has some negative side effects, the majority of Palestinian internists preferred the use of aspirin in primary Discussion prevention of CVDs. Physicians tend to prescribe aspirin less Long-term aspirin therapy is of definite value for patients who frequently when a patient suffers from other diseases in addition are at risk for developing CVD.2 Antiplatelet therapy reduces the to CVDs. Finally, we concluded that Palestinian physicians should risk of serious vascular events for all patients with coronary or be provided with approved guidelines to enhance their prescription peripheral arterial disease, and those at high risk of embolism by patterns. about 25%.5 Guidelines from the United States Prevention Services Task Force (USPSTF) suggest that in men at risk for coronary References disease, and lacking contraindications to aspirin use, the benefit of 1. Roth GA, Gillespie CW, Mokdad AA, et al. Aspirin use and knowledge in the community: a population-and health facility based survey for measuring local 3 aspirin outweighs the harm. health system performance. BMC cardiovascular disorders. 2014;14(1):16. Several studies have reported different rates of prescribing 2. Al Omari M, Khader Y, Al-azzam SI, et al. Knowledge, attitudes and current practice of Jordanian family physicians about prescribing aspirin in primary and aspirin. In the present study, the majority of Palestinian internists secondary prevention of vascular diseases: a self-reported survey. Eur J Cardio- (90%) prescribe aspirin for patients with vascular disease. There vasc Nurs. 2012;11(1):9-13. was not a statistically significant difference in the prescribing 3. Buring JE, Bogousslavsky J, Dyken M. Aspirin and stroke. Am Heart Assoc; 1998. 4. Raju N, Sobieraj-Teague M, Hirsh J, O’Donnell M, et al. Effect of aspirin on practices based on place of work. In a previous study done by the mortality in the primary prevention of cardiovascular disease. The American WHO in 2005, it was noted that about 81% of CVD patients of journal of medicine. 2011;124(7):621-9. the lower and middle socioeconomic status received aspirin.12 The 5. Trialists’Collaboration A. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in highest intake of aspirin (85%) was among patients with a recent high risk patients. Bmj. 2002;324(7329):71-86. MI.9 According to a study conducted in 15 European countries, 6. Cryer B, Bhatt DL, Lanza FL, et al. Low-Dose Aspirin-Induced Ulceration Is 13 Attenuated by Aspirin–Phosphatidylcholine: A Randomized Clinical Trial. The 90% of patients with coronary heart disease use aspirin. American journal of gastroenterology. 2011;106(2):272-7. The presence of another disease in addition to CVD, even 7. Hennekens CH, Dyken ML, Fuster V. Aspirin as a therapeutic agent in cardiovas- when it is not a contraindication to use aspirin, leads physicians cular disease. Circulation. 1997;96(8):2751-3. 8. Beaglehole R, Epping-Jordan J, Patel V, et al. Improving the prevention and man- to prescribe aspirin less frequently – possibly because of the fear agement of chronic disease in low-income and middle-income countries: a prior- of further complications. This decision may be due to the lack of ity for primary health care. The Lancet. 2008;372(9642):940-9. guidelines and this is in agreement with a previous study.11 Another 9. Campbell NC, Thain J, Deans HG, et al. Secondary prevention in coronary heart disease: baseline survey of provision in general practice. Bmj. possible reason for not prescribing aspirin is gastrointestinal and 1998;316(7142):1430-4. other potential side effects.2 A meta-analysis suggests that long- 10. Sweileh WM. Anti-platelet therapy in diabetic hypertensive patients with and without cardiovascular diseases in Palestine, from 2003 to 2008. CVD Prevention term aspirin therapy, even at a low dose, increases the risk of and Control. 2009;4(3):157-62. gastrointestinal bleeding.11 Other complicating factors, such as 11. Welton M, Croft P, Welton J. General practitioners’ use of aspirin in the second- asthma and bleeding disorders, were also associated with increased ary prevention of vascular events: knowledge, attitudes, and current practice. Brit- ish journal of general practice. 1999;49(445):607-10. aspirin use. 12. Mendis S, Abegunde D, Yusuf S, et al. WHO study on Prevention of REcur- For patients without CVDs, but with one or more risk factors, rences of Myocardial Infarction and StrokE (WHO-PREMISE). Bulletin of the the prescription of aspirin as primary prevention was reported by World Health Organization. 2005;83(11):820-9. 13. Group EIS. Lifestyle and risk factor management and use of drug therapies in 61% to 79% of Palestinian physicians depending on the number coronary patients from 15 countries; principal results from EUROASPIRE II and nature of risk factors. A similar study by Al Omari et al. showed Euro Heart Survey Programme. Eur Heart J. 2001;22(7):554-72. 2 14. Pearson TA. New tools for coronary risk assessment. Circulation. 2002;105(7):886- that the prophylactic use of aspirin ranged from 85% to 95%. 92. In contrast, a study from the UK reported that the prescription of aspirin for patients at risk of CVDs ranged from 17% to 54%.11 For patients with NIDDM, 66% of physicians in Nablus advised daily aspirin intake. Conversely, in Jordan and the UK, 85% and 17% of physicians recommended aspirin for NIDDM patients, respectively.2,11 It is noteworthy that the USPSTF, and the American Heart Association, recommend the use of aspirin for healthy people, between the age of 50 and 59, at risk of CVDs (14). The dose and formulation of aspirin is a concern for physicians who want to prescribe aspirin for patients with CVDs. Approximately 11% of physicians reported that they were confused about the appropriate dose. More than half (66%) of the physicians prescribe 100 mg aspirin. Only 16% of our participants prescribe 75 mg, which is significantly lower than the percentage (47%) in previous studies.2,11 This study has some limitations since it is the first of its kind from Palestine and was conducted at only one city (Nablus). Secondly, all information was based on a self- reporting questionnaire, which may not necessarily reflect the actual behaviors.

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‘Wrong treatment’: Doctors’ take on medical futility in a low-resource ICU

Tonia Chinyelu Onyeka (FWACS)1; Ikem Okonkwo (FNMC)2; Uzochukwu Aniebue (FWACOG)3; Innocent Ugwu (FWACS)2; Felix Chukwuneke (FWACS)4; David Agom (BSc)5

1Department of Anaesthesia/Pain & Palliative Care Unit, Multidisciplinary Oncology Centre, College of Medicine, University of Nigeria, Ituku-Ozalla Campus, Enugu, Nigeria 2Department of Anaesthesia, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria 3Department of Obstetrics & Gynaecology, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria 4Department of Oral and Maxillofacial Surgery, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria 5Department of Nursing, Ebonyi State University, Abakaliki, Ebonyi State, Nigeria

Introduction Abstract he word ‘futility’ is derived from the Latin word ‘futilis’ Background: Health caregivers in Intensive Care Units which means ‘pouring out easily’ or ‘worthless’ and the 1 (ICUs) in developed countries have documented accounts of terminology ‘futile care’ was first defined in 1980. The Tconcept of futility in itself dates back to the legend of Danaus futile care for patients admitted into the Intensive Care Unit (ICU). But, evidence gaps exist in medical literature from and Aegyptus who were two brothers who had fifty daughters and fifty sons respectively, with Aegyptus forcing Danaus’s daughters developing countries on futility. While costs of establishing and to marry his sons.2 All but one of the brides killed their spouses running ICUs are astronomical in resource-poor countries, on the wedding night, necessitating the gods to punish the girls by administration of medically futile care can further compound assigning them the task of filling jars which were perforated with problems for ICU patients, family caregivers, health caregivers holes. So in essence, the girls were never able to complete the task, and hospital establishments. We sought and analysed the this in itself representing futility.2 In addition, the Hippocratic oath opinions of anaesthetists working in ICUs, highlighting sworn by doctors on their induction day includes an assurance not the concept of medically futile care as perceived by health to manage patients who were “overmastered by their disease”.2 In caregivers in low-middle income ICUs. the course of treating patients, every doctor is expected to adhere Materials & Methods: Using a phenomenological to professional values even when these values differ from personal framework, this study involved face-to-face in-depth interviews values and beliefs.3 They are also expected to be able to discern conducted with 15 resident doctors working in two ICUs of a ethical issues in any futile care that may present in the course tertiary health institution in South-East Nigeria. Transcripts of their practice and take the most appropriate decisions.4 The were analysed using Interpretive Phenomenological Analysis philosophical aphorism as hypothesized by Plato and Aristotle (IPA). constrains the physician to consider what circumstances in the Results: Five core themes emerged: unnecessary procedures treatment processes are just and avoid emotions and desires to hold 4 and interventions; intrinsic and extrinsic factors of medically sway instead. futile care; family caregiver influences; negative notions of The concept of futility has been known to be very controversial 5 medical futility; ICU outcomes. One participant was of the and of great academic interest as its definition remains contentious. Futility may be classified as quantitative, qualitative and psychologic view that not intervening medically might be best for some and may be affected by factors like existing culture, traditions and patients admitted into the ICU. Other participants described beliefs of a people.6-8 Futility in medical care has been cited to be cases where patients received care which participants one of the most frequent reasons for seeking ethical consultations.6 considered futile, noted possible causes of futile treatments It has various definitions including clinical interventions not likely and proffered strategies to correct such situations. to serve a useful purpose in attaining specific goals of patient Conclusion: The surveyed doctors commonly view care to management or when physicians decide based on personal be futile in low-resource ICUs. Several factors are implicated experiences, shared experiences with colleagues or consideration including lack of goals in patient care, poor communication, of reported empirical data that a medical treatment is not lack of specialist training in intensive care and lack of useful.8,10 Some researchers claim that the basis for determining protocols. Medical futility, in the opinion of these doctors, may medical futility is flawed.7 In a bid to reduce conflicts between contribute substantially to the challenges of running an ICU. This calls for multiple strategies for its reduction so as to ensure efficient use of scarce resources and improved outcomes in Corresponding Author: ICUs located in resource-limited settings. Dr. Tonia C. Onyeka Email: [email protected] Tel: 08063563223

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‘Wrong treatment’: Doctors’ take on medical futility in a low-resource ICU physicians, family carers and patients caused by the multiplicity the ICU. At the conclusion of all interviews, audio recordings of definitions for medically futile care, many health institutions of the interviews were carefully listened to multiple times, in developed countries of the world have ethics committees and carefully transcribed verbatim by two of the authors (TCO, IO) similar institutional bodies to resolve such conflicts.8 In some to ensure that the participants’ accounts accurately reflected their places, processes dealing with such conflicts have been passed into perceptions on the subject matter. Afterwards, the transcripts were legislation.9 A review of available literature on the subject matter subjected to qualitative content analysis utilising the Interpretative of medical futility reveals that it has been extensively researched in Phenomenological Analysis (IPA) approach. This analysis involved North America, the Middle-East and Europe.1,6,14-19 This is in stark a thorough reading and re-reading of the transcripts several times contrast to this area in Africa where a paucity of research on the by three of the authors, to ensure participants’ opinions were subject matter exists. Available statistics indicate that about 12 000 accurately captured. This was followed by identifying emergent key futility cases occur each year in the United States of America.10 In themes that were expressed by the participants as well as those that less developed countries of the world – such as Nigeria – no such best conveyed the responses of the residents. As themes emerged, data exists. similar themes were grouped together in clusters and superordinate Health care providers in Intensive Care Units (ICUs) in the and subordinate themes identified. Finally, all authors reviewed developed world have documented accounts of futile care for findings of the analyses. patients admitted into the unit.11,12 While costs of establishing and running an ICU are astronomical, especially in resource- Results poor countries, administration of medically futile care can further All participants were males – four registers and eleven senior compound problems for ICU patients, family caregivers, health registrars (a total of fifteen residents [N = 15]) – who were all caregivers and hospital establishments as it has been established within two to five years of the residency training. Following analysis that futile care is sizable.13 The rationale for embarking on this study of their interviews, five main content areas emerged: unnecessary was to explore the concept of medically futile care as perceived by procedures and interventions, intrinsic and extrinsic factors of health care providers in a low-middle income ICU. medically futile care, negative notions of medical futility, family caregiver influences and ICU outcomes. Materials and Methods This study was conducted at a large tertiary health institution Theme 1 – Unnecessary procedures and interventions located in Enugu, South East Nigeria, which has two ICUs: a In several instances, participants commented on patients mixed 5-bed general ICU and a 4-bed cardiothoracic ICU, both receiving what they observed to be inappropriate care, excessive admitting paediatric and adult patients. The participants were all care or under-care in their ICU management (Box 1). One resident doctors in anaesthesia at various stages of their training participant noted that sometimes, not intervening might be the who were either doing their routine ICU posting or had just best for some patients admitted into the ICU. He gave an example completed it during the study period. They had between two weeks of a patient admitted under his care with severe head injury and and four years of working experience in the ICU and were all Glasgow coma score of 3, whose father was a poor farmer. The males. In the participants’ hospital, the ICU is a semi-open type patient was placed on mechanical ventilation but unfortunately where consultant anaesthetists and trainee doctor anaesthetists died after four days, accumulating a large bill that his father could under them are largely responsible for the patient’s care. The not pay. This consequently increased the burden of family, thus patient’s primary team only makes specialist inputs where causing more harm financially and emotionally to the family of necessary, hence the use of only anaesthesia doctors for this study. the patient. Participants described scenarios such as a patient with Following ethical approval obtained from the Hospital’s Ethics and inoperable intracranial pathologies admitted into the ICU rather Research Committee (HREC), all participants were assured of than referred to the Palliative Care Unit and being under pressure confidentiality and anonymity before face-to-face in-depth semi- from a senior colleague to give an intervention in a situation that structured interviews were conducted, utilizing a set of ten (10) the participant deemed medically futile (Box 2). predetermined questions (Table 1) and recorded with audiotapes. All participants agreed that ICU management of patients was Contemporaneous notes on non-verbal cues were made following resource-intensive. One participant commented, ‘If I ever have to each interview. Each interview session held in the anaesthesia come to the ICU to be admitted as a patient, I would rather prefer I die and my resident’s call room was conducted by the lead author and lasted family have the money that should have been spent on me’ while yet another between 25-40 minutes. participant remarked, ‘We have to give economically-sensitive care of The opinions of these doctors were sought concerning aspects patients in our resource-constrained ICU environment. If ABGs (arterial blood of patient care which they considered futile, possible causes of gases) are done hourly in developed countries because resources are available and futile treatments as well as proffering strategies to correct such medical insurance takes care of a good deal of the care, we need to remember that situations. Questions asked included instances of inappropriate here, people pay out-of-pocket and funeral services are expensive so these must be care, excessive care or under care, factors responsible for such care, put into consideration’. In general, participants seemed to show much factors with the highest impact on patient management as well as empathy (as suggested by the expression of non-verbal actions of family caregiver influences. Other questions included defining a sighing, distressed/agitated tone pitches and sad facial expressions) good outcome in ICU, bad outcome in ICU, defining a good death, towards the patients they had cared for in the ICU whom they giving their definitions of medical futility as well as describing deemed to have received medically futile care. the degree to which they perceived medical futility occurred in

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‘Wrong treatment’: Doctors’ take on medical futility in a low-resource ICU

Theme 2 – Intrinsic and extrinsic factors of medically such as that of a patient with traumatic brain injury who should futile care have had surgery but received conservative management instead When asked what they thought were the factors responsible and died as a result. They gave various definitions to a good for such care, participants gave a number of reasons which outcome in the ICU (Box 4), a bad outcome in the ICU (Box 4) included lack of established protocols for patient management and also proffered their perceptions of a good death in the ICU in the ICU, no well-outlined goals of treatment, inadequate (Box 4). In describing his concept of a good death in the ICU, training in intensive care medicine and lack of communication one participant remarked, ‘I consider a death in the ICU, a good between health caregivers and patient’s family (Box 2). Participants death when patient dies with dignity and dies surrounded by discussed having to care for patients whose care they felt should family members who have been counselled to accept the negative have received participation of the palliative care team but did not, outcome’. especially as they had deemed such cases end-of-life situations. They spoke of their frustration at not having clear protocols to Theme 5 - Negative notions of medical futility streamline patient admission into the ICU, hence avoiding wrong All but one of the participants reported having observed or admissions or late admissions, and no well-defined goals of care. administered what they believed to be medically futile care on at One participant cited a case where the patient’s family expected least one occasion in the ICU. The overwhelming tone for most a recovery while in reality the patient’s prognosis was very poor, participants was negative. The participant who claimed not to have and attributed this situation to lack of adequate information had any experiences of futile care was the youngest participant from the managing team. They emphasised the need for family in the study, having worked for less than one month in the ICU conferences to help put the patient’s illness in perspective, increase before this study. With regards to defining the term, ‘medical understanding of the medical care being administered, and reduce futility,’ participants had various definitions. Participants were of the numbers of medical procedures that may not be beneficial to the general opinion that the phenomenon of medically futile care patients on admission in the ICU. Participants also expressed their could be said to occur when a patient is unlikely to improve even desire to have some training in intensive care medicine, explaining when given the best kind of care obtainable at that time. One that it would help finetune their skills and give them confidence participant defined medical futility as, ‘carrying out an intervention in when making inputs into patient care, which is often disregarded. a patient that has been deemed unnecessary and of no benefit, but must be When participants were asked the factors with the highest done to give a semblance of effort being made to treat the patient.’ Another priority, unavailability of well-defined protocols, lack of specialist defined it as, ‘a situation where inputs made towards patient care are standard training in intensive care medicine, lack of goals of care and poor but because of patient’s clinical status, outcome would be poor.’ Two other communication were noted. participants defined medical futility as, ‘any intervention that will not likely change or improve clinical outcome’ and ‘giving medical care that will not Theme 3 – Family caregiver influences produce positive results.’ One pertinent issue discussed by the participants was the role In addition, participants had varying perceptions as to the of family members in the administration of medically futile care degree to which they felt that medical futility occurred in the ICU (Box 3). They stated that such influences were almost always from (rated on a scale of 0 to 10 where 0 means no futility and 10 means patient’s relatives who were usually either doctors, nurses or high- the worst degree of futility). Five participants gave a score of 10, profile individuals. One participant recollected receiving a phone two each gave scores of 9, 8 and 7 respectively and while one call, placed from outside the country, from the doctor-relative of participant gave a score of 1, another did not consider medical a metastatic cancer patient being mechanically ventilated who futility to exist at all in the ICU. In all, the general consensus of after demanding to know what was being done for the patient, participants in this study was that medical futility existed in the attempted to modify the patient’s medical care on the phone. ICU to a significant magnitude. Participants recalled requests made by families to keep patients on mechanical ventilation despite the fact that they knew such patients Discussion were clinically dead. In the view of the participants, sometimes the The admissions in this study by all but one anaesthesia resident notion for continued multi-organ support was fuelled by external doctor (93.3%) to the personal experience of futility in the ICU as factors such as religious factors (e.g. belief in the events of the well as the admissions by participants that medical futility exists afterlife) and cultural factors (e.g. belief in traditional medicine in the ICU to a significant extent seem to indicate futile care is a efficacy). In one situation, a family carer whose mother wasin significant problem within the context of ICU care. The results a diabetic coma and had gangrene from diabetic foot declined are comparable to a study conducted by Chamberlin et al. which surgical amputation of the foot, requesting her mother be left alone found that 91.3% of doctors admitted to occurrence of the futility to die rather than have her gangrenous foot be removed, so that phenomena.24 Hence, several studies have been conducted to seek she would have her feet intact in the afterlife following her death. the best ways to reduce the occurrence of non-beneficial treatments in the ICU. Anderek et al. in an exploratory trial to determine the Theme 4 – ICU outcomes efficacy of ICU ethics consultation in reducing futile treatments, When participants discussed the patients who in their opinion concluded that ethics consultations made minimal impact while had received medically futile care, they also discussed their Scneiderman et al. in exploring the impact of ethics consultation, interpretation of ICU outcomes and ICU death. Some participants concluded with a contrary opinion that such consultations resulted were of the opinion that futile care when given to a patient would in reduced length of stay for some ICU patients as well as reduction inevitably result in a bad ICU outcome. Participants told stories

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‘Wrong treatment’: Doctors’ take on medical futility in a low-resource ICU in life-sustaining treatments for other ICU patients who were not family meeting session is guaranteed to reduce the occurrence of able to recover for discharge.25,26 medically futile care.42 On perceived inappropriate care, participants were quick The influence of family caregivers in the decision to provide to cite several real-life scenarios of disproportionate care that medically futile care was one point raised by participants in this they encountered. This submission tallies with findings from two study. Some researchers have argued that some futile treatments multicentre, multinational studies by Piers et al. and reports from requested by family members may have a place in medical the United States which cite perceptions of European and Israeli practice.21 Religious requests made by families, such as the one clinicians and American clinicians respectively of disproportionate narrated by study participants involving the family carer who care being a leading form of inappropriate care in the ICU.27-29 declined foot amputation for her mother, have been noted to have The examples of ‘tracheostomies in patients not expected to survive beyond major influences in care decisions made by clinicians. Ayeh et al. 24 to 48 hours’ and ‘post-cardiac surgery patient with severe cerebral anoxia found physicians are more willing to accommodate requests to on mechanical ventilation for over 2 months’ were some of the situations continue life-sustaining treatments when the request was based on alluded to by the participants who felt these types of patients religious affiliations than on hopes of divine healing.44 Superdock should not have been in the ICU. This reality aligns with findings et al. are of the opinion that religion and spirituality (R&S) are from Chang et al. which suggests that ICU care may be inefficient important in decision-making by family caregivers of seriously-ill because most of its resources are devoted largely to patients unlikely patients as R&S provides personal comfort and direction to these to benefit from them.30 A survey of 808 medical ICU admissions caregivers.45 They posit that this stance complements the decision- revealed that more than 50% of the patients had priority ranks making and care given by healthcare providers to seriously-ill suggesting that they were relatively too well or too sick to be in the patients and enhances communication between family caregivers ICU or would have best been managed in the wards while 65% of and healthcare providers. Gelinas et al. were able to identify sources total ICU days were given to care that had a low likelihood of ICU of stress (organizational, professional, and emotional) related to the benefit or could be managed in the general ward.30 Also, frequent conflict clinicians have with family carers about discontinuing life- ICU use is associated with an increased tendency to carry out sustaining treatments and other issues, and suggested providing invasive procedures that are costly but do not lead to a reduction emotional support for ICU staff as well as education in end-of-life in mortality rates.31 In a study of Nigerian ICUs, 96% of junior care and palliative care, while maintaining a good relationship clinicians acknowledged high rates of inappropriate admissions with family carers and educating them on importance of reducing due to pressure from senior colleagues (93.7%), referring occasions of bodily injury and suffering to susceptible patients in clinicians (89.1%), and hospital management (87.5%).31 To avoid the ICU.46 inappropriate admissions, clinicians and hospital management are Another factor enumerated by respondents as being advised to adopt established guidelines for ICU triage.14,15 responsible for medically futile care is the non-regard for medical Communication was touted as a substantial factor in this opinion/input from junior clinicians, which in turn elicits a feeling study for inappropriate admissions and subsequent futile care. of ‘powerlessness’. This feeling can be related to similar feelings Participants identified the lack of discussions with or counselling of exposed by a qualitative study on medically futile care by Dzeng family members as being a crucial issue. This may often be caused et al. where internal medicine trainee physicians expressed by the fear-avoidance approach resulting from the inability of the inability to prevent potentially harmful and futile treatments, clinician to break ‘bad news.’ While good communication between often attributing it to the hierarchy in existence in their respective clinicians and family members is important, poor communication institutions.47 The differing roles of the trainees within this study between families and ICU doctors is the prevailing norm.34-16 A as ‘inexperienced’ underlings with little or no role in decision- study of family surrogates of patients in a Norwegian ICU revealed making and ‘frontline foot soldiers’ expressly carrying out the that opportunities for communication and consequent involvement instructions of the consultant in-charge, gives room for insecurity of family members in the decision-making process of terminating that confounds ability to deal with ethical conflicts. This perceived care rarely involved discussions on family and patient’s preference ‘powerlessness’ is touted to be an indicator of moral distress and is but rather dwelt on clinical details which were ambiguous, leaving equally common among ICU nurses.22,23 families with unanswered questions.17 These conflicts can be Passionate statements seen in Theme 1 which were voiced by resolved by the involvement of the hospital’s Clinical Ethics service some participants, displaying their empathic emotions. Besides as family conferences led by trained ethicists have been known to these verbal expressions, non-verbal actions of sighing, distressed/ produce successful results.9 Insufficient communication between agitated tone pitches and sad facial expressions were expressed clinicians (doctors and nurses) results in perceived conflicts and towards patients they had cared for in the ICU, whom they deemed often times ensues from unilateral decisions taken by doctors. to have received medically futile care. These cues were an indication Conflicts like these have been known to produce emotional distress of their reluctance to carry out certain procedures they perceived for nurses while patients are in their care, and emotional distress to be ‘harmful’, ‘disastrous’ or ‘not beneficial’ on patients. Such can result in reduced quality of care.18,19 When family carers expressions have been known to produce significant moral distress have good emotional support and better information about their in such doctors. In the study by Dzeng et al., trainee physicians patients, they could be encouraged to consider a palliative care used words such as ‘torture’, ‘abuse’ and ‘cruel’ to describe some of team involvement.20 The four competencies involved in patient and the end-of-life cases in their care, expressing associated feelings of family carer satisfaction in ICU (adept prognosis discussion, shared being ‘traumatized’ and ‘violated’.4,47 In this matter, doctors are not decision making, active listening and empathy), all packaged in one

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‘Wrong treatment’: Doctors’ take on medical futility in a low-resource ICU

alone in experiencing situations they consider to be medically futile The organisational system in place in this study ICU utilizes but are compelled by hospital standards to administer treatment. the services of doctor anaesthetists only, hence the justification for Nurses are known to have higher levels of moral distress than use of only doctors for this research. The purposive sampling of doctors.48 Borhani et al. postulate that the recurrent experience of a homogenous group of resident doctors, which utilized a small futile care can result in negative psychological changes in clinicians sample size, was advantageous as it allowed for in-depth interviews and thus increase their susceptibility to moral distress.49 Dzeng and thus detailed interpretive accounts on medical futility in the et al. surmise that administering perceived futile care to patients ICU. However, one may consider the recruitment of resident may trouble the consciences of these trainees, producing moral doctors only in this study – with no consultant anaesthetists distress while Rosenthal and Clay advocate for trainee education interviewed – as introducing the possibility of sampling bias, as and mentoring in ethics of end-of-life care as initiatives to reduce the perspectives of consultants may be different judging by their such distress.47,50 Chukwuneke suggests that in order to reduce the years of experience in the ICU. Besides, factors like age and occurrence of moral distress, the moral acceptability of obligation experience of the physician have been known to influence the final to duty should be the basis for a physician’s actions in the course moral decision taken in situations of ethical dilemma in medical of patient management.51 In addition, physicians should be practice.15 But the authors consider the first-person narrative of adequately informed that patients have fundamental rights no the resident doctors very relevant as they are the foot soldiers in the matter how bad their health condition may be and are entitled medical battlefield. Finally, participants’ quantitative assessment of to be given treatment until they die naturally. The duty of care futility can be considered to be subjective as there is no recognised implies physicians must protect the lives of patients and should objective quantitative measure of futility. never abandon life or hasten their death at any point.24 The constant barrage of ethical dilemmas faced by the Conclusion intensivist and the attendant moral distress portends negative Despite significant disparities between developed and consequences for patient care such as cynicism, burnout, decline in developing nations concerning availability of ICU resources, this empathy and ethical erosion.47,52 While this study did not examine study – which is the first of this kind from a developing nation in these issues in the participants, it has been noted that cynicism Africa – suggests that medical futility may be a constant feature in can cause young doctors to question the relevance of their care of ICUs of both resource-rich and resource-poor nations of the world. patients and the occurrence of severe burnout syndrome is high in Futile medical interventions are disadvantageous as they increase critical care doctors and nurses, especially in relation to end-of-life patient pain and discomfort, give a false sense of hope of progress care scenarios like decisions to forgo life-sustaining treatments.51-53 or recovery for family carers, delay palliative care interventions and In the environment of the participants of our study, ethics as a increase financial burden. The ICU anaesthesia resident doctors subject is not taught in undergraduate and postgraduate medical in this study seem to concur that futile care appears predominant curricula and this omission may contribute significantly to the in this low-resource ICU with several factors implicated including ethical dilemmas faced by doctors working in this low-resource lack of goals of treatment, no specialist training in intensive care ICU. Also, as these trainees are in the formative years of their medicine and lack of protocols. In addition, the identification of professional career, their experience of moral distress may result in poor communication as a contributory factor to the existence of reduction in empathy towards patient and the adoption of negative medical futility further highlights that appropriate communication coping strategies like emotional detachment and dehumanization tools should be incorporated to aid clinicians in supporting family as protective mechanisms to deal with the reality of medically futile caregivers along with medical decision-making and treatment.60 care.47,54 Positive coping strategies like weekly ‘death rounds’ in Medical futility, in the opinion of the health caregivers enrolled in which the medical team can deal with the emotions associated with this study, may contribute substantially to the challenges of running ethical decisions taken in the course of patient management have an ICU. been advanced as viable alternatives.25,26 While this study is particularly relevant to the study centre, The interpretive phenomenological analysis (IPA) approach to concerns regarding futile treatment in ICU pervade most medical this research was necessitated by the lead author’s daily interactions practices. For doctors working in low-resource ICUs, decisions to with the residents while at work.57 Phenomenology is touted to be admit patients should be based on the evidence of best practices.61 one of the richest forms through which life experiences can be In addition, the authors recommend the establishment of goals of interpreted – the so-called ‘lived experience’.27 In the case of the treatment, use of protocols for all procedures, clear delineation of respondents, one would ordinarily assume their daily activities duties for all staff in the ICU to avoid overlap of duties and patient in the ICU did not bother them beyond their general hope neglect, training doctors in intensive care and early introduction of and expectation of patient recovery. But use of IPA allowed an palliative care, to reduce the occurrence of medical futility.62 Other understanding of not only what the respondents feel about the recommendations include incorporation of bioethics in the course phenomenon of medically futile care and what the experience content of medical and nursing undergraduate and postgraduate means to them, but also how they experience such care, hence curricula, counselling and education of patients and their families granting an understanding of the phenomenon ‘from the inside’.59 on advance directives and the production of professional society/ The authors also considered use of this qualitative approach to the national guidelines relating to the provision of futile care. Finally, methodology as very appropriate especially because it is considered further studies involving family caregivers as well as multicentric site ideal when used in the study of complex biopsychosocial studies in resource-poor environments examining the perspectives phenomena, which occurs within the context of the ICU as well as of other cadres of clinicians in the ICU such as consultants and healthcare research.59 nurses are encouraged.

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Chest 2009; 136(4): 963–967 477 - 479 13. White DB, Pope TM. The Courts, Futility, and the Ends of Medicine. JAMA 44. Ayeh DD, Tak HJ, Yoon HD, et al. U.S. physicians’ opinions about accommo- 2012; 307(2): 151–152. dating religiously based requests for continued life-sustaining treatment. J Pain 14. Neville TH, Wiley JF, Yamamoto MC, et al. Concordance of Nurses and Physi- Symptom Manage. 2016; 51(6): 971–978 cians on Whether Critical Care Patients are Receiving Futile Treatment. Am J 45. Superdock AK, Barfield RC, Brandon DH, et al. Physicians’ opinions about ac- Crit Care. 2015;24(5):403-10. commodating religiously based requests for continued life-sustaining treatment. J 15. Neville TH, Wiley JF, Holmboe ES, et al. Differences between attendings’ and Pain Symptom Manage. 2016;51(6):971-8. fellows’ perceptions of futile treatment in the intensive care unit at one academic 46. Gélinas C, Fillion L, Robitaille MA, et al. Stressors experienced by nurses pro- health center: implications for training. Acad Med. 2015; 90(3): 324–330. viding end-of-life palliative care in the intensive care unit. Can J Nurs Res. 16. Aghabarary M, Nayeri ND. Reasons behind providing futile medical treatments 2012;44(1):18-39. in Iran: A qualitative study. Nurs Ethics. 2017;24(1):33-45. 47. Dzeng E, Colaianni A, Roland M, et al. Moral distress amongst American physi- 17. White B, Willmott L, Close E, et al. What does “futility” mean? An empirical cian trainees regarding futile treatments at the end of life: a qualitative study. J study of doctors’ perceptions. Med J Aust. 2016; 204 (8): 318 Gen Intern Med. 2016; 31(1): 93–99. 18. Teixeira A, Figueiredo E, Melo J, et al. Medical Futility and End-of-Life Decisions 48. Karanikola MN1, Albarran JW, Drigo E, et al. Moral distress, autonomy and in Critically ill Patients: Perception of Physicians and Nurses on Central Region nurse-physician collaboration among intensive care unit nurses in Italy. J Nurs of Portugal. J Palliative Care Med. 2012; 2:4 Manag. 2014;22(4):472-84. 19. Kompanje EJ, Piers RD, Benoit DD. Causes and consequences of disproportion- 49. Borhani F, Mohammadi S, Roshanzadeh M. Moral distress and perception of ate care in intensive care medicine. Curr Opin Crit Care. 2013;19(6):630-5. futile care in intensive care nurses. J Med Ethics Hist Med. 2015; 8:2. 20. Jauhar Sandeep. It’s not just about quality of life. 2015. The New York Times. 50. Rosenthal MS, Clay MC. Initiatives for Responding to Medical Trainees’ Moral [cited 2017 July 20] Available from: www.nytimes.com/2015/05/03/opinion/ Distress about End-of-Life Cases. AMA J Ethics. 2017;19(6): 585 – 594. sunday/sandeep-jauhar-its-not-just-about-quality-of-life.html 51. Chukwuneke FN. Medical incidents in developing countries: A few case studies 21. Whitmer M, Hurst S, Prins M, et al. Dimens Medical futility: a paradigm as old from Nigeria. Nig J Clin Pract. 2015; 18(7): 20 – 24. as Hippocrates. Crit Care Nurs. 2009; 28(2):67-71. 52. Fumis RRL, Junqueira Amarante GA, de Fátima Nascimento A, et al. Moral dis- 22. Lambden JP, Chamberlin P, Kozlov E, et al. Association of perceived futile or po- tress and its contribution to the development of burnout syndrome among critical tentially inappropriate care with burnout and thoughts of quitting among healthcare providers. Ann Intensive Care. 2017;7(1):71. care providers. Am J Hospice Palliat Med. 2019; 36(3): 200–206. 53. Eikeland HL, Ørnes K, Finset A, et al. The physician’s role and empathy - a 23. Huynh T, Kleerup E, Wiley J et al. The Frequency and Cost of Treatment Per- qualitative study of third year medical students. BMC Med Educ. 2014;14:165. ceived to Be Futile in Critical Care. 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22 UTMJ • Volume 96, Number 3, June 2019 Primary Research

Effect of weight loss diets on biochemical parameters and anthropometric measurements in prolactinoma patients

Esen Yeşil1; Gül Kızıltan1; Cüneyd Anıl2; Mehtap Akçil Ok1; Nilüfer Bayraktar3

1Department of Nutrition and Dietetics, Baskent University, Ankara, Turkey 2Ankara Güven Hospital, Ankara, Turkey 3Department of Medical Biochemistry, Baskent University School of Medicine, Ankara, Turkey

INTRODUCTION Abstract rolactinomas are the most common type of pituitary Background: The aims of this study were to determine adenomas. Macroprolactinoma is the term used for these tumors when their size is ≥1 cm. If the tumor’s size is <1cm, the effect of weight loss on biochemical parameters and it’sP referred to as a microprolactinoma.1,2 Prolactinomas in adults anthropometric measurements in prolactinoma patients occur more frequently in women (>70%), with the majority in the and to evaluate the effectiveness of weight loss diet along form of microprolactinoma.2 Tumor size is generally related with with medical treatment. prolactin (PRL) level.2 Methods: Twenty-two patients with prolactinoma were As is well-known, increasing estrogen secretion stimulates the growth and proliferation of the lactotrophs during pregnancy. As divided into two groups and one of the groups was applied a result, PRL secretion increases.3 PRL is identified as a major weight loss diet (diet group) while the other group was diet stimulating factor for lactation in the postpartum period. Some free (control group). Each participant was interviewed using metabolic effects of PRL comprise of providing pancreatic cell a structured questionnaire. The biochemical parameters development in the perinatal and postnatal periods to manage (fasting plasma glucose, fasting plasma insulin, prolactin, insulin release, nutrient uptake and body weight, to stimulating leptin, TSH, T4, cortisol, HbA1c, AST, ALT and blood citrate production in prostatic cells, preventing the negative effects of glucocorticoids on the immune system during stress lipids) of participants were analyzed and anthropometric periods, reducing reproductive functions, and suppressing sexual measurements were taken. impulsivity. Results: There was a significant change in mean BMI In addition, PRL hormone induces adipogenesis, which after treatment in diet group (p=0.000). The mean level inhibits lipolysis by altering the release of significant adipokines 4 of serum prolactin decreased from 45.1±31.63 ng/dL such as leptin, adiponectin, and interleukin (IL)-6. Treatment of hyperprolactinemia reduces cardiovascular disease risk factors, at baseline to 12.6±8.19 ng/dL after three months in endothelial dysfunction, and insulin resistance.3,4,5 diet group (p=0.006). Despite there being no statistically Several studies describe a higher body weight in patients with significant difference between diet and control group in hyperprolactinemia, the exact mechanism of which is not clear.6,7,8 terms of baseline level of prolactin measurement (p=0.800), A combination of factors like decreased dopaminergic tone, low statistically significant difference between the two groups adiponectin, and hypogonadism with or without associated leptin in terms of final level of prolactin measurement (p=0.027) resistance could contribute to weight gain. Also, hyperprolactinemia has been linked to alteration in glucose homeostasis, insulin was observed. There was a significant change in mean sensitivity, and lipid parameters.9 PRL is known to stimulate level of leptin after treatment in diet group (p=0.001). leptin synthesis and secretion.10 Leptin, the obese gene product, Conclusions: In addition to medical treatment, weight is synthesized by adipose tissue in the body. Body fat mass and loss diets sped up the healing process for hyperprolactinemia body mass index (BMI) determine serum leptin level. The role of and the reduction in body weight had positive effects on leptin is to regulate nutrient intake on the brain, modulate energy metabolism via negative feedback, and prevent the development the metabolic profiles of prolactinoma patients. of obesity.11 The aims of the present study were to determine the effect of weight loss on biochemical parameters and anthropometric measurements in prolactinoma patients and to evaluate the effectiveness of a weight loss diet along with medical treatment. We analyzed the effects of the weight loss diet on the body compositions Corresponding Author: Esen Yeşil - [email protected] of prolactinoma patients. Bağlıca Kampüsü Eskişehir Yolu 18.km 06790 Etimesgut, Ankara, Turkey

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Effect of weight loss diets on biochemical parameters and anthropometric measurements in prolactinoma patients

Materials and Methods Biochemical Analysis Study Design and Participants Blood samples were collected at the beginning and at the third The study sample was composed of 22 premenopausal women month of the study. Blood samples were obtained after a fast of with prolactinoma between the ages of 20-50 years, who were at least 12 hours and analyzed by the Başkent University Ankara referred to the outpatient clinic at Başkent University Hospital, Hospital Biochemistry Laboratory using standardized laboratory Endocrinology and Metabolism Department, Ankara, Turkey. The procedures. Serum glucose levels were measured by autoanalyzer diagnosis of prolactinoma was established by recording persistently (Abbott Aeroset, Toshiba, Japan) with the adapted hexokinase elevated PRL levels (PRL=25-100 ng/ml), coupled with symptoms method. The hemoglobin A1c (HbA1c) level was measured with of hyperprolactinemia, and a positive pituitary adenoma on high pressure liquid chromatography (HPLC) (DIAMAT; Bio-Rad enhanced magnetic resonance imaging. The participants were Laboratories, Milan, Italy). Total and high-density lipoprotein enrolled in the study at the time of diagnosis between September (HDL) cholesterol and triglyceride (TG) levels were measured 2014 and August 2015 and were receiving dopamine agonist by routine laboratory techniques using an automated analyzer treatment. The major inclusion criteria was to have BMI ≥25 kg/ (Hitachi 912, Roche-Hitachi Modular Analytics, Roche Diagnostics m2 (overweight and obese). Patients were excluded from the study GmbH, Mannheim, Germany). Low-density lipoprotein (LDL) if they were pregnant, lactating, or planning a pregnancy. As well, cholesterol was calculated using the Friedewald formula (LDL participants had no history of pituitary surgery or radiotherapy. cholesterol = TC – TG/5 – HDL cholesterol). Very low-density The diet group (n=11) recevied both a weight loss diet and started lipoprotein (VLDL) cholesterol was calculated using a formula dopamine agonist treatment. The control group (n=11) received (VLDL-cholesterol = serum triglyceride/5). Serum PRL, insulin, only dopamine agonist treatment. The participants’ bromocriptine and cortisol levels were measured with commercially available doses were not changed throughout the three months. Group chemiluminescence kits (Abbott Architect, Toshiba). For evaluating samples were selected randomly. Each participant was interviewed thyroid function, thyroxine (T4), and thyrotrophin-stimulating using a structured questionnaire to obtain demographic information hormone (TSH) were measured using immunochemiluminescent about education, occupation, health conditions at entry, nutrition assays on an automated analyzer (BioDPC, USA). Serum aspartate behaviors, and marital status. aminotransferase (AST) and alanine transaminase (ALT) levels This study was approved by the Baskent University Institutional were measured using standard clinical methods for automated Review Board and Ethics Committee (Project no: KA13/321) and analysis. Plasma leptin was evaluated by a highly sensitive direct supported by the Baskent University Research Fund. enzyme-linked immunosorbent assay (ELISA) using commercial kits (DIAsource LeptinEASIA Kit, KAP 2281 DIAsource Anthropometric Measurements Immunoassays S.A, Nivelles, Belgium). Anthropometric measurements were taken at the beginning and at the third month of the study. Height was measured with Statistical Analysis a fixed stadiometer with 1 mm precision. Body weight, fat mass, Statistical analyses were carried out by Statistical Package for fat, muscle, and water ratios were measured with light indoor Social Sciences (SPSS) for Windows, Release 21.0. Quantitative clothes, via Bioelectric Impedance Analysis (BIA) (ioi 353, Jawon data were expressed as mean (X̅ ) and standard deviation (SD). Medical, S. Korea). BMI was calculated as weight in kilograms Qualitative data were stated as number (n) and percentage (%) divided by the square of the height in meters (kg/m2). Waist and values. Normality was tested by Kolmogorov–Smirnov test. hip circumferences were measured with an inelastic tape measure, Normally distributed data were analyzed using a “Paired Samples halfway between the last rib and the iliac crest. Hip circumference t Test”. Comparison of means between the groups was analyzed was measured to calculate the waist-to-hip ratio (WHR). Waist to using an “Independent Sample t Test”. The Pearson correlation test height ratio (WHtR) was determined by dividing waist to height. was used for correlation analysis. p values < 0.05 were considered statistically significant. Intervention Weight loss management was planned and controlled by a Results dietitian for each patient after diagnosis. The diet group’s patients Microadenoma was detected in all participants. The mean had lost a minimum of 5 % of their initial body weight by applying age of participants was 37.2±10.21 years. Out of 22 patients, ten the weight loss diet for three months. Participants who were unable (45.5%) were married, 11 (50.0%) were single, and one (4.5%) was to lose weight were excluded from the study. During the follow-up, widowed or divorced. It was determined that 19 of the participants patients had multiple outpatient visits where adherence to the diet (86.4%) were graduates of undergraduate and graduate programs. was checked and regulated. During the course of the study, patients Out of 22 women, 20 had oligomenorrea and 11 had galactorrhea were prescribed a patient-specific balanced diet. The diet plan was (Table 1). individually calculated to provide a reduction from 500 to 1000 Anthropometric and biochemical measurements of participants kcal/day of the energy needs of the subject. Every two to three were revealed in Table 2. Although a statistically significant decrease weeks, anthropometric measurements were taken and, if necessary, was observed in the mean body weight in the diet group (p=0.000), adjustments were made to the diet to improve compliance. Three there was no significant difference observed in the mean body weight meals (breakfast, lunch, and dinner) and snacks were recommended. in the control group (p=0.192). When the first and last body weight The nutritionist provided personalized instructions by using food measurements were compared between the groups, no statistically exchange lists. Individual preferences for various food items were significant differences were found (p²=0.218, p³=0.892). At the integrated into the diet plan. begining of the study, means of BMI were 31.7±5.88 kg/m2 and

24 UTMJ • Volume 96, Number 3, June 2019 Primary Research

Effect of weight loss diets on biochemical parameters and anthropometric measurements in prolactinoma patients

28.4±5.05 kg/m2 in the diet and the control groups, respectively. Table 1. Demographic and Disease-Related Characteristics of Participants However, after three months, while the mean BMI decreased to Paramenters Diet Group Control Group Total (n:11) (n:11) (n:22) 28.9±5.52 kg/m2 in the diet group (p=0.000), there was no statistical difference in the control group’s BMI (28.5±5.00 kg/m2; p=0.334). n % n % n % When the first and last BMI were compared between the groups, no Age (X̅ ± 39.8±11.65 34.7±8.31 37.2±10.21 SD) (years) statistically significant differences were found (p²=0.180, p³=0.856). Marital Single 6 54.5 4 36.4 11 50.0 In the diet group, there were statistically significant differences Status seen in the mean levels of waist circumference, body fat weight Married 4 36.4 7 63.6 10 45.5 and percentage, body water weight, as well as levels of AST, TSH, Widow / Divorced 1 9.1 1 4.5 triglycerides, total cholesterol, and VLDL-cholesterol (p<0.05). Working Officer 3 27.3 3 27.3 6 27.3 status Similarly, a statistically significant difference in the mean level of Self-employment 3 27.3 3 27.3 6 27.3

HDL-cholesterol was observed in the control group (p=0.002). Unemployed 3 27.3 1 9.1 4 18.2 The level of total cholesterol decreased significantly in both groups Worker 2 18.2 2 9.1 (p=0.004; p=0.005). It was observed that PRL levels decreased in both groups. The Academician 1 9.1 1 9.1 2 9.1 mean level of serum PRL decreased from 45.1±31.63 ng/dL at Retired 1 9.1 1 4.5 baseline to 12.6±8.19 ng/dL after three months in the diet group Student 1 9.1 1 4.5 (p=0.006). Also, the mean level of serum PRL decreased from Education Primary school 1 9.1 1 9.1 2 9.1 Status 42.3±17.83 ng/dL at baseline to 22.9±11.68 ng/dL at the end of High school 1 9.1 1 4.5 the study in the control group (p=0.002). Even though there was no License and above 10 90.9 9 81.9 19 86.4 statistically significant difference seen between the groups in terms Irregular Yes 10 90.9 10 90.9 20 90.9 of PRL level at baseline (p=0.800), there was a statistically significant period difference in terms of PRL levels after three months (p=0.027). No 1 9.1 1 9.1 2 9.1 Despite a statistically significant decrease in the mean level of leptin Galactorrhea Yes 6 54.5 4 36.4 10 45.5 after treatment in the diet group (p=0.001), the decrease was not No 5 45.5 7 63.6 12 54.5 significant in the control group (p=0.065) (Table 2).

Table 2. Changes In Anthropometric And Biochemical Measurements In Diet And Control Groups

Diet Group (n:11) Control Group (n:11)

Before Treatment After treatment pa Before Treatment After treatment pa pb pc (X̅ ± SD) (X̅ ± SD) (X̅ ± SD) (X̅ ± SD) Body Weight (kg) 85.5±17.34 78.0±15.94 0.000* 76.4±16.22 77.0±16.03 0.192 0.218 0.892 BMI (kg/m2) 31.7±5.88 28.9±5.52 0.000* 28.4±5.05 28.5±5.00 0.334 0.180 0.856 Waist circumference (cm) 101.2±13.09 97.0±13.19 0.000* 93.8±13.47 94.8±12.88 0.118 0.206 0.699 Waist / Hip 0.8±0.10 0.8±0.08 0.635 0.8±0.05 0.8±0.08 0.314 0.304 0.915 Waist/ Height 0.6±0.07 0.5±0.07 0.068 0.5±0.12 0.5±0.07 0.399 0.705 0.928 Body Fat Weight (kg) 34.5±12.72 29.6±11.27 0.000* 26.1±10.27 26.6±10.13 0.303 0.107 0.528 Body Fat Percentage (%) 39.3±7.30 36.8±6.67 0.001* 32.7±6.49 33.7±5.71 0.346 0.057 0.259 Fatless Tissue Weight (kg) 49.9±9.65 48.3±6.84 0.328 50.0±7.36 50.3±6.48 0.569 0.975 0.490 Body Water Weight (kg) 38.7±5.80 36.0±4.90 0.029* 37.6±5.42 37.8±5.24 0.649 0.670 0.413 Fasting Glucose (mg/dL) 93.0±12.50 92.1±10.93 0.676 87.0±3.00 87.0±3.56 0.921 0.144 0.168 Fasting Insulin (IU/mL) 9.4±6.16 9.2±7.51 0.966 8.4±3.96 8.5±5.05 0.750 0.659 0.798 HbA1c (%) 5.4±0.40 5.3±0.37 0.284 5.1±0.14 5.1±0.11 0.659 0.016* 0.790 HOMA-IR 2.3±1.91 2.0±1.50 0.709 1.8±0.90 1.8±1.90 0.805 0.441 0.682 AST (U/L) 16.5±3.32 12.5±3.24 0.015* 18.8±3.51 17.7±4.36 0.528 0.135 0.005* ALT (U/L) 14.0±5.34 13.0±3.83 0.604 18.9±11.92 17.7±8.08 0.749 0.227 0.100 PRL (ng/dL) 45.1±31.63 12.6±8.19 0.006* 42.3±17.83 22.9±11.68 0.002* 0.800 0.027* Cortisol (μg/dL) 11.4±5.03 8.3±5.34 0.098 9.2±2.51 8.6±2.67 0.527 0.209 0.869 TSH (μIU/L) 2.0±0.70 1.5±0.62 0.005* 1.6±0.51 1.4±0.49 0.563 0.149 0.718 Free T4 (ng/dL) 1.1±0.17 1.1±0.22 0.557 1.1±0.22 1.1±0.23 0.745 0.967 0.898 Triglyceride (mg/dL) 123.1±50.10 95.1±42.45 0.030* 117.8±34.71 115.3±35.33 0.919 0.773 0.198 Total Cholesterol (mg /dL) 202.4±38.52 168.5±38.81 0.004* 205.7±37.93 176.3±23.96 0.005* 0.842 0.577 LDL-Cholesterol (mg/dL) 135.9±36.53 115.8±31.69 0.067 137.0±30.42 124.9±18.36 0.128 0.935 0.420 HDL-Cholesterol (mg/dL) 41.9±3.41 33.7±12.85 0.086 45.0±7.18 28.0±10.69 0.002* 0.200 0.269 VLDL-Cholesterol (mg/dL) 24.6±10.02 19.0±8.49 0.030* 23.5±6.94 22.4±7.06 0.919 0.773 0.198 Leptin (ng/dL) 16.1±8.86 9.7±5.79 0.001* 15.0±8.49 12.2±6.21 0.065 0.768 0.343 *p<0.05 pa: test of significance the difference between the measurements within the group pb: test of significance between the groups the mean of the first measurement pc: test of significance between the groups the mean of the last measurement (after 3 months)

UTMJ • Volume 96, Number 3, June 2019 25 Primary Research

Effect of weight loss diets on biochemical parameters and anthropometric measurements in prolactinoma patients

Table 3. Correlations Between Prolactin, Leptin Levels and Other Correlations between PRL, leptin levels and other biochemical Biochemical Parameters, Anthropometric Measurements parameters, and anthropometric measurements were revealed in PRL (ng / dL) Leptin (ng / dL) Table 3. In the present study, there was no statistically significant Diet Group Control Group Diet Group Control Group correlation between BMI and PRL levels in both groups at the end Body Weight (kg) r -0.103 -0.364 0.267 0.416 of the study (p=0.732; p=0.177). There were positive and significant p 0.762 0,272 0.427 0.203 correlations between serum leptin levels and waist circumference,

BMI (kg/m2) r -0.117 -0.439 0.274 0.601 waist/ height ratio, body fat percentage, fasting plasma insulin

p 0.732 0.177 0.415 0.050 levels and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) values in control group (p<0.05). No correlation was Waist circumfer- r 0.003 -0.223 -0.012 0.695 ence (cm) observed between serum leptin and other biochemical parameters p 0.994 0.509 0.972 0.018* in the diet group (p>0.05). Waist /Hip Ratio r 0.566 -0.066 -0.173 0.251 p 0.070 0.847 0.610 0.456 Discussion Waist/ Height Ratio r 0.079 -0.248 -0.044 0.785 Prolactinomas are a type of pituitary adenoma that secrete p 0.818 0.462 0.898 0.004* PRL hormone. The amount of secreted PRL is related to the

Body Fat Weight r 0.026 -0.176 0.344 0.507 size of the tumor. Tumor secretion is not the only known cause (kg) of hyperprolactinemia. There are also many physiological and p 0.940 0.604 0.301 0.111 pathological reasons for hyperprolactinemia, such as pregnancy, Body Fat r -0.051 -0.345 0.401 0.633 Percentage (%) lactation, stress, and multiple drugs which impair the dopamine 12 p 0.881 0.299 0.222 0.037* system. Excessive release of the PRL hormone has various metabolic effects on the body. Hyperprolactinemia is associated Lean Body Mass r -0.156 -0.364 0.056 0.237 (kg) with insulin secretion, increased adipokine release, immune p 0.646 0,272 0.869 0.483 system stimulation, increased nutrient intake, and increased body Fasting Plasma r -0.098 0.425 0.269 0.035 weight. Hyperprolactinemia can also lead to insulin resistance, Glucose (mg/dL) p 0.775 0.193 0.425 0.919 hyperinsulinemia, endothelial dysfunction, cardiovascular disease, 4 Fasting Plasma r 0.154 -0.406 0.051 0.772 and metabolic syndrome. The aim of this study was to examine Insulin (IU/mL) p 0.652 0.216 0.882 0.005* metabolic profile improvement by applying a weight loss diet

HbA1c (%) r -0.022 -0.252 -0.320 0.482 alongside dopamine agonist treatment. Prolactinomas are more common in women between 20 and 50 p 0.950 0.455 0.337 0.133 years of age.13 The sample of this study consisted of women and HOMA-IR r 0.148 -0.365 0.119 0.777 the mean age was 37.2±10.21 years. In a recent study, conducted p 0.664 0.270 0.727 0.005 between 2005 and 2007, 53.2% of individuals with pituitary gland AST (U/L) r 0.561 0.241 -0.165 0.067 tumors were women.14 p 0.073 0.476 0.628 0.845 Hyperprolactinemia is a common cause of galactorrhoea, ALT (U/L) r 0.267 0.313 -0.179 -0.111 which refers to milk secretion not due to breast-feeding, and has 15 p 0.426 0.348 0.598 0.746 been often accompanied by amenorrhea. The prevalence of hyperprolactinemia in patients with secondary amenorrhea or PRL (ng/dL) r 1 1 0.538 -0.268 oligomenorrhorea is 15-20%. Generally, 30% of women with p 0.088 0.426 galactorrhoea and infertility have hyperprolactinemia. On the other Cortisol (μg/dL) r 0.059 -0,246 0.167 -0.079 hand, 75% of women with hyperprolactinemia have amenorrhea p 0.863 0.466 0.624 0.817 and galactorrhea.16 In this study, 90% of women had menstrual TSH (μIU/L) r 0.374 -0.051 0.345 0.017 irregularities and 45% of them had symptoms of galactorrhea. p 0.258 0.881 0.298 0.961 In a study, it was stated that four months of dopamine agonist

Free T4 (ng/dL) r 0.375 0.594 -0.006 -0.125 treatment decreased the level of fasting plasma glucose and HbA1c in obese type 2 diabetic patients.17 In another study, it was p 0.256 0.054 0.985 0.715 determined that there was a significant increase in serum PRL Triglyceride r 0.115 -0.009 -0.232 0.443 (mg /dL) levels in obese and morbidly obese patients. In addition, serum p 0.736 0.980 0.493 0.172 PRL levels were stated to be significantly related to β-cell index Total Cholesterol r 0.104 0.232 -0.275 0.230 and BMI. However, there was no statistically significant correlation (mg /dL) p 0.761 0.492 0.413 0.496 between HOMA-IR values and serum PRL levels.18 Similarly, LDL-Cholesterol r 0.276 0.278 -0.249 0.161 in our study, there was no statistically significant correlation (mg /dL) p 0.411 0.408 0.461 0.637 seen between serum PRL levels and HOMA-IR in both groups

HDL-Cholesterol r -0.444 0.049 -0.064 -0.053 (p=0.664; p=0.270). (mg/dL) Abnormalities in thyroid functions affect the body’s energy p 0.172 0.887 0.852 0.876 balance.19 Drugs and hypothyroidism are among other causes Leptin (ng/dL) r 0.538 -0.268 1 1 of hyperprolactinemia.20 In this study, there was a significant p 0.088 0.426 decrease in TSH levels in the diet group (p=0.005). The decrease *p<0.05 seen in the control group was not statistically significant (p=0.563).

