Malignant Hyperthermia Association of the Volume 37 1 United States and the North American Winter 2019 Malignant Hyperthermia Registry of MHAUS

New Documentary of Former NHL Player Builds Awareness of MH Editor’s Note: In December 2018 a new documentary explained. “Because once you’re on the ice, it’s game premiered in , , simply titled Hodg- time. You don’t think of external things. You tune out so son. The documentary is the result of a partnership much.” between Cody Hodgson, a former National Hockey Indeed, perhaps Cody’s mental toughness League (NHL) player, and the RYR-1 Foundation. The played as big of role in getting him to the NHL as his documentary tells the story of Cody’s rise to the most physical ability. He was drafted 10th overall in the first elite level of professional hockey and his eventual round of the 2008 NHL Entry Draft. During the next forced retirement from the sport he loved by a diag- couple of years, though, Cody had to overcome a de- nosis of RYR-1 muscle disease – a genetic mutation bilitating back injury, a broken toe, and in that first NHL associated with malignant hyperthermia. Prior to the game, he was wearing a face mask to help protect a documentary’s premiere, MHAUS had the opportunity broken orbital bone suffered just two months earlier. to speak with Cody to discuss his NHL playing career, “Hockey has taught me valuable life lessons,” the circumstances surrounding his retirement, and he said. “It’s helped build character, to unite behind a his decision to partner with the RYR-1 Foundation team, and it taught me perseverance. You always have to help bring awareness to RYR-1-related diseases, to put forth your best effort despite adversity.” including malignant hyperthermia. The following article Cody arrived in the NHL with high expecta- is a result of our conversation with Cody and corre- tions. Prior to arriving in the NHL, Cody had compiled sponds nicely with MHAUS’ March MH Awareness and an impressive list of accomplishments, including rep- Training Month. After reading the article (and perhaps resenting his home country of Canada at two Interna- watching the documentary) consider how you might tional Federation-sanctioned events, where help build awareness and/or improve training for MH his teams captured gold and he led the tournaments in in your local area. Look to page 3 of this newsletter for scoring. how you can help save a life. In his first season with the Canucks, he skat- ed in their playoff push to the Stanley Cup, and in his For his entire life, Cody Hodgson trained his second season, his first full rookie season, he scored a body and mind to perform at an elite level very respectable 19 goals and was selected to perform with one objective in mind – to play in the in the NHL All-Star Game SuperSkills Competition. most prestigious professional hockey Indeed, Cody seemed well on his way to securing league in all the world, the National notoriety as a top NHL player. Hockey League (NHL). After much hard work and many accolades, that opportu- continued on page 3 nity finally arrived during the 2010-2011 NHL season when he took to the ice On the inside for the first time as a member of the Executive’s Corner ...... 2 Canucks. Do Your Part for MH Awareness & “I remember we were in Training Month ...... 3 Dallas, Texas, and I remember there was an ice storm outside, Genetic Test or Muscle Biopsy – and I remember my teammates Which is Right for You? ...... 5 hid my helmet on me,” he Hotline Case Study: Methylene Blue & recalled with a chuckle. Severe Serotonin Toxicity ...... 8 Admittedly, the initiation Just Out! Revised MH Emergency Therapy prank served to “break the ice,” Poster & Pocket Card...... 9 he said, (no pun intended) and the next day, in his second profes- Happenings ...... 12 sional hockey game, he scored his first . “I don’t remember hearing the cheers from the crowd during the score,” he Executive’s Corner ...