26 UTMJ • Volume 96, Number 3, June 2019 Primary Research

Effect of weight loss diets on biochemical parameters and anthropometric measurements in prolactinoma patients

Hypothyroidism has similarities with metabolic syndrome. Weight loss is observed in patients receiving dopaminergic Therefore, low TSH levels have been associated with desired agonist treatment. Decrease in body weight with dopamine agonist metabolic profiles.21 Previous studies have shown a significant therapy is associated with an increase in dopaminergic tone. In a and positive correlation between serum TSH and PRL levels in study, it was shown that two years of treatment with bromocriptine hypothyroid patients.22,23 In our study, a positive correlation was (dopamine agonist) reduced body weight. However, serum leptin observed between serum PRL and TSH levels of the subjects in levels did not show a statistically significant difference at the end the diet group, though insignificant. This result can be possibly of two years.27 Furthermore, Silva et al. evaluated 22 patients with attributed to an insufficient sample size. prolactinoma.29 After six months of dopamine agonist treatment, A randomized clinical trial showed that a 5% weight loss serum PRL levels returned to normal, and HOMA-IR values, improves lipid profile and reduces inflammation in obese serum fasting glucose, LDL-cholesterol, and triglyceride levels individuals.24 We observed an 8.7±3.06% decrease in weight decreased significantly (p<0.05). in the diet group. Wing et al. demonstrated that 5-10% of body In the literature, studies showing the effect of diets that induce weight loss improved hyperglycemia, blood pressure, triglyceride weight loss by changing lifestyle and eating habits are insufficient levels, and HDL-cholesterol levels.25 In this study, it is intended in prolactinoma patients. In the present study, although serum that the metabolic profile improves by applying the weight loss diet leptin levels decreased in both goups, the change was significant alongside dopamine treatment. A long treatment period is needed only in the group implementing the diet in addition to medical to see the effects of dopamine agonist therapy on body weight.26,27 treatment (p=0.001). Although dopamine agonist therapy may be It has also been reported that weight loss and normalization of considered as the potential driver of this situation, considering that serum insulin levels improve PRL response.28 In our study, at the both groups received that treatment, the significant difference may end of three months follow up, there was a statistically significant be attributed to the diet intervention in a relatively short time. decrease in body weight, body fat weight, body fat percentage, The main limitation of the present study was the small sample body water weight, BMI, and waist circumference in the diet group size. Besides, dopamine agonist treatment of all patients may be (p<0.05). It is believed that weight loss in a short time has a positive overshadowed by the effects of weight loss. effect on the disease process. In the literature, the extent of scientific research conducted thus Serum triglycerides, total cholesterol, and VLDL-cholesterol far is inadequate to truly determine the importance of weight loss levels were reduced amongst participants of the diet group in prolactinoma patients. This is the first study in Turkey about this (p<0.05). At the end of the three months, the improvement in lipid topic. More comprehensive studies with an increased number of profile is thought to be associated with a decrease in body weight cases need to be designed to emphasize the importance of weight and serum PRL levels. loss in prolactinoma patients. We determined a statistically significant decline in serum PRL levels of all subjects at the end of three months in both groups, Conclusion which may largely be attributed to dopamine agonist therapy. In conclusion, our findings indicate that in addition to Though there was no significant difference between the groups medical treatment of prolactinoma, applying a weight loss diet in terms of baseline measurements, the final PRL levels were has a positive effect on the recovery process of the disease. The significantly different. This may suggest that implementing the effect of dopamine agonist therapy on the metabolic profile weight loss diet alongside medical treatment in overweight or seems to improve more rapidly in the presence of a weight loss obese patients with prolactinoma has a positive effect on serum diet. Depending on the magnitude of weight loss, patients with PRL levels. The decrease in prolactin levels may explain the better prolactinomas may need lower doses with a shorter duration of metabolic profile of the diet group. dopamine agonist treatment, as well as avoiding many obesity- Leptin is important in the maintenance of the neuroendocrine related complications. Consequently, weight loss diet treatment system. In a controlled study, the relationship between serum PRL should be offered in addition to medical treatment for overweight and leptin was investigated. Patients with high PRL levels were and obese patients with prolactinoma. compared with normoprolactinemic subjects. There was a strong correlation between PRL and leptin levels. Hyperprolactinemic Acknowledgments individuals had higher leptin levels than the control group This study was approved by the Baskent University Institutional (p<0.05).30 In the present study, there were no statistically Review Board and Ethics Committee (Project no: KA13/321) and significant correlations between serum leptin and PRL levels in supported by the Baskent University Research Fund. both groups. In another study, 40 premenopausal women with prolactinoma or idiopathic hyperprolactinemia were compared References to 41 age-matched healthy premenopausal women. There were 1. Colao A. The prolactinoma. Best Prac Res Clin Endocrinol Metab. 2009;23(5):575–96. positive correlations between serum leptin levels and body weight, 2. Iglesias P, Diez JJ. Macroprolactinoma: a diagnostic and therapeutic update. BMI and waist circumference in the patient group (p<0.05).31 In QJM: An International Journal of Medicine 2013;106(6):495-504. 3. Ignacak A, Kasztelnik M, Sliwa T, et al. Prolactin–not only lactotrophin. A “new” our study, positive, but insignificant correlations between serum view of the “old” hormone. J Physiol Pharmacol, 2012;63(5):435-43. leptin levels and body weight, BMI, waist circumference, waist/hip 4. Bernabeu I, Casanueva FF. Metabolic syndrome associated with hyperpro- ratio, waist/height ratio, body fat percentage, and body fat weight lactinemia: a new indication for dopamine agonist treatment? Endocrine. 2013;44(2):273-74. in the diet group were observed. Increasing the number of cases 5. Capozzi A, Scambia G, Pontecorvi A, et al. Hyperprolactinemia: pathophysiology may reveal significant results. and therapeutic approach. Gynecol Endocrinol. 2015;31(7):506–10.

UTMJ • Volume 96, Number 3, June 2019 27 Primary Research

Effect of weight loss diets on biochemical parameters and anthropometric measurements in prolactinoma patients

6. Ben-Jonathan N, Hugo ER, Brandebourg TD, et al. Focus on prolactin as a meta- 20. Goel P, Kahkasha S, Gupta BK, et al. Evaluation of serum prolactin level in pa- bolic hormone. Trends in Endocrinology & Metabolism. 2006;17(3):110-16. tients of subclinical and overt hypothyroidism. Journal of clinical and diagnostic 7. Moore BJ, Gerardo-Gettens T, Horwitz BA, et al. Hyperprolactinemia stimulates research: JCDR. 2015;9(1):15-7. food intake in the female rat. Brain research bulletin. 1986;17(4):563-69. 21. Ruhla S, Weickert MO, Arafat AM, et al. A high normal TSH is associated with the 8. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treatment of hyper- metabolic syndrome. Clinical Endocrinology. 2010;72(5): 696-701. prolactinemia: an endocrine society clinical practice guideline. J Clin Endocrinol 22. Hekimsoy Z, Kafesçiler S, Güçlü F, et al. The prevalence of hyperprolactinaemia in Metab. 2011; 96(2):273-88. overt and subclinical hypothyroidism. Endocrine Journal. 2010;57(12):1011-5. 9. Pala NA, Laway BA, Misgar RA, et al. Metabolic abnormalities in patients with 23. Goswami B, Patel S, Chatterjee M, et al. Correlation of prolactin and thyroid hor- prolactinoma: response to treatment with cabergoline. Diabetology & metabolic mone concentration with menstrual patterns in infertile women. J Reprod Infertil. syndrome, 2015;7:99. https://doi.10.1186/s13098-015-0094-4 2009;10(3), 207-12. 10. Watanobe H, Schiöth HB, Izumi J. Pivotal roles of α-melanocyte-stimulating hor- 24. Fayh AP, Lopes AL, da Silva AM, et al. Effects of 5% weight loss through diet or mone and the melanocortin 4 receptor in leptin stimulation of prolactin secretion diet plus exercise on cardiovascular parameters of obese: a randomized clinical in rats. J Neurochem. 2003;85(2):338-47. trial. Eur J Nutr. 2013; 52(5):1443-50. https://doi: 10.1007/s00394-012-0450-1 11. Ašimi ZV. Body weight changes in female patients with prolactinoma treated with 25. Wing RR, Lang W, Wadden TA, et al. Benefits of modest weight loss in improving bromocriptin. Medicinski glasnik. 2007;4:71-3. cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. 12. Rabinovich IH, Gómez RC, Mouriz MG, et al. Clinical guidelines for diagnosis and Diabetes care. 2011;34(7):1481-6. treatment of prolactinoma and hyperprolactinemia. Endocrinología y Nutrición 26. Greenman Y, Tordjman K, Stern N. Increased body weight associated with prolac- (English Edition). 2013;60(6):308-19. tin secreting pituitary adenomas: weight loss with normalization of prolactin levels. 13. Uçan B, Delibaşı T. Prolaktinoma: Epidemiyoloji, Patoloji ve Patogenez. Türkiye Clinical Endocrinology. 1998;48(5),547-53. Klinikleri J Endocrin-Special Topics. 2012;5(2):22-6. 27. Doknic M, Pekic S, Zarkovic M. Dopaminergic tone and obesity: an insight from 14. Zhu X, Wang Y, Zhao X, et al. Incidence of pituitary apoplexy and its risk factors prolactinomas treated with bromocriptine. European Journal of Endocrinology. in Chinese people: a database study of patients with pituitary adenoma. PloS one. 2002;147(1):77-84 2015;10(9):e0139088. https://doi: 10.1371/journal.pone.0139088. 28. Kopelman PG. Physiopathology of prolactin secretion in obesity. 15. Huang W, Molitch ME. Evaluation and management of galactorrhea. American Int J Obes Relat Metab Disord. 2000;24(2):104-8. Family Physician. 2012;85(11):1073-80. 29. Santos‐Silva CM, Barbosa FR, Lima GA. BMI and metabolic profile in patients 16. Ciccarelli A, Daly AF, Beckers A. The epidemiology of prolactinoma. Pituitary. with prolactinoma before and after treatment with dopamine agonists. Obesity. 2005;8(1);3-6. 2011;19(4):800-5. 17. Pijl H, Ohashi S, Matsuda M, et al. Bromocriptine: a novel approach to the treat- 30. Balci H, Akgun Dar K, Gazioglu N, et al. The relationship between prolactin ment of type 2 diabetes. Diabetes Care. 2000;23(8):1154-61. (PRL), leptin, nitric oxide (NO), and cytokines in patients with hyperprolactinemia. 18. Top C, Cingözbay BY, Keskin Ö, et al. Normoglisemik obez hastalarda prolaktin ve Pituitary. 2009;12(3):170-6. https://doi: 10.1007/s11102-008-0140-4. insülin direnci ilişkisi. Uludağ Üniversitesi Tıp Fakültesi Dergisi. 2002;28(3):85-7. 31. Atmaca A, Bilgici B, Ecemis GC, et al. Evaluation of body weight, insulin resis- 19. Ekici A, Keleş H, Ekici M. Kronik obstrüktif akciğer hastalığı olan olgularda tiroid tance, leptin and adiponectin levels in premenopausal women with hyperprolac- fonksiyonları. Solunum Hastalıkları. 2006;17:161-6. tinemia. Endocrine. 2013;44(3):756-61. https://doi: 10.1007/s12020-013-9931-0.

28 UTMJ • Volume 96, Number 3, June 2019 Primary Research

Perioperative blood loss in South African primary hip arthroplasty patients

Mohamed S. Khattab (MD)1,a; Yoshan Moodley (PhD)2,b

1Department of Anesthetics, University of KwaZulu-Natal, Private Bag X7, Congella 4013, South Africa 2Faculty of Health and Environmental Sciences, Central University of Technology, Bloemfontein, South Africa aMaster’s student, bResearch associate

Introduction Abstract rimary hip arthroplasty has become a commonly per- Background: Perioperative blood loss in South formed surgery due to its success in the management African (SA) primary hip arthroplasty patients has of orthopaedic hip disorders. It is an extensive surgical not been described. This information could improve procedure,P and blood loss during the perioperative period is patient management during the perioperative period in inevitable.1,2 The usual perioperative blood loss for patients this setting. Our study objectives were to 1) determine undergoing primary hip arthroplasty varies according to set- perioperative blood loss in SA primary hip arthroplasty ting. Blood loss following primary hip arthroplasty in Chinese patients, and 2) determine which characteristics are settings ranges between 1155mL and 1785mL,3,4 while periop- associated with major perioperative blood loss in SA erative blood loss in a British setting was estimated at almost primary hip arthroplasty patients. 5 Methods: This was a retrospective cohort study of 1500mL. Newman and colleagues reported total blood loss 174 patients who underwent primary hip arthroplasty in an American setting to be 1386mL.6 In another American over a 22-month period at the Inkosi Albert Luthuli study, Grosflam and colleagues reported a range of blood loss Hospital, SA. All patients were part of a pre-existing following hip arthroplasty of between 1.4 and 5.8 units of red registry. Data for each patient included: Age, gender, cells (420-1740mL).7 In a Nigerian setting, blood loss following anthropometric measurements, comorbidity, orthopaedic primary hip arthroplasty was estimated at 1786mL.8 Excessive variables, laboratory test results, American Society of blood loss is associated with a higher risk of fatal and nonfatal Anesthesiologists Score, general anaesthesia, duration perioperative complications, and might also result in the need of surgery, preoperative tranexamic acid, postoperative for blood transfusion. There are several patient, anaesthetic, thromboprophylaxis, and perioperative blood transfusion. Estimated perioperative blood loss (in mL) was calculated and procedural characteristics associated with increased peri- using the Gross Equation. Minimum, maximum, mean, operative bleeding following primary hip arthroplasty in non- and median perioperative blood loss were calculated. South African (SA) settings.2 These include: older age, female Major perioperative blood loss was defined as an estimated sex, obesity, rheumatoid arthritis, hypertension, high American perioperative blood loss which was >75th percentile Society of Anesthesiologists (ASA) Score, long duration of op- obtained for the study sample. Data were analyzed using eration, general anaesthesia, not using tranexamic acid, and appropriate methods. not using postoperative thromboprophylaxis.2 Results: Perioperative blood loss ranged from 10.3 However, levels of perioperative blood loss in SA patients mL to 3041.8 mL. Mean perioperative blood loss was undergoing primary hip arthroplasty has not been described. 1103.1 ± 556.2 mL. Median perioperative blood loss was While there is uncertainty with regard to the expected blood loss 1008.8 mL, with an interquartile range of 706.2–1357.0 mL. Independent statistical associations were observed following primary hip arthroplasty in a South African setting, we between major perioperative blood loss and the following hypothesize that this would lie within the range reported for the characteristics: chronic obstructive pulmonary disease various countries above (between 420mL and 1786mL). Con- (OR: 3.01, 95% CI: 1.01–8.95; p=0.048), preoperative sidering the aforementioned association of excessive periopera- tranexamic acid (OR: 0.28, 95% CI: 0.13–0.63; p=0.002), tive blood loss with perioperative outcomes and blood product and perioperative blood transfusion (OR: 10.18, 95% CI: utilization, efforts in understanding perioperative blood loss 3.53–29.34; p<0.001). would be beneficial in improving patient management during Conclusion: The levels of perioperative blood loss the perioperative period in this setting. This is even more impor- observed in our sample of SA primary hip arthroplasty tant when one considers that if the perioperative blood loss for patients are consistent with the range of estimated primary hip arthroplasty in our SA setting lies within the range blood loss reported in the published literature for hip arthroplasty populations in other countries. SA primary reported for other non-SA settings, then it could possibly result hip arthroplasty patients who suffer major perioperative blood loss are more likely to have COPD or require perioperative blood transfusion. Preoperative tranexamic acid was protective against major perioperative blood loss. Corresponding Author: Mohamed S. Khattab [email protected]

UTMJ • Volume 96, Number 3, June 2019 29 Primary Research

Perioperative blood loss in South African primary hip arthroplasty patients in transfusions between 2 and 6 units of red cells in order to loss was appropriate as there is great variation in perioperative restore preoperative blood volumes. Blood products are a scarce blood loss reported between settings.3-8 resource in SA,9 and elective procedures are often cancelled or deferred as a result of low blood product stocks. The burden of Statistical Analysis certain bleeding risk factors could also be different between sur- The minimum, maximum, mean with standard deviation, gical populations from different settings, therefore necessitating and median with interquartile range (IQR) perioperative blood the identification of setting-specific characteristics associated loss were calculated using conventional methods.13 Potential with major perioperative blood loss. Therefore, the objectives associations between various characteristics and major periop- of this study were to 1) determine perioperative blood loss in erative blood loss were investigated initially investigated using SA primary hip arthroplasty patients, and 2) determine which univariate statistical methods (χ2 test, or Fisher’s exact test for characteristics (patient, anaesthetic, and procedural character- categorical variables and the Mann-Whitney test for continu- istics) are associated with major perioperative blood loss in SA ous variables). This was done in order to determine the distri- primary hip arthroplasty patients. bution of major perioperative blood loss between the different categories of characteristics, and also to select the most appro- Methods priate characteristics for inclusion in the multivariate statistical This was a retrospective cohort study involving adult pa- analysis. Characteristics with p<0.100 in the univariate analysis tients who were admitted for primary hip arthroplasty at the were selected for inclusion in the multivariate statistical analysis Inkosi Albert Luthuli Central Hospital (IALCH) in KwaZulu- (logistic regression) in an attempt to obtain the most parsimoni- Natal, SA, between 23 September 2014 and 28 July 2016. All ous model possible.14 The Hosmer-Lemeshow test was used to patients were part of a pre-existing registry. These patients assess the goodness of fit for the final logistic regression mod- were identified from theatre lists during the specified study -pe el. Results for the univariate statistical analysis are presented riod. Specific inclusion and exclusion criteria (Table 1) were as frequencies and percentages, or medians and IQR, where used when identifying eligible patients for the study sample. applicable. Results for the multivariate statistical analysis are presented as odds ratios (OR) with 95% confidence interval Table 1. Inclusion and exclusion criteria used in this study (CI). A p-value of <0.050 was considered to be a statistically Inclusion criteria Exclusion criteria significant result. All statistical analyses were performed using Patients aged 18 years or older Patients previously included in this study the Statistical Package for the Social Sciences (SPSS) version (i.e. patients were included only once in the analysis) 25.0 (IBM Corp, USA).

Patients who underwent primary hip Patients with height and weight missing arthroplasty at IALCH between 23 Sep- in their medical records (required for Study Ethical Approval tember 2014 and 28 July 2016 calculation of blood loss) This study received ethical approval from the Biomedical Research Ethics Committee of the University of KwaZulu- Data Natal, SA (Protocol: BE046/18). During the chart review process for the pre-existing registry, various patient, clinical, and procedural characteristics Results ® were collected for each eligible patient in a Microsoft Excel The process through which the final study sample of 174 pa- spreadsheet. This included patient age and gender, anthropo- tients was derived is shown in Figure 1. Perioperative blood loss metric measurements, comorbidity, orthopaedic condition and ranged from 10.3mL to 3041.8mL. Mean perioperative blood other orthopaedic variables, laboratory test results (including loss was 1103.1 ± 556.2 mL. Median perioperative blood loss pre- and postoperative haematocrit), American Society of An- was 1008.8 mL (IQR: 706.2–1357.0 mL). The 75th percentile aesthesiologists Score, general anaesthesia, duration of surgery, for perioperative blood loss in the study population was 1357 mL. preoperative tranexamic acid use, postoperative thrombopro- The distribution of various characteristics in the study sam- phylaxis use, and perioperative blood transfusion. In addition, ple is shown in Table 2. The median age of the study sample use of medications such as aspirin and nonsteroidal anti-inflam- was 56.0 (IQR: 44.8-65.0). The median height and weight of matory drugs was also recorded. Estimated perioperative blood the study sample were 162 cm (IQR: 155.9-169.3 cm) cm and loss (in mL) for each patient was calculated using the Gross 78.6 kg (IQR: 67.5-86.1 kg), respectively. A total of 96/174 10,11 Equation. The equation uses the estimated blood volume patients (55.2%) were female.There were 65/174 patients of the patient, as well as preoperative, lowest postoperative, and (37.4%) who had an ASA score ≥3. A total of 40/174 patients average haematocrit measurements to calculate estimated peri- (23.0%) were current smokers. The prevalence of comorbidity 10,11 operative blood loss. Major perioperative blood loss was de- ranged from 5.7% (10/174 patients) for cardiovascular disease fined as an estimated perioperative blood loss which was >75th to 48.3% (84/174 patients) for obesity. A total of 6/174 pa- percentile obtained for the study sample. We chose to use the tients (3.4%) were undergoing surgery for rheumatoid arthritis, 75th percentile of blood loss in mL (as estimated by the Gross an established risk factor for perioperative bleeding in primary Equation) as the threshold for major perioperative blood loss hip arthroplasty patients. Twenty-four patients (13.8% of the in this study, as values which lie above the 75th percentile for a study sample) had a fixed flexion deformity of >30 degrees. continuous variable are considered to be in the highest statisti- Mobilization using an assistive device was reported in 75.3% of 12 cal quartile for that variable. We also believe that determin- the study population (131/174 patients). Visual analogue score ing a setting-specific threshold for major perioperative blood (VAS) was ≥7 in 96/174 patients (55.2%). A total of 49/174 pa-

30 UTMJ • Volume 96, Number 3, June 2019 Primary Research

Perioperative blood loss in South African primary hip arthroplasty patients

Table 2. Distribution of characteristics in the study sample and results of tients (28.1%) could not walk a distance of 100m or more. Ur- the univariate statistical analysis* gent/emergent surgery was performed in two patients (1.1% of Characteristic Subcategory All patients Major peri- No major p-value the study population). General anesthesia was used in 90/174 (N=174) operative periopera- patient surgeries (51.7%). Surgery was performed via the pos- blood loss tive blood (n=43) loss (n=131) terior approach in 117/174 patient surgeries (67.2%). The du- Median age, N/A 56.0 (44.8- 58.0 (46.0- 55.0 (43.0- 0.656 ration of surgery was extended for 32/174 patients (18.4%). years (IQR) 65.0) 65.0) 65.0) With regard to perioperative medications which might have in- Median height, N/A 162.0 (155.9- 162.5 (157.0- 162.0 (155.0- 0.328 fluenced perioperative blood loss, preoperative tranexamic acid cm (IQR) 169.3) 172.0) 169.0) was administered in 116/174 patients (66.7%) and all patients Median weight, N/A 78.6 (67.5- 79.6 (70.3- 78.3 (66.4- 0.258 in the study population received postoperative thrombopro- kg (IQR) 86.1) 89.0) 85.4) phylaxis. No patients had used acetylsalicylic acid within three Gender 0.421 days prior to their surgery. A total of 24/174 patients (13.8%) Female 96 (55.2) 26 (60.5) 70 (53.4) received a perioperative blood transfusion. Male 78 (44.8) 17 (39.5) 61 (46.6) The results of the univariate statistical analysis are also ASA score ≥3 0.699 shown in Table 2. The proportion of patients with chronic obstructive pulmonary disease (COPD) was higher in the major Yes 65 (37.4) 15 (34.9) 50 (38.2) perioperative blood loss group versus the control group (20.9% No 109 (62.6) 28 (65.1) 81 (61.8) versus 9.2%, p=0.040). The proportion of patients who received Current smoker 0.641 preoperative tranexamic acid was lower in the major periopera- Yes 40 (23.0) 11 (25.6) 29 (22.1) tive blood loss group versus the control group (44.2% versus No 134 (77.0) 32 (74.4) 102 (77.9)

74.0%, p<0.001). The proportion of patients who received a Cardiovascular 0.710 perioperative blood transfusion was higher in the major peri- disease operative blood loss group versus the control group (39.5% ver- Yes 10 (5.7) 3 (7.0) 7 (5.3) sus 5.3%, p<0.001). There were four characteristics which met No 164 (94.3) 40 (93.0) 124 (94.7) the criteria (p<0.100) for inclusion in the multivariate statistical COPD 0.040 analysis: COPD, extended duration of surgery, preoperative Yes 21 (12.1) 9 (20.9) 12 (9.2) tranexamic acid, and perioperative blood transfusion. No 153 (87.9) 34 (79.1) 119 (90.8)

HIV 0.712

Yes 40 (23.0) 9 (20.9) 31 (23.7)

No 134 (77.0) 34 (79.1) 100 (76.3)

Diabetes 0.764

Yes 16 (9.2) 3 (7.0) 13 (9.9)

No 158 (90.8) 40 (93.0) 118 (90.1)

Median preop- N/A 67.5 (56.8- 66.0 (58.0- 68.0 (56.0- 0.303 erative serum 79.0) 73.0) 82.0) creatinine, μmol/l (IQR)

Median N/A 13.1 (12.1- 13.3 (12.3- 13.0 (11.9- 0.119 preoperative 14.1) 14.8) 13.9) haemoglobin, g/ dl (IQR)

Median preop- N/A 290.0 (250.5- 290.0 (252.0- 290.0 (249.0- 0.760 erative platelet 339.3) 333.0) 340.0) count, x109/l (IQR)

Obesity 0.662

Yes 84 (48.3) 22 (51.2) 62 (47.3)

No 90 (51.7) 21 (48.8) 69 (52.7)

Hypertension

0.432

Yes 80 (46.0) 22 (51.2) 58 (44.3)

No 94 (54.0) 21 (48.8) 73 (55.7)

Rheumatoid 0.638 arthritis

Yes 6 (3.4) 2 (4.7) 4 (3.1)

No 168 (96.6) 41 (95.3) 127 (96.9)

Figure 1. Derivation of the final study sample

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Perioperative blood loss in South African primary hip arthroplasty patients

Table 2. Distribution of characteristics in the study sample and results of Table 2. Distribution of characteristics in the study sample and results of the univariate statistical analysis* (continued) the univariate statistical analysis* (continued)

Characteristic Subcategory All patients Major peri- No major p-value Characteristic Subcategory All patients Major peri- No major p-value (N=174) operative periopera- (N=174) operative periopera- blood loss tive blood blood loss tive blood (n=43) loss (n=131) (n=43) loss (n=131)

FFD >30 degrees 0.407 Postoperative 0.999 thromboprophy- CNBE 40 (23.0) 13 (30.2) 27 (20.6) laxis

Yes 24 (13.8) 6 (14.0) 18 (13.7) Yes 174 (100.0) 43 (100.0) 131 (100.0)

No 110 (63.2) 24 (55.8) 86 (65.7) No 0 (0.0) 0 (0.0) 0 (0.0)

Mobilizes with 0.285 Perioperative <0.001 assistive device blood transfusion

Yes 131 (75.3) 35 (81.4) 96 (73.3) Yes 24 (13.8) 17 (39.5) 7 (5.3)

No 43 (24.7) 8 (18.6) 35 (26.7) No 150 (86.2) 26 (60.5) 124 (94.7)

VAS 7 0.347 ≥ *Results expressed as frequencies (%). CNBE 56 (32.2) 13 (30.2) 43 (32.8) p<0.050 was considered a statistically significant result. ASA: American Society of Anesthesiologists; COPD: Chronic obstructive pulmonary Yes 96 (55.2) 27 (62.8) 69 (52.7) disease; IQR: Interquartile range; N/A: Not applicable; CNBE: Could not be established; FFD: Fixed flexion deformity; VAS: Visual analogue score. No 22 (12.6) 3 (7.0) 19 (14.5) #Defined as duration of surgery >75th percentile obtained for the study sample. Walking distance 0.347 <100m The results of the multivariate statistical analysis are shown CNBE 69 (39.7) 13 (30.2) 56 (42.7) in Table 3. Of the four characteristics entered into the logistic Yes 49 (28.1) 14 (32.6) 35 (26.7) regression analysis, only three were found to be independently No 56 (32.2) 16 (37.2) 40 (30.6) associated with major perioperative blood loss. Harmful asso-

Urgent/emergent 0.999 ciations were observed for COPD (OR: 3.01, 95% CI: 1.01- surgery 8.95; p=0.048) and perioperative blood transfusion (OR: 10.18, Yes 2 (1.1) 0 (0.0) 2 (1.5) 95% CI: 3.53-29.34; p<0.001). A protective association was No 172 (98.9) 43 (100.0) 129 (98.5) observed for preoperative tranexamic acid use (OR: 0.28, 95%

Surgery with 0.332 CI: 0.13-0.63; p=0.002). The Hosmer-Lemeshow test indicat- general anes- ed that the model fit was appropriate (p>0.05). thesia Yes 90 (51.7) 25 (58.1) 65 (49.6) Table 3. Results of the multivariate statistical analysis*

No 84 (48.3) 18 (41.9) 66 (50.4) Characteristic Sub-Category OR (95% CI) p-value

Posterior ap- 0.732 COPD Yes 3.01 (1.01–8.95) 0.048 proach to hip No Reference - Yes 117 (67.2) 28 (65.1) 89 (67.9) Extended duration Yes 1.39 (0.52–3.74) 0.516 No 57 (32.8) 15 (34.9) 42 (32.1) of surgery#

Extended dura- 0.063 No Reference - tion of surgery# Preoperative Yes 0.28 (0.13–0.63) 0.002 Yes 32 (18.4) 12 (27.9) 20 (15.3) tranexamic acid

No 142 (81.6) 31 (72.1) 111 (84.7) No Reference -

Preoperative <0.001 Perioperative Yes 10.18 (3.53–29.34) <0.001 tranexamic acid blood transfusion

Yes 116 (66.7) 19 (44.2) 97 (74.0) No Reference -

No 58 (33.3) 24 (55.8) 34 (26.0) *Results adjusted for confounders. Only characteristics with p<0.100 in the univariate statistical analysis were included in the multivariate statistical analysis. Preoperative 0.999 #Defined as duration of surgery >75th percentile obtained for the study sample. aspirin within 3 p<0.050 was considered a statistically significant result. days OR: Odds ratio; CI: Confidence interval; COPD: Chronic obstructive pulmonary disease. Yes 0 (0.0) 0 (0.0) 0 (0.0) No 174 (100.0) 43 (100.0) 131 (100.0) Discussion Preoperative 0.752 Nonsteroidal The levels of perioperative blood loss observed in our sam- anti-inflamma- ple of SA primary hip arthroplasty patients are in keeping with tory drug within 3 days the range of estimated blood loss observed in the published lit- 3-8 Yes 56 (32.2) 13 (30.2) 43 (32.8) erature. However, around 25% our study population experienced blood loss equivalent to just over 3 units of packed red No 118 (67.8) 30 (69.8) 88 (67.2) cells, which is a scarce resource in our setting.9 Besides possible implications for healthcare resource utilization (i.e. utilization of blood products), excessive blood loss during the perioperative period might result in anaemia,15 which can predispose pa-

32 UTMJ • Volume 96, Number 3, June 2019 Primary Research

Perioperative blood loss in South African primary hip arthroplasty patients tients to a variety of postoperative complications.16,17 A recent contributing to haemostasis during the perioperative period.26 meta-analysis by Fowler and colleagues found that anaemic A systematic review and meta-analysis of randomized con- surgical patients were at an almost 3-fold higher risk of suffer- trolled trials of tranexamic acid in hip arthroplasty populations ing postoperative mortality when compared with non-anaemic reported significant reductions in total blood loss in patients surgical patients (OR: 2.87, 95% CI: 2.10–3.93).16 One of the who received tranexamic acid versus controls (mean reduc- studies included in the meta-analysis suggested that even mild tion of 289mL).26 In the same systematic review and meta- anaemia could be potentially harmful in surgical patients.17 analysis, fewer patients who received tranexamic acid required Furthermore, the study by Musallam and colleagues of 227,425 allogenic blood transfusion when compared with controls. Fur- noncardiac surgery patients (of which 30.4% were anaemic) thermore, the rate of perioperative complications was similar found that anaemia was associated with 45-77% higher risk between tranexamic acid and control groups.26 Therefore, we of cardiac complications, a 33-70% higher risk of respiratory recommend preoperative tranexamic acid be considered for complications, a 5-16% higher risk of neurological complica- the control of perioperative blood loss in SA primary hip ar- tions, and a 24-88% higher risk of sepsis when compared with throplasty patients, unless contraindicated. Contraindications a non-anaemic patient group.17 In a sub-analysis of the Euro- for tranexamic acid use include hypersensitivity, a history of pean Surgical Outcomes Study (EuSOS), Baron and colleagues thrombosis/thromboembolism or if a patient has an intrinsic reported increased length of hospital stay and postoperative risk for thrombosis/thromboembolism (for example a patient admission to intensive care in anaemic versus non-anaemic pa- with thrombophilia), a history of sub-arachnoid hemorrhage, tients (p<0.001 for both postoperative outcomes).18 Anaemia is or concomitant hormonal oral contraceptive use.27 also an important determinant of perioperative blood transfu- Our findings of an independent association between peri- sion, which in itself is associated with a higher risk of postop- operative transfusion and major perioperative blood loss is to erative complications.19,20 Most of the perioperative complica- be expected. Excessive blood loss might prompt surgeons or tions associated with anaemia are consequences of the hypoxia physicians to administer a blood transfusion.2 There is a pro- associated with the condition. Our results for blood loss suggest portion of patients however, where excessive blood loss and that primary hip arthroplasty patients in our setting are poten- subsequent transfusion can be avoided through careful patient tially at risk of anemia, and subsequent complications. management and risk reduction. In our setting this could be We found that patients with COPD were at a three-fold in- done through addressing the risk factors for major periopera- creased risk of major perioperative blood loss. This is not the tive blood loss (COPD in our setting) and implementation of first time that COPD has been found to be associated with ex- preventative strategies for perioperative blood loss (preopera- cessive perioperative blood loss in an orthopaedic surgery pop- tive tranexamic acid in our setting), as mentioned earlier. Blood ulation. Oberweis and colleagues reported a similar harmful products for transfusion are a limited resource in some settings, association between COPD and excessive perioperative blood and the use of these products is usually guided by strict peri- loss in an American orthopaedic surgery population (OR: 2.69 operative blood management protocols.28,29 Aside from the re- in the Oberweis study, and OR: 3.01 in our study).21 It is pos- source implications associated with perioperative blood transfu- sible that this finding might actually be related to the pharma- sion, perioperative blood transfusion itself has also been shown cologic management of COPD. Glucocorticoids are commonly to be associated with increased perioperative complications, an used to manage COPD. Studies of non-orthopaedic surgical association which is independent of anaemia.30 This further populations report increased perioperative blood loss in patients emphasizes the importance of addressing major perioperative taking glucocorticoids.22,23 Impaired surgical wound healing has blood loss. been postulated as the mechanism which contributes to this in- Our study was not without limitations. A larger sample creased blood loss in patients who use glucocorticoids.22 This size might have provided more significant data. This study also appears to be supported by studies of certain clotting factors, involved patient data from a single SA hospital, and so our which appear to be found in lower concentrations in patients study findings lack generalizability. There were some patients who are taking glucocorticoids versus patients who do not take who had missing data for height and/or weight, and we had these medications.24 A variety of approaches could be used to exclude these patients from the final study sample. In addi- to reduce the risk of major bleeding in patients with COPD. tion, there were other variables included in our analysis where Glucocorticoids might not be necessary in all COPD patients, a proportion of patient data was missing (specifically several and patients who do not require glucocorticoids should be ad- orthopaedic-related variables). There might have also been vised against the preoperative use of these medications.25 Non- additional variables relevant to perioperative blood loss in pri- pharmacologic approaches for the preoperative optimization mary hip arthroplasty patients, but which were not collected as of COPD, such as smoking cessation and promoting increased part of the retrospective patient registry and could therefore physical activity, should also be considered.25 Surgeons and not be investigated in this study. Examples of these variables anaesthesiologists should also consider deferring surgery in pa- include socioeconomic status, race, surgeon skill, and other tients with recent exacerbations of COPD,25 at least until these medications such as vitamin supplements and herbal medica- exacerbations have resolved. tions which might be associated with increased perioperative Preoperative tranexamic acid administration was found to bleeding. Socioeconomic status might impact individual food be associated with an almost four-fold reduction in the risk of security, and hence determine nutritional status.31 Malnutrition major perioperative blood loss in our study. This is an antifibri- is known to impair wound healing, and could therefore con- nolytic agent which inhibits dissolution of blood clots, thereby tribute toward perioperative blood loss.32 There is published

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Perioperative blood loss in South African primary hip arthroplasty patients

evidence to suggest that blood coagulates faster in persons of bin levels and iron status in a large multicentre cohort of patients undergoing major elective surgery. Anaesthesia. 2017;72(7):826-34. African ethnicity when compared with persons of Caucasian 16. Musallam KM, Tamim HM, Richards T, et al. Preoperative anaemia and post- ethnicity.33 It is therefore possible that patients of African eth- operative outcomes in non-cardiac surgery: a retrospective cohort study. Lancet. nicity could have achieved perioperative haemostasis quicker 2011;378(9800):1396-1407. 17. Fowler AJ, Ahmad T, Phull MK, et al. Meta-analysis of the association between and lost less blood than patients from other ethnic groups in preoperative anaemia and mortality after surgery. Brit J Surg. 2015;102(11):1314- this study. With regard to surgeon skill, Glance and colleagues 24. 18. Baron DM, Hochrieser H, Posch M, et al. Preoperative anaemia is associated found that in surgeries where trainee surgeons performed criti- with poor clinical outcome in non-cardiac surgery patients. Br J Anaesth. 2014; cal parts of the procedure under the supervision of specialist 113(3):416-23. surgeons, there was a significantly higher risk of intraoperative 19. Glance LG, Dick AW, Mukamel DB, et al. Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac transfusion as a result of blood loss than if the procedure was surgery. Anesthesiology. 2011;114(2):283-92. performed by a specialist surgeon alone.34 Lastly, medications 20. Whitlock EL, Kim H, Auerbach AD. Harms associated with single unit perioper- such as vitamin supplements, herbal medicines, and selective ative transfusion: retrospective population based analysis. BMJ. 2015;350:h3037. 21. Oberweis BS, Nukala S, Rosenberg A, et al. Thrombotic and bleeding complica- serotonin reuptake inhibitor antidepressants are known to in- tions after orthopedic surgery. Am Heart J. 2013;165(3):427-33.e421. crease perioperative blood loss.35 22. Winther Lietzen L, Cronin-Fenton D, Garne JP, et al. Predictors of re-operation due to post-surgical bleeding in breast cancer patients: a Danish population- based cohort study. Eur J Surg Oncol. 2012;38(5):407-12. Conclusion 23. Gribsholt SB, Svensson E, Thomsen RW, et al. Preoperative glucocorticoid use The levels of perioperative blood loss observed in our sam- and risk of postoperative bleeding and infection after gastric bypass surgery for the treatment of obesity. Surg Obes Relat Dis. 2015;11(6):1212-17. ple of SA primary hip arthroplasty patients are in keeping with 24. van Zaane B, Nur E, Squizzato A, et al. Systematic review on the effect of gluco- the range of estimated blood loss reported in the published lit- corticoid use on procoagulant, anti-coagulant and fibrinolytic factors. J Thromb erature. We found that patients who experienced major peri- Haemost. 2010;8(11):2483-93. 25. Vestbo J, Hurd SS, Agustí AG, et al. Global strategy for the diagnosis, manage- operative blood loss were more likely to have COPD or require ment, and prevention of chronic obstructive pulmonary disease: GOLD execu- a perioperative blood transfusion. Preoperative tranexamic acid tive summary. Am J Respir Crit Care Med. 2013;187(4):347-65. 26. Sukeik M, Alshryda S, Haddad FS, et al. Systematic review and meta-analysis of administration was found to be protective against major periop- the use of tranexamic acid in total hip replacement. J Bone Joint Surg Br. 2011; erative blood loss. Although our study has important implica- 93(1):39-46. tions for perioperative protocols in SA orthopaedic surgery set- 27. Tengborn L, Blombäck M, Berntorp E. Tranexamic acid—an old drug still going strong and making a revival. Thromb Res. 2015;135(2):231-42. tings, we recommend further prospective, multicenter research 28. Carson JL, Duff A, Poses RM, et al. Effect of anaemia and cardiovascular disease studies be conducted to confirm our findings and address the on surgical mortality and morbidity. Lancet. 1996;348(9034):1055-60. limitations we have outlined. 29. Demos HA, Lin ZX, Barfield WR, et al. Process improvement project using tanexamic acid is cost-effective in reducing blood loss and transfusions after total hip and total knee arthroplasty. J Arthroplasty. 2017;32(8):2375-80. Acknowledgements 30. Goodnough LT, Maniatis A, Earnshaw P, et al. Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: This work forms a component of the Master’s degree stud- NATA guidelines. Brit J Anae. 2011;106(1):13-22. ies of MSK. YM was supported by a fellowship awarded by the 31. Grammatikopoulou MG, Gkiouras K, Theodoridis X, et al. Food insecurity in- South African National Research Foundation (NRF). creases the risk of malnutrition among community-dwelling older adults. Maturi- tas. 2019;119:8-13. 32. Haydock DA, Hill GL. Impaired wound healing in surgical patients with varying References degrees of malnutrition. J Parenter Enteral Nutr. 1986;10(6):550-54. 1. Pabinger C, Geissler A. Utilization rates of hip arthroplasty in OECD countries. 33. Edelstein LC, Simon LM, Montoya RT, et al. Racial differences in human plate- Osteoarth Cart. 2014;22(6):734-41. let PAR4 reactivity reflect expression of PCTP and miR-376c. Nat Med. 2013; 2. Sizer SC, Cherian JJ, Elmallah RD, et al. Predicting blood loss in total knee and 19(12):1609-16. hip arthroplasty. Ortho Clin. 2015;46(4):445-59. 34. Glance LG, Mukamel DB, Blumberg N, et al. Association between surgical 3. Miao K, Ni S, Zhou X, et al. Hidden blood loss and its influential factors after resident involvement and blood use in noncardiac surgery. Transfusion. 2014; total hip arthroplasty. J Orthop Surg Res. 2015;10:36. 54(3):691-700. 4. Liu X, Zhang X, Chen Y, et al. Hidden blood loss after total hip arthroplasty. J 35. Manjuladevi M, Vasudeva Upadhyaya KS. Perioperative blood management. Arthroplasty. 2011;26(7):1100-5.e1. Indian J Anaesth. 2014;58(5):573-80. 5. Sehat KR, Evans RL, Newman JH. Hidden blood loss following hip and knee arthroplasty. Correct management of blood loss should take hidden loss into account. J Bone Joint Surg Br. 2004;86(4):561-65. 6. Newman JM, Webb MR, Klika AK, et al. Quantifying blood loss and transfusion risk after primary vs conversion total hip arthroplasty. J Arthroplasty. 2017; 32(6):1902-9. 7. Grosflam JM, Wright EA, Cleary PD, et al. Predictors of blood loss during total hip replacement surgery. Arthritis Care Res. 1995;8(3):167-73. 8. Ugbeye ME, Lawal WO, Ayodabo OJ, et al. An evaluation of intra- and post-operative blood loss in total hip arthroplasty at the National Orthopaedic Hospital, Lagos. Niger J Surg. 2017 23(1):42-46. 9. Solomon L, von Rahden RP, Allorto NL. Intra-operative cell salvage in South Africa: feasible, beneficial and economical. S Afr Med J. 2013;103(10):754-57. 10. Gross JB. Estimating allowable blood loss: corrected for dilution. Anesthesiology. 1983;58(3):277-80. 11. Gibon E, Courpied JP, Hamadouche M. Total joint replacement and blood loss: what is the best equation? Int Orthop. 2013;37(4):735-39. 12. McCluskey A, Lalkhen AG. Statistics II: Central tendency and spread of data, Cont Ed Anae Crit Care Pain. 2008;7(4):127-30. 13. Kaliyadan F, Kulkarni V. Types of variables, descriptive statistics, and sample size. Indian Dermatol Online J. 2019;10(1):82-86. 14. Bursac Z, Gauss CH, Williams DK, et al. Purposeful selection of variables in logistic regression. Source Code Biol Med. 2008; 3:17. 15. Muñoz M, Laso‐Morales M, Gómez‐Ramírez S, et al. Pre‐operative haemoglo-

34 UTMJ • Volume 96, Number 3, June 2019 Reviews

Current status and prospects for the application of cannabinoids in organ transplantation

Brian Earl (BScH)

Department of Medicine, University of Toronto, Medical Sciences Building, 1 King’s College Circle, Toronto, Ontario

Accordingly, medical marijuana use continues to increase, Abstract as indicated by the 342,103 Canadians registered as medical Graft versus host disease and allograft rejection are marijuana users as of September 2018.1 The possible applicability frequent complications of allogeneic hematopoietic stem of cannabinoids for managing inflammation and associated cell transplantation and solid organ transplantation, chronic inflammatory diseases has received less attention. In this respectively. The probability of developing either light, the field of transplant, which heavily relies upon managing condition is dependent upon the magnitude of genetic pathologic immune reactions, may represent a future direction for cannabinoid-derived therapeutics. This paper reviews the current disparity between donor and recipient. In both contexts, state of evidence on the role of cannabinoids in transplant-relevant alloimmune-mediated processes are responsible for disease immune processes as well as studies that investigated their direct pathogenesis and the subsequent complications that application in transplantation. are associated with significant morbidity and mortality. Existing prophylactic regimens consisting of intensive Cannabinoids and the Endocannabinoid System immunosuppression are limited by high incidences of graft Interest in the utility of cannabis is by no means a modern failure, infection, and toxicity. Cannabinoids are a diverse phenomenon. The plant Cannabis Sativa, from which marijuana family of natural and synthetic molecules that, through and other preparations are derived, has been used for millennia interaction with the endocannabinoid system, have potent to treat myriad illnesses as well as for recreation, the latter due immunoregulatory properties. However, the applicability to its potent psychotropic effects.2 These effects are mediated by of cannabinoids to the prevention of graft-versus-host a large number of biologically active constituents, with greater disease and allograft rejection has not been established. than 100 isolated structurally related cannabinoids, referred to as This article offers insight into our current understanding phytocannabinoids, in recognition of their exogenous and natural of the immunopathophysiology of graft-versus-host origin.3 The two most well studied cannabinoid molecules are non- disease and allograft rejection, relevant cannabinoid- psychotropic (−)-cannabidiol (CBD) and psychotropic (−)-trans- mediated immune modulation, and emerging evidence Δ9-tetrahydrocannabinol (THC), which orchestrate a complex on the role of cannabinoids in transplant immunology. array of physiologic responses by acting on the endocannabinoid With the need for more effective prophylactic strategies system (ECS), which is present in various cellular targets. The ECS comprises non-cannabinoid and cannabinoid receptors, and the concordant interest in cannabinoid-based predominately type-1 (CB1) and type-2 (CB2) cannabinoid therapeutics, it is pertinent to determine whether the receptors, their endogenous ligands known as endocannabinoids, endocannabinoid system can be therapeutically targeted most classically 2-arachidonyglycerol (2-AG) and anandamide in the post-transplant setting. (AEA), as well as associated regulatory and signaling complexes.4 In accordance with this diversity, the ECS is perceived to be present in and contribute to the regulation of physiologic processes in virtually all body systems. Current knowledge is that cannabinoid Introduction receptors are broadly distributed, with CB1 receptors ubiquitously here is a palpable high and growing interest for the potential expressed throughout the central nervous system and to a lesser medicinal applications of cannabinoids amongst the extent in the periphery, and CB2 receptors being largely expressed general population, exacerbated by the recent Canadian in immune and hematologic cells.5 With the presence of the ECS legalizationT of recreational cannabis. This fervor is fuelled by within essentially all immune cells, the system is appropriately media outlets that promote cannabinoids as future “wonder positioned to function in immune system homeostasis. drugs” and endorse them for the treatment of an array of illnesses The first evidence supporting an immunomodulatory role and ailments, with an emphasis on chronic pain management. for cannabinoids in humans was noted over 40 years ago when two separate groups identified that immune cells isolated from chronic marijuana smokers had suppressed responsiveness Corresponding Author: and functionality in various in vitro immune assays.6,7 These Brian Earl [email protected] seminal observations were substantiated by evidence that the

UTMJ • Volume 96, Number 3, June 2019 35 Reviews

Current status and prospects for the application of cannabinoids in organ transplantation extent of cannabis consumption in recreational cannabis users azathioprine), or calcineurin inhibitors (e.g., tacrolimus), as well as positively correlated with several anti-inflammatory measures alemtuzumab and anti-thymocyte globulin for T-cell depletion, in after controlling for potential covariates.8 These observational GvHD prevention. These strategies are only partial effective with studies acted as a framework for the flurry of discovery that has graft failure, infection and toxic side effects such as nephrotoxicity proceeded to uncover the mechanisms through which these agents and cardiotoxicity remaining long-term sequelae of therapy.19,20 participate in immune processes. It is now appreciated that the Accordingly, refined immunomodulatory strategies are needed to principle phytocannabinoids CBD and THC have a propensity for achieve sustained tolerance in either transplant context. suppressing quintessential pro-inflammatory mediators and thereby modulate disease outcomes in pre-clinical models of autoimmune Brief Primer on Transplant Immunology and inflammatory conditions.9–11 A principal impediment for The specific immune mechanisms that mediate GvHD and the clinical translation of cannabinoids such as THC is their allograft rejection are similar. CD4+ or T-helper (Th) cells are therapeutically undesirable psychoactive effects. However, these integral regulators of inflammatory responses that have the capacity unwanted effects are uniquely mediated through CB1 receptor to differentiate into diverse lineages, denoted by their unique activation. Studies employing CB2 genetic knockout models and transcription factor and cytokine profiles, which can potentiate selective agonists support the CB2 receptor for predominately or attenuate inflammation. Experimental models and patients mediating the immunoregulatory effects, developing interest for that develop acute GvHD and allograft rejection both present CB2-specific targeting of the ECS.12 In support of this, a conserved with a skewing towards pro-inflammatory Th1 and classically CB2 genetic polymorphism, known to decrease the receptor’s autoimmune-implicated Th17 cell lineages that are associated activity, is implicated in several chronic inflammatory conditions with disease initiation.21–23 This is complemented by observations including immune thrombocytopenic purpura, rheumatoid that regulatory T-cells (Tregs), which are the cellular antagonists arthritis, and celiac disease.13–15 Growing evidence supports the to these responses, are found in higher proportions in donor grafts utility of cannabinoid-based therapeutics directed at the CB2 associated with a reduced risk of GvHD.24 Furthermore, the more pathway as a novel approach for immunosuppression. robust reconstitution of these cells and their adoptive transfer to patients undergoing aHSCT are associated with a reduced Pathophysiology of GVHD and Allograft Rejection incidence of GvHD.24 Accordingly, lower frequencies of Tregs The immunoregulatory properties of cannabinoids could have also been identified in the circulation of patients suffering prove particularly beneficial in solid-organ transplantation (SOT) from acute liver or heart transplant rejection.25 Moreover, myeloid- and allogeneic hematopoietic stem cell transplantation (aHSCT), derived suppressor cells (MDSCs) are a heterogeneous population where control of alloreactive immune responses is important. of innate immune cells with the shared ability to actively oppose SOT involves the replacement of the diseased organ or tissue alloreactive T-cells. Consistent with the role of Tregs, MDSCs with a healthy equivalent, frequently from a genetically non- are postulated to play a supportive role in limiting the evolution identical donor, known as an allograft. Alternatively, aHSCT is of GvHD and rejection.26,27 These observations support the notion a potentially life-saving intervention for benign and malignant that strategies that can promote the expansion of Tregs and MDSCs hematologic conditions that involves eradication of the diseased while suppressing differentiation towards pro-inflammatory T-cell hematopoietic system with a cytotoxic conditioning regimen lineages may be effective in inhibiting the onset of GvHD and and subsequent replacement with donor-derived hematopoietic rejection post-transplant. These represent only a handful of the stem and progenitor cells.16 The principal limiting factors for diverse immune mechanisms postulated to be associated with the achieving favorable outcomes in SOT and aHSCT are allograft pathogenesis of GvHD and allograft rejection, and highlight the rejection and graft-versus-host disease (GvHD), respectively. These challenge in studying cannabinoid effect on the allogeneic response. two processes largely manifest due to incompatibility between the donor and recipient major and minor human leukocyte Cannabinoid-mediated Immune Modulation antigens (HLA), known as allorecognition, which incites tissue Consistent with the function of alloreactive T-cells as the destruction. In allograft rejection, recipient T-cells recognize common effector pathway for eliciting tissue damage in both GvHD foreign HLAs expressed by the transplanted organ through either and allograft rejection, consideration of the effects of cannabinoids direct interaction with donor antigen presenting cells (APCs) on T-cell function is imperative to their potential application or indirectly through recipient APCs that have engulfed these in transplantation. Indeed, in an in vitro system of cultured, antigens. This process is potentiated by a concordant onslaught antibody-stimulated human T-cells, supplementation with THC, of pro-inflammatory cytokines produced in response to ischemia- the selective CB2-agonist JWH015 and the selective CB1 agonist reperfusion injury of the allograft,17 the consequence of which MAEA all significantly inhibited the production of interleukin is targeted destruction of the transplanted allograft. In aHSCT, (IL)-2, considered the canonical mediator of non-directional substantial tissue damage caused by the conditioning regimen T-cell expansion.28 This subsequently translated into a pronounced results in the release of danger signals, which activate APCs that reduction in T-cell proliferation. These effects occurred through the then prime donor alloreactive cytotoxic T (Tc)-cells with the CB2 receptor during both basal and stimulated states. However, the potential to result in widespread tissue damage.18 Considering the CB1 receptor was only capable of eliciting these effects following mutual importance of T-cells to the pathogenesis of GvHD and cell stimulation.28 Yuan et al. also identified the CB2-mediated anti- allograft rejection, existing prophylaxis strategies have primarily proliferative effects of THC on naïve human CD3+ T-cells.29 In targeted these effectors using methotrexate, cyclophosphamide, the same experiments, pro-inflammatory tumor-necrosis factor α prednisone, cell-cycle inhibitors (e.g., mycophenolic acid and (TNF-α) and interferon-gamma (IFN-γ) secretion was decreased in

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Current status and prospects for the application of cannabinoids in organ transplantation

favour of increased IL-4, representative of a relative expansion of murine spleen T-cells with THC or selective agonists of the CB2 colloquially anti-inflammatory Th2 rather than Th1 cells.29 In an receptor induced a dose-dependent inhibition of their capability in vivo setting, treatment of a Legionella pneumophila infection to proliferate in response to co-culture with genetically distinct mouse model with THC robustly attenuated expression of the splenocytes, which was entirely mediated by CB2-dependent canonical transcription factor for Th1 differentiation, T-bet, while signaling. This observation was corroborated by the simultaneous also diminishing dendritic cells with surface ligands specific for suppression of IL-2 secretion.40 Under similar experimental Th1 differentiation.30 Moreover, using mouse models of multiple conditions the selective CB2 agonist, O-1966, not only suppressed sclerosis and delayed-type hypersensitivity, administration of the the proliferation of naïve Th and Tc cells but also further induced selective CB2 agonist Gp1a and THC, respectively, dramatically the differentiation of Tregs and secretion of their predominant reduced the quantity of Th1 and Th17 cells.31,32 Furthermore, anti-inflammatory cytokine IL-10, which is responsible for both CBD and THC are known to alter the gene expression suppressing antigen presentation and Th1 cytokine production.41 signatures in naïve Th cells to promote differentiation of functional This demonstrates that cannabinoids are effective at inhibiting Tregs capable of both suppressing the proliferation of naïve T-cells processes quintessential to allograft rejection and promoting those in culture and mitigating enterotoxin B-induced inflammatory implicated in the establishment of immune tolerance. Functionally, lung injury in mice.33,34 Collectively, these observations highlight in vivo level evidence demonstrated that CB2-/- mice developed the capacity for members of the cannabinoid family to act as more rapid allograft rejection in a model of fully mismatched homeostatic regulators of T-cell activation relevant to reducing cardiac transplantation in comparison to wildtype recipients.42 A transplant-associated alloimmunity. mechanistic explanation for this result is that BMDCs isolated from Cannabinoids, in general, also suppress the actions of myeloid CB2-/- mice following cardiac allograft rejection were found to cells, particularly APCs such as dendritic cells (DCs), which are secrete substantial quantities of the pro-inflammatory cytokines integral for initiating an inflammatory cascade and priming IL-12 and 23, which is concordant with observed increases in the immunocompetent donor T-cells in GvHD and graft rejection. prevalence of pro-inflammatory Th1 and Th17 cells.42 Although This is demonstrated by limiting human monocyte differentiation only pre-clinical, these studies affirm the ability for cannabinoids, in vitro into phenotypic DCs following THC exposure.35 Further, primarily acting through CB2, to regulate transplant-relevant human DCs cultured with THC had poor antigen uptake and a immune mechanisms that are capable of suppressing rejection. reduced capacity for antigen presentation and transformation of Moreover, THC treatment has been shown to promote graft naïve T-cells into active effector cells.35 This was influenced by a survival in a model of skin allograft rejection through CB1 receptor reduction of the DC cytokines IL-7, 12, and 15 that are important activation, with contribution, in part, by the induction of MDSCs.32 for the development of activated T-cells.35 In mouse bone marrow- Despite positioning CB1 as the principal receptor for coordinating derived DCs (BMDCs) treated with THC, there was a similar the tolerizing effects of cannabinoids in SOT, identifying which inability to appropriately express the co-stimulatory molecules cannabinoid receptor is the most influential may be context or required for effective naïve T-cell priming.36 A principle quality ligand-dependent. Regardless, the expanding body of literature of DCs and other innate immune cells is their ability to migrate supporting a role for cannabinoids in managing allograft rejection to sites of inflammation and to secondary lymphoid organs to is encouraging for their therapeutic consideration. It should also initiate adaptive immune responses. Adhikary et al. (2012), be noted that with the added immunosuppression imparted by demonstrated that CB2 receptor activation reduced the migration cannabinoids, there is a corresponding increased risk for infection of BMDCs to popliteal lymph nodes in mice, consistent with a that must be accounted for should these agents be incorporated in similar observation of impaired murine macrophage migration to allograft rejection prophylactic regimens. potent chemokines.37,38 Considering the integral role of both DCs and other myeloid cells in the activation of alloreactive T-cells in Cannabinoids and GvHD both GvHD and graft rejection, the capacity for cannabinoids Cannabinoids may also have activity in the setting of GvHD. to interrupt antigen presentation and T-cell transformation is Pandey et al. (2011), were the first to identify a GvHD-suppressing highly topical. Moreover, cannabinoids not only restrict many capacity for cannabinoids in vivo that was mediated through CB2 pro-inflammatory processes of myeloid cells but also promote receptor activation. They observed reduced severity of GvHD anti-inflammatory functions. A dose-dependent induction of sequelae including weight loss, splenomegaly, and pathologic increased MDSC frequency has been observed following THC inflammation of the colon and liver, as well as prolonged survival injection into healthy mice, with these MDSCs being capable following THC treatment in a murine model of GvHD.43 These of suppressing inflammation in a model of T-cell-mediated liver effects were mediated through the CB2 receptor. Consistent with disease following their adoptive transfer.39 Therefore, the regulation observations made in models of SOT, this treatment resulted in of innate immunity represents another mechanism of action for the suppression of donor Tc cells and their production of pro- cannabinoids. inflammatory cytokines such as IFN-γ, yet induced proliferation of donor Tregs. In conjunction with data from SOT experiments, Cannabinoids and Allograft Rejection a paradigm is developing whereby cannabinoids are capable of The demonstrated role for positive modulation of cannabinoid suppressing post-transplant alloimmune reactions by dampening signaling in regulating various immune mechanisms relevant pro-inflammatory cytokine release, skewing T-cell differentiation to transplantation has incited their direct study in this context. towards a regulatory phenotype and, in some circumstances, The mixed lymphocyte reaction is often employed as an in vitro elevating levels of MDSCs. surrogate of allograft rejection. Using this model, treatment of Notably, a recently conducted phase II clinical trial investigated

UTMJ • Volume 96, Number 3, June 2019 37 Reviews

Current status and prospects for the application of cannabinoids in organ transplantation the safety and efficacy of CBD addition to a GvHD prophylaxis contributory metabolisms by CYP and UGT enzymes that have regimen consisting of cyclosporine and a short course of shared affinity for exogenous cannabinoids.51–54 This posits a methotrexate for adult patients undergoing aHSCT for malignant theoretical risk for these agents to manifest clinically significant indications. Patients receiving CBD, compared to historical drug-drug interactions, mediating toxicity or graft rejection when controls, had a significantly prolonged median time to onset of co-administered with exogenous cannabinoids. These observations GvHD with a significantly lower risk of developing grades II to necessitate the design of large, controlled studies to ascertain the IV GvHD by day 100 post-transplant. A lower risk of developing incidence and magnitude of the adverse effects associated with the grades III to IV GvHD by day 100 was also noted, but this did addition of exogenous cannabinoids to existing immunosuppressant not achieve statistical significance. CBD administration was well regimens. tolerated with no adverse consequences. Despite these positive Understandably, cannabinoids should only be incorporated into outcomes, paradoxically, there was no difference in non-relapse existing protocols with recognition for potential drug interactions, mortality.44 This study presents promising findings but is limited by under close clinical supervision, and with consideration for the its single-arm design that compared outcomes to historical control route of administration. In particular, inhaled marijuana is patients. Ideally, a randomized double-blind placebo-controlled associated with macrovascular disease, obstructive lung disease, trial would more conclusively support the role of CBD in GvHD membranous glomerulonephritis, and other renal disease in the prevention. Rapid immune recovery post-aHSCT is important post-transplant period, as well as potential ramifications for other for limiting adverse events. Indeed, a study of a murine model of organ systems.55–57 These consequences underscore the importance aHSCT observed that both THC and CBD slowed lymphocyte of utilizing less harmful modes of administration and careful recovery, but not myeloid recovery, 3 weeks following transplant.45 monitoring of predicted drug interactions when considering This is a clinically relevant observation considering that delayed cannabinoids as a therapeutic option in transplantation. lymphocyte recovery is associated with increased susceptibility to opportunistic infections. Since cannabinoids are known to heighten Concluding Perspectives the risk of infection, both incidence of infection and lymphocyte Effective prevention and management of GvHD and recovery post-aHSCT should therefore be closely monitored in allograft rejection after aHSCT and SOT, respectively, have been future human studies. perpetually challenging and may be regarded as the “Holy Grail” in transplant medicine. Appropriate prophylaxis must incorporate Cannabinoid-Mediated Drug Interactions a fine balance of immunosuppression with proper engraftment of The potential inclusion of cannabinoids into therapeutic the transplanted organ, sufficient immunity from infection, and regimens for preventing GvHD or allograft rejection is mitigation of toxicity. In recent years, the cellular and molecular complicated by potential drug-drug interactions with existing mediators underlying the alloreactive immune response that immunosuppressants that are the standard of care. Exogenous orchestrate these conditions have become better understood. cannabinoids are substantially metabolized by, and capable of As research evolves, it is possible that more selective therapies inhibiting, certain cytochrome P-450 (CYP) enzymes in the satisfying this fine balance will emerge. Currently, newer targeted 3A, 1A and 2C families as well as UDP-glucuronyltransferase therapies are demonstrating promise and several multi-centre, (UGT) enzymes.46,47 Furthermore, cannabinoids from marijuana randomized trials are being undertaken.58 Moreover, plasma also demonstrate inhibition of the P-glycoprotein (P-gp) drug biomarkers are being investigated to identify patients at high risk transporter, which influences the tissue distribution of various for GvHD and allograft rejection to enable more appropriate and drugs.48 Many of these metabolic enzymes and transporters timely interventions.59 Targeted approaches have been proven are critical mediators of cannabinoid function and also regulate as efficacious, low toxicity approaches in other disease states. the pharmacokinetics of various immunosuppressants, such as However, it is unclear whether targeting single entities is optimal calcineurin inhibitors. for GvHD or allograft rejection prevention. Accordingly, a male patient receiving the calcineurin inhibitor For this reason, cannabinoids and therapeutics targeting tacrolimus for GvHD prophylaxis, and concurrently using the ECS may offer innovative immunoregulatory strategies with recreational edible marijuana, was identified with symptoms relatively limited side effect profiles. Numerous studies demonstrate of tacrolimus toxicity and a 4–5-fold elevated blood tacrolimus the powerful immunosuppressive effects of the cannabinoids and concentration, in accordance with a urine toxicology screen their derivatives in various model systems, including those that positive for THC.49 A subsequent case was reported of a recapitulate transplant. Despite expanding evidence that supports female patient enrolled in a CBD clinical trial for refractory a role for these agents in mitigating GvHD and allograft rejection, epilepsy simultaneously receiving a stable dose of tacrolimus, available data is almost entirely restricted to preclinical studies that who experienced a 3-fold rise in the dose-normalized blood may not recapitulate their activity in humans. Robust studies will concentration of tacrolimus and corresponding toxicity.50 This also need to be conducted that compare the efficacy, magnitude, and adverse effect was temporally associated with increasing doses adverse effects of the immunosuppression elicited by cannabinoids of CBD. Tacrolimus metabolism and distribution is regulated to that accomplished by existing immunosuppressants such as by CYP3A members and P-gp, thus offering the possibility calcineurin inhibitors. Importantly, monitoring the frequency of a cannabinoid-mediated drug-drug interaction. However, of opportunistic infections following the incorporation of causation cannot yet be established. Notably, other post-transplant cannabinoids into existing immunosuppressant regimens should immunosuppressants such as prednisone, mycophenolic acid, be made a focus. Furthermore, opposition to the theory that the cyclophosphamide, and other calcineurin inhibitors have CB2 receptor is principally responsible for cannabinoid-mediated

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Current status and prospects for the application of cannabinoids in organ transplantation

immunomodulation should be further investigated to determine 17. Marino J, Paster J, Benichou G. Allorecognition by T lymphocytes and allograft rejection. Front Immunol. 2016;7:582. DOI: 10.3389/fimmu.2016.00582 whether CB2 selective agents may represent viable therapeutics. 18. Zeiser R, Blazar BR. Acute graft-versus-host disease biology, prevention and The first-in-man study on the addition of CBD to standard therapy. N Engl J Med. 2017;377(22):2167. DOI: 10.1056/NEJMra1609337 GvHD prophylaxis produced promising results but also raised 19. Choi SW, Reddy P. Current and emerging strategies for the prevention of graft- versus-host disease. Nat Rev Clin Oncol. 2014 Sep;11(9):536–47. DOI: 10.1038/ important considerations. The potential for other cannabinoids to nrclinonc.2014.102 offer similar benefits in humans is unknown, and the long-term 20. Wong TC, Lo C-M, Fung JY. Emerging drugs for prevention of T-cell mediated effects of CBD and other cannabinoids on immune responses, rejection in liver and kidney transplantation. Expert Opin Emerg Drugs. 2017 Apr 3;22(2):123–36. DOI: ttps://doi.org/10.1080/14728214.2017.1330884 protection from infection, and appropriate hematopoietic recovery 21. Furlan SN, Watkins B, Tkachev V, et al. Systems analysis uncovers inflammatory after aHSCT have yet to be determined. A subsequent open-label, Th/Tc17-driven modules during acute GVHD in monkey and human T cells. Blood. 2016 Nov 24;128(21):2568–79. DOI: 10.1182/blood-2016-07-726547 phase 2a multi-centre study (clinicaltrials.gov: NCT03840512) 22. León-Rodríguez E, Rivera-Franco MM, Gómez-Martín D, et al. Differential is currently under way to investigate the efficacy of longer-term T cell subsets and cytokine profile between steady-state and G-CSF-primed CBD administration for GvHD prevention, which may provide bone marrow and its association with graft-versus-host disease. Leuk Res. 2017 Dec;63:47–52. DOI: 10.1016/j.leukres.2017.10.008 additional data to begin addressing some of these considerations. 23. Liu Z, Fan H, Jiang S. CD4 + T-cell subsets in transplantation. Immunol Rev. Similar trials in the context of allograft rejection prevention have 2013 Mar 1;252(1):183–91. DOI: https://doi.org/10.1111/imr.12038 not been carried out, but perhaps these studies in GvHD will 24. Di Ianni M, Falzetti F, Carotti A, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011 Apr provide a suitable foundation for future investigation. Ultimately, 7;117(14):3921–8. 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40. Robinson RH, Meissler JJ, Breslow-Deckman JM, et al. Cannabinoids inhibit T- 49. Hauser N, Sahai T, Richards R, et al. High on cannabis and calcineurin inhibi- cells via cannabinoid receptor 2 in an in vitro assay for graft rejection, the mixed tors: A word of warning in an era of legalized marijuana. Case Rep Transplant. lymphocyte reaction. J Neuroimmune Pharmacol. 2013 Dec 4;8(5):1239–50. 2016 Aug 9;2016:1–3. DOI: http://dx.doi.org/10.1155/2016/4028492 DOI: 0.1007/s11481-013-9485-1 50. Leino AD, Emoto C, Fukuda T, et al. Evidence of a clinically significant drug‐ 41. Robinson RH, Meissler JJ, Fan X, et al. A CB2-selective cannabinoid suppresses drug interaction between cannabidiol and tacrolimus. Am J Transplant. 2019 T-Cell activities and increases Tregs and IL-10. J Neuroimmune Pharmacol. 2015 May 21;ajt.15398. DOI: https://doi.org/10.1111/ajt.15398 Jun 16;10(2):318–32. DOI: 0.1007/s11481-015-9611-3 51. Picard N, Cresteil T, Prémaud A, et al. Characterization of a phase 1 metab- 42. Kemter AM, Scheu S, Hüser N, et al. The cannabinoid receptor 2 is involved olite of mycophenolic acid produced by CYP3A4/5. Ther Drug Monit. 2004 in acute rejection of cardiac allografts. Life Sci. 2015 Oct 1;138:29–34. DOI: Dec;26(6):600–8. https://doi.org/10.1016/j.lfs.2015.02.012 52. Bergmann TK, Barraclough KA, Lee KJ, et al. Clinical pharmacokinetics and 43. Pandey R, Hegde VL, Nagarkatti M, et al. Targeting cannabinoid receptors as a pharmacodynamics of prednisolone and prednisone in solid organ transplanta- novel approach in the treatment of graft-versus-host disease: Evidence from an tion. Clin Pharmacokinet. 2012 Nov 7;51(11):711–41. DOI: 10.1007/s40262- experimental murine model. J Pharmacol Exp Ther. 2011 Sep;338(3):819–28. 012-0007-8 DOI: 0.1124/jpet.111.182717 53. Helsby NA, Hui C-Y, Goldthorpe MA, et al. The combined impact of CYP2C19 44. Yeshurun M, Shpilberg O, Herscovici C, et al. Cannabidiol for the prevention of and CYP2B6 pharmacogenetics on cyclophosphamide bioactivation. Br J Clin graft-versus-host-disease after allogeneic hematopoietic cell transplantation: Re- Pharmacol. 2010 Dec;70(6):844–53. DOI: 10.1111/j.1365-2125.2010.03789.x sults of a phase II study. Biol Blood Marrow Transplant. 2015 Oct;21(10):1770–5. 54. Shu W, Chen L, Hu X, et al. Cytochrome P450 genetic variations can predict DOI: 10.1016/j.bbmt.2015.05.018 mRNA expression, cyclophosphamide 4-hydroxylation, and treatment outcomes 45. Khuja I, Yekhtin Z, Or R, et al. Cannabinoids reduce inflammation but inhibit in Chinese patients with non-Hodgkin’s lymphoma. J Clin Pharmacol. 2017 lymphocyte recovery in murine models of bone marrow transplantation. Int J Jul;57(7):886–98. DOI: 10.1002/jcph.878 Mol Sci. 2019 Feb 4;20(3). DOI: 10.3390/ijms20030668 55. Rai HS, Winder GS. Marijuana use and organ transplantation: A review and 46. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and implications for clinical practice. Curr Psychiatry Rep. 2017 Nov 27;19(11):91. inducers of human drug metabolizing enzymes: A systematic review. Drug Metab 56. Tetrault JM, Crothers K, Moore BA, et al. Effects of marijuana smoking on pul- Rev. 2014 Feb 25;46(1):86–95. DOI: ttps://doi.org/10.3109/03602532.2013.84 monary function and respiratory complications: A systematic review. Arch Intern 9268 Med. 2007 Feb 12;167(3):221–8. DOI: 10.1001/archinte.167.3.221 47. Fda. HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights 57. Thomas G, Kloner RA, Rezkalla S. Adverse cardiovascular, cerebrovascular, and do not include all the information needed to use EPIDIOLEX ® safely and effec- peripheral vascular effects of marijuana inhalation: What cardiologists need to tively. See full prescribing information for EPIDIOLEX. EPIDIOLEX ® (canna- know. Am J Cardiol. 2014 Jan 1;113(1):187–90. DOI: https://doi.org/10.1016/j. bidi ol) oral solution, CX [pending DEA scheduling action] Initial U.S. Approval: amjcard.2013.09.042 XXXX [pending controlled substance scheduling] [Internet]. [cited 2019 Jun 58. Hill L, Alousi A, Kebriaei P, et al. New and emerging therapies for acute and 19]. Available from: www.fda.gov/ chronic graft versus host disease. Ther Adv Hematol. 2018 Jan;9(1):21–46. DOI: 48. Vanhove T, Annaert P, Kuypers DR. Clinical determinants of calcineurin inhibi- 10.1177/2040620717741860 tor disposition: A mechanistic review. Drug Metab Rev. 2016 Jan 2;48(1):88–112. 59. Paczesny S. Discovery and validation of graft-versus-host disease biomarkers. DOI: 10.3109/03602532.2016.1151037 Blood. 2013 Jan 24;121(4):585–94. DOI: 10.1182/blood-2012-08-355990

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Effectiveness of an educational intervention to increase human papillomavirus knowledge in high-risk populations: A systematic review

Edwin N. Mogaka (PhD)1,2; Ahmed A. Fadairo (BSc)1; Kristin L. Cannon (BSc)1; Olusola A. Sadiku (BSc)1

1Medical University of the Americas, Charlestown, Nevis, West Indies and 27 Jackson Road, Devens, Massachusetts, MA 01434 2Davenport University, 6191 Kraft Ave SE, Grand Rapids, MI 49512

Introduction Abstract lobally, a considerable number of people die each year due Background: HPV vaccine has been described as a very to cancer. Of the different types of cancers, cervical cancer efficacious and safe vaccine, making it highly acceptable is one of the leading causes of death, and is defined as a malignantG tumor arising from cells originating in the cervix of the for the prevention of potential cervical cancer. However, 1 rejection of vaccine use is on the rise. This paper aims uterus. As the fourth most common cause of cancer-related deaths and the third most common cause of cancer in women, cervical to showcase the benefit of educational intervention as cancer is responsible for 4,000 deaths out of 12,000 diagnosed in the an avenue to increase the rate of vaccination among the United States annually.2 high-risk population. The risk factors associated with cervical cancer include multiple Hypothesis: Parental education on HPV vaccine will sexual partners, early onset of sexual activity, smoking, oral improve the rate of vaccination acceptance. contraceptive pills, immunocompromised status, family history of Methods: Databases including PubMed, Google Scholar, cervical cancer, and Human Papillomavirus (HPV) infection.3 It is Science-Direct and Web of Science were searched for safe to say that most cervical cancers occur as a result of genital studies pertaining to the effects of educational intervention HPV infection, which is referred to as the most common sexually on HPV vaccine receipt. transmitted disease in the world.4 Results: A total of 11 articles were included in this review. Over time, HPV infection can cause cervical cancer, which Eight studies targeted high-risk minors of recommended first progresses as cervical intraepithelial neoplasia (CIN) for an ages for the HPV vaccine. The parents of these minors extended period. An important determinant of progression of were then assessed pre- and post-intervention to study the CIN to cervical cancer is the body’s immune system. A deficiency effect of educational intervention on intent to vaccinate in the immune system may result in the development of cervical against HPV. Three studies focused on the effect of cancer. The progression from HPV infection to cervical cancer educational intervention targeted to adolescents and begins gradually from growth abnormality within the basal cells young adults ages 18–22 on intent to vaccinate against of the cervix, followed by extension to intermediate and finally the HPV. Results compared the intent to vaccinate in apex. The extent of the growth abnormality within the different layers of the cervix is categorized as CIN 1, 2, and 3 to signify groups exposed to the educational intervention versus the basal, intermediate and apical layers, respectively. High-risk groups without intervention. Percentage increase in the viral genotypes include HPV 16 and 18, which are responsible for intent to vaccinate was reported for all groups exposed progression of normal cervical cells to abnormal growth in CIN 1, to educational intervention versus groups without 2, 3, and cervical cancer.5 intervention. Much research has been done on cervical cancers and how Conclusion: The increase in the percentage of HPV causes the gradual changes in malignancy of the cervix. participants with intent to vaccinate reflects the importance HPV is said to affect regulatory genes leading to disruption of the of individual knowledge. Future studies should focus function of tumor suppressor genes, which is mediated through on methods that improve dialogue and acceptance with production of oncoproteins E6 and E7 by HPV.7 E7 is known to groups of different ethnicity and cultures. inactivate retinoblastoma tumor suppressor genes (RB) by hyper- methylation, which limits the ability of RB to inhibit the progression of malignancy during the cell cycle. E7 also affects E-cadherin, diminishing cell adhesion, and promoting invasion and metastasis from malignant tissues.6 E6 is responsible for disrupting cell cycle Corresponding Author: regulation through p53 tumor suppressor ubiquitination, leading Edwin N. Mogaka [email protected] or [email protected]

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Effectiveness of an educational intervention to increase human papillomavirus knowledge in high-risk populations: A systematic review to p53 degradation.7 Degradation of tumor suppressors leads to an to high-risk groups as a whole. These demographic groups are thus uncontrolled and constitutively functioning cell cycle. treated as one high-risk population for the purposes of this review. Since cervical cancer is common after HPV infection, effective measures to curb infection are important in reducing the incidence Methods of cervical cancer. The Papanicolaou test (or Pap smear) has proven Search Strategies to be effective in screening for cervical cancer, and prophylactic Databases including PubMed, Google Scholar, Science Direct, vaccines have been proven to prevent HPV infection by generating and Web of Science were searched for literature containing both immune recognition of HPV.8 medical and social science information relevant to the study Even though HPV vaccines are non-infectious, they are able in question. These studies consisted of surveys and case control to generate a humoral immune response because they are derived studies. The following keywords and associated Medical Subject from protein shells known as virus-like particles (VLP). These Heading (MeSH) terms were queried in PubMed: human vaccines are made as a bivalent vaccine (Cervarix) to protect papillomavirus vaccines, adverse effects, intervention studies, against the high-risk HPV genotypes 16 and 18, and sometimes behavioral research, parental hesitancy, attitude to health, and as a quadrivalent vaccine (Gardasil), which protects against HPV health education. The operator “and” was used to help widen the 16 and 18, as well as lower-risk genotypes 6 and 11. Studies of search in cases where articles were few or lacking. The combination both vaccines have shown 90% efficacy against HPV 16 and 18.8 examples included such phrases like, “Human papillomavirus However, since these vaccines are made to be primary prevention vaccines and adverse effects”, “Human papillomavirus vaccine methods, they do not show efficacy in women who have HPV and intervention studies”, “Human papillomavirus vaccine and infection that has already progressed to CIN 2 or 3.9 Following the behavioral research”, “Human papillomavirus vaccine and parental efficacy and success of the vaccines in curbing HPV infection, the hesitancy”, and “Human papillomavirus vaccine and attitude Food and Drug Administration (FDA) approved the vaccination to health and health education”. The key terms were also used of females between 9 and 26 years old. A 64% decrease in independently (without combinations) to help narrow the search. HPV infection was reported six years after vaccine introduction, The same keywords including those with the operator “and” were indicative of the vaccines’ success.10 queried in Science Direct, Google Scholar, and Web of Science. Despite the success of the HPV vaccines, increasing numbers The search was limited to literature published in English. Article of parents are declining the benefits of vaccination for their abstracts published between January 1st, 2000 and December 31st, adolescent children and indirectly exposing them to a greater 2018 were screened for relevance. Articles were reviewed if they risk of cervical cancer. Some parents have stated that the vaccine were free to access, provided full text, and had relevance to the comes with deleterious side effects such as pain, vomiting, dizziness, evaluation of the role of educational intervention on HPV vaccine myalgia, diarrhea, gastroenteritis, headache, hypertension, and uptake. The protocol for this review has been registered with the bronchospasm.8,11 In a survey, 16–55% of parents who declined PROSPERO registries of University of York in Britain. HPV vaccination for their adolescent child cited vaccine safety and side effects as their reasons.8 Studies have also shown that numbers Inclusion Criteria of parents who declined vaccination for the reasons of safety Studies were included if they reported on any of the following: and side effects have quadrupled from 4.4% to 16.4% between adverse reactions deterring further vaccination in a community; the years 2014 and 2017.8,11 With these numbers climbing, it is adolescent and parental knowledge about vaccines; educational necessary to examine methods that can improve vaccine uptake interventions to improve parental knowledge; and receipt, or and accommodate parents and adolescents, which will cause a willingness or intention to receive the HPV vaccine. further decrease in the rate of HPV infection.8,11 Another survey conducted on mothers refusing vaccines for their adolescent Data Extraction children showed that 6% to 12% of parents were concerned about The following data were extracted from included studies: increased sexual behavior of their children after receiving the methods detailing educational intervention; study design; vaccination.12 outcomes; assessment; participants; and results. The extracted Although HPV vaccines have been proven to reduce the data from all articles were then standardized by EM and KC. incidence of cervical cancer, the success of the vaccine also depends Independent data analyses were conducted by AF and OS, and on parents’ approval of the vaccine for their children within the conflicts reconciled through correspondence. EM and KC checked recommended ages.13 This paper aims to evaluate and elaborate the completed analysis against the extracted data for inconsistencies on the possible effects of an educational intervention containing and inaccuracies. Table 1 contains information extracted from information about HPV infection and vaccination on parents’ included studies. decision in allowing vaccination of their children against HPV infection, consequently impacting risk of future cervical cancer. Data Analysis Parameters used to qualify the population of interest as high-risk In this study, results are reported in percentages, and included: perceptions, lifestyle choices, low socioeconomic status, comparison made among the different results. This comparison lack of information, teenagers who are sexually active, minority measures the effectiveness of the intervention used in each study. status, and geographical locations. These factors predispose these In select cases, relative risk (RR) with a 95% confidence interval populations to HPV infection and its sequelae. In this review, (CI) is reported. The analysis includes pre- and post-intervention mention of either parents or adolescent children at high risk refers percentages as reported by the authors in their respective articles

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Effectiveness of an educational intervention to increase human papillomavirus knowledge in high-risk populations: A systematic review

for a quasi-experimental design study. Results from randomized Results controlled trials comparing vaccination intent between intervention Search Strategy and control groups were reported as percentages. A database search yielded 410 articles related to the topic of Although this review examines the effect of an educational discussion. Duplicate citations (n = 52) were identified and removed intervention on HPV vaccine uptake, most of the studies conducted during the first step of data collection from the four databases. In did not measure the rate of vaccination of participants pre- and the end and after the application of inclusion criteria, only a total post-intervention. Instead, most measured the intent of receiving of 11 papers were included in this review. Reasons for exclusion the vaccine as an alternative. Therefore, the intent to receive HPV included: lack of focus on HPV infection and HPV vaccination, vaccines was considered a proxy for acquiring HPV vaccine for the failure to assess the impact of education on HPV vaccines, studies purpose of this review. However, one article measured and reported that had no quantifiable outcomes and comparisons, and articles HPV vaccine uptake (3 dose course), and another article measured whose full text could not be accessed. Figure 1 below is a flowchart the attitude towards accepting HPV vaccine. Research has shown that summarizes the inclusion and exclusion of articles for this that intention to vaccinate is associated with vaccine uptake.29 This review. is based on the theory of planned behavior, which states that a person’s intent predicts the person’s behavior.29 Hence the reports Critical Appraisal obtained with such information can be used in this review. The overall risk of bias in the studies chosen for this review was assessed and then the studies were categorized as between moderate Critical Appraisal and good quality. This was due to the nature of the studies involved. The articles chosen for this review were evaluated for bias, Randomized controlled studies are usually of low risk for bias and suitability, and quality. To review the quality of the articles, a that is why some of the studies used in this review were randomized checklist from the Critical Appraisal Skills Programme (CASP) controlled trials.26 However, the studies evaluated here did not tool was used.26 Apart from following the CASP checklist, it report whether participants or researchers were blinded. Many was important that the articles had reported the criteria for studies also did not include standard-treatment or no-treatment participant eligibility (such as excluding participants with prior control groups. Although most studies included in this review did HPV vaccination), included a no-treatment or standard-treatment not report frequency of HPV vaccination receipt, intention and control condition, and reported in detail on interventions used and attitude toward receiving HPV vaccines was measured as a proxy. outcomes measured to help answer the primary research question. Each study was checked for bias and was given a quality rating from low to good.

PubMED Web of Science Science Direct Google Scholar January 2000 - December 2018 January 2000 - December 2018 January 2000 - December 2018 January 2000 - December 2018 201 Citation(s) 100 Citation(s) 93 Citation(s) 16 Citation(s)

410 Non-Duplicate Citations Screened

Inclusion/Exclusion 350 Articles Excluded Criteria Applied After Title/Abstract Screen

60 Articles Retrieved

Inclusion/Exclusion 48 Articles Excluded 1 Article Excluded Criteria Applied After Full Text Screen During Data Extraction

11 Articles Included

Figure 1. Flow chart of total articles included and excluded for this research

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Effectiveness of an educational intervention to increase human papillomavirus knowledge in high-risk populations: A systematic review

Parental Education Adolescent and Young Adult Education Parental education was important for this study since minors HPV vaccine is considered a primary preventive method eligible for, and recommended to receive, HPV vaccination require used to reduce the incidence of HPV infection. The vaccine is parental consent to receive the vaccine. This review included 8 said to have a maximum benefit at an early age before any sexual studies that investigated the effects of educational intervention activity. This is a result of HPV being the most contracted sexual on parents of minors eligible for the HPV vaccine. The studies disease.2 Therefore, the majority of individuals recommended for included in this review were obtained from different countries, the vaccines require parental consent. However, some studies that with 5 of them originating from the United States,14,16-19 2 from evaluate the effect of educational intervention on HPV vaccine China,20,22 and 1 from India.15 Of the 8 studies questioning the uptake were conducted using adolescents and young adults as effectiveness of the educational intervention on parents, 6were their participants. Of the articles discovered, 3 that measured designed as a quasi-experiment in which comparisons were made uptake were included into this review.21,23,24 These articles included between pre- and post-intervention parental intent to vaccinate participants with ages ranging between 18–26 years old. The their children.14-16,18,20 The remaining studies were designed as participants were either in high school or university. All 3 studies randomized controlled studies.17,19 Because of the way the studies involved were conducted in the United States.21,23,24 Two studies in this review were designed, comparisons were only made included both male and female participants,23,24 while the third immediately after educational intervention. Therefore, no follow- only included females.21 up assessments were carried beyond post-intervention for most Of the 3 studies, the educational interventions utilized were studies. of different forms. One utilized a 13-minute educational video as The modalities of educational interventions for parents in the the intervention.21 Another study utilized a 10-minute educational studies were of importance. Four of the studies introduced HPV discussion about HPV epidemiology, potential clinical sequelae of educational fact sheets as the method of intervention. These HPV infection, the connection between HPV and cervical cancer, contained information on HPV epidemiology, potential clinical and the HPV vaccine.23 The last study provided a theory-informed, sequelae of HPV infection, the connection between HPV and evidence-guided photographic short story about HPV infection, cervical cancer, and the HPV vaccine as a means of primary epidemiology, and vaccination.24 prevention, with some fact sheets more detailed than others.14,15,17,22 From these 3 studies, 2 were conducted as randomized Of the studies employing a fact sheet intervention, 3 out of the controlled trials,21,23 while the third was a quasi-experimental design 4 showed a 20% increase in the number of parents willing to in which participant intention to receive the HPV vaccine was vaccinate their children.14,15,22 One randomized controlled study compared pre- and post-intervention.24 One of the randomized used a fact sheet intervention, but did not completely report controlled trials was conducted by Vanderpool et al. to measure parental intent to vaccinate: only the post-intervention percentage actual HPV vaccination by randomizing participants into either of parents willing to vaccinate their children was reported as a group exposed to a 13-minute video presentation about HPV, 43%, reportedly a statistically significant increase in intention to or a control group that received only standard care. The study vaccinate their children compared to pre-intervention.17 These compared the number of participants in the intervention group results indicate that introducing parents to fact sheets containing who completed a 3-dose HPV vaccination schedule compared to information about HPV infection and vaccine can affect their the control group. This indicates that the intervention had a positive intent to vaccinate their children. effect on the number of vaccines administered.21 Unlike the other Apart from fact sheet interventions, other methods of 2 studies, Vanderpool et al. followed up with the participants for 9 educational intervention were utilized in other studies. One months after intervention using the medical record review. study involved an educational video about HPV infection and The second randomized controlled trial recruited 131 vaccination.16 Two studies involved a one-hour educational participants aged 18–26 years. The study randomized participants slideshow,18,20 while in another study, the researchers conducted into 2 groups, assessed and compared the results of participants’ their studies using a Spanish-language radio advertisement level of knowledge about HPV and its vaccine, and then surveyed (radionovela) as an educational intervention.19 The educational participants to measure their intent post-intervention. The video proved to be effective, with a reported increase in the intervention used in this study was a 10-minute brief educational intention to accept HPV vaccine. 76% of parents after watching program comprised of an informative discussion aimed at the educational video declared their intention to vaccinate their answering their concerns and correcting any misconceptions about children, compared to 47.1% pre-intervention, while in the control the vaccine. The result of the post-intervention survey indicated group, 71.2% intended to vaccinate their children post-intervention that 87% of the participants in the intervention group intended compared to the 30.8% pre-intervention. The Spanish-language to vaccinate, compared to 67% of the participants in the control radio advertisement was used as intervention to help inform group.23 Hispanic parents about HPV vaccination. It showed an increase The third study was designed as a quasi-experiment that used in the parents’ intention to vaccinate rise from 54% to 61%. a theory-informed, evidence-guided photographic short story Both of the studies that used the one-hour educational slideshow about HPV infection and vaccine. Results obtained from the study as an intervention showed increases in the parents’ intention to showed that 34% of participants had the intention to vaccinate vaccinate, with one showing an increase from 32.5% to 44.4%, post-intervention compared to 24% pre-intervention.24 All three while the other reported 58.9% post-intervention compared to studies showed a significant difference between vaccination intent 41.6% pre-intervention. when comparing intervention and control groups.

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Effectiveness of an educational intervention to increase human papillomavirus knowledge in high-risk populations: A systematic review

Table 1

Author/Year Study design Intervention (I) Control (C) Outcomes (O) Assessment (A) Total Participants Participants Results Participants willing to willing to (n) allow allow vaccination vaccination pre-interven- post-intervention (%) tion (%)

Davis K, et al./ Comparison Group introduced to Same group prior Parents’ acceptance Assessment of pre- 506 9 37 A change in acceptance to 2004.14 survey. Survey of HPV educational fact to intervention. of the HPV vaccine for and post- intervention vaccination was reported attitude and will- sheet. their adolescent. survey item. as +20% by the authors. ingness before and after intervention.

Basu P, and Mittal Comparison Group introduced Same group prior Parents’ acceptance Assessment of pre- 522 27 (w) and 24 74 (m and w). An increase in the accep- S./2007.15 survey. Survey of to fact sheet about to intervention. of the HPV vaccine for and post-intervention (m). tance of vaccination was attitude and will- cervical cancer and their adolescent. survey item. reported by the authors. ingness before and HPV vaccine followed after intervention. by a trained social worker for clarity.

Suarez Mora A, et Comparison Group introduced Same group prior Parents’ acceptance Assessment of pre- 104 47.1 (for 76 (for partici- A knowledge score al./ 2018.16 survey. Survey of to educational video to intervention. of the HPV vaccine for and post-intervention participating pating parents improvement was attitude and will- about HPV. their adolescent. survey item. parents them- themselves). reported after educational ingness before and selves). 30.8 71.2 (for intervention (mean = after intervention. (for children children and 14.1, p < .0001) and and grandchil- grandchil- remained elevated in dren). dren). the 44 participants that completed long-term follow-up (mean = 13.5, p < .0001).

Kennedy A, et al./ Randomized Educational flyer No informational Parents’ intention Assessment of survey 411 Unavailable. 43 Parents in intervention 2011.17 controlled trial. adapted from CDC. flyer. to vaccinate their item mailed to parents. group showed statistically adolescent when significant increase in recommended by intention to vaccinate physician. their children.

Spleen AM, et Survey of attitude Group introduced to Same group prior Intention of HPV vac- Assessment of survey 38 32.5 44.4 Authors reported that al./2012.18 and willingness one-hour educational to intervention. cine for daughters. item before and after within 1 month parents in- before and after slide presentation intervention. tent to vaccine daughters intervention. and health educators increased (p = 0.002). about HPV infection, disease, and vaccine.

Kepka D, et al./ Randomized Group introduced to Prostate cancer The likeliness of A post - intervention 88 54 61 Authors reported an in- 2011.19 controlled trial. a 5-minute Spanish radio announce- participant daughter single survey accessed crease in the likeliness of radionovela a about ment. receiving vaccine in after intervention. daughters receiving HPV cervical cancer, the next 12 months. vaccine after intervention. HPV infection, HPV vaccine.

Kwan T.T, et Survey of attitude Group introduced to Same group prior Likeliness of HPV vac- Assessment of survey 943 41.6 58.9 Authors reported 11.3% al./2011.20 and willingness one-hour educational to intervention. cine after intervention. item before and after increase in number of before and after slide presentation intervention. girls who indicated an intervention. followed by question intention to accept the and answer session vaccine post intervention. with gynecologist and oncologist.

Vanderpool RC, et Randomized Group introduced to CDC HPV vaccine 3 dose series comple- Assessing medical 344 35.7 43.3 43.3% of intervention al./2013.21 controlled trial. an educational video fact sheet and a tion of HPV vaccine. record up to 9 months group and 31.9% of con- about HPV and vacci- free t-shirt. after first dose of HPV trol group completed the nation, coupled with vaccine. 3 dose series (p = 0.03). CDC HPV vaccine information sheet and a free t- shirt.

Symphorosa Shing Comparison Group introduced to Same group prior Parents’ acceptance Assessment of pre- 170 32 52 A change in acceptance of Chee Chan, et al./ survey. Survey of one-page fact sheet to intervention of the HPV vaccine for and post-intervention vaccination was reported 2007.22 attitude and will- containing the effec- their adolescent. survey item. as +20% by the authors. ingness before and tiveness of the HPV after intervention. vaccine on reducing HPV infection.

Kester L.M, et al./ Randomized Group introduced No information pre- Likeliness of HPV vac- Surveys to assess HPV 131 67 86 The authors reported 2014.23 controlled trial. to a 10-minute edu- sented to group. cine after intervention. knowledge, vaccination that the intervention cational information history, and vaccination group had higher HPV session about HPV intent (for unvaccinated vaccination intent (86%) and vaccination. participants). compared to the control group (67%) (OR = 3.09; 95% CI = 1.02–9.3).

Chan A, et Comparison Group introduced to No information pre- Intention to vaccinate, Fisher's exact test 41 24 34 Authors reported an intent al./2015.24 survey. Survey of a theory-informed, sented to group intention to encourage comparing intervention to vaccinate (+18.4%, p attitude and will- evidence-guided pho- social networks to and control groups = 0.06), intent to encour- ingness before and tographic short story vaccinate, and attitude age others to vaccinate after intervention. about HPV infection towards vaccination (+10.5%, p = 0.14). and vaccine.

w = women; m = men

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Effectiveness of an educational intervention to increase human papillomavirus knowledge in high-risk populations: A systematic review

DISCUSSION shows the modality of educational intervention used by each study Eleven studies involving different educational interventions included in this review. and their impact on HPV vaccination were involved in this review. The importance and effectiveness of intervention modality These studies involved the assessment of educational interventions have been questioned by different studies. One study compared for parents of minors of recommended ages for HPV vaccination. the effectiveness of a video educational intervention to that of Intent to vaccinate was also measured in adolescent and young a written workbook in a hospital setting.30 Having stated that adults. Of the 11 studies, 8 reported parental interventions, and the strategy used in the delivery of an educational intervention measured their intent to vaccinate their children, while 3 studies is important, it was necessary to determine any difference targeted adolescents and young adults. Of the 11 studies involved intervention modality might have caused in the studies included in this review, only 1 was designed to actually measure the rate in this review. For the purpose of the comparison, the modalities of HPV vaccination in a 3 dose course. While it was difficult to of the educational intervention were grouped into two categories: obtain studies that assessed HPV vaccination, other studies were studies with printed materials and studies with video material. The obtained that were designed to measure the intention of HPV printed material category included any study with fact sheets, slides vaccination. These reports were accepted due to an understanding and presentation, or short stories.14,15,17,18,20,22,24 The video material that a receptive attitude towards HPV vaccine can be regarded as a category included any study that showed an educational video to precursor to vaccination. Intention to vaccinate is being treated as participants.21 For simplicity, the 2 studies that used Spanish radio equivalent to actual vaccination for the purposes of this systematic and group discussion were not included in any of the categories as review. they did not fit the criteria for both categories.19,23 Two selection groups were considered in this review. One Studies that focused on parental education were the first to be group consisted of parents of minors of recommended age, compared. From the 8 studies included in this review, only 1 can and the other group of adolescent and young adults. Because be categorized as video material,16 and 6 categorized as printed both groups were introduced to educational interventions, it was material. Only studies designed as a quasi-experiment were used necessary to compare the effectiveness between these groups. For for comparison. Results obtained from the group with video proper comparison, the designs used in the study were required material reported an increase in percentage of parents’ intent to be similar. Results obtained from randomized controlled trials to vaccinate their children from 30.8% to 71.2%. Groups with involving groups of adolescents and young adults were used as printed material also reported an increase in parents’ intent to a comparison to the randomized controlled trials involving the vaccinate their children. With the exception of one study,15 groups parents. with printed material only showed a 20% increase in parents’ Results from the examined studies indicated that the parents intent on average.14,18,20,23 The exception in the groups with printed in both randomized controlled studies showed similar trends. The material showed an increase in mothers’ intent from 30.8% to 74%. parents that were exposed to the educational intervention had a Although this is higher than the report from the group with video percentage increase in their intent to vaccinate their children material, it can be argued that the difference can be attributed to compared to parents that were not exposed. These results were the presence of a trained social worker at the end of the study. also similar to that of the groups of adolescent and young adults. The trained social worker provided clarity to the participants in The increase reported in these studies may be linked to the ability a question and answer period after the fact sheets were read. This of the population of interest to understand and appreciate the report differs from a similar study that suggested that both video importance of HPV vaccination post-intervention. In as much and printed materials are equally effective.31 as these studies reported an increase in the intention to vaccinate The effectiveness of the modality of educational intervention for groups of parents and of adolescent and young adults, and as could not be compared in groups with adolescent and young stated that intent to vaccinate is associated with vaccine uptake, it is adults. Only 3 studies were included in this group.21,23,24 Of the still important to note that confounding factors may be responsible 3, only 2 could be categorized as either video material or printed for participants’ changes in attitude and a follow-up is required in material. However, a proper comparison could not be made due some instances to ensure that the intention accurately translates to to both studies being designed differently. One was a randomized action and that educational intervention alone was responsible for controlled trial, and the other a quasi-experiment. the said phenomenon. At present, HPV infection and cervical cancer are associated Communication is a major component of an educational with lower socioeconomic status. Areas with poorer populations intervention. For maximum effect, it is paramount that the message and lower educational backgrounds have an increased rate of delivered is well understood by the recipients. Therefore, for HPV infection and higher prevalence of cervical cancer.27 Only 2 communication to be more efficient, the comprehension abilities of the 11 studies involved in this review focused on socioeconomic of the intended audience should be determined forehand. The status.19,23 Although the majority of the studies were not focused knowledge of the literacy level of the intended audience will on socioeconomic status, results obtained were similar to those determine the type of intervention to be used and will assist in the obtained in the other studies. creation and delivery of a suitable intervention.16 Studies in languages other than English were excluded from Aside from the information delivered by an educational this review. However, since it is understood that HPV infection intervention, the intervention modality can affect the outcome. and cervical cancer are prevalent in areas with socioeconomically Modalities often used in educational interventions include fact disadvantaged individuals, this can be a limitation to our review. sheets, presentations, and videos. The studies included in this Ethnic minority groups lack access to many services including review depict some of the various intervention modalities. Table 1 education and healthcare.32 Because of this they have been revealed