The Communicator is published four times each year by the Malignant Looking Forward into the New Year! Hyperthermia Association of the United States (MHAUS). The Communicator is MHAUS is on sion of the MH In-service Kit for those who intended to serve the information needs a forward trend want the availability of the presentation on of MH-susceptible families, health care their facility’s intranet, a VLOG (video blogs) professionals, and others with an that continues interest in MH. to address new from Dr. Henry Rosenberg, MHAUS Presi- challenges dent, on the MH Hotline, and his PowerPoint EDITOR presentation on the specifics of the MH Brian Kamsoke and areas for growth of the Hotline can be found under our “videos Editorial Advisory Panel organization tab” (in 2 parts) highlighting the hotline’s Henry Rosenberg, M.D., CPE to produce a evolution, function and history. Cynthia Wong, M.D. Lena Sun, M.D. strong impact Webinars are a new area of focus Tae Kim, M.D. on the need for for us. We will be making them available on Dianne Daugherty all healthcare a monthly basis with presentations on topics FOR MHAUS MHAUS Executive Director Henry Rosenberg, M.D., CPE facilities to be of interest to healthcare professionals (from President prepared for a a clinical standpoint) and MH-susceptible pa- malignant hyperthermia event and for patients tients and others interested in what malignant Ron Litman, D.O. hyperthermia means to a family, i.e., the ex- Vice President, Scientific Development to assure they research and share solid family health history with their healthcare pectations when you have MH, the resources Stanley Caroff, M.D. providers. Our focus is to be a solid source of available, and ideas as to how patients can Vice President – Director of NMSIS MH information for all healthcare profession- participate as a member of the team manag- Bonnie Denholm, DNP, RN, CNOR als and to deliver the same level of service ing their care by sharing personal informa- Vice President to MH-susceptible patients and their family tion only they know! To date, the webinars members. have provided specific information on how to Steven V. Napolitano, Esq. Secretary Although our year-end appeal for prepare an anesthesia machine for known donations has passed, I still encourage you MH-susceptible patients or how to quickly Joseph R. Tobin, M.D. to make a donation to MHAUS anytime purge the machine when an unexpected MH Treasurer throughout the coming year. Your support event occurs. This particular webinar was Dianne Daugherty furnishes programs designed to help in an attended by over 250 registrants and was a Executive Director MH crisis (like the MH Hotline), MH prepared- resounding success. Gloria Artist ness materials to assist those in control of MHAUS continues to be the place Hotline Coordinator their patient’s life so they quickly recognize to go for information about MH – for instance, and treat an unforeseen MH event before it we were asked to consider writing an article Fay Kovack on MH for AmBuzz, Joint Commission’s on- Fulfillment Coordinator turns into a nightmare that cannot be stopped. We are an organization dedicated to answer- line newsletter, and the article received quite Tina Roalef ing any malignant hyperthermia question from a bit of attention within those circles. We are Projects Coordinator doctors, nurses, any healthcare provider and gaining more and more Partner Memberships patients alike. Please give generously, every with other similar organizations: the Ambula- Malignant Hyperthermia (MH) is an dollar counts! tory Surgery Center (ASCA) being the most inherited muscle disorder which, when recent. Have you considered this paid mem- triggered by potent inhalation anesthetics In the past year MHAUS took on a and succinylcholine, may cause a life- monumental challenge: we needed to find bership option? A new benefit of an MHAUS threatening crisis. The incidence of MH a new home for the North American MH paid membership is access to our online is low, but, if untreated, the mortality rate webinars at no cost – non-members will be is high. Since the advent of the antidote Registry of MHAUS. Careful consideration for drug, dantrolene sodium, and with greater location, support from the facility’s hierarchy required to pay a small fee to view the highly awareness of the syndrome, the mortality and staff, technical prowess to maintain and, informational webinars with time allotted for rate has decreased. Great advances a question and answer period – where else in our understanding of MH have been more importantly, improve the Registry’s made since it was first recognized in the database were the main areas of concern. can you get access to the MH experts who early 1960s, but the nature of the funda- After months of searching, the MHAUS Board will respond directly to you? mental defect(s) is still unknown. of Directors determined the best location What are we looking at for the MHAUS advocates that all surgical for the present and future Registry was the future you may ask? Building the breadth of patients undergoing general anesthesia University of Florida – Gainesville. The transi- the MHAUS Board of Directors (BOD) and should receive continuous temperature monitoring, that adequate supplies of dan- tion was extremely involved, and not without Professional Advisory Council (PAC) as well trolene be stocked near the OR and that challenges, but under the directorship of Dr. as adding new MH Hotline Consultants is a thorough family histories be obtained. Nikolaus Gravenstein and his staff, the results definite focus for the coming year. Transition- Copyright 