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Effectiveness of an educational intervention to increase human papillomavirus knowledge in high-risk populations: A systematic review

to be skeptical and less receptive to vaccination.28 This could be informed, systematic review. Preventive Medicine. 2007;45(2-3): 107-114. doi: 10.1016/j.ypmed.2007.05.013 due to a difference in belief and culture. More research is need to 13. Zimet G. Improving adolescent health: Focus on HPV vaccine acceptance. better understand and formulate interventions that can improve Journal of Adolescent Health. 2005;37(6): S17-S23. doi: 10.1016/j.jado- dialogue and increase acceptance among groups that are different health.2005.09.010 14. Davis K, Dickman E, Ferris D, et al. Human papillomavirus vaccine acceptability from those of the Western world. In addition, the use of only free among parents of 10- to 15-year-old adolescents. Obstetrical & Gynecological articles limits access to a large inventory of information that could Survey. 2004;59(12): 820-822. doi: 10.1097/01.ogx.0000143866.29509.50 have strengthened the argument in favor of the interventions 15. Basu P, & Mittal S. Acceptability of human papillomavirus vaccine among the urban, affluent and educated parents of young girls residing in Kolkata, Eastern described in this review. India. Journal of Obstetrics and Gynaecology Research. 2011;37(5): 393-401. A majority of the parents referred to in this study were those doi: 10.1111/j.1447-0756.2010.01371.x 16. Suarez Mora A, Madrigal J, Jordan L, et al. Effectiveness of an educational from low socioeconomic standing. “High-risk” in the context of this intervention to increase human papillomavirus knowledge in high-risk minor- paper refers to the disadvantaged groups who, by a set of unique ity women. Journal of Lower Genital Tract Disease. 2018; 1. doi: 10.1097/ circumstances, are predisposed to HPV infection. According to lgt.0000000000000386 17. Kennedy A, Sapsis K, Stokley S, et al. Parental attitudes toward hu- Kahn, Lan & Kahn, economics, cultural beliefs, limited access man papillomavirus vaccination: Evaluation of an educational interven- to healthcare facilities, behavioral health practices, and illiteracy tion, 2008. Journal of Health Communication. 2011;16(3): 300-313. doi: are some of the factors that have influenced the lagging trends 10.1080/10810730.2010.532296 18. Spleen A, Kluhsman B, Clark A, et al. An increase in HPV-related knowledge of HPV vaccination among high risk populations leading to high and vaccination intent among parental and non-parental caregivers of adolescent prevalence of HPV in these groups.32 girls, age 9–17 years, in Appalachian Pennsylvania. Journal of Cancer Education. 2011;27(2): 312-319. doi: 10.1007/s13187-011-0294-z 19. Kepka D, Coronado G, Rodriguez H, et al. Evaluation of a radionovela to pro- Conclusion mote HPV vaccine awareness and knowledge among Hispanic parents. Journal of HPV vaccine acceptance has been associated with individual Community Health. 2011;36(6): 957-965. doi: 10.1007/s10900-011-9395-1 20. Kwan T, Tam K, Lee P, et al. The effect of school-based cervical cancer education knowledge about HPV infection and HPV vaccines. Exposure to on perceptions towards human papillomavirus vaccination among Hong Kong an educational intervention is important, as it will further increase Chinese adolescent girls. Patient Education and Counseling. 2011;84(1): 118-122. knowledge in society.28 This review provides an important link doi: 10.1016/j.pec.2010.06.018 21. Vanderpool RC, Cohen EL, Crosby RA, et al. "1-2-3 Pap" intervention improves between various educational interventions and vaccine acceptance. HPV vaccine series completion among Appalachian women. Journal of Com- A consensus was seen with roughly every study indicating an munication, 2013;63(1): 95-115. doi:10.1111/jcom.12001 22. Chan SS, Cheung TH, Lo WK, et al. Women’s attitudes on human papillomavi- increase in intent to accept vaccination. However, to further rus vaccination to their daughters. Journal of Adolescent Health, 2007;41: 204- increase the rate of HPV vaccination, future research should 207. doi:https://doi.org/10.1016/j.jadohealth.2007.04.011 be undertaken to understand better methods that can improve 23. Kester LM, Shedd-Steele RB, Dotson-Roberts CA, et al. The effects of a brief educational intervention on human papillomavirus knowledge and intention to dialogue and acceptance among groups that are different ethnically initiate HPV vaccination in 18–26 year old young adults. Gynecologic Oncology., and culturally from those of the Western world. 2014;132. doi:10.1016/j.ygyno.2013.12.033 24. Chan A, Brown B, Sepulveda E, et al. Evaluation of fotonovela to increase human papillomavirus vaccine knowledge, attitudes, and intentions in a low-income References Hispanic community. BMC Research Notes. 2015;8(1). doi:10.1186/s13104-015- 1. Qin C, Chen X, Bai Q, et al. Factors associated with radiosensitivity of cervical 1609-7 cancer. Anticancer Research. 2014;34(9):4649-4656. 25. Ajzen I. The theory of planned behavior. Organizational Behavior and Human 2. Watson M, Benard V, Thomas C, et al. Cervical cancer incidence and mortality Decision Processes. 1991;50(2): 179-211. doi:10.1016/0749-5978(91)90020-t among American Indian and Alaska Native women, 1999–2009. American Jour- 26. Brice, R. (2019). CASP - Critical Appraisal Skills Programme. [online] CASP nal of Public Health. 2014;104(S3): S415-S422. doi: 10.2105/ajph.2013.301681 - Critical Appraisal Skills Programme. Available at: https://casp-uk.net/#!casp- 3. Makuza J, Nsanzimana S, Muhimpundu M, et al. Prevalence and risk factors tools-checklists/c18f8 [Accessed 25 July 2019]. for cervical cancer and pre-cancerous lesions in Rwanda. Pan African Medical 27. Benard VB, Johnson CJ, Thompson TD, et al. Examining the association between Journal. 2015;22(26). doi: 10.11604/pamj.2015.22.26.7116 socioeconomic status and potential human papillomavirus-associated cancers. 4. Momenimovahed Z, & Salehiniya H. Incidence, mortality and risk factors of Cancer, 2008;113(S10): 2910-2918. doi:10.1002/cncr.23742 cervical cancer in the world. Biomedical Research and Therapy. 2017;4(12):1795- 28. Carnegie E, Whittaker A, Brunton CG, et al. Development of a cross-cultural 1811. doi: 10.15419/bmrat.v4i12.386 HPV community engagement model within Scotland. Health Education Journal. 5. Moosazadeh M, Haghshenas M, Mousavi T, et al. Efficacy of human papilloma- 2017;76(4): 398-410. doi:10.1177/0017896916685592 virus l1 protein vaccines (cervarix and gardasil) in reducing the risk of cervical 29. Patel D, Zochowski M, Peterman S, et al. Human papillomavirus vaccine intent intraepithelial neoplasia: A meta-analysis. International Journal of Preventive and uptake among female college students. Journal of American College Health. Medicine. 2017;8(1): 44. doi: 10.4103/ijpvm.ijpvm_413_16 2012;60(2): 151-161. doi: 10.1080/07448481.2011.580028 6. McCormick T, Canedo N, Furtado Y, et al. Association between human pap- 30. Hill A, McPhail S, Hoffmann T, et al. A randomized trial comparing digital video illomavirus and Epstein - Barr virus DNA and gene promoter methylation of disc with written delivery of falls prevention education for older patients in hos- RB1 and CDH1 in the cervical lesions: a transversal study. Diagnostic Pathology. pital. Journal of The American Geriatrics Society. 2009;57(8): 1458-1463. doi: 2015;10(1). doi: 10.1186/s13000-015-0283-3 10.1111/j.1532-5415.2009.02346.x 7. Williams V, Filippova M, Filippov V, et al. Human papillomavirus type 16 E6* in- 31. Krawczyk A, Lau E, Perez S, et al. How to inform: Comparing written and duces oxidative stress and DNA damage. Journal of Virology. 2014;88(12): 6751- video education interventions to increase human papillomavirus knowledge and 6761. doi: 10.1128/jvi.03355-13 vaccination intentions in young adults. Journal of American College Health. 8. Gonçalves A, Cobucci R, Rodrigues H, et al. Safety, tolerability and side ef- 2012;60(4): 316-322. doi: 10.1080/07448481.2011.615355 fects of human papillomavirus vaccines: a systematic quantitative review. The 32. Kahn JA, Lan D, and Kahn RS. Sociodemographic factors associated with high- Brazilian Journal of Infectious Diseases. 2014;18(6): 651-659. doi: 10.1016/j. risk human papillomavirus infection. Obstet Gynecol. 2007;110(1):87–95. doi: bjid.2014.02.005 10.1097/01.AOG.0000266984.23445.9c. 9. Cutts F, Franceschi S, Goldie S, et al. Human papillomavirus and HPV vaccines: a review. Bulletin of The World Health Organization. 2017;85(09): 719-726. doi: 10.2471/blt.06.038414 10. Daley E, Vamos C, Thompson E, et al. The feminization of HPV: How science, politics, economics and gender norms shaped U.S. HPV vaccine implementation. Papillomavirus Research. 2017;3: 142-148. doi: 10.1016/j.pvr.2017.04.004 11. Mitchell T, & Casella C. No pain no gain? Adjuvant effects of alum and mono- phosphoryl lipid A in pertussis and HPV vaccines. Current Opinion in Immunol- ogy. 2017;47: 17-25. doi: 10.1016/j.coi.2017.06.009 12. Brewer N, & Fazekas K. Predictors of HPV vaccine acceptability: A theory-

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Physicians in prehospital care: A review of the clinical and economic evidence

Daniel Kapustin1; Sparsh Shah1 1University of Toronto Faculty of Medicine, Toronto, Ontario

pharmacological interventions such as endotracheal intubations Abstract (ETIs) and the placement of intravenous lines or chest tubes. Prehospital care delivery varies across different In contrast, in countries such as France and Germany, prehospital care is often provided by physicians. In addition to geographies. Among the starkest differences is the role providing care otherwise offered by paramedics and specially trained of the physician in prehospital care and emergency nurses, emergency physicians and anesthesiologists are particularly medical services (EMS). In the ‘Anglo-American’ model, adept in airway management and performing cardiopulmonary ambulances are primarily staffed by emergency medical resuscitation (CPR). Unlike paramedics, who are often trained to technicians (EMTs), emergency medical responders follow guidelines and standard operating procedures, physicians (EMRs), and paramedics. In contrast, in the ‘Franco- have a level of advanced training that allows them to make more adaptable decisions based on the clinical scenario and presentation.1 German’ model, ambulances are commonly staffed by Moreover, as a result of extensive experience and training, their physicians. Physicians can theoretically provide superior implementation of standard procedures may allow for more prehospital care due to increased level of training, advanced decision-making on a case-by-case basis. Theoretically, judgement, and competency. However, physician-staffed physician-staffed EMS (PS-EMS), under the so-called ‘Franco- emergency medical services (PS-EMS) also increase the German’ model bear the potential for better survival outcomes due to the higher level of training, however this comes at a higher systems financial burden on the prehospital care system. This cost and therefore an additional strain on resources. review paper aims to summarize, compare, and analyze Though countries including France, Australia, Finland, Israel, the clinical and financial features of these two models in and Germany utilize physicians to provide ambulance-based order to identify the best staffing model. The information advanced care life support (ACLS), this practice has been abandoned 2 presented in this paper can aid medical administrators in in the United States to maximize physician resource efficiency. the decision-making process involved in optimizing their As a consequence of ethical, logistical, and fiscal feasibility, randomized control trials (RCTs) designed to examine patient prehospital care delivery system. outcomes between the two models are unlikely to be constructed. Any direct comparison of one country’s system to another lends itself to other confounding variables such as organizational, economical, and geographical factors.3 Nonetheless, there is an abundance of Introduction retrospective and prospective studies contrasting the relative efficacy of physician versus secondary operator-provided care on patient he role of physician-led prehospital care in the acute setting outcomes such as survival-to-hospital and survival-to-discharge rates. is controversial. In the United States, Emergency Medical A consequence of the absence in RCTs, however, is a prevalence Services (EMS) are predominantly staffed by emergency of selection bias among available studies. For instance, the largest medicalT technicians (EMTs), emergency medical responders study from Japan comparing outcomes in 126,000 EMS response (EMRs), and paramedics. In the ‘Anglo-American’ model, EMR cases relies on prehospital physician EMS teams whose availability training consists of 80 hours of education to provide basic care is restricted to geographical regions around specific emergency (management of airway, breathing, and circulation). These are often centers.22 It is therefore informative to draw conclusions from data volunteer crew which may provide basic emergency aid. In contrast, derived in published outcomes throughout a multitude of studies in EMT training is in excess of 200 hours and involves practical countries providing emergency ambulance-based care through both experience in both ambulances and emergency rooms. Importantly, physicians and secondary providers. EMTs can administer medications and care for patients in an Determining which staffing model optimizes and balances overall ambulance environment while EMRs cannot. Finally, paramedic patient outcomes with cost is an important, broad, and systems-level training requires over 1,000 hours and involves more thorough question which can aid in the decision-making surrounding health training on the anatomy, physiology, and pharmacology of patient services organization both in countries with established prehospital management. Both EMTs and paramedics are trained with advanced care and in countries that are currently building their prehospital oxygen and ventilation skills, pulse oximetry monitoring knowledge, care systems. There is no recent analysis currently within the and medication administration techniques. However, paramedics literature that summarizes and contextualizes clinical and economic are additionally trained in advanced invasive management and

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Physicians in prehospital care: A review of the clinical and economic evidence

evidence for the role of physicians in prehospital care. The goal Evidence Supporting the Franco-German Model of this review is to therefore synthesize and provide an updated A number of studies have suggested superior patient outcomes overview of the relevant evidence comparing the Anglo-American in cases where EMS care was provided by medical physicians and Franco-German EMS models in terms of provider skill level when compared to secondary providers (EMTs, paramedics, and and patient outcomes, as well as to provide analysis of the economic ambulance nurses). Importantly, a nationwide population-based and logistical considerations involved in the implementation of these observational study in Japan consisting of 95,000 patients evaluated models. survival outcomes among patients experiencing out-of-hospital Organizations can use the information summarized in this paper cardiac arrest.9 The study determined that advanced care life to either adopt, modify, or discard PS-EMS based on context specific support during cardiac arrest (which includes CPR, venous access, factors and healthcare needs of a region. To ensure clarity, this paper and intubation) provided by physicians resulted in superior one- will refer to systems that employ physicians in pre-hospital care as month survival (11.6%) when compared to the same care provided PS-EMS, and all other providers as non PS-EMS. by emergency life-saving technicians (ELSTs) (6.7%, p<0.01).9 Furthermore, when pre-hospital care included bystander-initiated Comparison of Emergency Responder Competencies CPR, subsequent one-month survival rates for patients managed A systematic search of the literature was carried out using by physicians (15%) remained significantly greater than for those multiple sources, including Medline and Medline in-process/epubs managed by ELSTs (9.6%, p<0.01).9 between 1990 and October 3rd, 2017. This search was restricted The study also demonstrated greater improvement of to articles written in English. The final search terms were in the neurological performance (as measured by the Glasgow-Pittsburgh form of: EMS + PS-EMS + Outcome. To understand differences cerebral performance category) in patients with ACLS provided by in outcomes for patients provided care by EMS, we first set out physicians.9 However, prehospital physician EMS service was limited to describe the relative competencies expected of physicians and to specific hospital regions. secondary emergency providers. In 2011, a study by Schuppen et al. The authors conclude that patients managed by EMS physicians in the Netherlands constructed a quantitative inventory describing were therefore managed at hospitals with which these physicians were the diagnostic, therapeutic, and clinical judgement competencies of affiliated, precluding the validity of this data. It is also noteworthy to both physicians and ambulance nurses involved in EMS-provided consider that certain treatments (such as therapeutic hypothermia care. Examples of such competencies relating to a response and percutaneous coronary intervention) are only available at certain protocol for ‘carbon monoxide poisoning’, for example, included Japanese centers. It is difficult to draw sound conclusions from such Glasgow Coma Scale (diagnostic), IV access (therapeutic), and the observational studies due to the presence of these confounders. consideration of endotracheal intubation (clinical judgement).4 In the context of traumatic brain injury (TBI), one unique study Through analysis of the National Protocol Ambulance Care, a total comparing outcomes between a helicopter-based PS-EMS and a of 438 competencies were identified among ambulance nurses. non-physician staffed ground EMS (GEMS) in Finland determined Moreover, while all these competencies were provided by physicians, 42% of patients had good neurological outcome (as measured by an additional 62 competencies were specific to physician-provided Glasgow Outcome Scores) in the PS-HEMS group compared to care, most of which were therapeutic competencies (such as 28% in the non PS-GEMS group.10 While the impact of physicians resuscitation and airway management).4 cannot be isolated due to the introduction of a helicopter service, While similar results may be expected across healthcare this study indicates that specific implementations of physician structures, a broader skill base does not necessarily imply physicians management may be superior to non-physician management. maintain greater performance in overlapping competencies An observational cohort study in Switzerland similarly with other providers. A Boston EMS comparison of paramedic evaluated mortality in 338 blunt polytrauma patients treated by and physician skill at analyzing 12-lead ECGs demonstrated no either EMTs or emergency physicians assisted by EMTs.11 While the significant differences in elucidating the presence of STEMI among crude mortality of patients treated by physicians (11.2%) was not patients.5 significantly lower than those treated by patients in the EMT group Accordingly, a randomized, prospective mock trial at the (14.1%), the number of deaths among patients treated by the EMT University of Pittsburgh compared paramedic and physician group showed a statistical trend exceeding the number of predicted agreement for clinical indicators of c-spine injury. Among the 50 deaths (p=0.066) as determined through anatomical characterization studied physician-paramedic pairs, the study demonstrated excellent of injury severity.11 agreement between both providers when evaluating simulated Taken together, these data continue to suggest a trend towards patients.6 Likewise, a multi-center study assessing the diagnostic improved patient survival when management occurs under physician accuracy of paramedics illustrated excellent concordance between care. Importantly, however, such studies do not offer an explanation emergency physician and paramedic diagnosis accuracy in the of the potential contributing factors to this differential in care. evaluation of patients presenting with chest pain or shortness of In a retrospective analysis of two helicopter emergency medical breath (kappa = 0.54, 0.61 for cardiac and pulmonary diagnosis).7 services (HEMS) models, one physician-staffed and one which was Additionally, a study from five regional air ambulances in the UK paramedic-staffed in Australia, the authors analysed outcomes in discovered that tracheal intubation success rates for OHCA by patients suffering from blunt trauma transported from the site of paramedics were equivalent to physician led intubation.8 These data injury.12 Adjusted W-score modeling indicated there would be an illustrate the importance of evaluating patient outcomes of in-field additional thirteen survivors per 100 patients treated in the physician performance to better assess differentials in care between physicians group compared to the paramedic group.12 The authors do note and secondary providers. that in 42% of patients (n = 67) managed by the physician team,

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Physicians in prehospital care: A review of the clinical and economic evidence transfusion with packed red blood cells took place – an intervention A similar study based in Norway compared clinical outcomes which exceeded paramedic protocol.12 Moreover, the physician team for out-of-hospital cardiac arrest (OHCA) in physician-manned performed a significantly greater number of intubations while the ambulances versus paramedic-manned ambulances.15 With a study mechanisms of injury and transport distances did not significantly cohort of 917 patients, despite higher quality CPR from physician- differ between groups.12 Ultimately, it is reasonable to suspect manned ambulances (shorter hands-off periods and pre-shock pauses) that differences in patient outcomes may therefore be related to a and an increased rate of intubation among the physician group (88% difference in the number and types of interventions performed by vs. 77%), there was no significant difference in short-term outcomes physicians when compared to paramedics. (defined as return of spontaneous circulation, and intensive care unit Nevertheless, there is also evidence suggesting that beyond admission) or long-term outcomes (survival-to-discharge) between the additional range of treatments performed by physicians, the the two groups.15 These results challenge the notion that advanced performance of physicians may differ from that of paramedics airway management techniques uniquely applicable to physician during a given intervention. A 1987 study evaluated mortality care are advantageous and afford superior patient outcomes. In outcomes in 574 blunt trauma patients managed by either a flight fact, a multicenter Ontario prehospital study demonstrated that the nurse and paramedic, or a flight nurse and physician pair.13 While addition of advanced-life-support interventions did not improve both teams were trained to perform the same procedures, patients OHCA survival rates among an already-optimized EMS system.16 treated by the flight nurse/physician team demonstrated a mortality Apart from survival, long-term quality of life has also been rate 35% lower than predicted, as well as significantly lower than examined as a primary outcome in EMS patients. In South-Western that of the flight nurse/paramedic team.13 Finland, a PS-HEMS was launched in 1988. Prior to the PS-HEMS, Interestingly, while the patients predicted to die (as per the patients were treated by ground-based non PS-EMS. One study Trauma and Injury Severity Score, TRISS) within the nurse/ compared 81 blunt trauma cases treated by the PS-HEMS to 77 paramedic team made up a majority of deaths in this group, several blunt trauma cases treated prior to the establishment of physician patients managed by the physician/nurse team initially expected to staffed HEMS.17 die survived their injuries.13 The authors attribute this difference to In the study, although physicians treated more aggressively the greater rate of implemented interventions by the physician/nurse (greater rate of intubation and cannulation), there was no difference team, including IV line insertion, intubation, and thoracostomy.13 in long-term survival.17 Furthermore, a questionnaire relating to In summary, evidence regarding advantages of PS-EMS is mixed. quality of life was sent out three years later to the survivors, and Differences among physicians and other emergency responders from showed no difference between the two groups.17 This evidence the perspective of clinical competency and procedural capability do stands in agreement with the previously presented data suggesting no not appear to translate to appreciable differences in EMS outcomes. significant advantages in mortality rates or quality of life offered by However, these data suggest potentially improved patient outcomes for the greater interventional capabilities of EMS physicians. In fact, the physician-led teams when compared to paramedic-staffed emergency authors suggest the introduction of such advanced techniques may service teams. While the precise mechanism for these differences allow for longer scene times, excessive fluid therapy, and potential remains unclear, the outlined evidence suggests that discrepancies in failures in procedures.17 applied interventions and interventional success rate may be at least Overall, the data presented illustrates the mixed nature of partially responsible for improvement in patient outcomes. conclusions regarding the superiority of patient outcomes when managed by physicians when compared to secondary emergency Evidence Supporting the Anglo - American Model providers. In particular, the literature suggests that the advanced In contrast, several studies show that performing advanced care interventional capacity offered by physicians may not provide specific to physician competency may not necessarily translate to adequate therapeutic benefit to justify the use of physicians over better outcomes. A large multicenter observational Canadian study paramedics and EMTs in prehospital care. compared survival rates of major survivable trauma in three different prehospital trauma care systems with access to a level one trauma Economic Analysis center: Montreal, where physicians provide advanced life support; Managers need to consider cost differences when determining Toronto, where paramedics provide advanced life support; and the optimal prehospital care model. A prehospital care system that Quebec City, where emergency medical technicians provide only improves survival but comes with an extremely high cost would basic life support.14 After examination of 9,405 patient outcomes, be neither practical nor efficient. One of the central arguments the assessed overall mortality rates from injuries for physicians were against a PS-EMS is the high cost burden of staffing ambulances 35%, 28% for paramedics, and 26% for EMTs.14 Physician-provided with physicians. This review will therefore examine the economic care was associated with a significantly increased mortality rate studies that exist in order to provide a more comprehensive, practical compared to paramedics and EMTs.14 comparison between the two prehospital care models. However, the authors note significant differences in mean In one Australian study, physician-staffed HEMS were compared injury severity scores (ISS) and motor vehicle collisions between the to non-PS ground EMS (GEMS). Specifically, the authors compared three examined cities.14 In particular, mean ISS scores were noted cost-effectiveness and survival in trauma patients (ISS>12 or TBI) to be significantly higher for patients treated by a physician, when between these groups over an eleven year period.18 Treatment compared to the other two groups.14 These confounders make data costs in this study accounted for costs in four phases: treatment in interpretation difficult, and illustrate the need to consider additional a referral hospital, transport to a trauma centre, treatment during studies in assessing the potential advantages of paramedic or EMT- the index hospitalisation, and treatment following discharge.18 The based care in the EMS environment. adjusted in-hospital mortality was determined using a logistical

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regression model.18 The model showed improved survival with the financial and survival improvements found in the previous two HEMS.18 Furthermore, the incremental cost-per-life-year-saved by studies from Australia and the Netherlands may be partly related to using HEMS for all trauma patients was estimated to be $96,524 the impact of physician presence, rather than the helicopter service AUD (~$75,000 USD at present day conversion rate, unadjusted itself. for inflation).18 However, this cost decreases by approximately Furthermore, an older study from Arizona performed a focused $46,000 (~$36,000 USD at present day conversion rate, unadjusted cost benefit analysis on the use of a paramedic, and determined for inflation) for severely injured trauma patients or TBI patients, that the cost-per-life-year-saved for paramedic care was $8,886 demonstrating greater effectiveness for HEMS in the setting of USD for OHCA.21 Despite being unadjusted for inflation, this cost more severe injuries.18 The average value of a statistical life year is significantly less than the cost-per-life-year of the implementation (VALY) in Australia was $124,095 AUD ($96,000 USD at present of HEMS in the aforementioned studies, which may in part explain day conversion rate, unadjusted for inflation), which is well above the popularity of the Anglo-American model. Specifically, it appears the incremental cost per life year using HEMS for trauma patients.18 that life-saving care can be delivered at a much lower cost, and the Because the incremental cost-per-life-year of the HEMS was less Anglo-American model asserts that the optimal role of physicians is than the Australian VALY, the authors concluded the HEMS model in hospitals rather than ambulances. was cost effective for all trauma patients, and even more effective For these studies, it is important to realize that a significant for severe trauma patients.18 This study suggests that the PS-HEMS limitation is that costs are estimates and that they are assessed may be valuable from both a survivability standpoint and a cost within the context of a particular healthcare system. This may not standpoint for severe trauma cases.18 However, this study is subject to be generalizable outside of the respective countries. However, costs confounding variables, as does not isolate for the effect of physician were rigorously analyzed in all studies and included the ongoing presence, since it compares helicopter services to ground services. costs of medical care post-hospital. Nevertheless, further costing Moreover, it is difficult to isolate HEMS services to only the most studies regarding PS-EMS in the literature is limited, especially when severe cases and therefore ensure optimal benefit for cost in this compared to survival studies. Although costs can vary from region setting. to region and can be difficult to estimate, they are an important Another study from the Netherlands calculated the cost parameter when determining the optimal model. Despite some effectiveness of a physician-staffed HEMS compared to a paramedic- studies which suggest that PS-EMS is ineffective, there is evidence staffed GEMS services.19 The authors incorporated emergency in the literature that shows a survival benefit associated with department costs, operating costs, costs of diagnostics, and having physicians respond to trauma and OHCA. However, the outpatient department visit costs in the calculation using cost-per- cost burden has been one of the main arguments against PS-EMS unit multiplied by volume.19 They determined that the incremental implementation, rather than lack of survival improvement. Having cost-effectiveness ratio for using physician-staffed HEMS over more costing analysis performed in a variety of regions can help paramedic-staffed EMS was €28,327 ($35,000 USD at present anchor managers to a costing estimate of a PS-EMS compared day conversion rate, unadjusted for inflation) per quality-adjusted- to a non-PS-EMS. Further economic analysis regarding the cost life-year (QALY) for severely injured trauma patients.19 These costs effectiveness of a physician in prehospital care setting is therefore are lower than the Australian study, and further support the cost needed. effectiveness of a PS-HEMS. Of note, restriction of these services to only severely injured trauma patients is difficult in practice and Discussion case severity may not be easily determined. It is therefore important A brief overview of the literature indicates there may be to consider that such cost-benefit analysis assumes optimized service improved short-term and long-term outcomes with physician staffed delivery. EMS when compared to non-PS-EMS, specifically in trauma Furthermore, use of QALY over VALY adds more rigour into and OHCA. However, these benefits are not consistent across the costing analysis as quality of life is a factor incorporated into the studies. Such differences may be attributed to potentially increased analysis. However, this study also suffers from the same limitations as confidence and clinical judgement of physicians. Moreover, a large the Australian study; the cost analysis does not isolate the additional number of the studies compare a PS-HEMS to a ground-based non cost of a physician, rather, the costs of the entire helicopter service PS-EMS. This is because many countries, when making a switch from is incorporated. Moreover, these two studies comparatively looked ground-based EMS to HEMS, undertook novel staffing protocols to at the physician versus paramedic model, but not specifically at the establish physician-staffed services. This makes it difficult to directly cost of a paramedic model. Indeed, there are inherent advantages compare physician impact on survival outcomes, as the addition of a and additional costs to a helicopter service, and closer comparisons helicopter service alone can improve outcomes. are needed to address physician and mode-of-transport factors Nevertheless, the few studies that directly compared physicians independently. to paramedics still demonstrated an improvement in survival Interestingly, one study took a comprehensive cost analysis outcomes, mostly in more severe injury cases. Further studies directly of HEMS against ground-based EMS in both Cornwall and in comparing PS-EMS to non-PS-EMS without the confoundment of London, regardless of whether it was physician-staffed or not.20 switching from GEMS to HEMS would help elucidate the impact In this study, estimated unit costs for building the components of of physicians on the morbidity and mortality in the prehospital each system were added, including capital, maintenance such as fuel care setting. Ultimately, the literature supports PS-EMS for the and supplies, staffing, and systemic costs.20 They concluded that the prehospital management of patients who are critically ill and addition of a HEMS did not improve trauma patient survival, and experience severe trauma or TBI. Whether this ought to translate to that there were no cost-benefit advantages.20 This may suggest that widespread implementation of a PS-EMS is unclear; however, this

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Physicians in prehospital care: A review of the clinical and economic evidence evidence may suggest a need for prehospital care systems to provide models that estimate the costs of both staffing models, which can PS-EMS to cases which have been determined a priori to maintain a help isolate for PS-EMS versus non PS-EMS. Ultimately, healthcare high likelihood of severe injury. managers should rely on data from the literature in combination Although controversial, several studies show improved technical with their own systems’ needs, goals, and resources to determine the skills and patient outcomes with the addition of a physicians to optimal prehospital care model in their own region. prehospital care. However, data regarding cost is limited. Even if there is a morbidity and mortality benefit to PS-EMS, healthcare References managers also have to factor in costs of a PS-EMS for such a large 1. Timmermann, A., Russo, S. G., & Hollmann, M. W. Paramedic versus emergency physician emergency medical service: role of the anaesthesiologist and the European intervention. Differences in systems, salaries, culture, investments, versus the Anglo-American concept. Curr Opin Anaesthesiol. 2008;21(2), 222-227. switching costs, and geography make costing analysis and comparison 2. Cummins, R. O., Ornato, J. P., Thies, W. H., et al. Improving survival from sudden cardiac arrest: the "chain of survival" concept. A statement for health professionals difficult amongst different regions. Based on the available data, we from the Advanced Cardiac Life Support Subcommittee and the Emergency cannot conclude with certainty whether PS-EMS system is more cost Cardiac Care Committee, American Heart Association. Circulation. 1991;83(5), 1832-1847. effective than a non PS-EMS. Having multiple studies performed 3. Haner A, P Örninge, A Khorram-Manesh. The role of physician–staffed in different regions under different systems can help narrow down ambulances: the outcome of a pilot study. Journal of Acute Disease. 2015;4(1), 63-67. cost estimates of PS-EMS in relation to survival benefits, yet it is 4. van Schuppen, H., & Bierens, J. Understanding the prehospital physician still important to keep in mind that in reality there will always be controversy. Step 1: comparing competencies of ambulance nurses and prehospital physicians. Eur J Emerg Med. 2011;18(6), 322-327. limitations for such comparisons. Unlike drug trials, managers and 5. Feldman, J. A., Brinsfield, K., Bernard, S., et al. Real-time paramedic compared administrators cannot achieve a definitive quantitative answer on with blinded physician identification of ST-segment elevation myocardial infarction: superiority of one option against the other, but rather factor in the results of an observational study. Am J Emerg Med. 2005;23(4), 443-448. 6. Sahni, R., Menegazzi, J. J., & Mosesso, V. N., Jr. Paramedic evaluation of clinical available numerical data in conjunction with their own applicable indicators of cervical spinal injury. Prehosp Emerg Care. 1997;1(1), 16-18. economical, political, social, and technological landscape to inform 7. Schaider, J. J., Riccio, J. C., Rydman, R. J., et al. Paramedic diagnostic accuracy for 22 patients complaining of chest pain or shortness of breath. Prehosp Disaster Med. such decisions. 1995;10(4), 245-250. Established health systems should critically analyze the literature 8. Fullerton, J. N., Roberts, K. J., & Wyse, M. Can experienced paramedics perform tracheal intubation at cardiac arrests? Five years experience of a regional air and take into account their own contextual factors to decide ambulance service in the UK. Resuscitation. 2009;80(12), 1342-1345. whether to remain with their current system or adopt/forego a 9. Yasunaga, H., Horiguchi, H., Tanabe, S., et al. Collaborative effects of bystander- initiated cardiopulmonary resuscitation and prehospital advanced cardiac life PS-EMS. Emerging prehospital care systems should act similarly, support by physicians on survival of out-of-hospital cardiac arrest: a nationwide assessing resources available and the goals of their system in order to population-based observational study. Crit Care. 2010;14(6), R199. determine the model that best suits their needs. 10. Pakkanen, T., Kamarainen, A., Huhtala, H., et al. Physician-staffed helicopter emergency medical service has a beneficial impact on the incidence of prehospital Although further costing studies as well as studies directly hypoxia and secured airways on patients with severe traumatic brain injury. Scand comparing physicians to alternative healthcare providers would J Trauma Resusc Emerg Med. 2017;25(1), 94. 11. Osterwalder, J. J. Mortality of blunt polytrauma: a comparison between emergency prove valuable, there are also numerous cultural barriers which physicians and emergency medical technicians--prospective cohort study at a level may facilitate or prevent adoption of either model across countries. I hospital in eastern Switzerland. J Trauma. 2003;55(2), 355-361. 12. Garner, A. A., & Schoettker, P. Efficacy of pre-hospital interventions for the It is important to recognize that implementing large scale shifts management of severe blunt head injury. Injury. 2002; 33(4), 329-337. in prehospital care delivery against cultural norms will always be 13. Garner, A., Rashford, S., Lee, A., et al. Addition of physicians to paramedic helicopter services decreases blunt trauma mortality. Aust N Z J Surg. 1999;69(10), difficult, despite further evidence showing benefits of one model 697-701. over another. 14. Liberman, M., Mulder, D., Lavoie, A., et al. Multicenter Canadian study of Overall, this paper takes an updated look at the evidence prehospital trauma care. Ann Surg. 2003;237(2), 153-160. 15. Olasveengen, T. M., Lund-Kordahl, I., Steen, P. A., et al. Out-of hospital advanced comparing the use of a PS-EMS system to a non-PS-EMS based life support with or without a physician: Effects on quality of CPR and outcome. system. Studies at a few centers have shown no improvement, or even Resuscitation. 2009;80(11), 1248-1252. 16. Stiell, I. G., Wells, G. A., Field, B., et al. Ontario Prehospital Advanced Life Support deterioration in care with physicians when compared to paramedics Study: Advanced cardiac life support in out-of-hospital cardiac arrest. N Engl J or EMTs. However, the breadth of literature shows physicians have Med. 2004;351(7), 647-656. 17. Lirola TT, Laaksonen MI, Vahlberg TJ, et al. Effect of physician-staffed helicopter additional competencies that may translate to improved morbidity emergency medical service on blunt trauma patient survival and prehospital care. and mortality in prehospital care, but the data is often challenging to European Journal of Emergency Medicine. 2006;13:335-339. 18. Taylor, C., Jan, S., Curtis, K., et al. The cost-effectiveness of physician staffed interpret and includes confounding factors. One consistent finding Helicopter Emergency Medical Service (HEMS) transport to a major trauma is that PS-EMS may be beneficial when injuries are more severe. centre in NSW, Australia. Injury. 2012;43(11), 1843-1849. Although the practicality of ensuring appropriate matching between 19. Ringburg, A. N., Polinder, S., Meulman, T. J., et al. Cost-effectiveness and quality- of-life analysis of physician-staffed helicopter emergency medical services. BrJ staffing and injury severity may prove to be difficult, managers Surg. 2009;96(11), 1365-1370. who oversee EMS may consider a rapid triage method for EMS 20. Snooks, H. A., Nicholl, J. P., Brazier, J. E., et al. The costs and benefits of helicopter emergency ambulance services in England and Wales. J Public Health Med. dispatchers that can effectively identify more serious injuries. Costing 1996;18(1), 67-77. analysis evidence may demonstrate some economic benefit in the use 21. Valenzuela, T. D., Criss, E. A., Spaite, D., et al. Cost-effectiveness analysis of paramedic emergency medical services in the treatment of prehospital PS-EMS, however, these studies are limited and do not adequately cardiopulmonary arrest. Ann Emerg Med. 1990;19(12), 1407-1411. isolate for the effect of the physician as they often compare a non 22. Gupta, A. Environment & PEST Analysis: An Approach to External Business PS-GEMS system to a PS-HEMS. Given that several factors Environment. International Journal of Modern Social Sciences, 2013;2(1), 34-43. determine an EMS system, it can be extremely difficult to isolate simply for the type of staffing model. The literature surrounding this topic can benefit from further cost-benefit analysis that performs a direct comparison between PS-EMS and non PS-EMS based services. An alternative would be to develop projections or simulation

52 UTMJ • Volume 96, Number 3, June 2019 Reviews

Zika virus: A current review of literature

Dr. Bera Ubeyd Yildiz1; Dr. Keramettin Yanik1; Dr Oguzhan Yakupoğlu1

1Private Hospital, Istanbul, Turkey

In this article, we review the literature available to clinicians for Abstract obtaining the necessary information regarding Zika virus infection. Zika virus is a mosquito-transmitted flavivirus belonging Epidemiology to the family Flaviviridae. Its spread has been an ongoing Zika virus (strain MR 766) was first isolated in 1947 at Yellow pandemic and the focus of a public health emergency Fever Research Institute, in Zika Forest, Uganda.1 The first three since 2007. Though Zika virus was first detected in 1947, cases of human infection were reported in Nigeria, in 1954.5 In its rapid spread, newfound modes of transmission, and Brazil, Zika virus was first detected in the northeast and was then recognized in other South American countries, including Ecuador, the absence of adequate treatments have recently brought Colombia, Suriname, French, Venezuela, Guyana, and Paraguay. this virus into the public eye. After an outbreak of Zika Symptomatic infections of Zika virus were restricted to small, virus in Brazil in 2007, many complications were suspected sporadic clusters of cases. Transmission has been documented in to be linked with to its infection. These complications Central America, Mexico, and the Caribbean, and has also occurred include Guillain-Barré syndrome, several congenital in travelers returning from infected regions to non-endemic areas, 6 malformations, microcephaly, and some neurological including Japan, the United States, Canada, and Western Europe. Until 2007, only 14 human cases had been identified, and these complications. There is no effective treatment nor vaccine came from exclusively Africa and Southeast Asia.7 The first major for Zika virus. Ongoing research focusses largely on outbreak of the virus infection was in Yap (Federated States of preventing infection in regions where transmission is most Micronesia) in 2007. Approximately 73% of Yap’s population common, especially in populations of pregnant women. was infected in this outbreak. A reported 18% of the infected 8 It is advisable for clinicians working in non-endemic areas individuals developed symptomatic clinical conditions. Outbreaks subsequently occurred in French Polynesia, New Caledonia, the to maintain a full awareness of Zika virus in order to Cook Islands, Easter Island, and the Americas, with sporadic properly manage this infection when it spreads into their exportations to Europe. Since January 2016, 20 countries including catchment areas. This review aims to summarize what is the Americas have reported Zika virus infections (Figure 1). currently known about the epidemiology, transmission, pathogenesis, clinical presentation, diagnosis, treatment, and prevention methods of the Zika virus.

Introduction ika virus is an arbovirus of the genus flavivirus. It was first isolated from a febrile rhesus macaque monkey in Uganda and subsequently in Aedes africanus mosquitoes fromZ the same region.1 Since 2007, Zika virus infection has spread quickly in many countries around the world. In 2015 the Brazillian government described relationships between infections of Zika virus and both Guillain-Barré syndrome and microcephaly.2

A public health emergency of international concern (PHEIC) Figure 1. World Map of Areas with Zika Virus, 2019 (source: https://ww- was declared with regard to Zika virus by The World Health wnc.cdc.gov/travel/page/zika-travel-information) Organization (WHO) in 2016. Over 4,000 neurological disorders and cases of microcephaly have been linked to the virus in affected Virology areas.3 However, Zika virus infections remain incompletely Zika virus is an RNA virus which is approximately 11kb in size. understood, because Zika causes self-limiting and benign illnesses It belongs to the family Flaviviridae.9 This virus is like other viruses in most people. Therefore, infection may possibly be underreported in the Flaviviridae family, including yellow fever virus, dengue in endemic areas.4 virus, and West Nile virus. It also has similar characteristics to the

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Zika virus: A current review of literature

Spondweni virus.10 The Zika virus is composed of single-stranded yet been observed.23 Other routes of Zika virus transmission include RNA, containing 10794 nucleotides encoding 3419 amino acids, organ transplantation, mucocutaneous exposure, hemodialysis, and this RNA is contained within a capsid, an envelope (E), a and monkey bites.25 It is as yet undetermined whether Zika virus precursor of membrane, and 7 non-structural proteins (Figure 2).11 can spread through respiratory droplets.26 This virus is 50 nm in diameter, and its envelope is structured in an icosahedral composition of surface proteins.12 The E protein is Clinical Presentations an important protein on the surface of the virus and plays a role in both membrane fusion and receptor binding.8

Figure 2. Structure of Zika virus (source: www.dreamstime.com)

Pathogenesis Cellular entry for the Zika virus follows the same steps as with other flaviviruses. The virus enters skin cells via cellular receptors, and goes on to access lymph nodes and the bloodstream. According to some studies, human skin fibroblasts, keratinocytes, and immature dendritic cells allow the virus entry. Several adhesion Figure 3. Symptoms of Zika virus (source: medicalnewstoday.com) factors (e.g. AXL receptor tyrosine kinase) enable viral infection, and increase the virus’s replication in skin fibroblasts.13 Most flaviviruses replicate within endoplasmic reticulum-derived vesicles following cellular entry, but Zika virus antigens have only been found in the nuclei of infected cells, demonstrating that the Zika virus replication process differs from other flaviviruses.14 Further research should be done in this area. The pathogenesis of congenital infections and neurological complications is explained by two different mechanisms. The first is direct viral damage, and the second is an immune-mediated mechanism of pathogenicity.15 According to studies on animal models (rats), the Zika virus is extremely neurotropic and can be transmitted through the placenta, causing growth retardation, Figure 4. Baby with Microcephaly in Zika virus disease (source: https:// apoptosis of neural progenitor cells, placental damage, fetal death, www.cdc.gov/pregnancy/zika/testing-follow-up/zika-syndrome-birth- defects.html) impaired neural proliferation, and development in an affected fetus.16,17 The incubation period of the Zika virus is not yet known. Most cases present 3-12 days after the mosquito bites.2 Case fatalities Transmission and severe illness are rare consequences of infection, and 80% Infected rhesus monkeys in their natural habitats can become a of cases are asymptomatic.27 Symptoms tend to be non-specific, source for human infection, transmitted through the bites of Aedes mild, and self-limiting. In almost all cases who acquire the virus via aegypti and Ae. Albopictus, which subsequently pass the infection to vector or sexual contact, the infection has a benign course without vulnerable human hosts.18 The most likely non-human animal complications. Symptoms of the infection include dermatologic reservoirs are Cercopithecus denti, Cercopithecus aethiops, Macaca mulatta, rashes, mild fever, myalgia, conjunctivitis, joint pain, malaise, and Chlorocebus sabaeus, Erythrocebus patas, Cercopithecus ascanius schmidti, headache (Figure 3).28 The most common manifestation is skin Pongo pygmaeus, Lophocebus albigena, and Colobus abyssinicus, as well rash, seen in 90% of cases. The skin rash is typically macular or as other mammals, such as rodents, zebras, and elephants.19 Zika maculopapular, often itchy, and with centrifugal evolution from the virus has been transmitted mainly by the bite of female Aedes trunk to the extremities that usually lasts 4-5 days.2 In 65-70% of mosquitoes.20 Risk of infection is also present in the settings of blood cases, the rashes may be preceded by 1-4 days of fatigue and fever transfusion, pregnancy, and sexual contact.20-22 Sexual transmission (typically <38ºC) for a maximum of 7 days.29-39 The next most is particularly common in patients who have blood in their semen. frequent symptom is arthralgia, seen in 65% of cases. Arthralgia is Transmission of the Zika virus from mother to infant can occur associated in 20-45% of cases with periarticular edema of the hands perinatally or in utero.23-24 Transmission via breastfeeding has not and feet, and less frequently also the knees and wrists. This edema

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Zika virus: A current review of literature

may persist for a long duration, on the order of weeks to months.31 however this does not shorten the diagnostic period.26 Persistence Nonpurulent and bilateral conjunctival infections may also occur of the virus in urine has been observed up to 10-20 days after in 55-60% of cases and resolve in 1-2 weeks.2,31 In a case series manifestation.40-41 As the precise timing of infection is difficult to of pregnant women with Zika virus infections, lymphadenopathy establish, a negative RT-PCR does not exclude the possibility of was found to be a common clinical manifestation in approximately Zika infection.42 Both symptomatic and asymptomatic pregnant 40% of cases, however, it was found in only 15% of cases during women with a risk of infection should undergo a laboratory test the French Polynesia outbreak.31 It is rare to be hospitalized for for Zika virus. Zika virus infection. The Zika virus fever can be distinguished from Flaviviral cross-reactivity can be problematic, especially for chikungunya and dengue fever by more significant edema in the patients infected with another flavivirus or previously immunized extremities, thrombocytopenia (rarely), and less severe malaise and (e.g. against yellow fever or Japanese encephalitis virus). These headaches.29 Furthermore, arthralgia in chikungunya fever tends to conditions can cause false-positive results in serologic tests. be more severe than in Zika virus fever. In comparison to dengue Hence, positive results should be confirmed by a plaque reduction fever, there are no hemorrhagic complications in Zika virus fever.32 neutralization test. Virus neutralization tests are the most specific Autoimmune and neurological complications of Zika virus tests for flavivirus. A complicated diagnosis may be considered the have been reported. The major complications associated with presence of potential co-infection with chikungunya or proven Zika virus infection are congenital microcephaly and Guillain- co-infection with dengue.43 Clinicians must therefore be careful to Barré syndrome (Figure 4). The incidence rate of Guillain-Barré correctly diagnose Zika virus infection. syndrome was 20-fold higher than otherwise expected in regions of the Zika epidemic.8 The risk of microcephaly is greatest in Treatment the first trimester of pregnancy.33 The clinical presentation of An effective treatment for Zika virus infection is not yet known.38 Zika infection is similar in pregnant and non-pregnant women. Supportive treatments may help patients, and this includes taking Congenital infections are possible even in asymptomatic women.34 rest, maintaining adequate hydration, and ensuring appropriate Persistent maternal viraemia may be a significant prognostic factor, nutrition. Aspirin and other nonsteroidal anti-inflammatory drugs as viral RNA was detected in maternal blood up to 107 days after are potentially dangerous until dengue infection is excluded, symptom onset. This may be the result of viral replication in either because of the risk of hemorrhage associated with dengue. There is the fetus or placenta.35-36 no antiviral drug against the Zika virus in vivo either.44 Antibiotics Heart complications and immune thrombocytopenic purpura like Duramycin have been reported to decrease the ability of the have been reported in a few cases of Zika infection. Clinical Zika virus to infect cells, but this is not strongly evidenced.45 To symptoms of this infection are similar in children and adults, date, no vaccine for the Zika virus is available, although research however, it should be considered that arthralgia may be difficult currently is underway on various pre-vaccine candidates.38,51,52 to detect in children and Zika can manifest instead as pain on Nevertheless, phase 3 efficacy trials are difficult to conduct due palpation, irritability, impaired walking, refusal to move, and to the unpredictability of Zika virus epidemics, the broad clinical difficulty with movement.37 manifestations of infection, inadequately sensitive and specific diagnostic assays, and the need for inclusion of a vulnarable target Diagnosis population. Clarification of immune correlates and surrogates is Clinical evaluations are not reliable for the diagnosis of a current priorty in the development of vaccines and drugs for Zika virus infection, and laboratory profiles are often normal. prophylactic treatment. Clinic manifestations are often insidous and include non-specific symptoms. When a clinician suspects Zika infection, viral RNA Prevention can be detected through reverse transcription polymerase chain At the present time, the most important prevention methods reaction (RT-PCR). Also, antiviral antibodies can be detected by against the Zika virus are the reduction of the mosquito population serologic tests such as IgM enzyme-linked immunosorbent assays and the removal of potential breeding sites of mosquitoes. (ELISAs) and plaque reduction neutralization tests (PRNTs).38 Mosquito control measures should be strictly applied to reduce The plaque reduction neutralization test is used to quantify the infection risk in endemic regions, because appropriate preventive titer of neutralization antibody for the virus. To date, there is no methods can break the chain of transmission. Individuals who live definite consensus as to which test is superior. The Centers for in or travel to endemic areas should protect themselves against Disease Control and Prevention (CDC) recommends performing infection using appropriate personal protections such as insect both serological tests and RT-PCR to in order to diagnose Zika repellents, mosquito nets, and wearing clothes that cover as much virus infection.38 RT-PCR is the preferred testing method during of the body’s surface area as possible.24 Using condoms is also an the acute phase of the disease. In contrast, serologic tests are not important step in preventing viral transmission. recommended during the acute phase due to the fact that Zika Scientists are still working on CRISPR/Cas9 genome editing virus IgM may be undetectable.10 IgM antibodies only appear in technology directed at preventing the transmission of various the blood toward end of first week of the disease.38 RT-PCR must diseases by mosquitos. Genetically-engineered insects which are less be performed during the viremic period, which is about 3-5 days threatening to humans have been designed to compete with wild- after onset of the illness.39 RT-PCR tests can be performed on the type populations. However, this is the source of several ethical and serum of infants or the umbilical cord tissue within 2 days of birth. social problems in some countries. Furthermore, there is significant In addition, placental tissue, cerebrospinal fluid, and amniotic fluid uncertainty around the long-term effects of these interventions on can be used for RT-PCR. The virus can be isolated from saliva, the ecosystem.

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Conclusion 24. Petersen EE, Erin Staples J, Meaney-Delman D, et al. Interim guidelines for pregnant women during a Zika virus outbreak – United States, 2016. MMWR Zika virus has been declared a public health emergency by the Morb Mortal Wkly Rep. 2016;65:30-3. WHO. As many as 1.3 million persons have been affected from 25. Leung GH, Baird RW, Druce J, et al. Zika virus infection in Australia following a monkey bite in Indonesia. Southeast Asian J Trop Med Public Health. the virus in Brazil alone. In addition, more than 20 countries have 2015;46:460-4. reported local transmission of the virus, which spreads with air 26. Mussoa D, Rocheb C, Nhana TX, et al. Detection of Zika virus in saliva. J Clin travel and international trade into regions where the virus is not Virol. 2015;68:53-5. 27. Ioos S, Mallet HP, Leparc Goffart I, et al. Current Zika virus epidemiology and endemic. Transmission is most common in locations with mosquito recent epidemics. Med Mal Infect. 2014;44:302-7. vectors. 28. Dar W, Sofi P, Ahmad R, et al. A Rare Complication of Dengue Fever. J Gen Pract. 2016;4:237. In non-endemic areas, Zika virus infection may not be 29. Mallet H, Vial A, Musso D. Bilan de l'épidémie à virus Zika en Polynésie Fran- correctly diagnosed due to its mild clinical course. Clinicians çaise 2013-2014. Bulletin d'information sanitaires, épidémiologiques et statis- tiques 2015. working in non-endemic areas should maintain a full awareness 30. Waddell LA, Greig JD. Scoping Review of the Zika Virus Literature. PLoS One. of Zika virus infections and should consider it as a part of any 2016;11:e0156376. 31. Chan JF, Choi GK, Yip CC, et al. Zika fever and congenital Zika syndrome: an relevant differential diagnosis. There is not enough knowledge unexpected emerging arboviral disease. J Infect. 2016;72(5):507-24. about immune correlates, transmission mechanisms, pathogenesis, 32. Ingrid Rabe. Zika virus – what clinicians need to know? Centers for Disease diagnostic tests, prevention methods, and effective treatments for Control and Prevention. 2016. 33. Malone RW, Homan J, Callahan MV, et al. Zika virus: medical countermeasure Zika virus, despite its ability to cause very severe and irreversible development challenges. PLoS Negl Trop Dis. 2016;10(3): e0004530. sequelae such as microcephaly. This virus can be transmitted by 34. França GVA, Schuler-Faccini L, Oliveira WK, et al. Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investiga- both animal and human vectors. A robust, multifaceted response to tion. Lancet. 2016;388:891-97. Zika virus involving public health authorities, government agencies, 35. Driggers RW, Ho CY, Korhonen EM, et al. Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. N Engl J Med. 2016;374:2142– medical practitioners, and researchers is currently underway, and 51. it is anticipated that this will increase the support for research on 36. Suy A, Sulleiro E, Rodó C, et al. Prolonged Zika virus viremia during pregnancy. N Engl J Med 2016;375:2611-13. the Zika virus. 37. Fleming-Dutra KE, Nelson JM, Fischer M, et al. Update: interim guidelines for health care providers caring for infants and children with possible Zika virus References infection-United States. MMWR Morb Mortal Wkly Rep. 2016;65:182-7. 1. Dick GW, Kitchen SF, Haddow AJ. Zika virus. I. Isolations and serological spec- 38. Hajra A, Bandyopadhyay D, Hajra SK. Zika virus: A global threat to human- ificity. Trans R Soc Trop Med Hyg. 1952;46:509-20. ity: A comprehensive review and current developments. North Am J Med Sci. 2. Silva DME, et al. Zika Virus Infection: New Findings Related to Neurological 2016;8:123-8. Complications. J Neonatal Biol. 2016;5:219. 39. Lanciotti RS, Kosoy OL, Laven JJ, et al. Genetic and serologic properties of 3. Public Health Emergency of International Concern (PHEIC) declared for Zika Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerg In- and clusters of microcephaly and neurological disorders. (February 2016). fect Dis. 2008;14:1232-9. 4. Musso D, Nilles EJ, Cao-Lormeau VM. Rapid spread of emerging Zika virus in 40. European Centre for Disease Prevention and Control. Interim guidance for the Pacific area. Clin Microbiol Infect. 2014; 20(10):O595-6. healthcare providers and Zika virus laboratory diagnosis. ECDC Technical 5. MacNamara FN. Zika virus: a report on three cases of human infection during Document, 2016. an epidemic of jaundice in Nigeria. Trans R Soc Trop Med Hyg. 1954;48:139- 41. Gourinat AC, O'Connor O, Calvez E, et al. Detection of Zika virus in urine. 45. Emerg Infect Dis. 2015;21:84-86. 6. Chen LH, Hamer DH. Zika virus: rapid spread in the western hemisphere. Ann 42. Rabe IB, Staples JE, Villanueva J, et al. Interim guidance for interpretation of Intern Med. 2016;164(9):613-5. Zika virus antibody test results. MMWR Morb Mortal Wkly Rep. 2016;65:543- 7. Hayes EB. Zika virus outside Africa. Emerg Infect Dis. 2009;15:1347-50. 46. 8. Duffy MR, Chen TH, Hancock WT, et al. Zika virus outbreak on Yap Island, 43. Chen LH. Zika virus infection in a Massachusetts resident after travel to Costa Federated States of Micronesia. N Engl J Med. 2009;360:2536-43. Rica: a case report. Ann Intern Med. 2016;164:574-6. 9. Chan JF, Choi GK, Yip CC, et al. Zika fever and congenital Zika syndrome: an 44. Retallack H, Di Lullo E, Arias C, et al. Zika virus cell tropism in the developing unexpected emerging arboviral disease. J Infect. 2016;72(5):507-24. human brain and inhibition by azithromycin. Proc Natl Acad Sci USA. 2016; 10. Faye O, Freire CC, Iamarino A, et al. Molecular evolution of Zika virus during 113: 14408–13. its emergence in the 20(th) century. PLoS Negl Trop Dis. 2014;8:e2636. 45. Dolma K. Zika Virus (ZIKV) Infection: A Review. J Res Development. 2016;4: 11. Haddow AD, Schuh AJ, Yasuda CY, et al. Genetic characterization of Zika virus 148. strains: geographic expansion of the Asian lineage. PLoS Negl Trop Dis. 2012; 46. Zika virus: Symptoms, Diagnosis, and Treatment, Centers for disease control 6(2):e1477. and prevention. (February 2016). 12. Atif, M, Azeem, M, Sarwar, MR. et al. Zika virus disease: a current review of the 47. Zika virus, World Health Organization. (February 2016). literature Infection. 2016; 44: 695. https://doi.org/10.1007/s15010-016-0935-6. 13. Hamel R, Dejarnac O, Wichit S, et al. Biology of Zika virus infection in human skin cells. J Virol. 2015;89:8880-96. 14. Buckley A, Gould EA. Detection of virus-specific antigen in the nuclei or nucleoli of cells infected with Zika or Langat virus. J Gen Virol. 1988;69:1913-20. 15. Adibi JJ, Marques ET, Jr., Cartus A, et al. Teratogenic effects of the Zika virus and the role of the placenta. Lancet. 2016;387:1587-1590. 16. Cugola FR, Fernandes IR, Russo FB, et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature. 2016;534:267-271. 17. Miner JJ, Cao B, Govero J, et al. Zika Virus Infection during Pregnancy in Mice Causes Placental Damage and Fetal Demise. Cell. 2016;165:1081-1091. 18. Rodriguez-Morales AJ, Bandeira AC, Franco-Paredes C. The expanding spectrum of modes of transmission of Zika virus: a global concern. Ann Clin Micro- biol Antimicrob. 2016;15:13. 19. Wolfe ND, Kilbourn AM, et al. Sylvatic transmission of arboviruses among Bor- nean orangutans. Am J Trop Med Hyg. 2001;64:310-6. 20. Zika virus transmission, Centers for disease control and prevention. (February 2016). 21. Kashima S, Slavov SN, Covas DT. Zika virus and its implication in transfusion safety. Rev Bras Hematol Hemoter. 2016; 38(1): 90-1. 22. Gautret P, Simon F. Dengue, chikungunya and Zika and mass gatherings: what happened in Brazil, 2014. Travel Med Infect Dis. 2016;14(1):7-8. 23. Hennessey M. Zika virus spreads to new areas – region of the Americas, May 2015 - January 2016. MMWR Morb. Mortal. Wkly. Rep. 2016;65:1031-4.

56 UTMJ • Volume 96, Number 3, June 2019 Reviews

Neurological sequelae of pediatric Plasmodium falciparum cerebral malaria in sub-Saharan Africa: A brief overview

Kelly A. A. Leslie (MD)1

1Department of Psychiatry, University of Toronto, 250 College St, Toronto, Ontario, Canada, M5T 1R8

Introduction Abstract alaria is an infectious disease caused by protozoan Cerebral malaria, characterized by multiple seizures, coma, parasites of the genus Plasmodium that are trans- and other neurological abnormalities, is a particularly mitted by Anopheles mosquitoes. In 2017, an esti- matedM 219 million people were infected with malaria worldwide, devastating complication of Plasmodium falciparum malaria. Children in sub-Saharan Africa comprise the most the vast majority of whom (92%) were located in sub-Saharan susceptible group to cerebral malaria worldwide, with more Africa,1 where it is one of the leading causes of death.2 Each year, than 575,000 cases each year. Long-term neurological Plasmodium falciparum malaria – the most lethal form of the disease deficits – including motor impairments, language – causes 435,000 deaths in this region.1 This form of malaria of- regression, cognitive deficits, behavioural abnormalities, ten produces fever, jaundice, anemia, hypoglycemia, metabolic and epilepsy – occur in approximately 25% of child acidosis, and multi-organ failure, and has the potential to develop survivors of cerebral malaria, which is now recognized into cerebral malaria. This particularly life-threatening compli- as the leading cause of childhood neurodisability in sub- cation occurs when parasitized red blood cells break through the Saharan Africa. These neurological sequelae generate an blood-brain barrier and sequester in the neural microvasculature. enormous economic and social burden as child survivors’ Cerebral malaria is characterized by multiple seizures and coma, impaired intellectual function and learning abilities have among other neurological signs.3 More than 575,000 cases of ce- a substantial impact on their prospects for education rebral malaria occur in children in sub-Saharan Africa each year, and future employment. The aim of this article is to meaning that they comprise the most susceptible group to the provide a brief overview of the current literature on the disease worldwide.4 neurological sequelae of pediatric cerebral malaria, as well Cerebral malaria has been linked to long-term neurological as offer suggestions for future research. While the current deficits in child survivors of the disease since the early 1970s, understanding of risk factors, disease mechanisms, and when British researchers working in Uganda observed a connec- treatments for these neurological deficits is lacking, recent tion between the onset of pediatric neurological disorders and a studies have shown great promise in revolutionizing the history of “catastrophic, feverish illness”, such as that observed way that cerebral malaria is diagnosed and treated. It is in cerebral malaria.5 The first comprehensive evaluation of the speculated that an inflammatory response to malarial neurological effects of pediatric cerebral malaria was conducted antigens in neural blood vessels triggers a cascade of events in Ghana in 1995.6 It was determined that poor performance in that ultimately results in cerebral tissue damage, high memory, attention, and sensory processing tasks were correlated intracranial pressure, and hemorrhaging into the brain, with a previous episode of cerebral malaria. Since then, however, resulting in long-term brain damage. Potential risk factors only a small number of studies have focused on the association for neurological deficits include the duration of coma, the between cerebral malaria and neurological sequelae. In fact, a occurrence of multiple seizures, and high fever. Malaria 2006 systematic review of the effect of Plasmodium falciparum ma- retinopathy, angiopoietin-1 and -2, and EEG patterns laria on cognition, which analyzed all relevant research that had are being investigated as potential biomarkers to improve been published at the time, included only eighteen studies.7 the definitive diagnosis of cerebral malaria. New drug Recently, however, substantial interest has been generated therapies that endeavor to prevent long-term neurological on this topic, with the publication of the first series of compre- deficits after cerebral malaria include erythropoietin and hensive, controlled prospective studies examining the neurologi- statins, as well as cognitive rehabilitation and physical cal sequelae following pediatric cerebral malaria8,9 as well as the and speech therapy, the latter having been shown to be publication of the first study to investigate the possibility of cog- successful among survivors. nitive rehabilitation in these patients.10 It has been determined that approximately 25% of child survivors of cerebral malaria exhibit long-term neurological deficits, including motor deficits, language regression, cognitive impairment, and behavioural ab- Corresponding Author: normalities for at least six months following an episode of cere- Kelly Leslie bral malaria, and 10% develop epilepsy.4 If these results can be [email protected] generalized, then it is hypothesized that neurological impairment

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Neurological sequelae of pediatric Plasmodium falciparum cerebral malaria in sub-Saharan Africa: A brief overview due to cerebral malaria may occur annually in 36,000 children majority of cases of severe and cerebral malaria occur in chil- between the ages of five to nine years old in sub-Saharan Af- dren under the age of five.4 The case fatality rate of cerebral rica.8 To exacerbate this problem, a 2008 review of retrospective malaria is estimated to be 15%. Among those who survive, more studies has suggested that these cognitive deficits may persist for than 20% will exhibit neurological deficits.11 as long as three to nine years after recovery from the original Generally, the neurological sequelae observed in survivors of episode of cerebral malaria.9 As a result, cerebral malaria is now cerebral malaria immediately after the malaria episode include recognized as the leading cause of childhood neurodisability in cortical blindness, deafness, severe cerebral palsy, hemiplegia, sub-Saharan Africa.11 hemiparesis, ataxia, spasticity, speech problems, cognitive im- Finally, in addition to inducing significant morbidity and pairment, and epilepsy.15 However, some of these symptoms mortality in children, cerebral malaria and its consequent neuro- resolve automatically. For instance, it has been shown that blind- logical sequelae also generate an enormous economic and social ness generally disappears completely after 6 months16 and gross burden in sub-Saharan Africa. Primary school students in Ke- motor deficits (hemiplegia, diplegia, quadriparesis, dystonia, and nya miss an average of 11% of school days per year as a result ataxia) disappear within several weeks.11 On the other hand, no of malaria.12 This absenteeism increases failure rates, repetition improvement has been shown in either speech problems (aphasia of school years, and drop-out rates, thus resulting in a notable and dysarthria), as assessed at the 6 month post-episode mark,16 loss of educational attainment that students may otherwise have nor subtle cognitive deficits.8 A 2008 study determined that at achieved. Even more alarming is the reality that fully one quar- two years after release from hospital, children who had experi- ter of survivors of cerebral malaria experience long-term neu- enced cerebral malaria had a 3.76-fold increased risk for a cogni- rological sequelae, including behavioural disorders, impaired tive deficit (specifically in the area of attention) compared with intellectual function and learning ability, and diminished ability age-matched controls,9 while a 2001 study determined that when to perform executive functions. Undoubtedly, this cascades into compared to controls, children who had experienced cerebral a negative impact on the survivors’ prospects for education and malaria exhibited significantly impaired attentiveness, behaviour, future employment.12 and language development at 42 months after hospital release.15 It is clear that the study of the neurological deficits observed More recently, a 2019 exposure-control study examining 85 sur- in survivors of pediatric cerebral malaria is of immense public vivors of cerebral malaria established that half of these survivors health significance. The aim of this article is to provide a brief were neurodevelopmentally impaired at one year after hospital overview of the symptoms and diagnosis, risk factors, pathogen- discharge, which is 4.5 times greater than for age-matched con- esis, and treatment of the neurological sequelae of cerebral ma- trols.16 Furthermore, patients who develop severe epilepsy as a laria, as well as to offer suggestions for future research. result of cerebral malaria generally do not improve over time, and a minority of those with multiple seizure types (experiencing Symptoms and Diagnosis more than 10 seizures a day) are not responsive to medication.17 In a 2007 retrospective study assessing neurological deficits in Symptomatology and Diagnostic Criteria 7,281 survivors of cerebral malaria, behavioural problems were The clinical manifestation of Plasmodium falciparum malaria observed in approximately 11% of patients, including hyperac- differs depending on the severity of the disease. Clinicians often tivity, violent and impulsive behaviour, hallucinations, excessive distinguish between uncomplicated malaria, severe (non-cere- eating, and fear or anxiety. These behavioural symptoms com- bral) malaria, and cerebral malaria when treating patients and menced several months after the patients were discharged from estimating their prospects for recovery.13 This clinical distinction hospital.18 Clearly, the neurological sequelae of cerebral malaria between different positions on the disease spectrum is important, can be devastating for patients and their families. as each is associated with a different prognosis, and only the patients suffering from cerebral malaria will develop neurological Screening deficits. There exists a relative ambiguity in the current diagnostic cri- The symptoms of the least severe form of malaria, uncompli- teria for cerebral malaria due to the high rates of asymptomatic cated malaria, consist of fever, chills, sweats, headache, nausea, parasitemia.19 At present, definitively diagnosing cerebral ma- vomiting, and general malaise. It is diagnosed by the detection of laria is quite challenging. According to an autopsy study, 23% of malaria parasites in the blood via microscopy and has excellent children who had met the diagnostic criteria for cerebral malaria survival prospects assuming that treatment is provided.13 Severe actually had a non-malarial cause of coma and death.11 This non-cerebral malaria, while demonstrating no neurological in- aforementioned ambiguity is further exacerbated in sub-Saharan volvement, is a medical emergency, wherein patients often suffer Africa by the paucity of neurodiagnostic resources. Therefore, from severe anemia, acute respiratory distress syndrome, hypo- considering the significance of the disease’s long-term neurologi- tension, multi-organ failure, hyperparasitemia, metabolic acido- cal consequences, it would be beneficial to develop a biomarker sis, and hypoglycemia.13 that could instantly determine the presence and severity of the By definition, cerebral malaria is diagnosed when a patient in disease, or the likelihood of the disease progressing further. a malaria-endemic region exhibits: (i) impaired consciousness at There are several cerebral malaria biomarker candidates cur- least one hour after a seizure, (ii) positive peripheral blood smears rently being researched. Malaria retinopathy appears to be one for asexual forms of malaria parasites, and (iii) other causes for of the most promising candidates given that in cases of cerebral encephalopathy are excluded.14 Since older children and adults malaria, examination of the ocular fundus by ophthalmoscopy in sub-Saharan Africa tend to develop immunity to malaria, the reveals hemorrhaging, retinal whitening, vessel abnormalities,

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Neurological sequelae of pediatric Plasmodium falciparum cerebral malaria in sub-Saharan Africa: A brief overview and papilledema.20 With regard to the pathophysiologic mecha- pertension, and hypoglycemia with language impairments, and nisms of these findings, papilledema is caused by raised intracra- (iii) prolonged coma, severe malnutrition, and hypoglycemia with nial pressure resulting from brain swelling, retinal whitening is a other cognitive deficits.26 In summary, it can be concluded that result of local tissue hypoxia, and abnormal retinal vessels are the development of neurological sequelae is associated with a caused by the sequestration of parasitized red blood cells.21 The more severe presentation of cerebral malaria. combination of these aforementioned retinopathy characteristics is unique to cerebral malaria and when used as a diagnostic tool, Pathogenesis it has been found to be 95% sensitive.11 Two other encouraging biomarker candidates are angiopoietin-1 and angiopoietin-2, which are vascular growth factors involved in endothelial activation and integrity. Elevated plasma or serum levels of these two factors are correlated with malaria of varying severity, and allow for the differentiation between uncomplicated, severe, and cerebral malaria.22 Compared to uncomplicated malaria, there are significantly lower levels of angiopoietin-1 and higher levels of angiopoietin-2 detected in patients with severe malaria or cerebral malaria. Further, in patients with severe malaria, there are significantly lower levels of angiopoietin-1 levels when compared to patients with cerebral malaria.23 Recently, electroencephalography (EEG) has begun to be investigated as a potential prognostic tool. A 2018 study of 281 children with cerebral malaria in Uganda and Malawi determined that specific EEG findings on admission – namely lower average voltage, lower maximum voltage, slower dominant fre- Figure 1. A photo of a section of the brain of a patient with pediatric quencies, focal slowing, and a lack of reactivity – were able to cerebral malaria, depicting a collection of parasitized erythrocytes in the 24 predict neurological morbidity and mortality. microvasculature of the brain.27 Given the multitude of biomarkers currently in development, it is hoped that they will soon serve an important role in the rapid and accurate diagnosis of cerebral malaria in children throughout sub-Saharan Africa.

Risk Factors In light of the fact that 25% of child survivors of cerebral malaria develop some form of neurological deficit, there is significant utility in determining not only which specific risk factors are associated with the development of neurological sequelae, but also why 75% of patients do not develop long-term symptoms.4 Precise knowledge of the factors involved would allow physicians to target specific components of the disease in in order to prevent unnecessary brain damage from occurring. Numerous studies have examined the potential risk factors that correlate with subsequent development of neurological sequelae; however, they report conflicting results. Some studies Figure 2. A photo of a section of brain from a fatal case of cerebral ma- maintain that the depth and duration of coma as well as the oc- laria, showing petechial hemorrhages in white matter, particularly in the currence of multiple seizures in the context of cerebral malaria subcortical rim and corpus callosum.14 are risk factors for neurological deficits,25 while others report that only the number of seizures before hospital admission and the Despite the recent increase in interest in the long-term del- duration of coma are relevant.8 Additional studies have impli- eterious neurological effects of cerebral malaria, researchers have cated intracranial hypertension and hypoglycemia,4 as well as not yet determined its precise pathogenic mechanisms. Gener- duration of fever.16 Finally, one cohort study has reported that ally, it is speculated that an inflammatory response to malarial a higher maximum temperature during fever is correlated with antigens in the neural microvasculature during an acute episode epilepsy and behavioural disorders, acute seizures during admis- of cerebral malaria triggers a cascade of events that ultimately sion are associated with the development of epilepsy, and male results in cerebral tissue damage and neurological deficits.4 sex is a risk factor for the development of general neurodisabil- At the beginning of an episode of cerebral malaria, several ity.11 A detailed 2006 retrospective analysis of hospital records of platelet molecules such as Toll-like receptors are thought to bind 143 children aged 6-9 years also made several associative claims: to antigenic molecules derived from malaria parasites in the (i) multiple convulsions were linked with motor impairment, (ii) bloodstream, thus activating the pathogenic inflammatory re- age younger than 3 years, severe malnutrition, intracranial hy- sponse and the patient’s own immune response.28 Proinflamma-

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Neurological sequelae of pediatric Plasmodium falciparum cerebral malaria in sub-Saharan Africa: A brief overview tory cytokines are then generated, which increase the expression while those that were solely given chloroquine still exhibited cog- of cell adhesion molecules on the endothelium, causing parasit- nitive impairment in measurements taken 30 days after the initial ized red blood cells to sequester in blood vessels (see Figure 1) malaria infection.34 These results indicate that reactive oxygen and leukocytes and platelets to adhere to the endothelium.29 The species may play a significant role in the development of neuro- sequestration of parasitized erythrocytes into rosette formations logical injury during cerebral malaria.34 obstructs tissue perfusion, causes local endothelial apoptosis, Another treatment candidate, a low-molecular weight thiol and results in local inflammation, which in concert reduce the called pantethine, has shown great promise as an upstream thera- integrity of the brain microvasculature and can cause vascular py to prevent the development of cerebral malaria and maintain leaks or hemorrhage into the brain (see Figure 2).30 Reduction the integrity of the blood-brain barrier: pantethine appears to of tissue perfusion impairs the delivery of nutrients and oxygen down-regulate platelet reactivity, which is thought to preclude the to the brain, which can cause hypoxic neural injury and may in previously described cascade of events that ultimately results in turn precipitate coma, seizures and further brain injury.4 High neural damage.31 intracranial pressure – indicative of ischemic damage – and ce- Erythropoietin, a cytokine with anti-apoptotic and anti- rebral edema have also been observed in severe cases of cerebral inflammatory effects, has also been targeted as a potential new malaria and their subsequent neurological deficits.30 treatment for cerebral malaria. This cytokine provides neuropro- The flagship study on in vivo magnetic resonance imaging tection, increases blood flow, and reduces apoptosis of endothe- in the context of cerebral malaria confirmed several theories of lium cells: in a murine model study, high doses of erythropoietin cerebral malaria pathogenesis: mice infected with Plasmodium ber- reduced mortality by 40-90% in mice suffering from cerebral ghei ANKA exhibited blood-brain barrier disruption and hem- malaria, and in a subsequent study involving children infected orrhages caused by inflammatory processes, the generation of with cerebral malaria, it was shown that the drug was associated major edema which exacerbated severe ischemia, and reduced with 80% reduced risk of developing neurological deficits.35 A brain perfusion.31 Subsequent MRI studies involving human pa- phase I study of the effects of erythropoietin in children with tients have demonstrated the concurrent involvement of vaso- cerebral malaria was successfully concluded in 2009.36 genic edema, likely caused by damage to the blood-brain barrier, Finally, in a more recent study, statins (HMG-CoA reductase as well as venous congestion, caused by parasitized red blood cell inhibitors) were tested in mice to determine whether or not they sequestration, in different parts of the brain, supporting the hy- could prevent neurological sequelae after cerebral malaria, given pothesis that both endothelial dysfunction and microvascular ob- that they are already known to prevent neuroinflammation. Mice struction by infected erythrocytes contribute to the pathogenesis in the study were either given chloroquine or both chloroquine of cerebral malaria.32 and lovastatin, and treatment with lovastatin correlated with a The mechanisms of specific neurological sequelae have also complete absence of cognitive dysfunction in measurements 15 been investigated. Increased levels of central nervous system tu- days after infection with Plasmodium berghei malaria.37 mour necrosis factor (TNF) correlate with long-term cognitive While none of these promising new drugs are currently in impairment and language deficits, and are thought to be caused clinical use yet, it is also valuable to recognize that current treat- by either global cerebral injury or damage to specific language ments of cerebral malaria such as intravenous artesunate can be centers in the brain.17 In addition, epilepsy is associated with fo- effective at reducing neurological sequelae if applied early and cal ischemic injury in border-zone regions of cerebral circula- aggressively.8 In addition, patients who already exhibit neurologi- tion.17 MRI scans performed one year after hospital discharge cal deficits as a result of past cerebral malaria can reduce their have shown a direct association between the severity of brain symptoms through rehabilitation therapy. Although research on atrophy and/or multifocal lesions on imaging and the severity of this topic is still lacking, it has been shown that physical therapy subsequent developmental and cognitive deficits.16 and speech therapy can eliminate motor and speech impairment and generally ameliorate brain function, and traditional Treatment and Rehabilitation cognitive rehabilitation can teach survivors cognitive strategies Acute cerebral malaria is treated parenterally with either cin- to enhance attention, concentration, and executive functioning.10 chona alkaloids (quinine or quinidine), or an artemisinin deriva- A landmark 2009 study also introduced the idea of computer- tive such as intravenous artesunate.27 These antimalarial drugs ef- based cognitive rehabilitation: children trained with a cognitive fectively kill and clear Plasmodium falciparum parasitemia from the rehabilitation computer program post-infection were shown to body.33 Mannitol has proven to be an effective treatment in cases improve significantly in visuomotor processing speed, working of cerebral malaria with evidence of increased intracranial pres- memory, and learning, compared to controls.38 This idea was ex- sure, and benzodiazepines show similar promise in limiting brain panded in a 2019 randomized controlled trial in Uganda, which damage in patients suffering from seizures, if provided quickly.27 demonstrated that pediatric cerebral malaria survivors who Several new drug therapies presently under development are completed two months of computerized cognitive rehabilitation also directed at preventing long-term neurological deficits after training (CCRT) scored better on evaluations of mental process- cerebral malaria . For instance, a 2010 murine model study coming than survivors who did not undergo the training, although pared the neurological outcomes of C57BL/6 mice, infected these benefits did not typically extend to one-year follow-up.39 with Plasmodium berghei ANKA and treated with either just the antimalarial drug chloroquine or a combination of chloroquine Future Directions and antioxidants.34 Strikingly, the mice that were given the com- While recent progress has been made in the development of bined treatment showed no long-term cognitive impairment, new diagnostic tools and treatment options for cerebral malaria

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Neurological sequelae of pediatric Plasmodium falciparum cerebral malaria in sub-Saharan Africa: A brief overview

and its subsequent neurological sequelae, it is clear that there is and strategies for improved neuro-cognitive outcome. Pediatr Res. 2010;68(4):267- 274. still significant room for improvement when it comes to under- 5. Egdell HG, Stanfield JP. Paediatric neurology in Africa: a Ugandan report. BMJ. 1972;1(5799):548-552. standing and treating this disease. 6. Dugbartey AT, Spellacy FJ, Dugbartey MT. Somatosensory discrimination deficits First of all, the diagnostic criteria for cerebral malaria ought following pediatric cerebral malaria. Am J Trop Med Hyg. 1998;59(3):393-396. 7. Kihara M, Carter JA, Newton CR. The effect of Plasmodium falciparum on cogni- to be redefined more specifically so as to eliminate misdiagnoses tion: a systematic review. Trop Med Int Health. 2006;11(4):386-397. and uncertainty with relation to the current severity or potential 8. Boivin MJ, Bangirana P, Byarugaba J, et al. Cognitive impairment after cerebral malaria in children: a prospective study. Pediatrics. 2007;119(2):360-366. progression of the disease. Easily accessible and accurate bio- 9. John CC, Bangirana P, Byarugaba J, et al. Cerebral malaria in children is associated markers for cerebral malaria should be identified and incorpo- with long-term cognitive impairment. Pediatrics. 2008;122(1):92-99. 10. Bangirana P, Idro R, John CC, et al. Rehabilitation for cognitive impairments af- rated into official diagnostic guidelines, in order to provide physi- ter cerebral malaria in African children: strategies and limitations. Trop Med Int Health. 2006;11(9):1341-1349. cians in resource-poor areas of sub-Saharan Africa with a more 11. Birbeck GL, Molyneux ME, Kaplan PW, et al. Blantyre Malaria Project Epilepsy definitive means of diagnosis for this disease. Study (BMPES) of neurological outcomes in retinopathy-positive paediatric cerebral malaria survivors: a prospective cohort study. Lancet Neurol. 2010;9(12):1173- More research needs to be completed regarding the risk fac- 1181. tors for the development of specific neurological sequelae and 12. Sachs J, Malaney P. The economic and social burden of malaria. Nature. 2002;415(6872):680-5. the mechanisms involved in the pathogenesis. In particular, there 13. Centers for Disease Control and Prevention. Malaria: about malaria [Internet]. is extremely limited current knowledge about the development Atlanta: US Department of Health & Human Services; [cited 2019 May 7]. Avail- able from: https://www.cdc.gov/malaria/about/disease.html of behavioural impairments, and why they tend to occur several 14. Idro R, Jenkins NE, Newton CR. Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol. 2005;4(12):827-840. months after infection with malaria. Once more specific risk fac- 15. Murphy SC, Breman JG. Gaps in the childhood malaria burden in Africa: cerebral tors are determined, physicians will need to work aggressively to malaria, neurological sequalae, anemia, respiratory distress, hypoglycemia, and complications of pregnancy. Am J Trop Med Hyg. 2001;64(1):57-67. reduce or prevent these risk factors from occurring, in order to 16. Langfitt JT, McDermott MP, Brim R, et al. Neurodevelopmental impairments 1 minimize neural damage during an episode of cerebral malaria. year after cerebral malaria. Pediatrics. 2019;143(2). 17. Idro R, Kakooza-Mwesige A, Balyejjussa S, et al. Severe neurological sequelae and In addition, once the mechanisms of cerebral malaria and its behaviour problems after cerebral malaria in Ugandan children. BMC Res Notes. neurological sequelae are better understood, more effective treat- 2010;3(104). 18. Idro R, Ndiritu M, Maitland K, et al. Burden, features, and outcome of neuro- ments, and perhaps vaccines, will be able to be developed. logical involvement in acute falciparum malaria in Kenyan children. JAMA. 2007;297(20):2232-40. Despite the large number of children and adults living with 19. Lindblade KA, Steinhardt L, Samuels A, et al. The silent threat: asymptomatic par- neurological deficits caused by cerebral malaria, there is only a asitemia and malaria transmission. Expert Rev Anti Infect Ther. 2013;11(6):626- 39. small number of studies examining the benefits of rehabilitation 20. Lewallen S, Bronzan RN, Beare NA, et al. Using malarial retinopathy to improve for these patients. More research needs to be conducted to de- the classification of children with cerebral malaria. Trans R Soc Trop Med Hyg. 2008;102(11):1089-94. termine the most efficacious methods of improving the cognitive 21. White VA, Lewallen S, Beare NA, et al. Retinal pathology of pediatric cerebral and motor symptoms of neurological sequelae. It would also be malaria in Malawi. PLoS One. 2009;4(1). 22. Lovegrove FE, Tangpukdee N, Opoka RO, et al. Serum angiopoietin-1 and -2 lev- helpful to locate a source of funding for large-scale rehabilita- els discriminate cerebral malaria from uncomplicated malaria and predict clinical outcome in African children. PLoS One. 2009;4(3):e4912. tion programs in sub-Saharan Africa, as those who would benefit 23. Conroy AL, Lafferty EI, Lovegrove FE, et al. Whole blood angiopoietin-1 and -2 most from rehabilitation are unlikely to be able to afford it. levels discriminate cerebral and severe (non-cerebral) malaria from uncomplicated malaria. Malar J. 2009;8(295). Perhaps most importantly, a greater effort should be made to 24. Postels DG, Wu X, Li C, et al. Admission EEG findings in diverse paediatric cere- eradicate malaria worldwide by targeting the Anopheles mosquito bral malaria populations predict outcomes. Malar J. 2018;17(208). 25. Mishra SK, Newton CR. Diagnosis and management of the neurological compli- vector. There has been an increase in the worldwide burden of cations of falciparum malaria. Nat Rev Neurol. 2009;5(4):189-98. malaria in recent years, due to increases in population in malari- 26. Idro R, Carter JA, Fegan G, et al. Risk factors for persisting neurological and cognitive impairments following cerebral malaria. Arch Dis Child. 2006;91(2):142-48. ous regions, the building of dams, the resistance to antimalarial 27. O’Connell D. Malaria: Fatal attraction. Nat Rev Microbiol. 2007;5(655). 28. Van der Heyde HC, Nolan J, Combes V, et al. A unified hypothesis for the genesis drugs and insecticides, and the reduction in funding of public of cerebral malaria: sequestration, inflammation, and hemostasis leading to micro- health programs in many sub-Saharan African countries. Fur- circulatory dysfunction. Trends Parasitol. 2006;22(11):503-8. 29. Combes V, El-Assaad F, Faille D, et al. Microvesiculation and cell interactions at ther, there is speculation that with global warming, the number the brain-endothelial interface in cerebral malaria pathogenesis. Prog Neurobiol. of countries endemic for malaria will increase.12 2010;91(2):140-151. 30. Dorovini-Zis K, Schmidt K, Huynh H, et al. The neuropathology of fatal cerebral malaria in Malawian children. Am J Pathol. 2011;178(5):2146-58. Conclusion 31. Penet MF, Viola A, Confort-Gouny S, et al. Imaging experimental cerebral malaria in vivo: significant role of ischemic brain edema. J Neurosci. 2005;25(32):7352-8. In summary, long-term neurological deficits occur in approxi- 32. Mohanty S, Benjamin LA, Majhi M, et al. Magnetic resonance imaging of cerebral malaria patients reveals distinct pathogenetic processes in different parts of the mately 25% of child survivors of cerebral malaria, which is now brain. mSphere. 2017;2(3). recognized as the leading cause of childhood neurodisability in 33. Jukes MCH, Walraven G, Pinder M, et al. Long-term impact of malaria chemo- 11 prophylaxis on cognitive abilities and educational attainment: follow-up of a con- sub-Saharan Africa. While current understanding of risk fac- trolled trial. PLoS Clin Trials. 2006;1(4). tors, disease mechanisms, and treatments for these neurological 34. Reis PA, Comim CM, Hermani F, et al. Cognitive dysfunction is sustained after rescue therapy in experimental cerebral malaria, and is reduced by additive anti- sequelae are lacking, recent studies have shown great promise in oxidant therapy. PLoS Pathog. 2010;6(6). revolutionizing the way that cerebral malaria is diagnosed and 35. Casals-Pascual C, Idro R, Gicheru N, et al. High levels of erythropoietin are associated with protection against neurological sequelae in African children with cerebral treated. malaria. Proc Natl Acad Sci U S A. 2008;105(7):2634-9. 36. Picot S, Bienvenu A-L, Konate S, et al. Safety of epoietin beta-quinine drug combination in children with cerebral malaria in Mali. Malar J. 2009;8(169). References 37. Reis PA, Estato V, Silva TI, et al. Statins decrease neuroinflammation and prevent 1. World Health Organization. World malaria report 2018. Geneva: World Health cognitive impairment after cerebral malaria. PLoS Pathog. 2012;8(12). Organization; 2018. 67 p. 38. Bangirana P, Giordani B, John CC, et al. Immediate neuropsychological and be- 2. Palombi L, Moramarco S. Health in sub-Saharan Africa: HIV, TB and malaria havioural benefits of computerized cognitive rehabilitation in Ugandan pediatric epidemiology. In: Bartolo M, Ferrari F, editors. Multidisciplinary Teleconsultation cerebral malaria survivors. J Dev Behav Pediatr. 2009;30(4):310-8. in Developing Countries. Springer; 2018. p. 3-16. 39. Boivin MJ, Nakasujja N, Sikorskii A, et al. Neuropsychological benefits of com- 3. Newton CR, Hien TT, White N. Cerebral malaria. J Neurol Neurosurg Psychiatry. puterized cognitive rehabilitation training in Ugandan children surviving severe 2000;69:433-441. malaria: a randomized controlled trial. Brain Res Bull. 2019;145:117-28. 4. Idro R, Marsh K, John CC, et al. Cerebral malaria: mechanisms of brain injury

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Closing the gap between industry and consumers in sunscreen application

David Jung1; Aryan Riahi (BSc)1

1MD Undergraduate Program, University of British Columbia, 317-2194 Health Sciences Mall, Vancouver, British Columbia

and immune system activation render it crucial to life. On the other Abstract hand, too much sun exposure is accompanied by sunburns and an 1 While sunlight is physiologically important for Vitamin increased risk of cancers of the skin. The latter include not only non-melanoma skin cancers (basal and squamous cell carcinomas), D3 production, excess sun exposure is linked to sunburns but also malignant melanoma (MM). In particular, MM poses a and skin cancers. Sun-protective behaviours are thus public health concern, with its incidence having increased at a warranted year-round, with sunscreens playing a critical faster rate than any other cancer in the past 30 years.1 role in protecting the skin from ultraviolet radiation. The In this commentary, we will explore healthy sun behaviours current method of quantifying the extent of protection to minimize adverse consequences of excess sun exposure, with a offered by sunscreens relies on sun protection factor (SPF). focus on sunscreen application. Discrepancies in application trends between industrial testing and practical application settings are Manufacturers assume evenly spread sunscreen with an discussed, and their consequences. We will explore previous efforts 2 application thickness of 2mg/cm when determining of mitigating this gap, and contend for future strategies aimed at SPF values for their products. These are unfortunately bringing manufacturers and consumers closer. not held in real-life, with consumers applying significantly less quantities of sunscreen. Such discrepancy between Sun-protective behaviours are warranted year-round and beyond the beach industry and consumers could lead to a false sense of UV rays are the main culprits for the adverse health consequences security, and ultimately decreased skin health of the associated with too much sunshine. They are categorized into UVA public. By bridging the gap through both consumer- or UVB subtypes. While both are associated with increased risks and industry-directed approaches, the morbidity, of skin cancer, UVB is also responsible for sunburns.2 In Canada, mortality, and healthcare expenditures associated with the most hazardous times for UV exposure from natural sunlight 3 excess sunlight exposure could be reduced. Specifically, are between 11 a.m. to 3 p.m.. Nevertheless, protection from sun exposure is a year-round commitment. UV rays deserve attention consumers should be recommended to apply sunscreens even on cloudy days, warranting sun protection in daily life beyond with higher SPF values. Public health initiatives could also the beach.3 target to increase the general awareness in the inadequacy To avoid excessive UV radiation, the Centers for Disease of practical sunscreen application trends of consumers. Control and Prevention recommends staying in the shade, and Industries could gradually alter their testing standards using clothing items and sunglasses to protect exposed areas.4 These strategies are especially important in babies, whose skin is far to preserve reproducibility while becoming closer to more sensitive than their adult counterparts.2 In particular, babies practical settings. under six months of age are recommended to not use sunscreens, limiting their options to avoidance of UV radiation.5 In the general population, the prevalence of outdoor activities warrants the use of sunscreen on top of avoidance strategies The Goldilocks of sunshine: getting just the right when sun exposure is inadvertent. Health Canada advises using amount broad-spectrum sunscreens with sun protection factors (SPF) of un exposure is like a double-edged sword. Physiologically, at least 30.2 Broad-spectrum products offer protection for both sun exposure is linked to Vitamin D3, also known as the subtypes of UV radiation. Sunscreen should be applied at least 1 “sunshine vitamin”. During its synthesis, sunlight is required 15 minutes prior to sun exposure, and reapplied every two hours.2 Sto convert 7-dehydrocholesterol to the precursor form of Vitamin Consideration for greater quantity or specific “water resistant” and D3. The beneficial effects of Vitamin D3 on calcium metabolism “sport” types should be made when swimming or rigorous sport activities are involved.2 Just as the use of sunscreen is important for protecting one’s Corresponding Author: skin, so is its proper application. Generous amounts should be David Jung [email protected] applied to areas of the body that are potentially exposed without

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Closing the gap between industry and consumers in sunscreen application

adequate coverage by clothing.2 These include the head and neck, hypothetical consumer, he or she would expect to be protected as well as exposed skin in the limbs. In general, adults require 35 against UV radiation for approximately 150 minutes after applying mL or seven teaspoons of sunscreen to cover their exposed skin. sunscreen of SPF 15. This expectation will guide the consumer in One teaspoon is recommended in each of the following anatomical keeping track of time, so that he or she will seek shade or reapply sites: head and neck, front torso, back, and one arm or leg. sunscreen afterwards. Nevertheless, the SPF value is only accurate when assumptions Well-intended mistakes in sunscreen application made in the industrial setting are followed in terms of sunscreen The potency of sunscreens to protect against UV radiation application thickness and evenness. When sunscreen is not applied is quantified using the SPF.6 SPF is calculated using the minimal as instructed the SPF value is unreliable and, as shown by consumer erythema dose (MED), which is defined as the lowest dose of studies, oftentimes can be lower than indicated. To further UV radiation required to evoke erythema following 24 hours of complicate matters, the relationship between sunscreen application exposure.7 The ratio of MED for sunscreen-protected versus bare thickness and SPF is not fully elucidated and may be exponential.12 skin is used as follows: This means that an application thickness of 1mg/cm2 (half of the recommended guideline used in industrial testing) will not result in MED with sunscreen halving of SPF. Instead, SPF will fall by the square root. SPF = MED without sunscreen Indeed, evenly applying sunscreen of 2mg/cm2 is critical for consumers to be accurate in their expectation of how much SPF is then interpreted with regards to the length of time that sun exposure time is afforded by their sunscreens. Failure to do consumers are protected against UV exposure. For example, a so may result in overestimation of the extent of protection, such hypothetical consumer may experience erythema after 10 minutes that consumers may expose themselves for longer amounts of UV of sun exposure in bare.9 When he or she applies sunscreen of SPF exposure time. The price of overstaying their time in sunshine may 15, this amount of time is extended to around 150 minutes.9 Special include not only sunburns, but also increased potentials for skin attention should be paid to family history of skin cancers, and skin cancers. types as fair-skinned individuals are at greater risk for UV damage.3 When testing the SPF for a given product in industrial settings, Manufacturers and consumers: Speaking the same certain assumptions are made. Sunscreen is applied at a thickness language of 2mg/cm2, and assumed to be applied evenly on the skin.8 These Closing the gap between industrial standards and everyday assumptions are held when testing a variety of sunscreen products, usage of sunscreen may encourage consumers to use sunscreens as as backed by the American Food and Drug Administration, and intended by manufacturers. By providing consumers with accurate the International Organization for Standardization.8 information in the degree of protection provided by their products, Neither of these assumptions are consistently respected in real- the skin health of general public may improve. The latter may life settings. Studies have repeatedly found sunscreen application lead to decreased morbidity, mortality, and health expenditures thickness for consumers to be far less than the recommended 2mg/ associated with excess UV exposure. cm2. For instance, a 2014 review by Petersen and Wulf found that consumers applied only 20-50% of the recommended application What has been done so far? thickness.8 The cosmetic acceptability of sunscreens can influence Previous efforts have been made to increase the sunscreen the quantity used, as Diffey and Grice found that the quantity of application thickness among consumers to match that of industry. physical sunscreens used was on average two-thirds of that for A study by Azurdia et al. attempted to educate patients with chemical sunscreens.10 While the two types of sunscreen differ dermatological conditions on their sunscreen application trends.13 in their ingredients, physical sunscreens are deemed to be less Educational efforts were comprised of in-clinic visits, where cosmetically acceptable by consumers.10 deficiencies in patients’ application of sunscreen were discussed. Sunscreen application is also very uneven, with certain areas of Using fluorescent spectroscopy, the patients’ application thicknesses the body receiving far less coverage than others.11 An investigation of sunscreen before and after the intervention were determined.13 of Danish beachgoers by Heerfordt et al. found that consumers Compared to the baseline of 0.11mg/cm2, sunscreen application apply more sunscreen to the forehead, abdomen, and chest thickness significantly increased to 0.82mg/cm2 and 1.13mg/cm2 compared to less covered areas of upper back, as well as posterior at two weeks and six months after the program, respectively.13 thighs and legs.11 This difference was the most exaggerated between In 2018, the aforementioned paper by Heerfordt et al. the forehead and upper back, with the former anatomical region evaluated the double application technique of sunscreen.11 32 receiving 12 times more sunscreen than the latter.11 The authors healthy volunteers were tested for the quantity of sunscreen used cited reduced accessibility as a factor for sunscreen application in following single and double applications. With the first application, the back, in that consumers found it more challenging to reach the participants applied sunscreen at a thickness of 0.6mg/cm2 back when applying sunscreen alone.11 and missed a median of 20% of body surface.11 After double application, the sunscreen thickness increased to 1.1mg/cm2 while Identifying the gap between manufacturers and the missed body surface decreased to 9%.11 Individually, volunteers consumers applied between 13-100% more sunscreen after the second Currently, there appears to be multiple discrepancies between application compared to one application alone.11 Unfortunately, industrial and practical environments for sunscreen application. an uneven nature of sunscreen application remained even after These may have profound consequences. Returning to our double application, as previously mentioned.11

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Closing the gap between industry and consumers in sunscreen application

Next steps: What could be done? aligned with the practical values used by consumers. To provide Although both of the above studies are promising in increasing incentives for the manufacturers, public health organizations the application thickness of sunscreen, neither were capable of could fund some of these studies. This is naturally more of a long- reaching an evenly spread sunscreen at 2mg/cm2. These results term goal, and other strategies ought to be used in the interim to indicate that attempts to change consumer behaviours do improve promote better public skin health. the application thickness, but they can be combined with further measures. Role for health care providers For starters, consumers can be recommended to apply As health advocates, health care providers have a responsibility sunscreens of higher SPF value. Current recommendations from the to speak for the improved health of the general public. By calling the Government of Canada and American Academy of Dermatology government for actions in changing consumer recommendations, Association encourage consumers to use sunscreens with SPF of 30 adopting public health initiatives, and requesting manufacturers to or higher. 2,14 While this may be adequate with the ideal sunscreen follow suit, we may be able to close the gap in sunscreen application. application pattern, practical application trends among consumers may warrant further protection. Instead of 30, guidelines could be References altered to recommend consumers to use products with higher SPF 1. Lindqvist PG, Landin-Olsson M. The relationship between sun exposure and all- cause mortality. Photochem Photobiol Sci. 2017;16(3):354-61. values, such as 50, 80, or even 100. By using sunscreens of higher 2. Canada H. Sunscreens - Canada.ca [Internet]. Canada.ca. 2019 [cited 2019 May protective abilities, the under-application among consumers may 24]. Available from: https://www.canada.ca/en/health-canada/services/sun- be counteracted. safety/sunscreens.html 3. Canada.ca. Health effects of ultraviolet radiation. 2011 [updated 2019 Jan 22]. Furthermore, consumer awareness in the discrepancy between Available from https://www.canada.ca/en/health-canada/services/sun-safety/ practical and industrial application trends of sunscreen could be health-effects-ultraviolet-radiation.html?wbdisable=true 4. Protect Your Students from Skin Cancer [Internet]. Centers for Disease Control increased through public health initiatives. Previous educational and Prevention. 2019 [cited 24 May 2019]. Available from: https://www.cdc. efforts had aimed to alter the sunscreen application behaviour of gov/cancer/skin/basic_info/sun-safety-tips-schools.htm a limited group of study population to apply greater quantities 5. Commissioner, O. o. t.. Should you put sunscreen on infants? Not usually. FDA; 2016 [updated 2016 July 6] Available from http://www.fda.gov/consumers/ of sunscreen. While they may not have been sufficient to meet consumer-updates/should-you-put-sunscreen-infants-not-usually the industrial criteria of 2mg/cm2, raising public awareness with 6. Diffey B. Sunscreen isn't enough. J. Photochem. Photobiol. 2001;64(2-3):105-8. regards to the gap that blatantly exists between consumers and 7. Sekar CS, Srinivas CR. Minimal erythema dose to targeted phototherapy in vit- iligo patients in Indian skin. Indian J Dermatol Venereol Leprol. 2013;79(2):268. manufacturers could be worth exploring. As of present, consumers doi:10.4103/0378-6323.107666 may be misled by their perception in the degree of protection offered 8. Petersen B, Wulf HC. Application of sunscreen--theory and reality. Photoderma- tol Photoimmunol Photomed. 2014;30(2-3):96-101. by sunscreens. Efforts can be made to break this overestimation 9. W.S. Badger Company. Badger Health Body Care [Internet]. What is SPF sun- of sunscreen capacity, and to bring the expectations of consumers screen? - sun protection factor explained. W.S. Badger Company;2019. Available closer to reality. These programs should target all ages, and deliver from https://www.badgerbalm.com/s-30-what-is-spf-sunscreen-sun-protection- factor.aspx the reality in the inadequacy of sunscreen application among 10. Diffey BL, Grice J. The influence of sunscreen type on photoprotection. Br. J. consumers. Consequences of UV damage, including sunburn and Dermatol. 1997;137(1):103-5. skin cancers, should also be included to increase awareness of the 11. Heerfordt IM, Torsnes LR, Philipsen PA, et al. Sunscreen use optimized by two consecutive applications. PloS One. 2018;13(3):e0193916. grave implications associated with excess sun exposure. 12. Faurschou A, Wulf HC. The relation between sun protection factor and amount Examples of such initiatives could include posters and free of sunscreen applied in vivo. The British journal of dermatology. 2007;156(4):716- 9. informational brochures distributed to the public at beaches, parks, 13. Azurdia RM, Pagliaro JA, Rhodes LE. Sunscreen application technique in photo- schools, and other public places where many individuals gather sensitive patients: a quantitative assessment of the effect of education. Photoder- and are potentially exposed to UV radiation. These could be matol Photoimmunol Photomed. 2000;16(2):53-6. 14. Sunscreen FAQs [Internet]. American Academy of Dermatology; 2019 [cited supplemented with advertisements on social media and television 24 May 2019]. Available from: www.aad.org/media/stats/prevention-and-care/ to reach a greater target audience. Public health experts could sunscreen-faqs be involved in designing these initiatives, and programs could in turn be assessed through randomized control trials to continuously monitor performance and determine avenues for improvements. Finally, the gap could also be tackled from the industrial perspective. Perhaps sunscreen manufacturers could also be included in the picture. Application thickness of 2mg/cm2 was originally selected as it was associated with the greatest reproducibility and lowest variability in industrial testing results.8 This allows manufacturers to be more confident in their SPF reporting, which in turn allows consumers to directly compare multiple products before making an informed purchase. And yet, generalizability may be low as thicknesses of 2mg/cm2 are not being followed by consumers. By requiring manufacturers to slowly change their industrial testing standards, the SPF value written on the bottle of sunscreens could reflect the true extent of protection. Manufacturers could be mandated to research the application thickness with satisfactory reproducibility, while remaining more

64 UTMJ • Volume 96, Number 3, June 2019 Commentaries

O Cannabis: What have we done by legalizing marijuana in pregnancy?

Daniel B. Hardy (PhD)

Associate Professor, Departments of Ob/Gyn and Physiology & Pharmacology; Scientist, Children’s Health Research Institute and Lawson Health Research Institute, Western University, London, Ontario

“The Canadian government is taking a public health approach these studies are confounded by sociodemographic factors and to legalizing, strictly regulating, and restricting access to cannabis.” 1 the fact that users often use other drugs (e.g., tobacco).11,15 In the state of Colorado, where cannabis has been legal for more than hose were the words of Minister of Health Ginette Taylor 5 years, one study demonstrated that prenatal cannabis exposure in November 2017, spoken as the government of Canada is associated with a 50% increased chance of having low birth began to put together Bill 45, known as The Cannabis Act. weight children independent of the level of education, age, race/ TOver a year has passed since the enactment of Bill 45 and ethnicity, and tobacco consumption [OR 1.5; 95% CI 1.1–2.1].7 So questions still remain regarding the safety of legal cannabis to the question remains, given the risk to fetal development, why do our pregnant population, both in the short- and long-term.2 Even mothers use cannabis in pregnancy? preceding the legalization of cannabis in Canada, a 2017 survey Many continue to use cannabis given the common perception by the Centre for Addiction and Mental Health (CAMH) indicated that it will reduce anxiety and pregnancy-induced nausea.16,17 that from 1996–2017, adults of reproductive age (i.e., 18–29 years) Cannabis use in pregnancy is also thought to improve mood, and in Ontario reported the biggest increase in cannabis use, from a recent study suggests that depressed women are 2.5 times more 18.3% to 39.1%.3 Moreover, in 2017, the proportion of Ontarians likely to use cannabis in pregnancy.17,18 For others, cannabis is reporting cannabis use in a span of just 1 year rose from 15.7% to ‘herbal’, ‘natural’, and a welcome part of a ‘pro-vegan’ diet.9,17 A 19.4%, representing a total of 2 million people.3 member of CannaMama, a support group in Colorado consisting These trends in usage are of great concern, especially when of more than 5,000 women who advocate for cannabis use in considering that over the last decade, cannabis use has progressively pregnancy, has been recently quoted as saying: increased in pregnant women, along with the perception that it “Cannabis is not crack. Cannabis is not heroin. Cannabis is not poses no risk in perinatal life.4,5 In the United States, the rates of alcohol. Our movement is to help women make a choice that they feel is self-reported or screened cannabis use in pregnant mothers aged safer than pharmaceuticals and over-the-counter medications.”19 18–24 years varied from as low as 6% to as high as 22%, with some The bigger issue regarding the perception of the safety of women acknowledging taking 1–2 joints per day.5,6 Among nursing cannabis by pregnant mothers emerges from a recent Canadian mothers, a cross-sectional study from the Colorado Pregnancy Risk integrative review.20 The authors found that the uncertainty of Assessment Monitoring System indicated that the incidence of adverse postnatal outcomes along with a lack of counselling by cannabis use was ~5%.7 In pre-legalization Ontario, a population- healthcare providers were main drivers of their decision to use based study using the Better Outcomes Registry and Network cannabis in pregnancy.20 Other reasons for using cannabis in (BORN) database indicated a self-reported cannabis rate of 6.7% that review included its supposed therapeutic effects and its lower in pregnant mothers aged 15–24 years in the lowest two area-level cost compared to tobacco.20 One of the overall conclusions from income quintiles.8 More striking, of all the cannabis users surveyed that study was that “women perceived a lack of counselling as an in that study, the majority (52%) were aged 15–24 years.8 While indication that adverse outcomes were not significant.”20 Herein post-legalization data is not available, surveys suggest that more lays a significant issue. The message from our governing bodies women intend to use cannabis in pregnancy, due in part to the regarding the safety of cannabis in pregnancy just may be too perception that if it is legal, it must be safe.9,10 passive. For example, the Health Canada website states that, “until A recent Southwestern Ontario study has revealed that maternal more is known about the short and long-term effects of cannabis, it cannabis use in pregnancy is the third highest risk factor for low is safest to avoid using cannabis when pregnant and breastfeeding.”21 birth weight babies [odds ratio (OR) 2.72; 95% confidence interval But is that a strong enough message in the interim? (CI) 1.67–4.42].11 While three systematic reviews and meta-analyses Moving forward, two essential issues require immediate have further validated the relationship of maternal cannabis use attention. First, the paucity of research examining the with low birth weight and adverse neurodevelopmental outcomes, specific contributions of components of cannabis (i.e., Δ9- tetrahydroocannabinol (Δ9-THC) and cannabidiol (CBD)) on short-term pregnancy outcomes should be examined, but more importantly, its long-term effects on the exposed offspring must Corresponding Author: be studied. This needs to be addressed explicitly in animal models 8,11–15 Daniel B. Hardy given the confounding issues of clinical studies. The second [email protected] issue – an issue that is always problematic in biomedical research

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O Cannabis: What have we done by legalizing marijuana in pregnancy?