2019 by MHAUS are encouraging and exciting. I would recom- ing new members onto the Board of Directors mend everyone visit our website and click provides varied feedback and insight needed on the Registry’s tab to view and access for a solid foundation and focus on the future. the report forms online. Exertional heatstroke and muscle pain are of Our internet impact is also increas- significant interest within the MH community. ing through our website. We placed on our website a 2-year online subscription ver- continued on page 11 3 continued from front page and sending it to a genetic testing lab. As expected, when the results returned, Cody was diagnosed with a vari- Do Your Part for However, over the next few ant within the RYR-1 gene. However, at years Cody battled injuries and struggled that point, Cody didn’t know for sure if he MH Awareness & with consistency on the ice. Some of his was susceptible to MH as well; for while health issues were to be expected in the genetic testing is often helpful in deter- Training Month rough and tumble world of professional mining whether a patient is predisposed hockey, but the other health issues ap- to a medical condition like malignant March is “MH Awareness and Train- peared out of the realm of normal wear hyperthermia, it doesn’t offer certainty. As ing Month,” and MHAUS is asking and tear on the body. Cody explained, “I wanted to be certain.” for your help to post selfies on the “I really struggled with these So Dr. Riazi ordered a muscle MHAUS Facebook Page. Visit: issues for an extended period of time,” he biopsy. A muscle biopsy, referred to medi- https://www.facebook.com/mhaus. recalled. “I seemed to get muscle tears cally as a caffeine-halothane contracture malignant.hyperthermia.associa- frequently, and I was in pain for a few test (CHCT), must be performed at a tion.us. Help draw attention to the years. By my last year, I was suffering special muscle biopsy center because dangers of MH and to the need for whole body shakes and tightness.” it requires skeletal muscle biopsy from further education. During that last season Cody a patient’s thigh. The test then must be What else can you do? also experienced difficulty breathing and conducted immediately to assess muscle Share the link to Cody Hodgson’s contractile properties upon exposure to documentary Hodgson about his life ryanodine receptor agonists (e.g., caf- as a professional hockey player in the feine, halothane. Cody’s results from the NHL and his battle with RYR-1 dis- test revealed abnormally high levels of ease (often a precursor to malignant contractile force – an indication of MH hyperthermia). Visit: https://www. susceptibility. (For more information about ryr1.org. genetic testing and the muscle biopsy test Furthermore, patients and and which test might be right for you, see families are encouraged to document page 5 of this newsletter). their health history and wear identifi- According to the RYR-1 Founda- cation tags that can alert healthcare tion, common symptoms related to a mu- professionals to the disorder. For tation of the RYR-1 gene include weak- more information about the medical ness of the eye muscles and generalized alert tag, visit: https://www.mhaus. muscle weakness, typically affecting the org/patients-and-families/identifi- muscles closest to the torso of the body. cation-tag-program/ Some individuals experience muscle You are also encouraged cramping and pain, difficulties exercis- to work together with healthcare ing, and intolerance to heat. Breathing professionals in your community to problems associated with RYR-1-related build awareness about Malignant diseases can range from non-existent to Hyperthermia. How can you do that? severe and are due to weakness in the MHAUS provides sample letters on Cody Hodgson on the ice with the Nashville muscles of the chest wall. Mild breath- its website that you can download Predators during the 2015-2016 season. ing problems can include sleep apnea, and mail to your local medical facili- requiring breathing support during sleep. ties informing them about MH-sus- Severe breathing problems require con- ceptible patient care. This includes a at times would black out. He began to fear tinuous support. sample letter for student care. Visit: the worse and underwent various tests for Cody finally had his answer. “In https://www.mhaus.org/patients- cancer, heart disease, and autoimmune the grand scheme of things, I was re- and-families/mh-letters-and-forms/ diseases. He even began taking medica- lieved. I was thankful it wasn’t something What about medical profes- tion for anxiety and blood pressure, but like brain cancer. It was something that sionals? Healthcare professionals none of these medications eased his was at least manageable.” are encouraged to keep MH training symptoms. Although no cure exists for current in order to rapidly recognize Finally in 2016, through a pro- RYR-1-related diseases, the disease and diagnose the disorder and to cess of elimination, Cody was led to Dr. is manageable through a combination maintain an appropriate supply of Sheila Riazi at the Anesthesia Depart- of drug therapy and active awareness. the drugs and equipment needed to ment with the University of Toronto. Riazi, (MHAUS provides resources on its successfully treat an MH emergency who heads the Malignant Hyperthermia website to help MH-susceptible patients and transfer plans to transport a MH- Investigation Unit at the university, re- protect themselves by informing medi- suspected patient. MHAUS provides viewed Cody’s test results and suspected cal professionals within their