– is a lack of knowledge translation (i) from the bench to the to the variations in cannabinoid composition between patients, clinic, and (ii) from the clinician to the patient. animal studies are highly valued for their ability to delineate the With regards to the role of Δ9-THC, the major psychoactive specific contribution of perinatal Δ9-THC and/or CBD towards cannabinoid in cannabis, on fetal development, animal models neurodevelopment and postnatal brain function. The pregnant rat have demonstrated that exposure of pregnant dams to cannabis dam has been a useful model to examine the effects of exposure of or Δ9-THC leads to placental dysfunction and low birth weight Δ9-THC in pregnancy on several indices of social behavior and offspring.22–24 This is alarming considering that the concentration mental capacity in postnatal life. Specifically, perinatal Δ9-THC- of Δ9-THC in cannabis has increased from 3% up to 22% over exposed offspring exhibit increases in anxiety (decreased time in the last decade due to selective plant breeding.25 Moreover, animal inner part of open field test and increased investigation time), studies have indicated that Δ9-THC can cross the placenta and impaired social interaction, anxiogenic-like profile (elevated plus 10–28% of maternal concentrations are detected in the fetal maze test), and have enhanced presynaptic dopamine D2 receptor plasma, with 2–5-fold higher concentrations in fetal tissues.26,27 In responses including immobility and inhibition of locomotion.42–45 human studies, it has also been demonstrated that Δ9-THC can With respect to addiction, elegant studies have demonstrated that pass into breast milk, and that chronic use of cannabis results only Δ9-THC-exposed females exhibited greater morphine self- in 8-fold higher concentrations in milk compared to maternal administration behavior due to sex-specific increases in the density circulation.28 In addition to the limited research related to Δ9- and binding of mu opioid receptors in the prefrontal cortex, THC, little is known regarding the contributions of CBD, the hippocampus (CA3 area), and the amygdala.46 To date, these studies major non-psychoactive component of cannabis, alone on fetal have assessed long-term hippocampal function after perinatal or neonatal development. Furthermore, it is uncertain how the Δ9-THC exposure, but future studies are needed to address the content of CBD, a phytocannabinoid known to counteract many short and long-term effects of cannabinoid exposure during the of the negative effects of Δ9-THC, may influence cannabis- lactation period alone. This is imperative considering the behavior induced fetal growth restriction. patterns of women who smoke in pregnancy, especially those who For the past couple of decades, there has been a growing think that smoking during breastfeeding alone is safe in the long- body of research examining the role of the endocannabinoid term for offspring health.47 Moreover, adolescent rodent studies system in pregnancy on neurodevelopment in postnatal life. from our Addiction Research group at Western University indicate The endocannabinoid system is involved in a diverse range of that exposure to Δ9-THC or other CB1R agonists adversely physiological processes including cognition, learning, memory, impacts working memory, spatial working memory, and cognitive nociception, mood, inflammation, energy and balance, and flexibility,48 suggesting that the brain in early life could be quite metabolism.29 While both cannabinoid receptors (CB1R and vulnerable to Δ9-THC or CBD during lactation, a period of CB2R) are expressed in peripheral tissues (i.e., placenta, pancreas, developmental plasticity. adipose, liver, and heart) in fetal and postnatal life, CB1R is primarily Aside from the brain, activation of cannabinoid receptors detected in the brain during development and in postnatal life.30–36 by Δ9-THC or CBD in peripheral tissues (e.g., pancreas, heart, Both CB1R and CB2R can bind to Δ9-THC with greater affinity adipose, and liver) during pregnancy could also directly influence then CBD.32 In rats, CB1R is first detected in the forebrain around the development of those organs, and consequentially, their gestational days 11–14, coinciding with the increased expression function in postnatal life.30–36 In addition, Δ9-THC in pregnancy of neurotransmitters.36 CB1R in humans is detected by week 14 may have indirect effects on long-term non-communicable diseases of gestation in the hippocampus with subsequent expression in the given that it impedes fetal growth, which is a strong predictor amygdala by week 20.37 In both species, the higher expression of of metabolic disease risk in human offspring.23,49 With respect to CB1R in fetal compared to postnatal life has been suggested to play heart development, the role of CB1R and CB2R has been scarcely a key role in developmental events including cell proliferation and explored. One in vitro study has indicated that the cannabinoid migration, metabolic support, axonal elongation, and ultimately, receptor ligand anandamide impairs neonatal cardiomyocyte size, synaptogenesis and myelogenesis.38 While activation of CB1R by but the effects of Δ9-THC or CBD in pregnancy on the developing Δ9-THC might seem to be beneficial to the fetus in the short- heart is unknown.50 We recently investigated if exposure to Δ9- term, chronic exposure to cannabis in pregnancy leads to several THC in pregnant rats influences postnatal cardiovascular deficits in brain function in postnatal life.6,39–41 The Mental Health function. Part of our rationale came from recent in vitro studies Practices and Child Development Study (MHPCD) demonstrated that demonstrated that Δ9-THC directly leads to endoplasmic that cannabis use in pregnancy results in decreased mental scores reticulum stress and mitochondrial dysfunction, which are key (e.g., Bayley Scales of Infant Development) as early as 9 months instigators of fetal growth restriction and cardiac dysfunction.51–53 of age.6 As these children get older, maternal cannabis use led to We demonstrated that daily injections of 3 mg/kg Δ9-THC lower scores in short-term memory and verbal and abstract/visual from gestational day 6 to birth leads to fetal growth restriction reasoning in 3 year old children, with deficits in sustained attention without any adverse effects to maternal food intake, weight gain, by 6 years, and problems in abstract and visual reasoning in 10 gestational length, or litter size.54 Others have demonstrated that year olds.6,40,41 Another study demonstrated long-lasting effects, as this dose of Δ9-THC in rats results in circulating concentrations of young 18–22 year olds exposed to cannabis in pregnancy exhibited 8.6–12.4 ng/ml Δ9-THC, which is consistent with that reported altered neuronal functioning during visuospatial working memory in (i) cannabis smokers (13–63 ng/ml from a 7% Δ9-THC content processing.39 cigarette) 0–22 hours post inhalation, and (ii) in fetal tissues (4–287 However, given the intrinsic limitations of these clinical studies, ng/ml) of pregnant cannabis smokers.55–57 At birth, there was an including the fact that cannabis users also use other drugs, and due approximate 25% decrease in the heart to body weight ratio in

66 UTMJ • Volume 96, Number 3, June 2019 Commentaries

O Cannabis: What have we done by legalizing marijuana in pregnancy?

these Δ9-THC exposed offspring while echocardiographic analysis References revealed this was accompanied by lower cardiac stroke volume.54 1. Crépault JF Cannabis legalization in Canada: Reflections on public health and the governance of legal psychoactive substances. Front Public Health. 2018;6220. By 3 weeks of age, after the Δ9-THC offspring exhibited postnatal doi: 10.3389/fpubh.2018.00220. catch-up growth, both a decrease in stroke volume and cardiac 2. Bobila Walker Law LLP Canabis Law Group. Introduction to the cannabis act: 54 Questions and answers [Internet]. 2017 [updated 2017 September 11; cited output were observed. Given the short-term impact of Δ9-THC 2019] Available from: http://www.cannabis-regulations.ca/cannabis/govern- on heart function, future studies are warranted to examine the ment-canada-introduction-cannabis-act-questions-answers/ effects of perinatal exposure of Δ9-THC and/or CBD on long- 3. Ialomiteanu AR, Hamilton HA, Adlaf EM, et al. CAMH Monitor e-report: Substance use, mental health and well-being among Ontario adults, 1977–2017. term cardiovascular function along with adiposity, glucose/insulin (2018). homeostasis, and liver function including drug metabolism. 4. Jarlenski M, Koma, JW, Zank J, et al. Trends in perception of risk of regular marijuana use among U.S. pregnant and non-pregnant reproductive-aged women. Am. J. Obstet. Gynecol 2017. doi: 10.1016/j.ajog.2017.08.015 Future Directions 5. Young-Wolff KC, Tucker LY, Alexeeff S, et al. Trends in self-reported and bio- As previously mentioned, future research is required to examine chemically tested marijuana use among pregnant females in California from 2009-2016. JAMA 2017;318:2490. doi: 10.1001/jama.2017.17225. the effects of cannabis components on fetal developmental and 6. Richardson GA, Ryan C, Willford J, et al. Prenatal alcohol and marijuana expo- postnatal health. While animal studies have shed some light on sure: Effects on neuropsychological outcomes at 10 years. Neurotoxicol Teratol the adverse effects of Δ9-THC in perinatal life on long-term 2002;24:309–320. 7. Crume TL, Juhl AL, Brooks-Russel A, et al. Cannabis use during the perinatal pe- neurodevelopmental outcomes, the safety of CBD in pregnancy riod in a state with legalized recreational and medical marijuana: The association also needs to be addressed. As the majority of cannabis strains are between maternal characteristics, breastfeeding patterns, and neonatal outcomes. high in Δ9-THC and low in CBD,25 such studies would collectively J. Pediatr 208;197:90–96. doi: 10.1016/j.jpeds.2018.02.005. 8. Corsi DJ, Hsu H, Weiss D, et al. Trends and correlates of cannabis use in preg- help identify which strains of cannabis may or may not be linked nancy: A population-based study in Ontario, Canada from 2012 to 2017. Can J to adverse perinatal outcomes. Furthermore, as cannabinoid Public Health 2019;110:76–84. doi: 10.17269/s41997-018-0148-0. 30–36 9. Mark K, Gryczynski J, Axenfeld E, et al. Pregnant women’s current and in- receptors are also expressed in peripheral organs, research tended cannabis use in relation to their views toward legalization and knowl- must be aimed at exploring the different development windows edge of potential harm. J Addict Med 2017;11: 211–216. doi: 10.1097/ (i.e., gestation, lactation, or both) of cannabinoid exposure on ADM.0000000000000299. 10. Volkow ND, Compton WM, Wargo EM. The risks of marijuana use during preg- postnatal metabolic health. This is critical given Δ9-THC can cross nancy. JAMA 2017;317:29–130. doi: 10.1001/jama.2016.18612. into maternal, fetal, and neonatal circulation to influence organ 11. Campbell EE, Gilliland J, Dworatzek PDN, et al. Socioeconomic status and development.26–28 Moreover, as researchers determine the effects of adverse birth outcomes: A population-based Canadian sample. J Biosoc Sci 2018;50:102–113. doi: 10.1017/S0021932017000062. cannabinoids on long-term disease risk, it is imperative that we also 12. English DR, Hulse GK, Milne E, et al. Maternal cannabis use and birth weight: identify any sex-specific outcomes resulting from these clinical and A meta-analysis. Addiction 1997;92:1553–1560. 13. Gunn JK, Rosales CB, Center KE, et al. Prenatal exposure to cannabis and ma- animal studies. To date, ~70% of the studies examining the effects ternal and child health outcomes: A systematic review and meta-analysis. BMJ of perinatal Δ9-THC exposure on neurodevelopmental outcomes Open 2016;6:e009986. doi: 10.1136/bmjopen-2015-009986. in rodents only looked at male offspring,42–46 even though we now 14. Conner SN, Bedell V, Lipsey K, et al. Maternal marijuana use and adverse 46 neonatal outcomes: A systematic review and meta-analysis. Obstet Gynecol know there are sex-specific effects. 2016;128:713–723. doi: 10.1097/AOG.0000000000001649. In Canada, while we still have a long way to go in providing 15. Metz TD, Stickrath EH. Marijuana use in pregnancy and lactation: A review a healthy research budget for our biomedical researchers, the of the evidence. Am. J. Obstet Gynecol. 2015;213:761–778. doi: 10.1016/j. ajog.2015.05.025. Canadian Institutes for Health Research (CIHR) has just recently 16. Westfall RE, Janssen PA, Lucas P, et al. Survey of medicinal cannabis use among recognized cannabis research as a priority with the release of both childbearing women: Patterns of its use in pregnancy and retroactive self-assessment of its efficacy against ‘morning sickness’. Complement Ther Clin Pract Team and Catalyst grants related to “Cannabis Research in Urgent 2006;12:27–33. doi: 10.1016/j.ctcp.2009.07.001 Priority Areas”. With that said, it would have been beneficial to 17. Chang, J. C. et al. Beliefs and attitudes regarding prenatal marijuana use: Per- have these research initiatives well in place preceding the passing spectives of pregnant women who report use. Drug Alcohol Depend 196, 14–20 (2019). doi:10.1016/j.drugalcdep.2018.11.028 of Bill 45. Regardless, the outcomes of these current and future 18. Brown, R. A., Dakkak, H., Gilliland, J. & Seabrook, J. A. Predictors of drug use studies will be important for clinical and regulatory agencies during pregnancy: The relative effects of socioeconomic, demographic, and around the world, such as Health Canada, for providing functional mental health risk factors. J Neonatal Perinatal Med 12, 179–187 (2019). doi: 10.3233/npm-1814 evidence to support policy and decision-making. 19. Schumacher M. CannaMamas support smoking cannabis during pregnancy, Oc- However, research and policy will have limited impact on tober 10th. The National Post (2018). 20. Bayrampour H, Zahradnik M, Lisonkova S, et al. Women’s perspectives about maternal-fetal health if information is not properly disseminated cannabis use during pregnancy and the postpartum period: An integrative review. to the patient. Given what underlies a patient’s decision to use Prev Med 2019;119:17–2. doi: 10.1016/j.ypmed.2018.12.002. cannabis in pregnancy,17,20 all stakeholders in Obstetrics and 21. Health Nexus. Risks of cannabis on fertility, pregnancy, breastfeeding and par- enting [Internet]. Best Start; 2019 [updated 2019].Available from: http://www. Gynaecology, Pediatrics, and Family Medicine must be well beststart.org informed to counsel patients with evidence-based data. Secondly, 22. Vargish GA, Pelkey KA, Chittajallu R, et al. Persistent inhibitory circuit defects through open dialogue we further need to understand why these and disrupted social behaviour following in utero exogenous cannabinoid exposure. Mol. Psychiatry 2016. doi:10.1038/mp.2016.17 patients are choosing to use cannabis pre- and postpartum, 23. Chang X, Bian Y, He Q, et al. Suppression of STAT3 signaling by Δ9- especially given that socioeconomic status may influence their tetrahydrocannabinol (THC) induces trophoblast dysfunction. Cell Physiol Bio- 8,11–15 chem 2017;42:537–550. doi: 10.1159/000477603. decisions. With greater counseling and evidence, we should be 24. Benevenuto SG, Domenico MD, Martins MA, et al. Recreational use of marijua- able to reduce the incidence of neurodevelopmental and metabolic na during pregnancy and negative gestational and fetal outcomes: An experimen- adversity in a generation of children, who without choice, are tal study in mice. Toxicology 2017;376: 94–101. doi: 10.1016/j.tox.2016.05.020. 25. ElSohly MA, Mehmedic Z, Foster S, et al. Changes in cannabis potency over the exposed to cannabinoids in fetal life. last 2 decades (1995-2014): Analysis of current data in the United States. Biol. Psychiatry 2016;79:613–619. doi: 10.1016/j.biopsych.2016.01.004.

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O Cannabis: What have we done by legalizing marijuana in pregnancy?

26. Hutchings DE, Martin BR, Gamagaris Z, et al. Plasma concentrations of delta- 44. Campolongo P, Trezza V, Cassano T, et al. Perinatal exposure to delta-9-tetra- 9-tetrahydrocannabinol in dams and fetuses following acute or multiple prenatal hydrocannabinol causes enduring cognitive deficits associated with alteration of dosing in rats. Life Sci. 1989;44:697–701. cortical gene expression and neurotransmission in rats. Addict Biol 2007;12:485– 27. Bailey JR, Cunny HC, Paule MG, et al. Fetal disposition of delta 9-tetrahydrocan- 495. doi: 10.1111/j.1369-1600.2007.00074.x nabinol (THC) during late pregnancy in the rhesus monkey. Toxicol Appl Phar- 45. Trezza V, Campolongo P, Cassano T, et al. Effects of perinatal exposure to delta- macol 1987;90:315–321. 9-tetrahydrocannabinol on the emotional reactivity of the offspring: A longitudi- 28. Perez-Reyes M, Wall ME. Presence of delta9-tetrahydrocannabinol in human nal behavioral study in Wistar rats. Psychopharmacology (Berl.) 2008;198:529– milk. N Engl J Med 1982;307:819–820. doi: 10.1056/NEJM198209233071311. 537. doi: 10.1007/s00213-008-1162-3. 29. Silvestri C, Di Marzo V. The endocannabinoid system in energy homeostasis and 46. Vela G, Martin S, Garcia-Gil L, et al. Maternal exposure to delta9-tetrahydrocan- the etiopathology of metabolic disorders. Cell Metab. 2013;17:475–490. doi: nabinol facilitates morphine self-administration behavior and changes regional 10.1016/j.cmet.2013.03.001. binding to central mu opioid receptors in adult offspring female rats. Brain Res 30. Ramírez-López MT, Arco R, Decara J, et al. Exposure to a highly caloric palat- 1998;807:101–109. doi:10.1016/s0006-8993(98)00766-5 able diet during the perinatal period affects the expression of the endogenous 47. DiClemente CC, Dolan-Mullen P, Windsor RA. The process of pregnancy smok- cannabinoid system in the brain, liver and adipose tissue of adult rat offspring. ing cessation: Implications for interventions. Tob Control 2000;9 Suppl 3:III16– PLoS ONE 2016;11:e0165432. doi: 10.1371/journal.pone.0165432. 21. doi: 10.1136/tc.9.suppl_3.iii16 31. Malenczyk K, Keimpema E, Piscitelli, et al. Fetal endocannabinoids orchestrate 48. Renard J, Rushlow WJ, Laviolette SR. What can rats tell us about adolescent can- the organization of pancreatic islet microarchitecture. Proc Natl Acad Sci U.S.A nabis exposure? Insights from preclinical research. Can J Psychiatry 2016;61:328– 2015;112:E6185–6194. doi: 10.1073/pnas.1519040112. 334. doi: 10.1177/0706743716645288. 32. Pertwee RG, Howlett AC, Abood ME, et al. International Union of Basic and 49. Barker DJ. The fetal and infant origins of adult disease. BMJ 1990;301:1111. doi: Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands: 10.1136/bmj.301.6761.1111 Beyond CB1 and CB2. Pharmacol Rev 2010;62:588–631. doi: 10.1124/ 50. Lu Y, Akinwumi BC, Shao Z, et al. Ligand activation of cannabinoid receptors pr.110.003004. attenuates hypertrophy of neonatal rat cardiomyocytes. J Cardiovasc Pharmacol 33. Sun X, Dey SK. Endocannabinoid signaling in female reproduction. ACS Chem 2014;64:420–430. doi: 10.1097/FJC.0000000000000134. Neurosci 2012;3: 349–355. doi: 10.1021/cn300014e 51. Wang XM, Wang YC, Liu XJ, et al. BRD7 mediates hyperglycaemia-induced 34. Coskun ZM, Bolkent S. Oxidative stress and cannabinoid receptor expression in myocardial apoptosis via endoplasmic reticulum stress signaling pathway. J Cell type-2 diabetic rat pancreas following treatment with Δ9-THC. Cell Biochem Mol Med 2017;21:1094–1105. doi: 10.1111/jcmm.13041. Funct 2014;32:612–619. doi: 10.1002/cbf.3058 52. Barra NG, Lisyansky M, Vanduzer TA, et al. Maternal nicotine exposure leads 35. Buckley NE, Hansson S, Harta G, et al. Expression of the CB1 and CB2 re- to decreased cardiac protein disulfide isomerase and impaired mitochondrial ceptor messenger RNAs during embryonic development in the rat. Neuroscience function in male rat offspring. J Appl Toxicol 2017;37:1517–1526. doi: 10.1002/ 1998;82:1131–1149. jat.3503. 36. Trezza V, Cuomo V, Vanderschuren LJMJ. Cannabis and the developing brain: 53. Lojpur T, Easton Z, Raez-Villanueva S, et al. Δ9-Tetrahydrocannabinol leads to Insights from behavior. Eur J Pharmacol 2008;585:441–452. doi: 10.1016/j. endoplasmic reticulum stress and mitochondrial dysfunction in human BeWo tro- ejphar.2008.01.058. phoblasts. Reprod Toxicol 2019;87:21–31. doi: 10.1016/j.reprotox.2019.04.008. 37. Wang X, Dow-Edwards D, Keller E, et al. Preferential limbic expression of 54. Lee K, McCarthy K, Laviolette SR, et al. Exposure to Δ9-tetrahydrocannabinol the cannabinoid receptor mRNA in the human fetal brain. Neuroscience during rat pregnancy leads to impaired fetal growth and postnatal cardiac dys- 2003;118:681–694. function. 6th Annual Meeting of the Canadian National Perinatal Research 38. Fernández-Ruiz J, Gómez M, Hernández M, et al. Cannabinoids and gene ex- Meeting, Montebello, Quebec, Abstract P08 (2019). pression during brain development. Neurotox Res2004; 6:389–401. 55. Falcon M, Pichini S, Joya J, et al. Maternal hair testing for the assessment of 39. Smith AM, Fried PA, Hogan MJ, et al. Effects of prenatal marijuana on visuo- fetal exposure to drug of abuse during early pregnancy: Comparison with testing spatial working memory: An fMRI study in young adults. Neurotoxicol Teratol in placental and fetal remains. Forensic Sci Int 2012;218:92–96). doi: 10.1016/j. 2006;28:286–295. doi: 10.1016/j.ntt.2005.12.008 forsciint.2011.10.022. 40. Day NL, Richardson GA, Goldschmidt L, et al. Effect of prenatal marijuana 56. Klein C, Karanges E, Spiro A, et al. Cannabidiol potentiates Δ9- exposure on the cognitive development of offspring at age three. Neurotoxicol tetrahydrocannabinol (THC) behavioural effects and alters THC pharmacokinet- Teratol 1994;16:169–175. ics during acute and chronic treatment in adolescent rats. Psychopharmacology 41. Leech SL, Richardson GA, Goldschmidt L, et al. Prenatal substance expo- (Berl.) 2011;218:443–457. doi: 10.1007/s00213-011-2342-0. sure: Effects on attention and impulsivity of 6-year-olds. Neurotoxicol Teratol 57. Schwope DM, Karschner EL, Gorelick DA, et al. Identification of recent can- 1999;21:109–118. nabis use: Whole-blood and plasma free and glucuronidated cannabinoid phar- 42. Newsom RJ, Kelly SJ. Perinatal delta-9-tetrahydrocannabinol exposure dis- macokinetics following controlled smoked cannabis administration. Clin Chem rupts social and open field behavior in adult male rats. Neurotoxicol Teratol 2011;57:1406–1414. doi: 10.1373/clinchem.2011.171777. 2008;30:213–219. doi: 10.1016/j.ntt.2007.12.007. 43. Castaldo P, MagiS, Cataldi M, et al. Altered regulation of glutamate release and decreased functional activity and expression of GLT1 and GLAST glutamate transporters in the hippocampus of adolescent rats perinatally exposed to Delta(9)- THC. Pharmacol Res 2010;61:334–341. doi: 10.1016/j.phrs.2009.11.008.

68 UTMJ • Volume 96, Number 3, June 2019 Commentaries

Freedom of Expression Litigation and the Harms of Cannabis

Melanie L. McPhail, LLM & Jacob J. Shelley, SJD

n April 2016, the Canadian federal government announced explicitly identify harm reduction as an underlying principle, the its intention to legalize and regulate recreational cannabis. Canadian government has identified harm reduction as a broader Minister of Health Jane Philpott indicated that legalizing policy goal with respect to all drugs.9 Additionally, minimizing recreationalI cannabis would “keep marijuana out of the hands harm has long been a motivating factor for legalization of of children and profits out of the hands of criminals.”1 In April recreational cannabis, as articulated in the final report of the Task 2017, the government released the proposed legislation, to come Force on Cannabis Legalization and Regulation.10 Specifically, the into effect no later than July 2018, legalizing recreational cannabis government has taken a “public health approach” to minimizing use for adults in Canada.2 The Cannabis Act, Bill C-45, was to harm, although some have suggested that this is an unclear and operate concurrently with the medical cannabis regulations, the undefined standard.11 Access to Cannabis for Medical Purposes Regulations.3 Since the initial Some of the harms that legalizing cannabis for recreational announcement in April 2016, academics, politicians, scientists, use aims to reduce are those associated with the criminalization doctors, and citizens have been clamouring for answers to a of cannabis, including: interacting with the black market,12 illegal seemingly endless list of questions. What age should the minimum crops, adulterated products, barriers to seeking treatment, and age of purchase be set at? Who should be able to sell cannabis? the burden imposed on the Canadian legal system. In addition Will using cannabis legally in Canada exclude me from travelling to to displacing the criminal market, the Cannabis Act aims to protect the United States? How will legalization impact rates of cannabis youth by enacting criminal penalties for those that sell or provide use among youth? Are health care professionals trained to inform cannabis to youth. patients about cannabis use? While legalization allows the state to regulate cannabis, it Underlying many of these questions is a central concern about does not necessarily reduce the harms and health risks that are the harms associated with cannabis use.4,5 Numerous organizations associated with cannabis use.13 Whether legalization has a positive have written position statements on the risks and harms associated or negative impact on public health and safety will depend on how with cannabis use and researchers continue to assess the evidence.6 regulatory decisions are made, implemented, and enforced. Indeed, While the debate about potential harm rages on, an important legalization comes with its own harms including increased rates concern about the new legislation has received relatively little of use and associated risks, normalization of use, and potential attention even though it could have significant legal and economic increased access of cannabis to minors. Cannabis use is not risk- consequences. For example, can the advertising of cannabis, free, and any legalization regulatory scheme should attempt to cannabis products, and cannabis services7 legally be prohibited or mitigate or eliminate harms where possible. restricted? Given the recency of the implementation of the Cannabis Act, The purpose of this commentary is to examine how freedom it is too early to assess whether legalization has reduced harms. of expression litigation concerning cannabis advertising and What is clear is that many organizations have welcomed the move. marketing will force the courts to consider whether cannabis is a For example, in 2014 the Centre for Addiction and Mental Health legitimate public health harm. It begins with a discussion about (CAMH) released a policy framework for cannabis that advocated legalization as a harm reduction strategy before moving to examine for a public health approach, concluding that “legalization, the importance of “harm” in the constitutional analysis involved in accompanied by strict health-focused regulation, is the most freedom of expression litigation. This example serves to highlight promising means of reducing … risks and harms.”14 CAMH, the impact that harm will inevitably play in any constitutional however, notes that it is necessary for the public to know about the litigation pertaining to the Cannabis Act or Cannabis Regulations. How risks associated with cannabis use,15 a sentiment echoed by many the government and litigants, and ultimately, the courts categorize public health and medical organizations, like the Canadian Public the harm of legal recreational cannabis use will have significant Health Association.16 implications on the constitutionality of various policy tools. The notion of harm will be particularly important if the regulatory framework is subject to any constitutional analysis. If Legalization of Recreational Cannabis and Harm the Cannabis Act or the Cannabis Regulations are challenged, potential Reduction harms will be considered against the actual or potential benefits by Harm reduction is often used to refer to the policies and the court when assessing the objective of the impugned legislation, programs established that aim to minimize the “negative health, as well as the proportionality of the legislation. Therefore, a social, and legal impacts associated with drug use, drug policies, court will need to be presented with the best current knowledge and drug laws.”8 One of the goals of a harm reduction approach regarding the potential for harm with recreational cannabis use, is to reduce the harm of drug laws. While the Cannabis Act does not as well as possible benefits. However, because cannabis is a class of

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Freedom of Expression Litigation and the Harms of Cannabis products rather than a homogeneous product, research does not That said, in RJR-MacDonald, the SCC did consider whether tobacco always account for variation between specific products and how advertising itself was harmful thereby entitling Parliament to prohibit they are used, such as cannabinoid content, history of use, method or regulate it under the criminal law. Comparing tobacco advertising of delivery, or individual factors that impact the effects of cannabis, to other types of speech that Parliament had criminalized, such as such as age, experience, and tolerance. It is beyond the scope of obscenity, the SCC did not see a clear comparison.26 Any challenge this commentary to review the current state of evidence and is to the Cannabis Act will likely argue that the legislation is both ultra vires ultimately unnecessary. Instead, what follows is an articulation of the federal government and that it infringes freedom of expression, why a consideration of “harm” in the context of cannabis will have and thus consideration of whether the Act prevents harm, which significant policy implications in Canada. would enable the federal government to utilize its criminal law power, is an important consideration. The Concept of Harm in Freedom of Expression Litigation (ii) Role of Harm in Section 2(b) Analysis Section 2(b) of the Canadian Charter of Rights and Freedoms While the Charter protects the freedom of commercial expression, protects the rights everyone has to freedom of expression. Deemed there has been some question about whether commercial speech a fundamental right, “everyone” here includes corporations. In should be afforded protection where the product (or service) being Irwin Toy v Quebec (AG), the Supreme Court of Canada (SCC) held promoted is harmful. In Ford v Quebec (Attorney General), the SCC that commercial speech, including advertising and marketing, supported the argument that Parliament cannot “suppress truthful benefits from Charter protection.17 Thus, legislative attempts to and non-misleading advertising of lawful products on the grounds limit commercial expression, such as restrictions or prohibitions that the information to be conveyed would have a harmful effect.”27 on advertising cannabis, can be subject to Charter litigation. Given This suggests that the potential harm a product may inflict is not that subdivision B of the Cannabis Act and Part 7 of the Cannabis a sufficient reason to strip commercial expression of protection. Regulations attempt to restrict advertising, it is entirely possible that In contrast, the Attorney General in RJR-MacDonald argued that these provisions will be challenged. freedom of expression does not protect “promotion [of] activities The concept of harm plays a significant role in freedom relating to a product described as being harmful, if not fatal to one’s of speech litigation. Unfortunately, the way that courts have health.”28 The Attorney General filed evidence in an attempt to considered and treated harm in these cases has been inconsistent, demonstrate the harmful nature of tobacco use and that advertising and even contradictory. In some instances, the concept of harm is used to increase consumption.29 The trial court was not convinced prevails throughout the entire judicial decision and serves as an by this argument. Justice Chabot held: “[a]ssuming…that the animating force of the court’s decision,18 whereas in other decisions evidence before the Court clearly established the harmfulness of harm is not mentioned at all.19 While this may be explained by the tobacco, the Court must nonetheless conclude that the [Act] does facts of each case, it nevertheless results in confusion concerning not in any way address this harm.”30 what constitutes harm and how this will factor into the court’s Justice Chabot stressed that it was not the advertising that decision. The following are four ways that the concept of harm caused harm, but the use of tobacco.31 Chabot J interpreted the has factored into the leading SCC freedom of expression cases Attorney General’s argument to be that tobacco is so harmful that that deal with commercial expression: (1) at the division of powers any expression connected to it, except for the State’s, should be analysis, (2) in determining whether section 2(b) has been infringed, prohibited, and found this position to be “unacceptable under (3) in the use of evidence, and (4) in the Oakes analysis. the Canadian Charter.”32 At the Court of Appeal, the respondent tobacco companies defended their right to advertise a product (i) Harm in the Division of Powers Analysis widely recognized to be harmful.33 The Court of Appeal recognized First, harm is relevant in the division of powers analysis. The that the issue was a balancing of the companies’ right to promote Constitution Act20 divides powers between the federal and provincial their economic interests and the public health concerns connected governments. Often courts are charged with determining which to smoking tobacco.34 The SCC held that the specific form of level of government has authority over a particular area. The expression examined in RJR-MacDonald, tobacco advertising, federal government’s involvement in matters protecting the public’s was not closely linked to the core values underlying freedom of health relies on its authority over criminal law.21 One way to justify expression as articulated in Ford and Irwin Toy. the use of its criminal law power is for the federal government to In Ford and Irwin Toy the SCC identified three reasons for demonstrate that a matter poses “a significant and serious risk of protecting expression: (1) truth-seeking; (2) participation in social harm or causing significant and serious harm to public health, and political decision-making; and (3) cultivating individual self- safety, or security.”22 fulfillment and human flourishing.35 According to the SCC, tobacco This has been affirmed in various cases before the SCC. In R v advertising serves no political, scientific, or artistic purposes, but is Keegstra, Chief Justice Dickson (as he then was), stated that “[i]t is well intended to inform consumers about a product that is ultimately accepted that Parliament can use the criminal law power to prevent harmful and to persuade them to purchase it.36 Given that it was the risk of serious harms.”23 In R v Swain, Chief Justice Lamer (as not closely linked with the rationales for protecting expression the he then was), stated that “it has long been recognized that there court held that it was entitled to a very low degree of protection. also exists a preventative branch of the criminal law power.”24 In In contrast, expression that is closely linked to the underlying RJR-MacDonald v Canada (AG), the SCC confirmed that the power rationales will be afforded a high degree of protection. In sum, the to legislate with respect to dangerous goods also includes the power potential or actual harm that a product may pose is not sufficient to introduce legislation regarding health warnings on said goods.25 to strip it of constitutional protection entirely, but may result in a

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Freedom of Expression Litigation and the Harms of Cannabis

lesser degree of protection. Additionally, as will be discussed below, of harm as sufficient to satisfy this step. In Butler, the avoidance it will also inform the section 1 Oakes analysis. of harm was identified by the applicant as one pressing and substantial objective for overriding the constitutional protection (iii) Harm and Evidence afforded to the distribution of obscene materials. The respondents Scientific evidence can play a key role in a court’s decision re-characterized this as the state acting as a “moral custodian.”44 when assessing harm, although courts have inconsistently utilized In its decision, the majority referred to Keegstra, where the SCC scientific evidence. In some cases, significant amounts of scientific accepted that the prevention of the effects of hate propaganda evidence have been necessary to satisfy a court, whereas in other was a legitimate objective.45 In Keegstra, the harm was two-fold: instances a common sense causal relationship has been satisfactory. hate speech directly harms those to whom the speech is directed In the trial decision of RJR-MacDonald, for example, the Attorney and it harms society at large. The majority questioned whether General introduced a significant amount of evidence relating to hate propaganda was significant enough in Canada to warrant the health harms of tobacco use. However, Chabot J stated that Parliamentary intervention before ultimately concluding that it was not the court’s role to decide whether tobacco is or is not it “was not insignificant.”47 In fact, the majority noted that hate harmful, stating “the expert scientific evidence…was…irrelevant propaganda harms not only the persons on the receiving end of to the case.” 37 This failure to rule on the harmful effects of tobacco the hate propaganda, but also those who spew hate propaganda, was the Appellant’s first ground of appeal to the Court of Appeal.38 noting, “breeding hate is detrimental to society for psychological At the SCC, Justice La Forest (in dissent) disagreed with Chabot J’s and social reasons and that it can easily create hostility and finding, noting “the nature and scope of the health problems raised aggression which leads to violence.”48 Based on jurisprudence, by tobacco consumption are highly relevant to the s. 1 analysis, avoidance of harm appears to be sufficient to pass the pressing and both in determining the appropriate standard of justification and substantial requirement of the section 1 analysis. in weighing the relevant evidence.”39 When the court is satisfied that the avoidance of harm isa In contrast, in R v Butler the majority accepted that it would pressing and substantial objective and thus can justify a limitation be difficult to show a direct link between obscenity and harm, but on a Charter right, this determination impacts the remainder of accepted that “it is reasonable to presume that exposure to images the Oakes test depending on how narrowly or broadly the harm bears a causal relationship to changes and attitudes and beliefs.”40 is categorized. If the harm being avoided or mitigated is defined Further, the Court noted “[w]hile the accuracy of this perception broadly, it is generally easier for it to pass the rational connection is not susceptible of exact proof, there is a substantial body of test, because it will be easier to connect the infringement of opinion that holds that the portrayal of persons being subjected the right to the objective of avoiding or mitigating the harm in to degrading or dehumanizing sexual treatment results in harm, question. In Butler, Justice Sopinka conceptualized the harm in particularly to women and therefore to society as a whole.”41 Based question broadly, and in so doing, made it difficult for the statutory on this jurisprudence, the role of scientific and medical evidence in definition of obscenity that was under consideration to fail the determining the harm of cannabis use is unpredictable. As will be rational connection test.49 When harm is defined more narrowly, discussed, in the case of cannabis, harm is not nearly as clear-cut however, it will be more difficult to pass the rational connection as it is for tobacco or obscenity, and so how much evidence the test, because it will necessarily be more difficult to connect the court considers, if any, could have a significant impact on theOakes infringement to the objective. analysis. Harm is also considered in the minimal impairment analysis. In RJR-MacDonald, the SCC advised the legislature that it needed to (iv) Harm and the Oakes analysis differentiate between harmful advertising and benign advertising, While the Charter protects freedom of expression, section suggesting that restrictions must be sufficiently specific to prevent 1 of the Charter provides the state an opportunity to limit the articulated harm, and no more.50 If the harm is defined more rights, provided that any such restrictions are “reasonable limits broadly, this will afford the defendant government greater latitude prescribed by law as can be demonstrably justified in a free and than if the harm is articulated more specifically, which will require democratic society.”42 To ascertain whether a limitation on a right an equally specific response. It was at this stage the Tobacco Products is justified, the court relies on a test articulated in R v Oakes.43 The Control Act failed the Oakes test. Indeed, the Court did not think test has four stages: (1) there must be a pressing and substantial that the limitation was minimally impairing, characterizing the objective for the law; (2) the means chosen to achieve the objective ban implemented by the legislation as a total ban. In the follow-up must be rationally connected to the limit on the Charter right; (3) case of Canada (AG) v JTI-MacDonald, where the Court assessed the limit must minimally impair the right; and (4) there needs to be the successive legislation, the Tobacco Act, the Court found that the proportionally between the benefits of the limit on the right and its revised legislative scheme constituted a “partial ban” and thus deleterious effects. When assessing a limit on aCharter right, should passed this part of the Oakes test.51 the court find that the limit does not satisfy any one of these tests, Finally, the nature of the harm also impacts the proportionality the limitations is not justified, and therefore renders the legislation analysis. In Justice Sopinka’s dissenting decision in RJR-MacDonald, (or sections challenged) unconstitutional and of no force or effect. he stated: “I believe that any concern arising from this technical Judicial reasoning suggests that the degree of harmfulness of infringement of their rights is easily outweighed by the pressing the product being advertised may affect all stages of the Oakes health concerns raised by tobacco consumption.”52 In that case, the analysis. In determining whether the objective of the impugned significant harms associated with tobacco use made it easy for the legislation is pressing and substantial, harm is a central concept. dissenting opinion to justify the negative impact of the legislation Courts have consistently accepted the avoidance or mitigation on the advertiser’s rights, a position that was later affirmed in

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JTI-MacDonald.53 In JTI-MacDonald, the Court found significant CBD ratio increases the risk of adverse side effects, psychosis, and benefits associated with decreasing tobacco use and discouraging addiction.57 Additionally, higher potency forms of cannabis are young people from becoming addicted to tobacco, and that the being used with greater frequency, and hash oil concentrates, also deleterious effects on the right to freedom of expression were slight known as “wax”, “dabs”, or “shatter”, may contain as much as 80- in comparison. Specifically, a unanimous Court noted, “[w]hen 90% THC.58 The use of high potency products similarly increases commercial expression is used, as alleged here, for the purpose of the risk of adverse effects. inducing people to engage in harmful and addictive behavior, its While it is beyond the scope of this commentary to provide value becomes tenuous”, suggesting that it will be easier to restrict a comprehensive summary of all the research on the safety and commercial expression if a product is harmful.54 From this, it is risks of cannabis use, what can be stated is that while cannabis use likely that the harms associated with cannabis use will play a role is not risk-free, compared to other common substances, including in the Oakes analysis. alcohol, tobacco, and opioids, the cannabis-attributable disease burden is lower.59 Additionally, cannabis is not presently associated Freedom of Expression and the Harms of Cannabis with the social effects of drugs like alcohol and tobacco. Itis The harmfulness of cannabis will inevitably play a role commonly noted that alcohol is far more dangerous and represents in determining whether advertising restrictions are a justified a far greater harm than cannabis, and presently alcohol advertising infringement on freedom of expression. How narrowly or broadly is widespread and, when compared to tobacco or regulations about the government characterizes the harm will impact the rational cannabis under the Cannabis Act, quite permissive. The fact that connection stage of the Oakes test, and the degree of harm will also the alcohol industry has been successful in lobbying against state affect the proportionality analysis. The more potential for harm, intervention should not be a reason to avoid pursuing meaningful the easier it will be for Parliament to justify their actions. Tobacco regulation of cannabis products. However, when restrictions on advertising litigation is informative. In both RJR-MacDonald and cannabis advertising are brought to the court, it will be imperative JTI-MacDonald, the Court accepted the clear risks associated with for the state to present convincing evidence of the harms associated tobacco use. Unfortunately, the risk of harm is not as clear with with cannabis. There is also an opportunity as the regulation of cannabis. For example, cannabis has numerous medical applications, recreational cannabis evolves to reconsider what constitutes a and many more currently under investigation, and therefore has public health harm. the possibility to provide benefit to Canadians. Tobacco, on the other hand, has little, if any, medical benefits to users. Additionally, Conclusion determining the harmfulness of cannabis use has been complicated Over the past few decades, tobacco control efforts have had by politics. Canada is still transitioning from a Conservative a significant impact on where and how tobacco products can be government that focused on the adverse effects of cannabis, while advertised, sold, and used. There may be a temptation to simply ignoring the possible benefits, to a Liberal government that has apply the lessons of tobacco to cannabis, but this is short sighted prioritized legalization. Contextually, this means that Canadians and is unlikely to find success in the courts if challenged. Harm is are not starting from neutral ground. Care must be taken not to a central consideration in the constitutional analysis a court will over-correct for the conservative views of cannabis use by overly undertake in freedom of expression litigation. While commercial focusing on the benefits it offers. But the historical vilification of speech may not garner the same level of protection as other types cannabis use is a relevant contextual factor out of which cannabis of speech, it nevertheless remains a protected form of expression. legalization arises, and should inform the analysis. How the courts accept and rely on evidence relating to the harms To be sure, there are risks associated with the use of cannabis. associated with cannabis use, as well as how broadly or narrowly There are some widely accepted risks of using cannabis, but they the courts define the harms, will have a significant impact not are primarily acute, such as anxiety and paranoia, or associated only on freedom of expression litigation, but any constitutional with smoking, such as bronchitis or decreased lung function. While challenges to the Cannabis Act or Cannabis Regulations. there are long-term effects associated with regular cannabis use, such as decreased cognitive abilities, most long-term effects appear References to be reversible with the termination of cannabis use.55 Additionally, most of the adverse effects are associated with long-term, regular 1. Health Canada. Plenary Statement for the Honourable Jane Philpott Minister of Health – UNGASS on the World Drug Problem [Internet]. Ottawa: Government cannabis use, and a very small portion of the Canadian population of Canada; c2016 [updated 2016 April 20; cited 2019 June 19]. Available from: matches this description. While the majority of tobacco users https://www.canada.ca/en/health-canada/news/2016/04/plenary-statement- for-the-honourable-jane-philpott-minister-of-health-ungass-on-the-world-drug- smoke daily, most cannabis users use infrequently. Unfortunately, problem.html?=undefined&wbdisable=true? the science on the effects of cannabis are overwhelmingly 2. Government of Canada. Legalizing and strictly regulating cannabis: The facts unsettled, and more research is needed. However, the potency of [Internet]. Ottawa: Government of Canada; c2018 [updated 2018 October 18; cited 2019 June 19]. Available from: https://www.canada.ca/en/services/ cannabis, measured by its tetrahydrocannabinol (THC) content, health/campaigns/legalizing-strictly-regulating-cannabis-facts.html has increased exponentially over the last few decades. Selective 3. Access to Cannabis for Medical Purposes Regulations, SOR/2016-230 [re- breeding for the illicit market has resulted in higher concentrations, pealed]. 4. Canadian Centre on Substance Use and Addiction. Cannabis (Canadian Drug with most cannabis now containing over 10% THC, and even up Summary) [Internet]. [Place unknown]: Canadian Centre on Substance Use and to 30% in the case of some medical cannabis products. While Addiction; c2018 [updated 2018; cited 2019 June 19]. Available from: http:// www.ccsa.ca/Resource%20Library/CCSA-Canadian-Drug-Summary-Canna- THC concentrations have risen, cannabidiol (CBD) content has bis-2018-en.pdf decreased, dropping to below 0.2%.56 The increasing THC-to-

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Freedom of Expression Litigation and the Harms of Cannabis

5. Akhigbe J, Ebbadi V, Huynh K, et al. The Public Health Implications of the Le- 29. RJR-MacDonald Inc. v Canada (Attorney General), [1991] RJQ 2260, 82 DLR galization of Recreational Cannabis [Internet]. Toronto: Ontario Public Health (4th) 449 (QL) (Sup Ct) at 9-10. Association; c2017 [cited 2019 June 19]. Available from: https://opha.on.ca/ 30. RJR-MacDonald Inc. v Canada (Attorney General), [1991] RJQ 2260, 82 DLR getmedia/6b05a6bc-bac2-4c92-af18-62b91a003b1b/The-Public-Health-Impli- (4th) 449 (QL) (Sup Ct) at 14. cations-of-the-Legalization-of-Recreational-Cannabis.pdf.aspx?ext=.pdf 31. RJR-MacDonald Inc. v Canada (Attorney General), [1991] RJQ 2260, 82 DLR 6. Memedovich KA, Dowsett LE, Spackman E, et al. The adverse health ef- (4th) 449 (QL) (Sup Ct) at 14. fects and harms related to marijuana use: An overview review. CMAJ 2018 32. RJR-MacDonald Inc. v Canada (Attorney General), [1991] RJQ 2260, 82 DLR August;6(3):E339–E346. (4th) 449 (QL) (Sup Ct) at 25. 7. For the sake of brevity, through the paper the use of the word cannabis includes 33. RJR-MacDonald Inc. v Canada (Attorney General), [1993] 102 DLR (4th) 289, cannabis accessories and cannabis services, unless indicated otherwise. RJQ 375 (QL)(CA) at 20. 8. Harm Reduction International. What is harm reduction? [Internet]. [Place un- 34. RJR-MacDonald Inc. v Canada (Attorney General), [1993] 102 DLR (4th) 289, known]: Harm Reduction International; c2019 [cited 2019 June 19]. Available RJQ 375 (QL)(CA) at 25. from: https://www.hri.global/what-is-harm-reduction 35. Irwin Toy v Quebec (AG), [1989] 1 SCR 927. Available from: https://scc-csc. 9. Government of Canada. Harm Reduction: Canadian Drugs and Substances lexum.com/scc-csc/scc-csc/en/item/443/index.do Strategy [Internet]. Ottawa: Government of Canada; 2018 [Updated 2018 Au- 36. RJR-Macdonald v Canada (AG), [1995] 3 SCR 199. Available from: https:// gust 13; cited 2019 June 19]. Available from: https://www.canada.ca/en/health- scc-csc.lexum.com/scc-csc/scc-csc/en/item/1290/index.do at para 75. canada/services/substance-use/canadian-drugs-substances-strategy/harm-re- 37. RJR-MacDonald Inc. v Canada (Attorney General), [1991] RJQ 2260, 82 DLR duction.html (4th) 449 (QL) (Sup Ct) at 28–29. 10. Task Force on Cannabis Legalization and Regulation. A Framework for the Le- 38. RJR-MacDonald Inc. v Canada (Attorney General), [1993] 102 DLR (4th) 289, galization and Regulation of Cannabis in Canada: The Final Report of the Task RJQ 375 (QL) (CA) at 28. Force on Cannabis Legalization and Regulation [Internet]. Ottawa: Government 39. RJR-Macdonald v Canada (AG), [1995] 3 SCR 199. Available from: https:// of Canada; 2016 [Updated 2016 November 30; cited 2019 June 19]. Available scc-csc.lexum.com/scc-csc/scc-csc/en/item/1290/index.do at para 66. from: https://www.canada.ca/en/health-canada/services/drugs-medication/ 40. R v Butler, [1992] 2 SCR 452, SCJ No 15. Available from: https://scc-csc.lexum. cannabis/laws-regulations/task-force-cannabis-legalization-regulation/frame- com/scc-csc/scc-csc/en/item/844/index.do at para 103. work-legalization-regulation-cannabis-in-canada.html 41. R v Butler, [1992] 2 SCR 452, SCJ No 15. Available from: https://scc-csc.lexum. 11. Crépault JF. Cannabis legalization in Canada: Reflections on public health and com/scc-csc/scc-csc/en/item/844/index.do at para 50. the governance of legal psychoactive substances. Front Public Health. 2018 42. Canadian Charter of Rights and Freedoms, s 8, Part 1 of the Constitution Act, Aug;6:220. doi: 10.3389/fpubh.2018.00220 1982, being Schedule B to the Canada Act 1982 (UK), 1982, c 11. Available from: 12. Harms associated with black market cannabis include: greater likelihood of en- https://laws-lois.justice.gc.ca/eng/const/page-15.html. countering weapons, adulterated or contaminated products, increased personal 43. R v Oakes, [1986] 1 SCR 103. Available from: https://scc-csc.lexum.com/scc- risks of harm (e.g., assaults), blackmail, and consumers being less likely to contact csc/scc-csc/en/item/117/index.do the police or other authorities for fear of legal ramifications. 44. R v Oakes, [1986] 1 SCR 103. Available from: https://scc-csc.lexum.com/scc- 13. Crépault JF. Cannabis Policy Framework [Internet]. [Place unknown]: Centre csc/scc-csc/en/item/117/index.do at para 77. for Addictions and Mental Health; 2014 [cited 2019 June 19]. Available from: 45. R v Oakes, [1986] 1 SCR 103. Available from: https://scc-csc.lexum.com/scc- https://www.camh.ca/-/media/files/pdfs---public-policy-submissions/camh- csc/scc-csc/en/item/117/index.do at para 87. cannabispolicyframework-pdf.pdf 46. R v Keegstra, [1990] 3 SCR 697, SCJ No 131. Available from: https://scc-csc. 14. Statement on Legalization on Cannabis [Internet]. [Place unknown: Centre lexum.com/scc-csc/scc-csc/en/item/695/index.do at paras 60-62. for Addiction and Mental Health; c2019 [cited 2019 June 19]. Available from: 47. R v Keegstra, [1990] 3 SCR 697, SCJ No 131. Available from: https://scc-csc. https://www.camh.ca/en/camh-news-and-stories/camh-statement-on-the-legal- lexum.com/scc-csc/scc-csc/en/item/695/index.do at para 59. ization-of-cannabis 48. R v Keegstra, [1990] 3 SCR 697, SCJ No 131. Available from: https://scc-csc. 15. Crépault JF. Cannabis Policy Framework [Internet]. [Place unknown]: Centre lexum.com/scc-csc/scc-csc/en/item/695/index.do at para 10. for Addictions and Mental Health; 2014 [cited 2019 June 19]. Available from: 49. R v Butler, [1992] 2 SCR 452, SCJ No 15. Available from: https://scc-csc.lexum. https://www.camh.ca/-/media/files/pdfs---public-policy-submissions/camh- com/scc-csc/scc-csc/en/item/844/index.do at paras 88, 92 [Sopinka J catego- cannabispolicyframework-pdf.pdf rized the harm generally as “the harm associated with the dissemination of por- 16. Canadian Public Health Association. A public health approach to the legaliza- nography.” Earlier, he stated that the materials in question cause similar harms tion, regulation and restriction of access to cannabis [Internet]. [Place unknown]: as those recognized by the courts in the past, namely, they “seriously offend the Canadian Public Health Association; 2017 Oct [Updated 2017 November 6; cited values fundamental to our society.”] 2019 June 20]. Available from: https://www.cpha.ca/public-health-approach-le- 50. RJR-Macdonald v Canada (AG), [1995] 3 SCR 199. Available from: https:// galization-regulation-and-restriction-access-cannabis scc-csc.lexum.com/scc-csc/scc-csc/en/item/1290/index.do at para 188. 17. Irwin Toy v Quebec (AG), [1989] 1 SCR 927. Available from: https://scc-csc. 51. Canada (Attorney General) v JTI-MacDonald Corp., 2007 SCC 30. Available lexum.com/scc-csc/scc-csc/en/item/443/index.do from: https://scc-csc.lexum.com/scc-csc/scc-csc/en/item/2369/index.do 18. RJR-Macdonald v Canada (AG), [1995] 3 SCR 199. Available from: https:// 52. RJR-Macdonald v Canada (AG), [1995] 3 SCR 199. Available from: https:// scc-csc.lexum.com/scc-csc/scc-csc/en/item/1290/index.do scc-csc.lexum.com/scc-csc/scc-csc/en/item/1290/index.do at para 118. 19. Rocket v Royal College of Dental Surgeons (Ontario), [1990] 2 SCR 232. Avail- 53. Canada (Attorney General) v JTI-MacDonald Corp., 2007 SCC 30. Available able from: https://scc-csc.lexum.com/scc-csc/scc-csc/en/item/628/index.do from: https://scc-csc.lexum.com/scc-csc/scc-csc/en/item/2369/index.do 20. Constitution Act, 1867, 30 & 31 Victoria, c. 3. (UK). 54. Canada (Attorney General) v JTI-MacDonald Corp., 2007 SCC 30. Available 21. RJR-Macdonald v Canada (AG), [1995] 3 SCR 199. Available from: https:// from: https://scc-csc.lexum.com/scc-csc/scc-csc/en/item/2369/index.do at scc-csc.lexum.com/scc-csc/scc-csc/en/item/1290/index.do para 47. 22. RJR-Macdonald v Canada (AG), [1995] 3 SCR 199. Available from: https:// 55. Maisto SA, Galizio M, Connors GJ. Drug use and abuse. 7th ed. Stamford, CT: scc-csc.lexum.com/scc-csc/scc-csc/en/item/1290/index.do at para 200. Cengage Learning; 2015. p. 498. 23. R v Keegstra, [1990] 3 SCR 697, SCJ No 131. Available from: https://scc-csc. 56. ElSohly MA, Mehmedic Z, Foster S et al. Changes in cannabis potency over the lexum.com/scc-csc/scc-csc/en/item/695/index.do at para 114. last 2 decades (1995-2014): Analysis of current data in the United States. Biol 24. R v Swain, [1991] 1 SCR 933, SCJ No 32. Available from: https://scc-csc.lexum. Psychiatry. 2016 Apr; 79(7):613-9. doi: 10.1016/j.biopsych.2016.01.004 com/scc-csc/scc-csc/en/item/753/index.do at para 999. 57. Pierre JM. Risks of Increasingly potent cannabis: The joint effects of potency 25. RJR-Macdonald v Canada (AG), [1995] 3 SCR 199, online: https://scc-csc. and frequency: As THC levels rise, the risk of psychosis, cognitive deficits, and lexum.com/scc-csc/scc-csc/en/item/1290/index.do at para 41. structural brain changes increases. Curr Psychiatry. 2017 Feb;16(2):15–20. 26. RJR-Macdonald v Canada (AG), [1995] 3 SCR 199. Available from: https:// 58. Pierre JM. Risks of Increasingly potent cannabis: The joint effects of potency scc-csc.lexum.com/scc-csc/scc-csc/en/item/1290/index.do at paras 203, 206. and frequency: as THC levels rise, the risk of psychosis, cognitive deficits, and 27. Ford v Quebec (Attorney General), [1988] 2 SCR 712, SCJ No 88. Available from: structural brain changes increases. Curr Psychiatry. 2017 Feb;16(2):15–20. https://scc-csc.lexum.com/scc-csc/scc-csc/en/item/384/index.do at para 47. 59. Imtiaz S, Shield KD, Roerecke M, et al. The burden of disease attributable to can- 28. RJR-MacDonald Inc. v Canada (Attorney General), [1991] RJQ 2260, 82 DLR nabis use in Canada in 2012. Addiction. 2016 Apr;111(4):653-62. doi: 10.1111/ (4th) 449 (QL) (Sup Ct) at 3. add.13237

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Cannabis & driving research: Lessons from an unlikely teacher

Liliana Alvarez (PhD)1

1School of Occupational Therapy, Faculty of Health Sciences, Western University, 1201 Western Road, London, Ontario

own. The need for evidence and the expertise of multidisciplinary Abstract teams across the country constitute an ideal platform for evidence- The legalization of Cannabis has important implications informed action around cannabis legalization, but only if we for the life of Canadians including community mobility, can overcome the common pitfalls of siloed and disjointed work, law enforcement, and injury prevention, among others. an almost universally perceived barrier to the advancement of 5,6 In this context, and at the intersection between these effective public health initiatives. Furthermore, with legalization, dimensions of civic participation and public health, establishing collaborations that leverage resources and expertise requires a proactive and pre-emptive approach to cannabis- impaired driving emerges as a concern among the related challenges, instead of the reactive care framework that general public, and a risk for Canadian drivers and characterizes the Canadian health system.7 road users. The scientific community and government The critical need for collaborative and proactive cannabis- agencies have recognized a general need to build a body related research in the Canadian context is heightened by the of evidence around cannabis-related research. However, apparent increase in cannabis consumption since legalization. common pitfalls to the generation of timely, suitable, and Through an online survey (n = 1,001 general population; 1,500 effective research must be avoided. This commentary past-year cannabis users) conducted from December 13th to 21st, presents a reflection on the role research must play in the 2018, Resonance Consultancy and Valens Groworks found that: development of proactive and pre-emptive action and 23% of respondents have used cannabis since legalization; 16% of applies it to the field of impaired driving. The latter is surveyed established cannabis users have increased their cannabis achieved by drawing on the example of alcohol-related use in the months after legalization; and 5% of respondents indicated research as a blueprint on the path to injury prevention in having used cannabis for the first time.8 This is not surprising given the context of cannabis-impaired driving. that a careful examination of evidence from American states where legalization is in place indicated Canada should expect an increase in cannabis use, as well as in the incidence of risky behaviours such as driving under the influence of cannabis (DUIC), especially among youth.9-12 This is concerning given that youth between the Introduction ages of 15 and 24, who represent 13% of the driving population, n October 17th, 2018, Canada became the second have the highest rates of cannabis use in Canada and account for country to enact the legalization of recreational cannabis, more than 20% of road traffic fatalities and injuries.13 Thus, it is joining Uruguay as the only countries with such federal necessary to generate contextually relevant data that can guide Olegislation.1-3 This legislative change has important implications the development and implementation of feasible and effective for the life of Canadians beyond access to regulated product, interventions, with high levels of uptake and acceptability among including but not limited to: public health, injury prevention, those at-risk. Although cannabis legalization in the Canadian community mobility, and law enforcement. Canadian provinces context is in its infancy, and although there are several challenges must now navigate these and other emerging challenges associated for the development of contextually relevant evidence as outlined, with the enactment of this legislation, a process for which the there is an unlikely teacher that has been immersed in the Canadian generation of scientific evidence is paramount. In fact, the context for decades, journeying from prohibition to legalization federally commissioned 2016 Task Force on Cannabis Legalization to becoming part of the social and economic fabric of Canadian and Regulation report states that their recommendations “reflect societies: alcohol. A careful and critical examination of approaches the fact that the current scientific understanding of cannabis to alcohol and the development of evidence around alcohol- impairment has gaps and that more research and evidence, related impairment can serve as a blueprint to avoid repeating the investments in law enforcement capacity, technology and tools, and same mistakes, and enhancing our ability to develop a proactive comprehensive public education are needed urgently.”4 However, framework to cannabis-impaired driving research and education, the Canadian scientific community now faces a challenge of its in the context of injury prevention.