community a slew of helpful information on its a mutation of the RYR-1 gene was caus- about the dangers of MH and by wearing website. Visit: https://www.mhaus. ing his symptoms. a medic alert bracelet which will inform org/healthcare-professionals/be- The first step in confirming the prepared/ diagnosis was ordering a genetic test. The test involves taking a sample of blood continued on page 5 4 5 continued from page 3 with the Nashville management and how they kept checking on me during my time in the hospital.” Are You Prepared medical professionals in the event a pa- Soon after Cody left the hos- tient is unconscious). pital he was offered a job through the for an MH Crisis? In order to stabilize Cody’s Predator’s organization coaching their condition, he began taking 3-4 Dantrium® Little Preds Learn to Play Program. As Order a Mock Drill Call capsules per day under close supervi- a partnership between the NHL and the Today to Find Out sion. After four months, his dosage was NHL Players Association, the program reduced to one per day and now he only involves teams from 15 cities to teach Imagine you’re in the midst of takes a capsule when needed. young hockey players ages 4-9 the skills a routine operation when sud- Although Cody’s disease is now that will make them successful on the ice, denly things go terribly wrong. under control, he knew his professional but also those same valuable life lessons Now you’re in the midst of an MH hockey career was over. “After a couple Cody learned as he grew up through the emergency. It’s unlikely you or your of months, I realized I would never play ranks of professional hockey. Now, as an team have ever experienced an again. And that was hard. But I’m thankful ambassador to the game he loves, he MH crisis. Will you and your team for the opportunity. I played in the NHL for gets to influence a whole new generation know what to do? six years and had the opportunity to com- of players. Practice makes perfect, pete against the top players in the world. Through his partnership with the I enjoyed traveling to all the cities and I RYR-1 Foundation, Cody gets to serve they say. And, thankfully, you or developed lifelong friendships with many another ambassador role by visiting with your team don’t need to experi- of my teammates. Playing in the NHL was other RYR-1 patients and, with the help of ence a real MH crisis in order to a dream come true.” the Hodgson documentary, bring aware- become proficient in handling the Fortunately, Cody had the op- ness of RYR-1 muscle disease to the emergency. MHAUS provides a portunity to continue his involvement with larger community. host of tools and guidelines to help the NHL at a different level. While he was “We’re finding more and more you navigate the crisis – including in the hospital undergoing treatment, people with it and hopefully with this 24 hour access to the MH Hotline the , the NHL team documentary we can shine some more where you’re connected almost im- for which Cody played his last season, light on it.” mediately to an MH expert to help contacted him. “I was really impressed guide you through the procedure. And now, you can practice an MH Hotline call with an actual A Genetic Test or Muscle Biopsy MH expert by ordering a Mock Drill Call through MHAUS. For only – Which Test is Right for You? $100.00 can buy you peace of mind. The first distinction to note is that the OR by a surgeon and the specimen test- muscle biopsy (CHCT) remains the ed immediately in a laboratory that has Here’s how it works: “gold standard” for diagnosing malignant the equipment and expertise to diagnose q Once your order is placed, the hyperthermia. It is very sensitive (detects MH. Such MH diagnostic centers are MH Hotline Coordinator will con- all those who are MH susceptible) but not listed on the MHAUS web site. On the highly specific (only about 85% to 95% other hand, the genetic test requires only tact you to arrange a date and time. (Allow at least 2 weeks). of those diagnosed by the CHCT actually a blood sample that can be sent to a lab q are at risk for MH). The genetic test, on by mail. (MHAUS generally recommends Then, call the hotline number the other hand, is very specific (if one of PreventionGenetics located in Marshfield, provided at the same point you the known mutations are found, then the Wisconsin, although a few other labs are would in an actual MH case. q patient is sure to be MH susceptible) but also equipped to do the genetic test.) Identify this is a Mock Drill. it’s not as sensitive (about 70% of known Generally speaking, most biopsy centers q Be prepared to hold while being MH susceptibles have a DNA variant will require that the patient be at least 10 connected to a MH expert. associated with MH susceptibility). Since years of age. q The MH expert will treat this all the DNA changes predictive of MH are In either case, cost is an issue as a real call and ask for clini- not known, a patient may have a DNA because insurance may not cover the cal details to guide you through variant that is not known to be predictive expense for either procedure. A patient procedures. of MH for certain. In addition, there are receiving the test is urged to consult with now three genes that are predictive of MH his/her insurance provider before under- MH Mock Drill training can im- susceptibility. As the testing improves, going either test. A muscle biopsy can prove preparation for your entire such variants, known as VUS or variants cost several thousand dollars when one team. Please schedule your call of uncertain significance, may be found to includes the facility fee, the