Cannabis: Implications of a Legalization Approach In order to fully consider the lessons learned from alcohol and Corresponding Author: Liliana Alvarez its potential applicability to cannabis, it is necessary to highlight [email protected] the distinction between legalization and decriminalization that

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Cannabis & driving research: Lessons from an unlikely teacher

characterizes the global landscape of recreational cannabis. public education, especially among certain demographics such Decriminalization approaches, still within a framework of as youth, with individuals aware of legalization but unaware of prohibition, attempt to decrease the disproportionate arrests and specific impact on health, or even uses that could still lead to charges for simple possession by utilizing non-criminal penalties.14 criminal charges.19,23 A concerning example of these criticisms While cannabis remains illegal under a decriminalization approach, materializes in DUIC: 1) cannabis is known to increase the risk individuals in possession of cannabis less than a pre-established of motor vehicle collisions (MVCs) and the death rates among quantity do not face prosecution, and criminal sanctions for the vulnerable road users24-26; 2) in the absence of a confirmed body behaviour are removed.15 In doing so, decriminalization aims to of evidence regarding concentration, variability among methods also address the social determinants that have so heavily influenced of consumption, and methods to determine cannabis metabolic cannabis possession arrests, namely age, race, and ethnicity, rates on-road, law enforcement personnel will be making risky which persist in spite of similar patterns of recreational use judgement calls about whether to lay charges for impaired across racial and ethnic groups.14,16,17 Decriminalization is often driving20,27; and 3) young drivers are aware of cannabis legalization criticized for failing to address issues resulting from a prohibition but express lack of concern regarding DUIC21 in spite of the framework, including the development of illicit markets and the fact that they constitute an overrepresented population in MVC potential negative health effects of cannabis production without fatalities,28 and that impaired driving remains illegal.29 Although regulatory oversight.14 In adopting a legalization framework, the the criticisms to legalization have practical implications for fitness- Canadian federal government has aligned with a discourse around to-drive research, and are therefore compelling from the point of commitment to public health, by establishing and enforcing strict view of this commentary, it is important to note that such criticisms quality and safety regulations around production, distribution, may also be influenced by moral narratives around substance use. and sales, as well as programs to support addiction treatment and Daniell Malleck has written extensively on this issue,30 and has education.4 In spite of this goal, criticism of legalization persists used alcohol as a comparison for how Canadians have developed a given its practical implications for public health and safety. Figure morality of health that extends to cannabis use.31 1 summarizes three of the most wide-spread criticisms facing cannabis legalization in Canada, and uses DUIC as an example to Alcohol: An Unlikely Teacher illustrate the risks that these criticisms convey.15,18-21 During the early 1900s the Canadian Federal Government The criticisms can be broadly summarized in three categories: required all provinces to pass alcohol prohibition laws in order 1) the evidence, with various studies supporting the negative to assist with the war efforts.31 These laws, first implemented in effects of cannabis on physical health (e.g. carcinogenesis and Prince Edward Island, were also the result of years of advocacy of reproductive health) and mental health (e.g. gateway sequence the temperance movement, a social and political movement that to addiction and increased risk of schizophrenia);15 2) potentially promoted moderation or abstinence as a way to alleviate social rushed implementation, given that provinces must promptly enact issues including crime.32 Soon after the war, however, Canadians regulations to control the market which might result in insufficient faced the repeal of prohibition laws and journeyed towards the time to integrate available evidence or developing consultative and legalization of alcohol across provinces. By 1948, all Canadian collaborative approaches across stakeholders;19,22 and 3) insufficient provinces had repealed prohibition laws and alcohol was produced, distributed, and sold across the country.32 Similar to cannabis legalization, provincial governments were charged with regulating the distribution of alcohol and enacting its regulations, and there was much social debate and expressions of concern and fear.33 With this backdrop, it would be hard to imagine then that the evidence surrounding alcohol consumption and the ever-evolving efforts for knowledge translation would become strong public health initiatives to prevent inappropriate use, such as drinking and driving. Since then, much evidence has emerged on the impact of alcohol on human health. This has led to the development of evidence-based guidelines to advise Canadians on the risks of alcohol consumption, and the strategies to minimize negative effects for those who choose to drink. For example, the Canadian Centre on Substance Use and Addiction produced Canada’s Low-Risk Drinking Guidelines recommending a maximum of 10 drinks/week for women without exceeding 2/day; and 15 drinks/ week for men, without exceeding 3/day.34 In the context of impaired driving, the cumulative evidence against the use of alcohol has led to wide-spread public health initiatives and education efforts. Systematic literature reviews conclude that alcohol consumption can negatively impact driving performance.35,36 Furthermore, recent evidence suggests that Figure 1. Summary of legalization criticisms and examples from impaired promising advances in drinking and driving prevention among driving concerns. Note: MVCs= Motor vehicle collisions; DUIC= Driving under the influence of cannabis youth might be possible through the implementation of short (<5

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Cannabis & driving research: Lessons from an unlikely teacher hrs of contact) interventions.36 But these initiatives, or the fact that health and social issues, and the decrease in evidence informed almost every driver in Canada has heard or read in some format strategies to sustain political and social efforts.38,47 that drinking and driving is an extremely risky behavior, did not Although this commentary does not constitute a systematic develop overnight. As described by the Canadian Public Health review of the literature around alcohol-impaired driving research, Association: the progress made in combating alcohol-impaired driving and “for nearly 90 years, government agencies, police services, traffic the remaining challenges illuminate at least four lessons we can safety organization, public health and victims groups have been working learn from almost nine decades of efforts in this area. Table 1 to end impaired driving… Though significant progress has been made summarizes four proposed lessons in the path to cannabis-related in the fight against impaired driving, particularly in the 1970s and injury prevention as it relates to alcohol-impaired driving. 1980s, there is still much work to be done.” 37 Table 1. Lessons learned from alcohol-impaired driving research Where We’ve Been and Where to Go From Here 1. We must partner effectively with drivers, driving school instructors, advocacy Over the last century, multiple stakeholders including groups, government agencies, public health units, and victim groups, if we are to researchers, government agencies, and advocacy groups, have develop feasible and effective interventions that are also acceptable and suitable for high-risk populations such as youth. Not doing so can lead us down the path contributed collectively to the adoption of evidence-based of developing efficacious interventions in the lab that produce little impact on the ground, and do not attend to the specific risk profiles and predictors of impaired strategies and initiatives addressing alcohol-impaired driving. The driving. adoption of evidence-informed blood alcohol concentration (BAC) 2. We must develop nation-wide and multidisciplinary research partnerships that level limits for drivers, increased sanctions for drivers under the leverage the financial, human, and infrastructure resources that enable the study of the effects of cannabis on driving performance. By not doing so, we risk the influence of alcohol, and increased public attention and education replication of efforts, limit the validity of our findings, and prolong the knowledge around the dangers and moral implications of alcohol-impaired translation timeline. 38 driving, are among such initiatives. Over the years, especially in 3. We must prioritize not only the development of guidelines around what the 80s and 90s, such initiatives resulted in significant reductions in constitutes cannabis-impairment when driving and how to detect it, but also understanding the individual, social, and cultural factors that influence a driver’s 38,39 alcohol-related fatalities and severe injuries. The development decision to consume cannabis and drive. of such initiatives, however, did not follow a smooth and prompt 4. We must develop a body of evidence around the efficacy of education strategies linear trajectory from identifying the dangers and concerns to including messaging, delivery method, and content regarding cannabis-impaired driving. developing and implementing the necessary solutions. For example, developing the necessary evidence on the effectiveness of alcohol- impaired driving reduction strategies required not only disciplinary Conclusions single component studies, but comprehensive, thorough, A recent Canadian Automobile Association (CAA) poll revealed multicomponent programs that integrated community mobilization that 69% of Canadians are concerned that roads will become more efforts.40 Such programs have been effective in reducing alcohol- dangerous with cannabis legalization.48 But legalization is here and related crashes by addressing access to alcohol, responsible service we must own the challenge of building a body of evidence around provision and training, sobriety road checkpoints, public education, its effects that enables proactive and pre-emptive action. Alcohol law-enforcement, and media advocacy among others.40 Given reminds us this is not the first time that a substance that sparks their scope, such programs require greater financial and human debate and controversy has made its way to Canadian regulated resources, as well as partnerships across stakeholders. Furthermore, markets. However, it took decades to develop the synergies and earlier research efforts faced multiple methodological challenges, partnerships required to effect change in the alcohol-impaired including: the need for larger samples of individuals, communities, driving landscape. In addition, years of intervention research were and localities to test the effectiveness of initiatives and interventions; necessary in order to realize the critical need to understand the the timing at which different initiatives were launched in different determinants of impaired driving, as well as the need to examine communities, which in turn makes it difficult to assess the effects of educational strategies among other issues. And the work is not specific interventions; a lack of, or difficulty in, accessing detailed complete. We must learn the lessons alcohol can teach us, and information about BAC levels in motor vehicle collision reports; move forward into collective dedicated action. The stakes are too and funding to conduct large scale studies that could consider high and the cost, human lives, inadmissible. representative population and environmental conditions.39,40 As a result, decades of alcohol-related research efforts to overcome References such challenges identified the need for: linkages and coalitions 1. Walsh J, Ramsey G. Uruguay’s drug policy: Major innovations, major challenges. that enable coordinated and collaborative approaches to DUI Foreign Policy at Brookings; 2016. prevention;41 evidence-informed programs that enhance youth’s 2. Laursen L. Canada today becomes the second country to legalize weed. Here's what it can learn from the first. Fortune. 2018. personal skills and that understand and address the personal, social, 3. Lemon J. Which countries could legalize marijuana in 2019? Newsweek. 2018. and cultural determinants of DUI;42,43 initiatives that integrate 4. McLellan AA, Ware M, Boyd S, et al. A framework for the legalization and regulation of cannabis in Canada. Ottawa, ON: Health Canada; 2016. Contract No.: DUI interventions with other road safety initiatives such as other 160248. 44 risky behaviors; and a need to consider the effectiveness of DUI 5. Johnson R, Grove A, Clarke A. It's hard to play ball: A qualitative study of knowl- education including delivery methods, messaging, and reach.45,46 edge exchange and silo effects in public health. BMC health services research. 2018;18(1):1. Since the beginning of the 21st century, however, progress on 6. Ogilvie KK. The silo syndrome in Canadian health care. Health Research Foun- the reduction of alcohol-impaired driving fatalities and injuries dation Medal of Honor Gala; Montreal, QC: Policy Magazine; 2014. p. 1-2. stagnated and rates have plateaued as a result of multiple factors 7. MaRS. Transforming Health: Shifting from reactive to proactive and predictive care. 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8. Resonance Consulting. The future of cannabis in Canada: A post-legalization 30. Malleck D. When good drugs go bad: Opium, medicine, and the origins of Can- study of national sentiment. Kelowna, BC: Resonance Consulting & Valens Gro- ada’s drug laws. Vancouver, Canada: UBC Press; 2016. 320 p. Works. 2019. 31. Malleck D. What alcohol prohibition can teach us about the legalization of can- 9. Kalant H. A critique of cannabis legalization proposals in Canada. International nabis. The Globe and Mail. 2018;Sect. Opinion. Journal of Drug Policy. 2016;34:5-10. 32. Decarie G. Temperance movement in Canada. In: Yarhi E, editor. The Canadian 10. Palamar JJ, Ompad DC, Petkova E. Correlates of intentions to use cannabis Encyclopedia: Wilson-Smith, A. 2013. among US high school seniors in the case of cannabis legalization. International 33. Malleck D. Try to control yourself: The regulation of public drinking in post- Journal on Drug Policy 2014;25(3):424-35. prohibition Ontario, 1927-44. 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Effects of brief alcohol inter- 14. Drug Policy Alliance. Marijuana decriminalization and legalization. New York, ventions on drinking and driving among youth: A systematic review and meta- U.S.: Drug Policy Alliance; 2018. analysis. Journal of addiction & prevention. 2015;3(1):11. 15. Svrakic DM, Lustman PJ, Mallya A, et al. Legalization, decriminalization & me- 37. Canadian Public Health Association. Fighting the good fight: Impaired driving dicinal use of cannabis: a scientific and public health perspective. Missouri medi- in Canada n.d. [Available from: https://www.cpha.ca/fighting-good-fight-im- cine. 2012;109(2):90-8. paired-driving-canada. 16. Mitchell O, Caudy MS. Race differences in drug offending and drug distribution 38. Fell JC, Beirness DJ, Voas RB, et al. Can progress in reducing alcohol-impaired arrests. Crime & Delinquency. 2017;63(2):91-112. driving fatalities be resumed? Results of a workshop sponsored by the Transpor- 17. Nguyen H, Reuter P. How risky is marijuana possession? Considering the role of tation Research Board, Alcohol, Other Drugs, and Transportation Committee age, race, and gender. Crime & Delinquency. 2012;58(6):879-910. (ANB50). Traffic Injury Prevention. 2016;17(8):771-81. 18. Bojkovsky C, Callan D, Childs JD, et al. Legalizing and regulating cannabis in 39. Voas R, Fell J. Preventing impaired driving opportunities and problems. Alcohol Saskatchewan. Saskatchewan, Canada: Johnson Shoyana Graduate School of Research & Health. 2011;34(2):225-35. Public Policy; 2017. 40. Shults RA, Elder RW, Nichols JL, et al. Effectiveness of multicomponent pro- 19. Cecco L. Dazed and confused: Canada cannabis legalization brings complex new grams with community mobilization for reducing alcohol-impaired driving. laws. The Guardian. 2018 October 16, 2018;Sect. Canada. American Journal of Preventive Medicine. 2009;37(4):360-71. 20. Connolly A. Here are the challenges police could face in laying charges for pot- 41. DeJong W, Hingson R. Strategies to reduce driving under the influence of alco- impaired driving. Global News. 2018 October 16, 2018;Sect. Canada. hol. Annual Review of Public Health. 1998;19(1):359-78. 21. Jonah B, Todd V. Public opinion survey of drugs and driving in Canada. Cana- 42. Cestac J, Kraïem S, Assailly J-P. Cultural values and random breath tests as mod- dian Council of Motor Transport Administrators. 2013. erators of the social influence on drunk driving in 15 countries. Journal of Safety 22. DeVillaer M. Cannabis law reform in Canada: Pretense & perils. Hamilton, Research. 2016;56:89-96. Ontario: The Peter Boris Centre for Addictions Research-McMaster University. 43. Fernando M, Buckland J, Melwani P, et al. Perceived driving safety and estimated 2017. blood alcohol concentration (BAC) the morning after drinking amongst young 23. Karbakhsh M, Smith J, Pike I. “Where does the high road lead?” Potential impli- Australians attending a music festival: a cross-sectional survey. Substance abuse cations of cannabis legalization for pediatric injuries in Canada. Canadian Jour- treatment, prevention, and policy. 2018;13(1):25-. nal of Public Health. 2018;109(5):752-5. 44. Hingson R, McGovern T, Howland J, et al. Reducing alcohol-impaired driving 24. Li M-C, Brady JE, DiMaggio CJ, et al. Marijuana use and motor vehicle crashes. in Massachusetts: the Saving Lives Program. American Journal of Public Health. Epidemiologic reviews. 2012;34(1):65-72. 1996;86(6):791-7. 25. Asbridge M, Hayden JA, Cartwright JL. Acute cannabis consumption and motor 45. Paz A, Copeland D, Maheshwari P, et al. The effectiveness of driver education vehicle collision risk: systematic review of observational studies and meta-analysis. and information programs in the state of Nevada. Open Journal of Applied Sci- BMJ. 2012;344:e536. ences. 2015;5(1):13. 26. Bondallaz P, Favrat B, Chtioui H, et al. Cannabis and its effects on driving skills. 46. Yadav R-P, Kobayashi M. A systematic review: effectiveness of mass media cam- Forensic Sci Int. 2016;268:92-102. paigns for reducing alcohol-impaired driving and alcohol-related crashes. BMC 27. Canadian Police Association Position Paper: Legalization of recreational mari- public health. 2015;15:857. juana [press release]. Ottawa, Ontario2017. 47. Sweedler BM, Biecheler MB, Laurell H, et al. Worldwide trends in alcohol and 28. MADD Canada. Youth and Impaired Driving 2018 [Available from: https:// drug impaired driving. Traffic Inj Prev. 2004;5(3):175-84. madd.ca/pages/programs/youth-services/statistics-links/. 48. Canadian Automobile Association. Canadians worried roads will be unsafe when 29. Royal Canadian Mounted Police. Youth impaired driving n.d. [Available from: marijuana legalized. 2016 [Available from: https://www.caa.ca/canadians-wor- http://www.rcmp-grc.gc.ca/cycp-cpcj/id-cfa/index-eng.htm. ried-roads-will-be-unsafe-when-marijuana-legalized/.

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Growing up high: Understanding the impacts of adolescent cannabis use on mental health and brain development

Steven R. Laviolette (Ph.D.)

Department of Anatomy & Cell Biology, Dept. of Psychiatry, Schulich School of Medicine & Dentistry, University of Western Ontario

Introduction Abstract What’s so Special about the Adolescent Brain? Adolescence represents one of the most crucial n humans and most other mammalian species, adolescence periods of human brain development. This unique represents a critically important window for brain neurodevelopmental window involves a complex interplay development. Combined with the surge in puberty-related sex of synaptic re-modelling, the establishing of cortical and hormones,I critical periods of synaptic pruning and re-modelling sub-cortical emotional processing and cognitive neural are ongoing processes within the adolescent neocortex, allowing circuits along with a greater propensity for engaging for the fine-tuning of synaptic communication and plasticity associated with normal cognitive development and higher-order in risky behaviours and experimentation with illicit executive control functions over adaptive behaviours.1,2 Notably, drugs. A growing body of both clinical and pre-clinical critical regulatory pathways between higher cortical regions such evidence has demonstrated that exposure to cannabis, as the prefrontal cortices and sub-cortical emotional processing and more specifically, Δ-9-tetrahydrocannabinol (THC), circuits such as the mesolimbic pathway, comprising the ventral the primary psychoactive compound in cannabis, can tegmental area (VTA) and nucleus accumbens (NAc) and the strongly increase the likelihood of developing serious amygdaloid nuclei, are in the process of maturation. Indeed, these higher cortical regions are amongst the last to develop to maturity neuropsychiatric disorders in later life. Adolescent THC in the mammalian brain, which has critical implications for the exposure is linked to long-term cognitive impairments, ability (or lack thereof) of adolescents to regulate sub-cortical emotional dysregulation, mood disorders and increased neural regions such as the mesolimbic system and amygdala, vulnerability to schizophrenia. The interplay between all of which are crucial emotional processing centres3,4 and are adolescent THC exposure and mental health risks have known to be pathologically dysregulated in a wide array of mental health disorders, including depression, anxiety, addiction been linked to a wide array of underlying neurobiological and schizophrenia. The brain’s cannabinoid signaling system is pathologies, including structural and morphological found ubiquitously in the brain. However, high concentrations alterations in brain circuits linked to cognitive function and of central cannabinoid receptors (CB1Rs), upon which extrinsic emotional regulation. Despite this growing body of data, cannabinoids such as THC act on, have been found to be there remains considerable confusion and misinformation localized in neural regions critical to emotional regulation and regarding how and why adolescent cannabis use can cognitive processing, including the brain regions described above 5,6, wherein they can potently modulate affective and ultimately increase these psychopathological risk factors. cognitive functions associated with mood disorders, addiction Nevertheless, the confluence of clinical and pre-clinical and schizophrenia-related symptoms.7-11 neuroscience research related to these questions is finally Historically, Canada has consistently been a global leader in providing much needed insight into the relative risks and adolescent cannabis usage rates. Indeed, as recently as 2013, it was identifying useful biomarkers that may ultimately allow us reported that Canadian adolescents (11 to 15 years) maintained the highest rates of cannabis consumption when compared to 29 to establish more reliable criteria and guidelines for safer similar advanced economies.12-14 This report revealed that 28% cannabis access and help mitigate these risks to mental of Canadian adolescents had consumed cannabis at least once health. over the past year. In addition, there is evidence for increasing frequency of usage, as a growing percentage of Canadian adolescent users (22% of boys and 10% of girls) report being daily or weekly users.12-14 Given that legalization has only recently taken place in Canada, the ways in which changes to cannabis Corresponding Author: access may influence these rates are not yet known. Nevertheless, Steven R. Laviolette clear and consistent evidence both from clinical and pre-clinical [email protected]

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Growing up high: Understanding the impacts of adolescent cannabis use on mental health and brain development

research studies has demonstrated a link between adolescent Research in our laboratory and others has identified the primary exposure to cannabis and increased vulnerability to a variety of neurobiological mechanisms by which CBD produces its anti- neuropsychiatric conditions. These studies have found evidence psychotic effects; primarily, by counteracting dysregulation of for enduring cognitive deficits along with more severe psychiatric the brain’s dopamine (DA) pathway and normalizing DA activity symptoms ranging from depression and anxiety to psychosis. states in the brain’s mesolimbic pathway, the major brain circuit Interestingly, this evidence has also revealed that adolescent that is associated with schizophrenia-related psychoses.23,24 In fact, cannabis exposure tends to target a specific set of brain circuits CBD has been shown to acutely decrease the activity states of the and neurochemical signaling pathways which seem to interact brain’s DA neurons and improve cognitive deficits associated with with the presence of pre-existing genetic markers that may render schizophrenia-like DA neuron dysregulation.23,24 Interestingly, certain individuals particularly vulnerable. CBD also modulates several molecular signaling pathways in opposite directions to that of THC, demonstrating a remarkable The Impact of Adolescent Cannabis Exposure on opposing role for CBD in the etiology of THC’s mental health- Mental Health Outcomes related side effects. While the psychotropic side-effects of acute cannabis had These critical distinctions between CBD and THC also have been documented for decades in the medical literature, in tremendous implications for public health policy concerning 1987, Andreasson et al15 published a watershed, large-scale adolescent access to specific, high-potency strains of cannabis, retrospective clinical study showing that, in a sample of >45,000 and there is a clear need for evidence-based frameworks by Swedish military conscripts, increased use of cannabis during which restrictions on sales of high-potency cannabis products adolescence was linked to a 4-fold increase in the likelihood to young adults should be implemented. In Canada, while of being diagnosed with schizophrenia as a young adult. This there are Provincially determined age of access restrictions association held even after accounting for confounds from other to the legal purchase and consumption of cannabis, policies psychiatric co-morbidities and social backgrounds. Since that concerning which specific products and/or potency levels should time, dozens of similar epidemiological studies have confirmed be regulated on the basis of age, are not clearly established. Thus, this correlation, not only for schizophrenia-related symptoms, but while there is clear neurobiological evidence for continued brain for long-term cognitive impairments as well.16-20 development into the mid-twenties,28,29 the potential effects of Nevertheless, the implications from these clinical studies exposure to high potency cannabis products beginning as late as is not as straightforward as one might assume. For example, 18 or 19 years of age are not understood and have been poorly retrospective clinical epidemiological studies cannot accurately studied. Nevertheless, there is a growing body of both clinical account for how much THC an individual might have been and pre-clinical research demonstrating profound alterations to exposed to historically, nor the psychotropic potency of cannabis normal neurodevelopmental trajectories following adolescent strains used. In addition, retrospective self-reporting of cannabis exposure to THC. consumption frequency may not be accurate. More importantly, correlation does not equal causation. In the absence of basic, What Does THC do to the Developing Adolescent mechanistic evidence, it is entirely possible that individuals pre- Brain? disposed to developing schizophrenia are simply more likely to Human epidemiological studies exploring the effects of seek out cannabis in the first place and that these neuropsychiatric adolescent cannabis exposure on later mental health trajectories symptoms would manifest themselves regardless of cannabis are limited not only in terms of establishing causality, but also exposure. in terms of the identification of the precise brain mechanisms It is important to consider that cannabis is a highly underlying these effects, particularly at the molecular and single- complex plant, containing over 120 distinct phytochemicals. neuron levels of analysis. On the other hand, translating data We are only now beginning to scratch the surface in terms of from rodent studies to the human context can be challenging. understanding what each component can do physiologically and For example, while adolescent cannabis use typically involves more importantly, how these different components interact to voluntary inhalation of smoked cannabis cigarettes, most rodent produce their psychotropic effects in the human brain. Besides studies rely on systemic modes of THC administration such as THC, cannabidiol (CBD), is the largest non-psychoactive intra-venous, oral of intra-peritoneal injections administered by component of the plant and is relatively well-characterized the experimenter. Nevertheless, there is considerable congruence both pharmacologically and in terms of its effects in the brain. between clinical and pre-clinical studies that have empirically More importantly, CBD has been shown to counteract many studied the neurodevelopmental and acute effects of cannabis on of the psychotropic, neuronal and molecular effects of THC. the brain. Accordingly, the strain of cannabis one is exposed to and its relative As discussed previously, schizophrenia-related psychoses concentrations of THC vs. CBD, is of tremendous importance have been the most examined epidemiological correlate of in determining psychiatric risk from cannabis exposure. For adolescent cannabis exposure. Schizophrenia is a devastating example, CBD not only mitigates many of the psychotropic and neuropsychiatric disorder impacting ~ 1% of the global psychiatric side-effects of THC21-24, growing evidence suggests population. In industrialized countries such as Canada, rates that CBD may serve as an effective anti-psychotic treatment.25,26 of schizophrenia have been gradually increasing for several Not surprisingly, strains of cannabis with high levels of THC decades.30,31 The symptom profile of schizophrenia is remarkably and relatively lower levels of CBD (e.g. sinsemilla), have been complex, making it difficult to treat and diagnose and also to model shown to be the most strongly associated with psychosis risk.27 effectively in non-human experimental models. Nevertheless,

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Growing up high: Understanding the impacts of adolescent cannabis use on mental health and brain development the core endophenotypes of schizophrenia are well-established use. For example, individuals who had genotypic abnormalities and many of them can be successfully modelled in pre-clinical associated with regulation of protein kinase B (Akt), were at behavioural assays using rodents. For example, the ‘positive’ increased risk of neuropsychiatric symptoms following adolescent symptoms of schizophrenia include paranoia, hallucinations, cannabis use.37,38 Consistent with these studies, adolescent THC anxiety and psychosis, all of which have been functionally linked exposure in rodents was found to dramatically downregulate to dysregulation of the brains mesocorticolimbic DA signaling levels of Akt in the prefrontal cortex.32 Similarly, genetic markers system. Indeed, the only effective anti-psychotic medications associated with the dopamine D2 receptor have been linked to currently available all target the brain’s DA ‘D2’ receptor system THC-induced psychiatric risk factors,39,40 consistent with pre- by blocking its activation. Animal models using rodents have clinical findings showing strongly dysregulated DA transmission successfully modelled these effects of DA dysregulation by using following adolescent or acute THC exposure.32,41 These pharmacological administration of drugs like amphetamine, findings underscore the important point that certain genetic which cause overactivation of the DA signaling pathway. In predispositions most likely need to be present to experience contrast, the ‘negative’ symptoms of schizophrenia involve adolescent cannabis-induced psychopathology. The task for symptoms such as social withdrawal, anhedonia, problems with clinical and pre-clinical research is to more clearly elucidate what filtering relevant cognitive information, emotional dysregulation, these biomarkers are and find appropriate prognostic tools that memory impairments and deficits in cognitive flexibility. will allow us to identify which individuals might be at increased Currently, there are few pharmacological treatment options that risk of neuropsychiatric disorders following adolescent cannabis successfully target these emotional and cognitive symptoms of use. In addition, determining how these genetic pre-dispositions schizophrenia. might interact with environmental factors linked to cannabis use Rodent models of adolescent cannabis exposure have will provide further causal understanding of gene-environment generally used chronic, escalating schedules of exposure to interactions underlying adolescent cannabis use and the later THC to mimic the effects of chronic cannabis use during critical development of neuropsychiatric disorders. periods of neurodevelopmental vulnerability. Results from This brief overview of recent empirical findings demonstrating these studies have been largely consistent with clinical human the neuropathological sequelae associated with adolescent findings, demonstrating that exposure to THC during short cannabinoid exposure, highlights the ongoing progress being windows of adolescent brain development can trigger a host made in the field. However, an equally important consideration is of schizophrenia-like endophenotypes, including both positive how might these cannabinoid-induced neuropathological events and negative-like symptom clusters. For example, Renard et al.32 be mitigated or even reversed following adolescent exposure? Can reported that chronic THC exposure in rats during just 10 days of these broad molecular and neuronal adaptations be corrected or adolescent brain development induced increased anxiety, memory are we past the point of no return once the adolescent brain has impairments, social withdrawal and significant deficits in cognitive been already exposed to high levels of THC? filtering, lasting all the way to early adulthood. Remarkably, these effects were absent in experimental groups receiving THC Can we Reduce or Reverse the Impacts of Cannabis during adulthood, underscoring the exquisite sensitivity of the Exposure on the Developing Brain? adolescent brain to THC. Even more striking, rats exposed to As discussed previously, given the ability of CBD to THC during adolescence displayed a highly robust and persistent counteract many of THC’s psychotropic and neurophysiological dysregulated state of their DA neurotransmitter system, consistent effects, one of the most important factors determining psychiatric with human schizophrenia. In addition, examination of specific risk from cannabis exposure relates to the potency of THC. molecular biomarkers in the prefrontal cortical regions of these Recently, alternative cannabis use formats such as vaping groups revealed several striking similarities to findings in human instruments and extracted, purified THC preparations such as schizophrenia patients. For example, adolescent THC-exposed ‘shatter’, have been reported to contain dramatically higher THC rats displayed massive downregulation in a signalling pathway concentrations (e.g. ~70-95% THC in some preparations). These called glycogen-synthase-kinase-3 (GSK-3), an effect that is increasingly popular delivery formats typically contain THC in also found in post-mortem samples of schizophrenia patient the absence of any CBD, meaning that the mitigating effects of populations33 and is linked to hyperactive signaling through the CBD on THC-related psychotropic side-effects are completely DA D2 receptor system.34 Interestingly this same study reported absent. Accordingly, regulation of both the delivery formats of strong downregulation of two other important molecular cannabinoids and limitations on THC concentrations will be pathways, the mammalian target of rapamycin (mTOR) and critically important for reducing the risks of cannabis exposure p70-S-6-kinase, both of which are strongly decreased in major during neurodevelopment, even among young people at legal age depression35 , suggesting that psychiatric risk factors from long- for cannabis consumption. term THC exposure may extend beyond schizophrenia-related However, beyond the importance of THC content regulation symptoms to mood and anxiety disorders as well, as recently in cannabis products, recent pre-clinical evidence has suggested suggested in human clinical studies.36 that the effects of adolescent THC exposure on neuropsychiatric Interestingly, pre-clinical rodent studies have also confirmed risk factors might be treatable and/or reversible, even after several clinical reports demonstrating that genetic biomarkers chronic exposure periods. Using a translational rodent model of associated with the regulation of specific molecular pathways in adolescent THC exposure, our lab recently discovered that one the brain are strongly predictive of determining who is most likely of the major neuropathological effects of neurodevelopmental to experience psychiatric side effects from adolescent cannabis THC exposure involves a long-term loss of the inhibitory

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Growing up high: Understanding the impacts of adolescent cannabis use on mental health and brain development

neurotransmitter, γ-amino-butyric-acid (GABA), directly in References the prefrontal cortex region of the brain.42 Similar to many of 1. Bossong MG, Niesink RJ (2010) Adolescent brain maturation, the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia. the molecular adaptations following THC exposure discussed Prog Neurobiol. 92:370-85. previously, this loss of GABA in the frontal cortex is one of the 2. Chambers RA, Taylor JR, Potenza MN (2003) Developmental neurocircuitry hallmark pathological features associated with schizophrenia.43 of motivation in adolescence: a critical period of addiction vulnerability. Am J Remarkably, we found that when GABA signals were restored in Psychiatry. 160:1041-52. 3. Giedd JN, Blumenthal J, Jeffries NO, et al. (1999) Brain development during the frontal cortex, virtually all of the schizophrenia-like symptoms childhood and adolescence: a longitudinal MRI study. Nat Neurosci. 2:861-3. of adolescent THC exposure, including dysregulation of the DA 4. Andersen SL (2003) Trajectories of brain development: point of vulnerability system, was completely reversed. While it will be essential to or window of opportunity? Neurosci Biobehav Rev. 27:3-18. 5. Tsou K, Brown S, Sanudo-Pena MC, et al. (1998) Immunohistochemical replicate such findings in full-scale human trials, such pre-clinical distribution of cannabinoid CB1 receptors in the rat central nervous system. data provides some compelling evidence that the long-term Neuroscience 83:393-411. effects of adolescent cannabis exposure may be reversible, with 6. Marsicano G, Lutz B (1999) Expression of the cannabinoid receptor CB1 in appropriate pharmacological interventions. distinct neuronal subpopulations in the adult mouse forebrain. Eur J Neurosci 11:4213–4225. Thus, basic neuroscience research into identifying the 7. Ahmad T, Sun N, Lyons D, et al. (2017) Bi-directional cannabinoid signalling in precise mechanisms underlying the neuropathological effects of the basolateral amygdala controls rewarding and aversive emotional processing adolescent THC exposure on the brain must be integrated with via functional regulation of the nucleus accumbens. Addict Biol. 22:1218-1231. extensive clinical testing to more effectively devise methods of 8. Draycott B, Loureiro M, Ahmad T, et al. (2014) Cannabinoid transmission in the prefrontal cortex bi-phasically controls emotional memory formation via reducing cannabis-related risks to brain development. functional interactions with the ventral tegmental area. J Neurosci. 34:13096- 109. Where do we go from here? 9. Laviolette SR, Grace AA. (2006) Cannabinoids Potentiate Emotional Learning Plasticity in Neurons of the Medial Prefrontal Cortex through Basolateral Moving forward, advancing our understanding of cannabis- Amygdala Inputs. J Neurosci. 26:6458-68. related neurodevelopmental risk factors must include ongoing 10. Ahmad T, Lauzon NM, de Jaeger X, et al. (2013) Cannabinoid transmission identification of specific biomarkers that may render specific in the prelimbic cortex bidirectionally controls opiate reward and aversion individuals more or less susceptible to cannabis-related signaling through dissociable kappa versus μ-opiate receptor dependent mechanisms. J Neurosci. 33:15642-51. neurodevelopmental risks. To date, only a small handful of 11. Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. (2010) Opposite effects of genetic susceptibility markers have been identified which seem delta-9-tetrahydrocannabinol and cannabidiol on human brain function and to be related to a person’s increased likelihood of suffering psychopathology. Neuropsychopharmacology. 35:764-74. 12. United Nations Children’s Fund. Child well-being in rich countries. A from cannabis-related psychiatric disorders. No doubt, complex comparative overview. Innocenti Report Card 11. Florence, Ital: United psychiatric conditions such as depression, anxiety, schizophrenia Nations Children’s Fund; 2013. and addiction are linked to a multitude of genetic susceptibility 13. Spithoff S, Kahan M (2014) Cannabis and Canadian youth: evidence, not markers and it is therefore critical to round out our understanding ideology. Can Fam Physician. 60:785-7. 14. Centre for Addictions Research of BC. Cannabis use in British Columbia: of these specific genetic loci and the downstream molecular and patterns of use, perceptions, and public opinion as assessed in the 2004 neurochemical pathways they control. Beyond genetics, basic Canadian addiction survey. Victoria, BC: Centre for Addictions Research of neuroscience research continues to characterize the specific BC; 2006. 15. Andréasson S, Allebeck P, Engström A, et al. (1987) Cannabis and schizophrenia. effects of adolescent cannabinoid exposure on neurotransmitter A longitudinal study of Swedish conscripts. Lancet. 2:1483-6. pathways and neural circuits that are fundamentally altered 16. Helle S, Ringen PA, Melle I, et al. (2016) Cannabis use is associated with 3 by adolescent cannabinoid exposure. The identification of years earlier onset of schizophrenia spectrum disorder in a naturalistic, multi- these biomarkers will allow for the development of potential site sample (N=1119). Schizophr Res. 170:217-21. 17. Aas M, Melle I, Bettella F, et al. (2018) Psychotic patients who used interventions aimed at reversing neurodevelopmental damage cannabis frequently before illness onset have higher genetic predisposition to induced by chronic cannabinoid exposure. More importantly, schizophrenia than those who did not. Psychol Med. 48:43-49. by identifying how the specific phytochemical constituents 18. Ringen PA, Nesvåg R, Helle S, Lagerberg TV, Lange EH, Løberg EM, Agartz of cannabis (such as THC) are producing deleterious effects I, Andreassen OA, Melle I. (2016) Premorbid cannabis use is associated with more symptoms and poorer functioning in schizophrenia spectrum disorder. in at risk individuals, we will be better positioned to develop Psychol Med. 46:3127-3136. safer formulations, prognostic screens and delivery formats for 19. Boydell J, van Os J, Caspi A, et al. (2006) Trends in cannabis use prior to first cannabis that may mitigate many of these mental-health related presentation with schizophrenia, in South-East London between 1965 and 1999. Psychol Med. 36:1441-6. risk factors. 20. Gobbi G, Atkin T, Zytynski T, et al. (2019) Association of Cannabis Use in Adolescence and Risk of Depression, Anxiety, and Suicidality in Young Adulthood: A Systematic Review and Meta-analysis. JAMA Psychiatry. Feb 13. doi: 10.1001/jamapsychiatry.2018.4500. [Epub ahead of print] 21. Englund A, Morrison PD, Nottage J, et al. (2013) Cannabidiol inhibits THC- elicited paranoid symptoms and hippocampal-dependent memory impairment. J Psychopharmacol. 27:19-27. 22. Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. (2010) Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 35:764-74. 23. Norris C, Loureiro M, Kramar C, et al. (2016) Cannabidiol Modulates Fear Memory Formation Through Interactions with Serotonergic Transmission in the Mesolimbic System. Neuropsychopharmacology. 41:2839-2850.

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24. Renard J, Loureiro M, Rosen LG, et al. (2016) Cannabidiol Counteracts 35. Jernigan CS, Goswami DB, Austin MC, et al. The mTOR signaling pathway Amphetamine-Induced Neuronal and Behavioral Sensitization of the in the prefrontal cortex is compromised in major depressive disorder. Prog Mesolimbic Dopamine Pathway through a Novel mTOR/p70S6 Kinase Neuropsychopharmacol Biol Psychiatry 35:1774–1779. Signaling Pathway. J Neurosci. 36:5160-9. 36. Cuttler C, Spradlin A, McLaughlin RJ. A naturalistic examination of the 25. Leweke FM, Piomelli D, Pahlisch F, et al. (2012) Cannabidiol enhances perceived effects of cannabis on negative affect. Journal of Affective Disorders. anandamide signaling and alleviates psychotic symptoms of schizophrenia. 2018 April 6; [Epub ahead of print]. Transl Psychiatry. 2:e94. 37. Colizzi M, Iyegbe C, Powell J, et al. (2015) Interaction between DRD2 and 26. Leweke FM, Mueller JK, Lange B, et al. (2016) Therapeutic Potential of AKT1 genetic variations on risk of psychosis in cannabis users: a case-control Cannabinoids in Psychosis. Biol Psychiatry. 79:604-12. study. NPJ Schizophr. 1:15025. 27. Di Forti M, Marconi A, Carra E, et al. (2015) Proportion of patients in 38. Di Forti M, Iyegbe C, Sallis H, Kolliakou A, et al. (2012) Confirmation that the south London with first-episode psychosis attributable to use of high potency AKT1 (rs2494732) genotype influences the risk of psychosis in cannabis users. cannabis: a case-control study. Lancet Psychiatry. 2:233-8. Biol Psychiatry. 72:811-6. 28. Ben Bashat D, Ben Sira L, Graif M, et al. (2005) Normal white matter 39. Colizzi M, Iyegbe C, Powell J, et al. (2015) Interaction Between Functional development from infancy to adulthood: comparing diffusion tensor and high b Genetic Variation of DRD2 and Cannabis Use on Risk of Psychosis. Schizophr value diffusion weighted MR images. J Magn Reson Imaging 21:503–511. Bull. 41:1171-82. 29. Lebel C, Beaulieu C (2011) Longitudinal Development of Human Brain Wiring 40. Kuepper R, Morrison PD, van Os J, et al. (2010) Does dopamine mediate the Continues from Childhood into Adulthood. J Neurosci 31:10937-10947. psychosis-inducing effects of cannabis? A review and integration of findings 30. Dealberto MJ. (2013) Are the rates of schizophrenia unusually high in Canada? across disciplines. Schizophr Res. 121:107-17. A comparison of Canadian and international data. Psychiatry Res. 209:259-65. 41. Fitoussi A, Zunder J, Tan H, et al. (2018) Delta-9-tetrahydrocannabinol 31. Bray I, Waraich P, Jones W, et al. (2006) Increase in schizophrenia incidence potentiates fear memory salience through functional modulation of mesolimbic rates: findings in a Canadian cohort born 1975-1985. Soc Psychiatry Psychiatr dopaminergic activity states. Eur J Neurosci. 47:1385-1400. Epidemiol. 2006 41:611-8. 42. Renard J, Szkudlarek HJ, Kramar CP, et al. (2017) Adolescent THC Exposure 32. Renard J, Rosen LG, Loureiro M, et al. (2017) Adolescent Cannabinoid Causes Enduring Prefrontal Cortical Disruption of GABAergic Inhibition and Exposure Induces a Persistent Sub-Cortical Hyper-Dopaminergic State and Dysregulation of Sub-Cortical Dopamine Function. Sci Rep. 7:11420. Associated Molecular Adaptations in the Prefrontal Cortex. Cereb Cortex. 43. Lewis DA, Curley AA, Glausier JR, et al. (2012) Cortical parvalbumin 27:1297-1310. interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci. 33. Kozlovsky N, Belmaker RH, Agam G. (2001) Low GSK-3 activity in frontal 35:57-67. cortex of schizophrenic patients. Schizophr Res. 52:101-105. 34. Sutton LP, Rushlow WJ. 2012. The dopamine D2 receptor regulates Akt and GSK-3 via Dvl-3. Int J Neuropsychopharmacol 15:965–979.

82 UTMJ • Volume 96, Number 3, June 2019 Perspectives

Palliative care for homeless patients: A practical approach for medical students

Mithunan Ravindran (BHSc)1; Nishwa Shah (BHSc)1; Naheed Dosani (MD)2

1Faculty of Medicine, University of Toronto, Toronto, ON, M5S1A8, Canada 2Division of Palliative Care, Department of Family & Community Medicine, University of Toronto, Toronto, ON, M5S1A8, Canada

aspired to explore strategies to bridge policy and clinical practice to provide equitable EOL care for homeless and transiently housed Abstract patients. After a year of planning, Dosani founded and launched In this article, Dr. Naheed Dosani, the founder of PEACH on the day he graduated in July 2014. We sat down with the Palliative Education and Care for the Homeless Dr. Dosani, who shared his thoughts on a variety of topics from (PEACH) program, shares his insight on topics ranging the barriers to accessing palliative care faced by the homeless from integrating structural vulnerability into clinical population to strategies that medical students can use to translate their own ideas into real-world initiatives. practice to engendering changes within the community PEACH delivers community-based hospice palliative care to through translation of an idea into a real-world program. society’s most vulnerable individuals, regardless of housing status or PEACH is a community-based organization that aims to other social factors such as poverty or substance use. The program provide high-quality and easily accessible palliative care integrates housing, mental health, and healthcare providers to plan to individuals that are homeless. We explore key tenants an individual’s care while recognizing – but not judging – that of palliative care such as harm reduction and trauma- person’s circumstances. Since 2014, PEACH has made a significant impact on patient outcomes for Toronto’s homeless population. informed care and their applicability for homeless or Based on a 2015 retrospective evaluation of 42 individuals transiently housed patients. Dr. Dosani describes the followed by PEACH, 78% died at their preferred location, 64% unique elements of PEACH and the Journey Home never interacted with acute care, and 83% were reconnected with Hospice (JHH), including accepting referrals from their family and friends. The PEACH team has inspired those in care workers, and the practical logistics of building this other cities including Edmonton, Calgary, Victoria, and Seattle to develop similar programs. Dr. Dosani’s leadership also inspired the successful program in just a few short years. development of Journey Home Hospice (JHH) – Toronto’s first hospice for homeless patients – which opened in May of 2018. Throughout our discussion, Dr. Dosani emphasized how an understanding of the concept of structural vulnerability efore he was the founder of the Palliative Education and has shaped his career and the care he provides. In this context, Care for the Homeless (PEACH) program, Dr. Naheed structural vulnerability refers to the increased likelihood of a Dosani was a family medicine resident at the University patient experiencing negative health outcomes as a result of factors Bof Toronto, with an interest in inner-city health. During one of at the societal and systems level.1,2 Socioeconomic and racial his family medicine rotations, Dr. Dosani was deeply impacted by hierarchies are examples of societal obstacles while immigration the story of a patient at a local men’s homeless shelter who was and employment statuses represent systems level barriers to in crisis. The patient was in his early thirties, suffering from pain healthcare3. It is important to consider these socioeconomic associated with head and neck cancer while simultaneously battling factors in clinical practice to avoid imparting blame or negative mental health issues, addiction and homelessness. Despite working assumptions to individual patients.3 closely with him to develop trust and a management plan, Dr. While completing his palliative care electives, Dr. Dosani could Dosani returned to the shelter one day to learn that the patient had not help but notice that there was minimal – if any – representation overdosed the night before and had died. This experience had a of structurally vulnerable patients. These anecdotal observations profound effect on Dr. Dosani since this patient did not have access were mirrored by reports in the literature, which revealed that to high-quality end-of-life (EOL) care. Ultimately, Dr. Dosani’s despite high levels of resiliency, structurally vulnerable patients face disproportionate barriers to accessing EOL.4 Specific barriers this work identified included having to prioritize survival over accessing EOL, normalizing dying in day-to-day life, the lack of structurally vulnerable patients being identified for EOL, concerns Corresponding Author: Nishwa Shah about provider safety and professional risk, and an overly “silo-ed” [email protected] healthcare system.4 While there are many nuances to consider,

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Palliative care for homeless patients: A practical approach for medical students structural vulnerability as a concept offers an opportunity to While the literature on trauma-informed care showcases reframe the clinical approach to patients facing significant barriers its correlation with improved patient outcomes, this concept is to accessing EOL. challenging to teach in medical school.10,11,12,13 It is important to One of the tenants of the PEACH program is harm reduction be well-informed about the unique issues facing homeless patients to facilitate effective care for homeless people with substance who may benefit from palliative care before engaging with these use issues. For context, it is estimated that 60% of the homeless populations. Gathering knowledge and skills, as Dr. Dosani population in Toronto has ongoing and regular issues with alcohol points out, should always begin with consulting the literature but and illicit drug use.5 It is unrealistic to expect substance users to can also involve attending talks, volunteering in the community, suddenly abstain at the end of their life, due to the difficulties and, more recently, Twitter. While evidence has supported the of overcoming addiction.6 However, because many palliative efficacy of workshops and lectures in imparting skills to healthcare care services utilize an abstinence-based approach, this forms professionals, a more practical measure of readiness for working a significant barrier to accessing EOL care for this population.6 with vulnerable populations is self-assessed efficacy.14 Knowledge Harm reduction emphasizes interventions that minimize the and skills acquisition will lead naturally to connecting with role negative effects of drug use (e.g. overdose, toxicity) without models, which has been shown to be among the most important requiring abstinence as a condition to access services.7 elements of medical education in this field, as well as participating Through PEACH, Dr. Dosani and his team have integrated in shadowing experiences.14 For students who want to similarly harm-reduction strategies, such as off-site drug use protocols in introduce innovation into palliative care, Dr. Dosani’s advice is various housing settings around the city. In addition, PEACH has reassuringly straightforward. Dr. Dosani believes it is important to also provided the necessary training for social and health service keep the foundations of your potential idea rooted in evidence and staff to feel comfortable implementing this evidence-based best expert opinion but also to incorporate the lived experiences of the practice. Delivering services via a harm-reduction approach helps patients whom you are endeavouring to help. to promote a trusting and safe therapeutic relationship wherein patients are more willing to adhere to the provider’s suggestions.7 References While building a trust-based relationship, providers are able to 1. Bourgois, P. & Hart, L. K. Commentary on Genberg et al. (2011): the structural vulnerability imposed by hypersegregated US inner-city neighborhoods--a monitor a patient’s health and provide resources to those in need of theoretical and practical challenge for substance abuse research. Addiction 106, EOL services. Thus, harm-reduction services often act as a critical 1975–1977 (2011). 7 2. Holmes, S. M. Structural vulnerability and hierarchies of ethnicity and citizen- point-of-entry to EOL care. ship on the farm. Med. Anthropol. 30, 425–449 (2011). One of the foundations of the PEACH program is the use 3. Bourgois, P., Holmes, S. M., Sue, K. et al. Structural Vulnerability: Operational- of trauma-informed care by the healthcare team. This approach izing the Concept to Address Health Disparities in Clinical Care. Acad. Med. 92, 299–307 (2017). emphasizes that appreciating a patient’s unique history with 4. Stajduhar, K. I. et al. ‘Just too busy living in the moment and surviving’: barri- traumatic experience is integral to building a trusting relationship ers to accessing health care for structurally vulnerable populations at end-of-life. and providing optimal care. Trauma-informed care is particularly BMC Palliative Care 18, (2019). 5. Grinman, M. N. et al. Drug problems among homeless individuals in Toronto, important when working with homeless individuals because Canada: prevalence, drugs of choice, and relation to health status. BMC Public this population has a statistically higher chance of experiencing Health 10, (2010). 6. McNeil, R. & Guirguis-Younger, M. Harm Reduction and Palliative Care: Is trauma, both in childhood and their adult life. Adopting a trauma- There A Role for Supervised Drug Consumption Services? Journal of Palliative informed approach is not accomplished through any single Care 28, 175–177 (2012). particular technique or checklist. It requires constant attention, 7. McNeil, R. et al. Harm reduction services as a point-of-entry to and source of end-of-life care and support for homeless and marginally housed persons who use caring awareness, sensitivity, and possibly a cultural change at an alcohol and/or illicit drugs: a qualitative analysis. BMC Public Health 12, (2012). organizational level.8 8. Infographic: 6 Guiding Principles To A Trauma-Informed Approach | CDC. Dr. Dosani believes that the key to building capacity for (2018). Available at: https://www.cdc.gov/cpr/infographics/6_principles_trau- ma_info.htm. (Accessed: 28th April 2019) palliative care services among structurally vulnerable people 9. Sawatzky, R. et al. Conceptual foundations of a palliative approach: a knowledge lies within a community-centred approach. This population synthesis. BMC Palliat. Care 15, 5 (2016). 10. Khanna, S. K., Cheyney, M. & Engle, M. Cultural competency in health care: often has difficulty trusting the healthcare system due to prior evaluating the outcomes of a cultural competency training among health care experiences of stigma and discrimination. As a result, they are professionals. J. Natl. Med. Assoc. 101, 886–892 (2009). more likely to avoid mainstream medical care and often interact 11. Beach, M. C. et al. Cultural competence: a systematic review of health care provider educational interventions. Med. Care 43, 356–373 (2005). with case workers, home support workers, and harm reduction 12. Oral, R. et al. Adverse childhood experiences and trauma informed care: the workers.4 Therefore, integrating palliative approaches to care future of health care. Pediatr. Res. 79, 227–233 (2016). between these providers and inner city services, such as shelters, 13. Reeves, E. A synthesis of the literature on trauma-informed care. Issues Ment. Health Nurs. 36, 698–709 (2015). can have a significant impact on reaching structurally vulnerable 14. Wear, D. & Kuczewski, M. G. Perspective: Medical Students’ Perceptions of the populations.4,9 This involves providing knowledge and ongoing Poor: What Impact Can Medical Education Have? Academic Medicine 83, 639– mentorship to healthcare professionals to incorporate palliative 645 (2008). principles (e.g., alleviation of symptoms, focus on quality of life, social, spiritual and peer support) into everyday care taking place in the community4. PEACH accepts referrals from non-physicians, because it recognizes that social workers, harm reduction workers, and nurses are often in the best position to identify patients in need. Creating this low-threshold for referrals reduces barriers for structurally vulnerable people to access EOL.

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A medical student’s comparison between pre-medical and pre-clinical education

Yue Bo Yang

Introduction medical students nation-wide. This is a stark contrast to my pre- hree major transitions exist as a medical trainee: pre- medical education where lecture notes and course-guides were clinical to clinical, clinical to resident, and resident to sufficient and readily available. attending. Perhaps less addressed is the transition from pre-medicalT to pre-clinical education, one that is often buried There will be a “Fire Hydrant” of Content under the jubilation of acceptance into medical school. Advice The total time spent in class in my pre-medical studies was concerning this rather precarious transition is plagued with over- roughly 20 hours per week, whereas I spent roughly 35 hours per generalizations: “have fun and enjoy the experience”1, “buy a good week in class during my pre-clinical studies. Furthermore, unlike in computer”2, and of course, “be yourself.” In this article, I compare undergraduate studies where students select their own schedules, the differences concerning my undergraduate pre-medical and pre- classes at UBC medicine are pre-scheduled with consecutive classes clinical experiences. However, given the diversity of pre-medical and only short 5-10 minute intermissions between, making it studies and variations in pre-clinical education between institutions, challenging to focus and absorb presented information. I also found I emphasize that this is a personal opinion and acknowledge its the basic science in medicine to be taught at a faster pace, albeit with limited generalizability. I write this viewpoint having completed lesser detail and greater volume than my pre-medical education a Bachelor of Science (BSc) degree before entering medicine and which focused on a greater understanding of curated topics. Given from the perspective of a 3rd year University of British Columbia this diversity and volume of content in pre-clinical studies, known medical student. colloquially as the “fire hydrant” of information, certain strategies have become commonplace amongst my peers to extract the most It is Harder to Seek In-Person Support for Academic relevant details – that is, to focus on what is clinically applicable: Help or Tutoring medications, imaging and blood tests, and symptoms and signs are As medical students in the pre-clinical setting, we receive known informally as “high-yield” information. Now, my goal is not lectures from a diverse group of physicians, allied healthcare to undermine the importance of other content, but in reality, there workers, basic scientists, and patients or patient advocates each are limitless potential rabbit-holes in pre-clinical studies. Thus, week. However, this makes individual face-to-face sessions difficult students must focus on what is most clinically relevant to help them to schedule given the majority of lecturers are busy practicing excel on the wards, as understanding and memorizing everything healthcare professionals who teach only on a part-time basis. In presented is not possible (for most). comparison to my pre-medical studies where one professor taught one class and advertised set office hours that students could drop-in You will be Evaluated Subjectively to, contact with physicians and allied healthcare workers is often In my undergraduate science degree, objective measures of limited to e-mail. To further complicate matters, there is a shortage assessment were hailed as trustworthy and fair: blinding of markers of tutors in pre-clinical studies, as those qualified are limited to to test papers/assignments were implemented to ensure that each healthcare professionals and upper year medical students with time- students’ grade was created as unbiased as possible. Although at constrained schedules of their own. Whereas in my pre-medical UBC medicine our written exams are objective, our Work-Based studies, upper-year or graduate students were easily accessible via Assessments (WBA) are subjective by their very nature. WBAs are tutor registries. Another option for those seeking help in pre-clinical used to evaluate students in clinical skill sessions, family practice studies is to ask for clarification within peer-groups, but often visits, and Case-Based Learning (CBL). A preceptor evaluates answers are based on speculation and have their uncertainties. students regarding areas such as knowledge, professionalism, Furthermore, the quality of responses inevitably differs based on teamwork, and communication, based on what they see in a who one asks and has in their social circle. This all amalgamates particular session(s). Though preceptors have guidelines to follow into somewhat of an inequity unique to pre-clinical education: for assessment, there is a large subjective component. As an those at arms-reach from a physician, upper year student, or a illustration, CBL is an environment where students are sorted into knowledgeable social circle are at an advantage compared to those small groups and collectively analyze a written clinical case. As who are not. For the majority of students, this creates the need to new findings are presented, the case posits questions which allow become proficient at using external resources to supplement course students to demonstrate knowledge and soft skills. However, the lectures. Popular resources are Toronto Notes3 and USMLE First distinction compared to undergraduate science is that no one asks Aid,4 which are condensed UBC-unaffiliated study guides with any particular individual to display their knowledge. It is completely pertinent clinical information. Osmosis5 is another platform that at the students’ discretions to contribute information and they are hosts condensed yet informed medical videos popular amongst graded accordingly based on their contributions. In clinical skills

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A medical student’s comparison between pre-medical and pre-clinical education sessions, students are evaluated based on the quality of their patient undergraduate studies. Indeed, acceptance into medicine and the interviews and physical exam skills. In family practice sessions, months thereafter deserve celebration as it is often the culmination preceptors similarly evaluate students based on direct observations. of countless years of perseverance. However, we must not forget Factors such as the leniency or difficulty of the preceptor in grading, about the stark contrasts between pre-medical and pre-clinical and even how prepared and knowledgeable other group members education, catching many off-guard each year. are may all subjectively influence an individual’s WBA. Although subjective evaluation is common for some degrees, compared to Acknowledgements my undergraduate BSc, this subjective evaluation was novel for I would like to thank Dr. Joana Gil-Mohapel and Dr. Sarah me in the transition to medical school. However, I realize that it is Brears for providing feedback concerning the accuracy and content an integral and invaluable part of medical education as medicine of the manuscript. I would like to thank Andrew Meijer and Azzra is a subjective field. Patients’ conceptions about their healthcare Mangalji for proof-reading the manuscript. provider is innately subjective, having great influence on the patient-physician relationship and perceived care. In order to work References in a team-based environment, communication, collaboration, and 1. Falcone J. Five tips for a smooth transition to med school. 2017 [cited 2018 December 14]. Available from: https://www.medschooltutors.com/blog/five- teamwork skills are vital, which are evaluated and responded to tips-for-a-smooth-transition-to-med-school subjectively by colleagues. My advice is to familiarize oneself with 2. Brandt M. From pre-med to med: Making the transition to medical school [Internet]. Houston: Baylor college of medicine; 2014 [cited 2018 December subjective evaluation by asking questions and practicing speaking 14]. Available from: https://blogs.bcm.edu/2014/06/13/from-pre-med-to- out-loud in front of one’s group early-on. med-making-the-transition-to-medical-school/ 3. Chen A, Tran C. Toronto notes. Toronto, ON: Type & Graphics Inc. 4. Le T, Bhushan V, Sochat M, et al. First aid for the USMLE step 1 2015. New You will Spend Most of Your Time within the Bubble York: McGraw-Hill Medical. known as Medicine 5. Tackett S, Slinn K, Marhsall T, et al. Medical education videos for the world: Regardless of background, most undergraduate pre-medical an analysis of viewing patterns for a youtube channel. Academic medicine. 2018;93(8):1150-6. studies consist of a diversity of classes spanning from creative writing to computer programming or mass spectrometry. New faces from various faculties populate each class. However, medicine is different in that every class is taken with the same people. As such, all class time is spent with one’s medical peers. Furthermore, the majority of clubs that medical students join are linked to the medical undergraduate society, which again, consists primarily of students in medicine. For the sports enthusiasts, there are also medicine- exclusive intramural teams. In a nutshell, it is easy to become by consumed by the ever-expanding bubble known as medicine, both from an academic and social perspective. This is not necessarily a detrimental phenomenon, as medicine is a challenging career that requires immersion. However, it creates difficulty in maintaining diverse commitments in one’s life. From my perspective, I enjoy a breather from medicine every now and then, and feel it contributes to my mental well-being, and would encourage incoming students to stay grounded in a few commitments outside of medicine.

Faculty is there to Help You when you Need It From my experience compared to pre-medical undergraduate studies, the UBC Faculty of Medicine cares more about my success and well-being and genuinely wants me to succeed. In medicine, students that could benefit from additional support are identified via examinations and WBAs and are given copious support from faculty, ranging from stress counselling, to creating academic plans. On top of this, students are given remedial examinations in the case of a failing grade. In contrast, during my BSc degree, I felt that if I underperformed on an examination it was completely at my own discretion to seek help and it was solely my responsibility to advocate for myself. In medicine, the faculty truly does advocate for us.

Conclusion It is my hope that this article offers a more realistic perspective on the transition to medical school to specifically an audience of matriculating 1st year medical students from pre-medical

86 UTMJ • Volume 96, Number 3, June 2019 Interviews

Interview with Dr. Snead

UTMJ Interview Team (Happy Inibhunu and Annie Yu)

r. O. Carter Snead III, M.D., controlled trials for statistical proof of efficacy. However, FRCP(C) is the Co-Lead there can be a large difference between statistical of Project ECHO Ontario: proof of efficacy and clinical efficacy. For example, EpilepsyD Across the Lifespan, a with epilepsy, you can have a pediatric patient who Clinician Scientist in the Division of has 100 seizures a week, whom you give drug X. With Neurology at the Centre for Brain & the administration of the drug, you ask the question: Mental Health and a Senior Scientist does drug X have anticonvulsive properties as effective in the Neuroscience & Mental Health as anticonvulsive drug Y? After going through the Program at the Research Institute process previously discussed, there might be a statistical of the Hospital for Sick Children, reduction in seizures in the children treated with Drug a Professor of Pediatrics, Medicine X. For example, patients on Drug X might go from a (Neurology), & Pharmacology with mean of 100 seizures a week to 80 seizures a week. So, Dr. O. Carter Snead III the Faculty of Medicine at University Drug X reduces the seizures statistically, but practically of Toronto, and a Member of the Institute of Medical Sciences speaking in terms of quality of life and clinical efficacy, within the School of Graduate Studies at the University of both from the perspective of the clinician caring for the Toronto. trail and from the patient's family's perspective, Drug X Prior to his relocation to Toronto in 1996, Dr. Snead was head is not very effective since the child continues to have 80 of the Division of Neurology at Children's Hospital Los Angeles seizures per week. and Vice Chair of the Department of Neurology and Professor With that background, the least compelling evidence of Paediatrics, Pharmacology, and Neurology at the University of is Level IV, which includes case reports or retrospective Southern California School of Medicine. studies. Until recently, all of the clinical reports of In Toronto, at the Hospital of Sick Children, Dr. Snead's efficacy for cannabis or its active anticonvulsant work in clinical and basic research in childhood epilepsy led cannabinoid compound, cannabidiol [CBD] fell into to invasive brain monitoring for children who are candidates this category. Now there is good Class 1 & 2 evidence for epilepsy surgery and the ground-breaking study of for the clinical efficacy of CBD in epilepsy, but the magnetoencephalography as a non-invasive diagnostic tool to evidence for other uses of cannabis such as for pain, select children for epilepsy surgery. Currently, his research is gastrointestinal problems, anxiety, and depression centered on developments in the field of drug resistant epilepsy remains predominantly Class IV evidence. and the role of THC/CBD oil.

UTMJ: How about the preclinical research on cannabis? UTMJ: Can you tell us more about the current research process on cannabis? CS: In preclinical studies, researchers create an animal model of a disease where drug X is applied to see its CS: Research in cannabis has been geared towards a wide effects. From these studies, if it is deemed that the drug is array of clinical applications. With regards to the effective in animals, the next step is to take it into clinical research process, there is substantial anecdotal evidence, trials. Phase I clinical trial asks the question of whether but we need more rigorous evidence to approve a drug the drug is safe by looking for toxicity and determining for use in the world of evidence-based medicine. This the pharmacokinetics of the drug, how it behaves, its means Level I or Level II evidence, which represents concentrations, and the dynamics of the movement of randomized double-blinded clinical trials. Such a study concentrations of drug from the blood to the brain. requires both a control group and a treatment group. Phase II clinical trials are open trials in patients while Sometimes, it could be a crossover trial, in which people Phase III trials are double-blinded. While there was a are on placebo for a while and then they switch over to lot of preclinical stuff in CBD and marijuana in animals, the active drug, and vice versa. Other times, patients are the results were conflicting. The problem is that when we either on the placebo or the drug treatment all the way talk about marijuana, it’s not just a wild marijuana plant through. that people smoke for a high; it has at least 26 different The FDA, the Food and Drug Administration in cannabinoids in it. The most active ones are thought to the United States, requires two randomized double-blind be tetrahydrocannabinol (THC) and CBD. Also, there

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are organic compounds, like terpenes, which may or which I previously alluded to, plus the anecdotal clinical may not have a beneficial effect. In terms of clinical literature, and thought it would be worth a try to give her efficacy in epilepsy the animal data suggest that CBD marijuana. However, he understood that you cannot give has anticonvulsant properties, but the evidence for THC marijuana with regular levels of THC to a three-year-old in this regard is contradictory. child. Somehow, he discovered the Stanley Brothers who grew not only regular marijuana, but also made hybrid marijuana plants, so they could alter the levels of THC. UTMJ: Based on these various studies, is there convincing They worked in Oregon where medical marijuana was evidence that cannabis is effective for any disease? legal. The grandfather asked them to make a hybrid plant that had increased levels of CBD and decreased CS: The literature is replete with studies in which cannabis, levels of THC, which the brothers agreed to try to do. cannabidiol, and THC have been used for anxiety, They called it Charlotte's Web. After Charlotte's Web was depression, pain, and epilepsy. However, beyond given to Charlotte, she had a miraculous reduction in her epilepsy there is very little, except anecdotal, evidence seizures. She became almost seizure-free and still is to this that cannabis works for anything. There are a lot of day. After CNN’s report on her, there was an explosion people who use it for all kinds of ailments, and they think of interest amongst the general public. Keep in mind it works. In terms of epilepsy, prior to 2013, cannabis that epilepsy is the second most common neurological wasn't used at all on children, for obvious reasons. disease anywhere, the first being headaches, and it is the However, many [adult] patients with epilepsy do smoke most common and serious chronic neurological disease marijuana. so there are lots and lots of people out there, both adults and children, who suffer from this disorder.

UTMJ: So how did cannabis research first start in the field of epilepsy? UTMJ: And did more patients begin using Charlotte’s Web?

CS: In 2013, there was a show on CNN about a child with CS: Patients with drug resistant epilepsy, that is with seizures Dravet syndrome, a genetic and severe type of epilepsy, that don’t respond to treatment with two or more who had a miraculous response to treatment with a anticonvulsant drugs represent 1/3 of all patients with marijuana oil extract which contained CBD. This epilepsy and are desperate to find anything that could syndrome was named after Charlotte Dravet, a French help control their seizures. After the public learned pediatric neurologist, who in 1986 describes a specific about Charlotte’s Web, there was this enormous pressure group of patients who had epilepsy. These patients brought to bear on the medical community for the seemed normal when they were born and did well compound to be available in the United States. As well, in their first year of life, but suddenly started having we in Canada too were deluged with requests from seizures later on. Their seizures were often associated patients for Charlotte's Web oil. with a fever, were quite prolonged, and often involved We couldn't get it from the States because at that one side of the body more than the other. Over time, time medical marijuana was not legal; however, our these seizures became drug refractory and became a patients where ingenious. We had a few patients who terrible part of their lives. Further, these children showed just moved to Colorado so they could get it. There were regression in their development, so they lost their ability other patients who went there, got it, and smuggled it to walk normally and their language was delayed. In the back. Some even tried to extract the oil themselves and early 2000’s, the genetic mutation for this disorder was measure the CBD. In an extreme case, there was one discovered, which turned out to be SCN1A, a subunit of little girl who was nine months old and had horrible a sodium channel. There are various types of mutations epilepsy. She was having many seizures every day and of this gene, likely linked with the various severities of her father was determined to get Charlotte’s Web, was the disease. successful, and she became seizure free. Along the way, people discovered serendipitously these cocktails of drugs that were more or less effective for this disorder, but the seizures associated with Dravet UTMJ: You mentioned that the drug, despite popular demand, remained very difficult to control. In 2013, Sanjay Gupta, can’t be obtained in Canada. What are the legal a neurosurgeon at Emory and a CNN correspondent, restrictions on the clinical use of cannabis? did a show on this little girl called Charlotte in Colorado. Charlotte had a particularly severe form of Dravet CS: As I said earlier, drugs must have two studies showing syndrome, where she had 50 seizures a day. its efficacy and one study showing its safety. Following Her grandfather was quite a vigorous advocate on the enormous interest in CBD oil that was generated by her behalf. He took it upon himself to go to the literature the CNN show a drug company in the U.K. created a because she had failed every legal anticonvulsant pure CBD compound called Epidiolex, and there was medication. He looked into the preclinical literature, for a multinational group that organized rigorous clinical

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Interview with Dr. Snead

trials of Epidiolex in patients with epilepsy, with an aim UTMJ: How effective is cannabis in drug-resistant epilepsy? towards FDA approval. The first study showed safety and ultimately two or three additional studies were published CS: As I started to say, cannabis is not a magic bullet; it works that showed efficacy. Hence, Epidiolex was approved last well about a third of the time. Potential side effects are year in the United States, but is not available in Canada. a psychotic reaction, possibly due to the THC, or even Then, in 2015, the Supreme Court lifted restrictions worsening of the seizures. Because of these side effects, on the medical usage of marijuana’s derivatives. Prior physicians have to be very careful. That is why only to this ruling, patients could only have a limited amount experienced professionals manage these patients. of dried marijuana and they could only smoke it. The Additionally, it is a hassle to obtain the drug. It is not Supreme Court had decided that this restriction did like a prescription drug where you write a prescription not keep up with the evidence, so there was no longer and then the patient goes to the drugstore to get it. What restriction on medical marijuana in any formulation. happens is the family decides they want to use CBD, and This ruling led to an explosion of an industry in Canada in conjunction with their doctor, they pick out which which is now further supported with the legalization of CBD/THC formulation they want. The family then marijuana in Canada; there are now 65 to 70 producers needs to notify the maker of the product and then the that make CBD-THC products with varying ratios of maker of the product contacts the physician to confirm. CBD to THC. You can now obtain formulations all the Then they send the product to the family. The physician way from 50 to 1 (50 parts of CBD to one-part THC) and the family work out the dose. to 1 to 1. Importantly, our group believes that there is a therapeutic advantage with THC. in other words, the combination of THC and CBD is probably better than UTMJ: Why is Epidiolex not available in Canada, as it is in the CBD alone. The issue is what is the optimal ratio, since United States? we are limited in children by how much THC we can give them. CS: Epidiolex is not available at all in Canada. The As we sit here, CBD is used widely and legally in both unavailability of this new anticonvulsant compound with Canada and the United States. The Stanley Brothers proven efficacy in Canada represents a generic problem have a website called Realm of Caring, which I refer my for new drugs in Canada, at least for epilepsy, in my patients to in order to get Charlotte's Web. The product experience. In the States, before the drug company funds is delivered across the border after the Supreme Court’s a large study, they do a marketing survey to see how decision. I had several my patients write letters to Health many potential patients there are and what the sales are Canada, emphasizing that they had benefited from going to be. If the marketing data supports the financial Charlotte's Web. investment and promises profits, the drug company will go through the expensive process of getting approval from FDA and then marketing the product. Following UTMJ: What do you think lies in the future of cannabis research? FDA approval and marketing of the drug in the U.S., the drug company next needs to decide about whether to CS: Once a drug becomes legal and widely used, it is very bring that drug to Canada. hard to study it in a rigorous way. If drug X is proven The decision is based on what kind of regulatory to be effective and available for treatment of a type of hoops they must jump through, how much it is going to seizures you cannot ethically do a clinical trial of drug cost, and what the market in Canada is like. There is X and assign patients to a placebo. Besides, patients will a process in Canada called the Special Access Program use drug X anyway if they can get it. So, the question of to get drugs that are not available in Canada, but, it what is the best CBD to THC ratio may be insoluble in still takes a long time and is not always successful. The terms of generating any robust evidence. It is important bottom line is that currently there is no pressure on the to understand that cannabis is not a magic bullet. This makers of Epidiolex or Health Canada to approve this is a new anticonvulsant drug with proven efficacy in drug, particularly in light of the availability of such a certain types of epilepsy in adults and children. Our plethora of THC/CBD containing compounds in policy now is that if the child fails two or three drugs Canada and the family asks me about CBD, we are willing to give it a try. Currently, the biggest problem is that the drugs are extremely expensive, and they are not covered by UTMJ: Do you find that there is significant pushback or any healthcare plan. The families tell me it's like making restrictions from the medical field or any other groups another mortgage payment every month. against cannabis research?

CS: There was some initial pushback, with two to three years of working on an agreement in the epileptic community, on how to move forward with the development of cannabis usage in epileptic pediatric patients. However,

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Interview with Dr. Snead

I think what has really helped here is there is clear UTMJ: Do you have any advice for aspiring physician-scientists evidence now that cannabis works. The evidence has like yourself who are interested in new, controversial been published in very high impact journals, such as research topics? the New England Journal of Medicine and The Lancet Neurology. Nonetheless, there are side effects, primarily CS: The main thing is to find a good mentor because these gastrointestinal ones, and many drug-drug interactions days it is extremely hard to be a clinician-scientist. between CBD/THC and those drugs commonly used Your clinician colleagues think that when you are in a for treatment of seizures in Dravet Syndrome and laboratory, you are not seeing patients, so you are not other types of epilepsy. However, all that said I think doing anything useful. Meanwhile, research colleagues more and more epileptologists are using these CBD/ think you are a dabbler because you are not doing THC formulations more and more in patients with drug research fulltime. resistant epilepsy. But there is obviously a tremendous amount of The Canadian Pediatric Society came out with a exciting intellectual benefits, such as understanding the position statement a year or two ago which discouraged pathophysiology of whatever disease you are interested any usage of CBD in Pediatric patients. This was a in and bringing that understanding to the bedside. bit premature since carefully controlled clinical trials It makes you a better teacher because you are able to looking at the anticonvulsant effects of CBD in children explain basic mechanisms of disease better if you are with epilepsy already were underway. Now there is little investigating these mechanisms yourself. question that CBD works as anticonvulsant drug in Lastly, I think if you are interested in being a children with epilepsy, in particular, those with Dravet clinician-scientist, you need to stage your training. The Syndrome. most important aspect of your training is your clinical training. In your clinical training, you obtain a deep understanding of medicine and what you might be interested in. Once you have gained that understanding and identified an area of interest about which you are passionate, then focus on that. The first thing I would advise is to get as well-trained clinically as you possibly can and focus on the research aspect of your career following the acquisition of your clinical skills.

90 UTMJ • Volume 96, Number 3, June 2019 Interviews

Interview with Dr. Ruth Ross

UTMJ Interview Team (Mana Modares and Jeff Park)

r. Ruth Ross, PhD, is a brain, but it’s also everywhere. And if a receptor is professor and the Chair everywhere, it’s a kind of like blessing and a curse. Or, of the Department of both an opportunity and a threat You could potentially PharmacologyD and Toxicology at target this receptor to a number of things like improving the University of Toronto. Her sleep and alleviating pain, but because it’s everywhere, background is in pharmacology, having you’ve got to deal with the side effects as well. So people completed both her undergraduate are taking THC, which is a CB1 agonist. Inevitably, it and graduate degree at the University can be tricky to separate the medical benefits, if there of Edinburgh in Scotland. After a are any, from the potential side effects. You can’t always five-year career break, in 1995, Dr. extricate them. In pharmacology, we are often looking Ross applied to the Career Reentry for something like “subtype selective beta 2-adrenergic Fellowship and met a mentor who molecule” rather than something that hits all of the Dr. Ruth Ross has been a long-standing expert in the receptors throughout the body. field of cannabinoid pharmacology. Ever since, Dr. Ross has been What I have been working on is understanding the immersed in cannabinoid pharmacology research. Her research is CB1 receptor to find out ways to harness some of its directed at gaining insight into the deleterious effects of cannabis therapeutic benefits without some of its side effects. We use and the therapeutic potential for cannabis to be used as a discovered what is known as an allosteric binding pocket medicine. Dr. Ross is also on the steering committee for the of on the receptor. When molecules bind to the allosteric the Toronto Cannabis and Cannabinoid Research Consortium binding pocket on the CB1 receptor, they either tune the (TC3), a newly launched partnership of researchers from the endocannabinoid signaling up or down. In some diseases University of Toronto and its affiliated hospitals to investigate the like fatty liver disease, the endocannabinoid system seems health effects of cannabis and its related compounds. to be overactive and what you want is to tune the system down to reduce the liver problems. And in other cases, you might get an underactive endocannabinoid system, UTMJ: What is it like to have your research area receive so in which case you may want to tune it up. In pain, what much attention, especially now that cannabis has been happens is that your system is producing a whole bunch legalized? of endocannabinoids to enable analgesia, and we want to find a way to tune that system up to get more benefits. RR: People get involved in science not because it is a widely That is what we are working on in our lab. Number popular area of interest, but because it is something they one, we are trying to understand the endocannabinoid find fascinating, and you never know what direction it is system, how it works, when it is overactive, and when going to go in. It is fascinating to see how this has evolved it is underactive. Number two, we are trying to make into something that everyone is interested in, which is molecules that are more selective to be able to tune a nice place to be, but it is also quite strange because the effects up or down as desired. Oh, and I forgot to everyone thinks they are an expert. Based on what they mention, I am also looking at preclinical models of read on the internet. There are a few people who have psychosis. We have genetic models of psychosis. We are been working on this for a long time who have maybe looking at the effects of THC and CBD in these models, a bit more breadth and depth of knowledge. However, because right now there is a lot we don’t know about the it is nice for your research area to be something that effects of cannabidiol and THC in psychosis. everyone is interested in.

UTMJ: How do you think your research has highlighted some of UTMJ: Could you give us some insight into your research? the benefits and harms of cannabis and cannabinoids?

RR: The endocannabinoid system is a key homeostatic system, RR: Cannabis is not just one thing. There are 60 different particularly in the brain and in many other physiologies. cannabinoids in cannabis. Pharmacologically speaking, It’s involved in mood, memory, pain, metabolism, sleep, we know that THC acts on the CB1 receptors. If you take and more. One of the key receptors is the CB1 receptor. THC out of cannabis, a lot of the effects associated with It is one of the most highly expressed receptors in the cannabis disappear, so we know that quite a lot of effects

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are mediated by THC acting on the CB1 receptors. But cannabis, but it's not the same debilitating withdrawal then there are many other effects of cannabidiol that we someone would have with opioids or nicotine. Data don’t understand. We are not sure what those molecular is showing that young people are using it as coping targets are. Other effects may be due to the whole plant mechanism to help with anxiety or stress. there is data to extract but again, we don’t fully understand it yet. The show that young people who use cannabis to self-medicate whole plant extract might have different effects from the to relieve stress may be more likely to become dependent individual components alone. on it. The endocannabinoid system is an adaptive coping The most clearly established medical use of cannabis mechanism; your endocannabinoid system gets activated is with pain. But even if cannabis is established to work, when you are in a stressful situation to reduce stress. We you still have to ask how it compares to the standard of adapt to stress and learn how to develop healthy coping care. For instance, how does THC compare to something mechanisms. The endocannabinoid system is involved like gabapentin in treating multiple sclerosis? It's not just in that. But if you are using something like THC to whether or not it works, but also whether it is actually dampen your stress, you are switching off your own better. I think that still remains to be seen. Some patients endocannabinoid system as well as your adaptive stress find that cannabis works well for their pain. It might coping mechanism because now it's got a CB1 agonist be helpful for certain patients in certain situations, but on board. So that's maybe how people can become as of this moment, we are still working all of that out. dependent. Next time something stressful happens, the Certainly in palliative care, it helps people sleep, helps coping mechanism is to use cannabis rather than our stimulate appetite, and helps with some analgesia. Those own healthy coping mechanism. With that said, the are specific circumstances in which it is useful. People latest figure we have is that 10% of all cannabis users have been talking about using cannabis in anxiety, develop dependence, but that number is as high as 17% PTSD, depression, autism, and in all sorts of things, but in younger people. That’s millions of people. The higher we do not have the data yet on the safety and efficacy the dose, the higher the frequency, and the earlier you of cannabis use in these contexts. People are also using start using cannabis, the more likely you will develop very high doses of cannabidiol. We have no data, no problematic cannabis use epidemiology on what happens with high doses of CBD. People have just started using high doses of CBD. We don’t know what the effects on the population or the UTMJ: What do you think is least understood about cannabis individual would be, and this will probably only emerge use that is not being emphasized enough to the public? with time as we start to get more data. So we are really in the dark. High doses of CBD don’t seem to cause much RR: People are using much higher doses [of THC] than in terms of acute toxicities but there are other concerns before. There was a study published recently by a group around the liver effects, especially in older people. What of psychiatrists looking at whether there is an increased we don't know is whether there will be unintended incidence of psychosis in London, Amsterdam, and Paris consequences from side effects 10 or 20 years down the because of the availability of high dose cannabis. There road. Other harms include potential risk of psychosis are lower doses in Paris, whereas in Amsterdam and and symptom exacerbation. Cognitive impairment and London the doses are high. They defined “high dose” as memory are probably not affected permanently but is >10%, but now most of the licensed producers are often affected short-term during cannabis use. Also in young selling 20-25% [THC], which is a very high dose. That people, particularly adolescents and those under the age is another thing, how are we judging the dose? Should of 25, high dose and frequent use are associated with we be dialing it right back to the 4% people were using? various outcomes like developing depression later in life. People say that the epidemiology shows [that cannabis is Those are some of the things we are aware of. safe] and therefore, it is safe to use, but the epidemiology is based on 30 or 40 years of maybe 4-5% [THC], it’s not based on 30 years of 20% [THC]. That is another UTMJ: The popular belief is that cannabis is not addictive or total unknown - what are the consequences of the higher not as addictive as other substances. Can you give us a doses? The advice is always “start low and go slow” but little more insight into how addictive cannabis really is? what “go” implies is that you can keep [increasing the dose], but I would say if you are going to use it “start RR: We use the word "dependence" with cannabis because low and stay low”. But people develop tolerance and it's not as physiologically addictive as opioids. One desensitization. They would no longer feel its effects with recognized potential harm of non-medical cannabis use a low dose because they have become tolerant. Inevitably is cannabis use disorder, which occurs in 10% of people they increase the dose, which is not good because the using cannabis. That's when you want to stop using it but higher the dose the more likely [it is to precipitate] you can't; it's affecting your life, your motivation, your harmful consequences and also more likely [for the user] grades, and your mood. This is called a dependence to develop dependence. It is important to stay at a low and not an addiction. People definitely suffer from dose and use infrequently. withdrawal, like anxiety, trouble sleeping, and craving

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Interview with Dr. Ruth Ross

People say it has been used as a medicine for thousands funding to conduct good clinical studies on medical use of years but the reality is that the medical use previously in various conditions. These trials cost many millions of would have been, for example, for premenstrual pain for dollars. a specific length of time, at a low dose, and a specific It is interesting from a patient perspective because formulation. Now we’re in the realm of medical the reality is that for some people with certain illnesses, cannabis being used at high doses chronically, which is cannabis could be an important therapeutic. The very different from saying that we have been using it for question I have is: who is going to spend the money on thousands of years as a medicine. I think we need to those clinical trials now that it’s legal? Companies can understand what the effects are of acute vs. chronic use. now sell cannabis without the very strong evidence that What is a medical dose? Is it 20-25% [THC], or is that would have been required before had it been, through too high? What happens when users develop tolerance a more medical regulatory framework. Then patients - can you really use this as a medicine if people are would have been prescribed a product that someone going to develop tolerance very quickly? These are the had spent millions of dollars on to know if it’s safe and questions that need to be asked. effective. Whereas now, what is the incentive to spend money on these clinical trials? Patients are going to be UTMJ: What do you think about the timeline of cannabis the ones not getting the information that they need. legalization? Patients [and physicians] really need to know if it works or not and if it does [then physicians] should absolutely RR: We urgently needed to decriminalize because there were be prescribing it, but maybe [they] are reluctant to inequalities and harms from people having criminal prescribe it because no one spent money on the clinical records due to possessing small amounts of cannabis. trials. I’m concerned that we keep medical use in patients What has very much concerned me is the rush to legalize as a real priority for gathering evidence. in a “for-profit big cannabis” model like “big tobacco”. We could have decriminalized as a first step, and then we could have slowly looked at potential ways in which we UTMJ: Can you tell us a little about Toronto Cannabis and could legalize, and made sure we had more information Cannabinoid Research Consortium? in place before we legalized. I have been very concerned about the rate at which legalization happened, how RR: Toronto Cannabis and Cannabinoid Research quickly it happened, and also with the idea of creating Consortium (TC3) is comprised of researchers from a billion-dollar industry. Legalization per say is not CAMH, UHN, and various University of Toronto necessarily bad - what I would like to see is legalization departments. There are three pillars: the preclinical with public health at the absolute heart of it. I would like research to understand the chemistry and biology of to see legalization with the goal of reducing the number of cannabis and cannabinoids; the clinical research; and problematic cannabis users, not increasing ‘the market’, public health. The goal initially is to get people together, with people not starting using until they are a lot older if have research days, talk to one another and share ideas. at all, keeping at a really low dose, and medical use only We are all in this one giant Canadian ‘experiment’. being based on evidence of safety and efficacy with no For example, we have people taking high doses of over-inflated claims of efficacy. People are free to choose CBD but we don’t know what the consequences are. to use cannabis, but it really important that they have Public health researchers might start to identify some as much information as possible on the effects. Keeping populations that may be exhibiting some symptoms as cannabis out of the hands of young people has not really a result. We then need to get basic scientists looking into been addressed at all by legalization because it is still this with preclinical models in place in order to identify illegal for young people, and if they see normalization the mechanism of action and the molecular target. and sophisticated products among young adults, is that The consortium has over 60 principal investigators. going to make them more likely to use later? I don’t think University of Toronto’s research network, particularly that issue has been addressed either. Decriminalization that of the Faculty of Medicine, is just huge. There followed by regulated not-for-profit legalization would is just so much opportunity to answer some of the have potentially provided a safe source of cannabis that key questions around the safety, the harms, and the was not from the criminal market and wasn’t laced with mechanisms. We hope to use some preclinical models other products. to identify key dosing regimens and key risks and then The good news is that everyone’s now interested in quickly get that information to people working in clinic. it - people now want to know if it is safe. Is it effective? Another example is maternal use of cannabis. We are More research funding is becoming available, which is really concerned about people using cannabis when great. We will eventually answer some of these questions they are pregnant or breastfeeding because it crosses about safety. Canada has the second highest use in the placenta and the brain blood barrier. We urgently the world next to America. It is a good thing that the need to get some really good information on what the research is happening and that some funding is being public health implications of that are. These are some of made available, but we will need significant amounts of the things that the consortium will enable us to do. We

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Interview with Dr. Ruth Ross

have some really important questions to which we need have information about the safety because you know answers really quickly. that target is expressed in certain diseases, or organs, and you can start looking at that. With cannabidiol all we have this polypharmacology, and we don’t know UTMJ: What do you think are future directions in cannabinoid what the target is. All the other questions I have already research or questions that remain unanswered that mentioned around maternal use, and mental health should be explored further? concerns are also important. There is a lot of debate around the age of use - how risky is it? Is the risk inflated RR: Key research questions include: understanding the at 21 vs. 31 [years]? endocannabinoid system - how is it regulated? How does it change in different diseases and in different individuals? For example, recently a woman was UTMJ: What is one piece of advice or words of wisdom you identified in Scotland who had an abnormal gene for would want future medical professionals to know about FAAH, which is the gene for the enzyme that metabolizes the use of cannabis in their practice? one of the endocannabinoids. This is an example of a really interesting polymorphism that tells us something RR: Don’t do anything that is not based on solid evidence. about the endocannabinoid system. She doesn't feel any We need to get the evidence and make sure the source pain and any wounds heal very quickly, but her memory of information is unbiased with no conflict of interest. is not very good. Many medical prescribing disasters have been caused The other big questions are around the idea of the by misinformation, prescribing drugs based on the effects of cannabis - does it really work as a medicine? Is information that was misleading or incorrect – provided it safe? In what conditions does it work in and in which by people marketing and profiting from sales. We medical conditions is it contraindicated? There are big need to make sure that doesn’t happen again. Clinical questions around cannabidiol. Everyone is taking CBD professionals need good unbiased information Let’s not and we need to start to identify what the molecular repeat history by overstating benefits and understating target is. We know the molecular target for THC and harms. We can do better than that. once you know the molecular target, you immediately

94 UTMJ • Volume 96, Number 3, June 2019 Interviews

Interview with Dr. Alan Bell

UTMJ Interview Team (Nicholas Scrivens)

r. Alan Bell is a family physician it first became legal to prescribe. I found it useful in a and clinical researcher in select group of patients. I’ve got a broad-based practice Toronto, Canada. He is with roughly 2000 registered patients, and I have DAssistant Professor in the Department authorized cannabis for 60-70 of those patients. I am by of Family and Community Medicine no means a cannabis physician or a pain physician, but I at the University of Toronto. He is have incorporated cannabis into my toolbox to help my a recipient of the Canadian College patients manage their conditions. I authorize cannabis of Family Physicians Award of mostly to help manage pain for patients who have failed Excellence. other therapies. I try my best to prescribe as few opioids as possible, and cannabis has helped me reduce the His activities include: quantity of opioids that I prescribe. • Primary Panel and Past Chair Dr. Alan Bell – Canadian Cardiovascular Society Antiplatelet Guideline Committee UTMJ: How has medical cannabis changed the lives of your • Primary Panel – Canadian Cardiovascular Society Atrial patients? Fibrillation Guideline Committee • Thrombosis Canada – Board of Directors and Vice President AB: Many patients in primary care have chronic pain. It's • Hypertension Canada – Board of Directors a very common condition, particularly in the geriatric • Canadian Stroke Network Professional Development population. We try to manage it as best we can with the Committee safest drugs as possible. This includes acetaminophen, • Heart & Stroke Foundation Structural Heart Disease Council then gabapentinoids for neuropathic pain, and then Dr. Bell is the only primary care physician to chair a CCS we may have to include opioids. So, I will use a low- guideline committee. His involvement in continuing medical dose codeine preparations and I will also use NSAIDs, education includes the development and presentation of many but I am reluctant to use both of these in vulnerable national projects. He has served as faculty and chair of countless populations. For opioids there is the risk of addictions committees and advisory boards dedicated to serving the common and falls, and in the case of NSAIDS, there are interests of the medical profession and the public. His research, complications from GI, renal, and cardiac toxicity. You commentaries and letters have been presented and published do your best with these drugs, but many of your patients internationally. will continue to fail, and when they do, I will typically introduce a cannabis product. The recent explosion in licensed producers for cannabis products has introduced UTMJ: What has your medical professional journey been like a wide variety of formulations that can be helpful for and how did you become involved in the area of medical patients. In my experience, patients don’t want to smoke cannabis? anything, they don’t want to vaporize anything, and they also don’t want to get high. So, with a patient who has AB: I am a family physician that practices cradle-to-grave chronic pain that is not responding to standard therapies, care in Toronto, and I've been at it since 1981. I am I will introduce oral CBD and titrate upwards and then an academic family physician and I am involved in a introduce low amounts THC. This is limited by the side number of organizations, particularly in cardiovascular effect of euphoria, because when most patients get high, medicine. I am involved in academic medicine and they don’t want to take it anymore. Often, I will see a teaching, including the Family Medicine Longitudinal patient who does not respond to other therapies who will Experience (FMLE), and I do clinical research in my respond nicely to cannabis, and I will be able to reduce practice where I am the lead investigator for clinical trials the doses of the other medications that they are taking, at our site. However, I am mostly a family physician. I try particularly opioids. to incorporate as much as possible into my practice to So, the typical patient could be a 70-year-old with help me and my patients. I tend to use advanced therapies chronic osteoarthritic pain who is on non-steroidal anti- in all therapeutic areas and cannabis has been a natural inflammatories and codeine, who continues to suffer and evolution for me to use with patients with certain health have poor sleep. Introducing cannabinoids will allow issues. I first started prescribing cannabis in 2003 when me to discontinue the NSAID and reduce the dose of

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Interview with Dr. Alan Bell

codeine. The patient will either respond or not respond, to your patients. There is a lot of reluctance, but it is but in my experience the number needed to treat (NNT) not all that complicated. The current formulations is three, meaning 1 in 3 patients will respond well and make it fairly easy for physicians to prescribe cannabis. the cannabis will improve their lives. Cannabis has to For example, the licensed producers will provide highly be viewed as a lower potency analgesic, to which not accurate information on the content of CBD and THC everyone will respond. But the same is true for NSAIDS, in their formulations. Physicians get confused about gabapentinoids, and opioids. The difference with opioids methods of administration, smoked, vaporized, or is that you will get your pain response, but there is an oral. As a result, physicians remain confused and the increased risk to the patients due to side effects and the regulatory bodies continue to frighten physicians about potential for addiction. In the case of cannabis, you may prescribing cannabis. Physicians are worried about the not always get your pain response, but you can improve implications of prescribing cannabis and the safety of the quality of life, functionality, and sleep of patients patients; for example, in motor vehicle accidents. They without the side effects. don’t realize that the same problems exist when we prescribe opioids. However, physicians have embraced opioids to the point where we have an opioid crisis. UTMJ: The research on medical cannabis is not robust. How does this affect physicians and their ability or willingness to prescribe it? UTMJ: Is cannabis overlooked as a potential way to mitigate the opioid crisis? AB: The literature is certainly not robust. If we look at some of the meta analyses with regard to cannabis and pain, AB: Yes, overlooked and I would say ignored. Can cannabis some show positive and some negative associations, cure the opioid crisis? Probably not. There is some and none will show a clear effect. There a number of evidence showing that cannabis can be opioid sparing. reasons for this. First, the funding for research is limited. There is also data from the United States showing a We don’t have the Merks or Pfizers or the world pouring reduction in opioid overdoses in states where cannabis hundreds of millions of dollars into studies to get the has been legalized. There is certainly some scientific necessary patient populations and duration of therapy to evidence showing that medical cannabis can have an show a direct effect. Second, patients are highly variable impact of the opioid crisis. However, we haven’t done the in their response. The variation in response can be hard research necessary to prove this, and we probably due to the patients and the cannabis itself. Unlike pure won’t. molecules, which we typically use in medicine, cannabis If you look at the Canadian Pain Society Guidelines is a wide variety of molecules that we are providing for neuropathic pain, cannabis is the third-line therapy to the patients. There is CBD, THC, dozens of other after opioids and tramadol. I’m not clear on why we have cannabinoids, and other chemicals such as terpenes and a high toxicity and potency agent (opioids) ahead of a flavonoids, for which we don’t know the effect yet. The low potency and virtually zero toxicity agent (cannabis). patients are given a wide variety of substances, so I think So increasingly, I am using cannabis ahead of opioids for that the variation in response is to be expected. So, what the management of neuropathic pain. we are left with is what I like to refer to as n of 1. Which means that if we give the cannabis to patients and they respond, great, and if they don’t, that’s okay. This means UTMJ: How has the legalization of recreational cannabis that we may need to try different titrations. affected the prescription of medical cannabis?

AB: Certainly, I think that the legalization of cannabis has UTMJ: What are some of the barriers for physicians to become been a positive move. Open-minded physicians are comfortable prescribing cannabis for their patients? starting to view cannabis as an option, but the majority of physicians still do not. One of the big barriers has AB: I spend a significant amount of time teaching cannabis been the position of the Canadian Medical Association medicine. I give a presentation to the College of Family (CMA), which has been that with the legalization of Physicians every year on cannabis authorization. Despite cannabis there is no need for two tracks for recreational the fact that cannabis is legal now in Canada, there and medical cannabis. I believe that this is an incredibly remains a huge stigma among physicians and patients. backwards position. It is clear that there is a difference There is a large number of physicians that are unwilling between getting high and treating medical conditions. to prescribe cannabis because of this stigma. There is I can’t believe that an organization like the CMA does also a large number of physicians who are not making not recognize that. It takes a skilled clinician in order the effort that is needed to be comfortable incorporating to appropriately prescribe and titrate cannabis to get a cannabis into their practice. So just like it takes some therapeutic value without the euphoric effects. Trained knowledge and training to provide insulin to diabetic medical professionals are required to guide patients with patients, the same effort is required to provide cannabis regard to their use. I wouldn’t want my patients to be

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Interview with Dr. Alan Bell

guided in their use by a “bud-tender” in a cannabis store. their pain, sleep, and quality of life. Patients receiving We can’t expect patients to be able to manage their own palliative care often like a little bit more THC, as they medical conditions with cannabis. I think the CMA’s find it helpful. Cannabis is effective in anxiety, and position has been a large step backwards in the adoption anxiety disorders such as PTSD. There are a number of of cannabis into practice. high-quality studies in the literature to support this. The problem that we face though, is that most of the data has been for very high doses of CBD, and high doses of CBD UTMJ: Since legalization, have patients been more willing to are expensive. If I titrate a patient’s dose of CBD to 40 self-medicate with cannabis? mg per day, this is about $5 per day. So, with high doses of CBD, cost becomes a limiting factor. This is a similar AB: I think very much so. With all of the hype of legalization, issue for treating epilepsy. Cannabis, and in particular patients are coming to their physicians and asking for CBD, is the best thing that we have for Lennox-Gastaut guidance. Physicians may refuse to help and may send syndrome and refractory epilepsy in children and adults. them in a different direction. Some may go to cannabis Unfortunately, the doses are sky high, up to 300-400 mg clinics, some of which are excellent. The patients may per day for patients. It is difficult for patients to afford also go to “bud-tenders” at cannabis stores, some of this. This points again to the importance of separate which are illegal. These patients are getting advice from streams for recreational and medical marijuana. With untrained individuals and getting advice that may not recreationally sourced cannabis, there would be sales be the best for their conditions or their health. So yes, tax and a sin tax in addition to the already high cost for legalization has had a huge impact on the population the CBD. We need a separate stream to also encourage of patients looking towards cannabis to treat their reimbursement for the costs of medical cannabis in conditions, but they may be frustrated when seeking refractory epilepsy and other medical conditions. Lastly, advice from physicians. I have found medical cannabis to be helpful for patients with MS. Virtually all of my patients with MS use cannabis, and most used cannabis before they became UTMJ: What are some of the risks or adverse effects associated my patients. It provides a clear benefit for their pain and with the use of medical cannabis? muscle spasm. This is an area where there is no doubt for the benefit of cannabis. AB: Cannabis does not come without harms. Most of the data on harms comes from the recreational use of cannabis, which is often of high THC content. Addiction UTMJ: It is a challenging and evolving area of medicine, but is certainly a harm associated with cannabis. There is a how can medical students and physicians become more 9-10% rate of addiction for individuals who use cannabis, knowledgeable and comfortable in this area? which is roughly the same for benzodiazepines, but much lower than for alcohol and other drugs of abuse such AB: Well, I can tell you that I have had discussions with Dr. as opioids. There is also the risk of psychosis. There Young, Dean of Medicine, and Dr. Kidd, Chair of the are certainly risks with breastfeeding and pregnancy, Department of Community and Family Medicine, and however, we really don’t have much data on this. With cannabis will be incorporated into the undergraduate the use of high THC products, there is the risk of cyclical curriculum next year. Another way to become more vomiting syndrome. There are certainly toxicities and informed is to read the literature. There is an organization risks, like there are with all medications. But we know called the Canadian Consortium for the Investigation of that there has never been a recorded death as a result of Cannabinoids (CCIC). They have excellent publications, cannabis use. presentations, and resources available. It would also be helpful to attend the CCIC annual meeting. I would recommend attending seminars and webinars on the UTMJ: Other than pain, what areas of medicine can cannabis topic. I encourage medical students and residents to seek be helpful in the management of conditions? out information from reliable sources, which will allow them to stay on the cutting edge and to see the exciting AB: Patients will come in having read that cannabis can be advances in cannabis. This will help your confidence in useful for a large number of conditions, such as glaucoma cannabis as a medication and to better understand how to or asthma. However, I don’t think that there is much use incorporate this into your practice. Lastly, it's important for cannabis in this area. to be open-minded. We are physicians and scientists, let's I have found medical cannabis useful in pain, palliative keep our minds open to alternative treatments that can care, chemotherapy induced nausea and vomiting, help our patients. anxiety conditions, refractory seizures, and multiple sclerosis (MS). In terms of palliative care, patients with chronic cancer pain have been very happy to accept cannabis into their treatment regimen. It improves

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Instructions to Authors 2018-2019

The University of Toronto Medical Journal (UTMJ; http://www.utmj.org) is an established peer-reviewed international medical journal that has been student-run since 1923. This year, we are celebrating the publication of our milestone 96th volume. The journal has a circulation of 1500 print copies per year and is available online. We are inviting submissions for our issues.

The University of Toronto Medical Journal (UTMJ), an official 3. that neither the submitted manuscript nor any similar paper, journal of the University of Toronto Faculty of Medicine, is other than an abstract of preliminary communication, has devoted to the publication of significant, original studies and been or will be submitted to, or published, in any other primary review articles in all areas of basic, clinical, translational, and scientific journal; epidemiological medical research, as well as medical education, 4. that all of the authors are aware of, and agree to, the content medical ethics, medical jurisprudence, and the history of of the manuscript and that authorization has been given to use medicine. Submissions of editorials, letters, and comments any information conveyed by either personal communication or regarding matters pertinent to the areas above are also welcomed. release of unpublished experimental data; In addition, submission of case reports will be entertained. All 5. three to six key words describing the paper, to assist in the submissions must be in the English language. selection of the reviewers; 6. the authors’ full names, highest degree obtained, and medical Procedure for Submission school class (if applicable). Text files should be submitted as a Microsoft Word document, preferably using the template available for download from the Organization UTMJ website (www.utmj.org). Images should be submitted as a Papers should conform strictly to UTMJ style. Previous issues TIFF, JPEG, or Photoshop document with a resolution of at least of the UTMJ will provide authors with assistance in the proper 300 dpi at the intended print size (at least 3” in width). In the event arrangement of manuscripts see online at http://www.utmj.org. that an electronic figure cannot be obtained, submit the original Papers are to be written in clear, grammatical English. Data must be figure to the above address with a self-addressed, stamped envelope presented concisely. The manuscript should be typed using 12 point for the return of the figure. Times New Roman font with double spacing throughout, allowing for 1 inch margins. Submissions should not exceed a maximum Please submit articles using our online submission sys- of 5000 words and shorter papers are preferred. Consecutive tem at www.utmj.org numbering of all pages is required, with the title page as page 1.

Articles are accepted on a rolling basis. Title Page The title page should include a) the complete names of all authors, The paper should be submitted by an author, preferably the highest degree obtained, medical school class (if applicable), and principal author, who should indicate in a covering letter: appointments; b) the complete address to which correspondence 1. that the paper is being submitted for consideration for should be addressed including email, telephone, and fax; c) three publication in the UTMJ; to six key words describing the text. To facilitate the peer review 2. the exact address to which all related correspondence should process, this information must not appear on any other part of the be sent and the email, telephone, and fax numbers at which the manuscript. Make sure that the manuscript includes a contact email author can be reached; address. Everything should be contained in a single file.

UTMJ • Volume 96, Number 3, June 2019 99 Abstract Tables The second page of every manuscript must contain only the abstract, Tables should be on a separate page with a short title and be which should be a single paragraph not exceeding 300 words. The numbered and referred to in the text. Column headings and abstract should be comprehensive to readers, and abbreviations and descriptive matter in table should be brief. Vertical rules should not reference citations should be avoided. be used.

Sections of the Manuscript Please subdivide original manuscripts into the following Illustrations sequence of sections: Title Page, Abstract, Introduction, Each figure should be designed to fit into an area of either one or Materials and Methods, Results, Discussion, Acknowledgements, two columns of text. Photographs and illustrations must be of good References, Legends to figures. Subheadings (within the quality. The figures are to be numbered consecutively in Arabic Materials and Methods, Results or Discussion sections) are numerals, and each one must be referred to in the text as Figure 1, encouraged if they facilitate the presentation of material. etc. On the manuscript indicate the most appropriate position for Figures should be presented in separate files. the figure. Figure legends should be on a separate, numbered page and titles for figure legends should be in the form of a concluding References statement. Define all symbols and abbreviations used in the figure. Please note that authors are responsible for obtaining permission All figures are to be attached separately or to the end of the article. from copyright holders when utilizing any copyright protected material within their manuscripts (e.g. reproduced figures, tables, Drug Names etc.). Both non-proprietary (generic) and trade names should be provided for all drugs mentioned. Documents and articles from the World Wide Web should only be used when an equivalent printed source is not available. Review Process Submitted articles will be reviewed by both a faculty member and Additionally, authors will be responsible for the accuracy of the a medical student, both of whom will have expertise in the field of references. In the text, a reference should be cited by an Arabic the submitted paper. The results of this review process will then superscript and placed after comma (,) period (.), or end bracket [)] be reviewed by the Associate Editors, who on the basis of both etc. The list of references should be provided in the order described the reviewers’ comments and their own, will come to a decision above and should follow the order in which they appear in the text. as to recommend the manuscript for publication in the UTMJ. All References must adhere to the following style. Incorrect formatting rejected papers will then have a final evaluation by the Editors and of references may result in the rejection of an article. if confirmation of rejection is established, the Editors will inform the authors of the decision of the review process. Rejected papers Please refer to the International Committee of Medical Journal are encouraged to be resubmitted only if all of the reviewers’ Editors Uniform Requirements for Manuscripts Submitted to comments have been considered and corresponding changes Biomedical Journals guidelines listed in this website: http://www. made in the manuscript. The revised re-submitted articles will be nlm.nih.gov/bsd/uniform_requirements.html. considered new submissions and will be subjected to the standard review process by the UTMJ.

100 UTMJ • Volume 96, Number 3, June 2019

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