physician’s TWO WEEKS in advance with the be indicative of MH susceptibility. fees and the laboratory fee; similarly, a MHAUS Hotline Coordinator. Call A second distinction to note is genetic test can cost upward of several 607-674-7901 or email gloria@ that the muscle biopsy is a more invasive thousand dollars depending on the extent mhaus.org. procedure than a genetic test since a muscle biopsy must be performed in the continued on page 11 6 7 8 Methylene Blue and Severe Serotonin Toxicity Editor’s note: Serotonin toxicity due to giving the neuromuscular junction. tion, lower extremity rigidity, hyperthermia, methylene blue to patients taking serotonin reuptake The serum calcium level was tachycardia and diaphoresis. No neuro- inhibitor antidepressants is not related to MH sus- leptic had been given. The question arose ceptibility -- it may occur whether or not a patient is 8 mg/dL. This patient’s serum calcium, MH-susceptible. While severe serotonin toxicity may while decreased, was not low enough why the patient, who was not taking an mimic an MH crisis, there are important differences in to account for the clinical findings. With MAO inhibitor or thought to have taken an diagnosis, response to non-depolarizing (curare-like) acute hypocalcemia, one also would overdose of Zoloft, developed serotonin paralytics, and treatment not expect increased muscle tone to be toxicity. Review of the literature revealed a remarkably similar case of a female by Harvey K. Rosenbaum, M.D. limited to the lower extremities. Health Sciences Professor of Anesthesiology, David Thyroid storm may cause hyper- taking fluoxetine (Prozac) who received Geffen School of Medicine at UCLA and MH Hotline thermia, agitation, and sweating but it is 7.5 mg/kg methylene blue during general Consultant for MHAUS not associated with muscle rigidity. anesthesia for a parathyroidectomy and In 2005, I received an MH Hotline call The patient was sedated with had early postoperative agitation, ocular from an anesthesiologist whose patient propofol and lorazepam and muscle re- clonus, myoclonus, increased muscle had undergone thyroidectomy for treat- laxation was maintained with vecuronium tone, and sweating(2). In addition, Wegen- ment of multinodular goiter with hyper- overnight. The patient was successfully er et al had shown that the acute injection thyroidism. The patient was a 50-year-old weaned and extubated on the afternoon of methylene blue increased CNS levels 90-kg female who was euthyroid on of post-operative day 1, with no neuro- of serotonin by more than 2-fold in rats(3). propylthiouracil. She underwent a lung logic sequelae. In 1986, Naylor, using po methylene blue resection 3 months earlier with no known 300 mg/day, reported a reduction in the complications. She had COPD and was Serotonin Toxicity (Serotonin duration and severity of depression in taking Prednisone and Levalbuterol. She Syndrome) is characterized by: patients with bipolar affective disorder(4). was induced with propofol and relaxed 1) agitation or confusion, which are non- I speculated that methylene blue caused with succinylcholine. Maintenance of specific signs; an abrupt increase in CNS serotonin level anesthesia was with sevoflurane/air/oxy- 2) involuntary increased motor activity in this patient chronically taking Zoloft. gen. She was given 50 mL 1% methylene progressing from tremor, shivering This case was described in 2006 blue iv to identify the parathyroid glands. and hyperreflexia with mild serotonin on the MHAUS website’s “Case of the The 4-hour anesthetic (0800 – 1200) was toxicity to elicited or spontaneous Month.” Dr. Ken Gillman, a psychiatrist uneventful. clonus, including ocular clonus. Unlike and recognized authority on serotonin In the post-anesthesia care unit nystagmus, ocular clonus has move- toxicity, read this report and agreed (PACU), the patient became progressively ments of equal speed in both directions with the diagnosis of severe serotonin agitated, tachycardic and diaphoretic. and lacks a slow component. Clonus is toxicity. Gillman strongly speculated that Oxygen saturation was 88% on 6 L/ not observed in neuroleptic malignant methylene blue was an MAOI(5). In 2007, min. O2 by face mask. Methemoglobin syndrome; he collaborated with Rona Ramsay and level was < 0.3%. While muscle tone in 3) autonomic nervous system findings confirmed that methylene blue is a potent the arms was normal, she had severe include tachycardia, hypertension or MAO-A inhibitor(6). Its metabolite Azure lower extremity rigidity. The patient was hypotension, and pupillary dilatation; B is also a potent MAO-A inhibitor(7). reintubated following propofol and 10 mg 4) The onset of serotonin toxicity is typi- Ramsay et al showed nearly complete vecuronium. The lower extremity rigidity cally much faster -- minutes to hours MAO-A inhibition at a methylene blue rapidly resolved with paralysis. -- than seen in neuroleptic malignant concentration of 1 μM. An injection of The patient was also taking syndrome. This is particularly so when 0.75 mg/kg methylene blue will result in a buspirone for anxiety and the serotonin either the MAOI (monoamine oxidase peak plasma concentration of 1.6 μM; the re-uptake inhibitor (SRI) Zoloft (sertraline) inhibitor) or the medication with SRI concentration inside cells is likely to reach for depression. Metoclopramide had been (serotonin reuptake inhibitor) activity is a level that inhibits MAO-A, even at this ordered but had not been given. An MRI given intravenously; low dose(8). was performed and did not show an acute 5) Severe cases may develop life-threat- In addition to treating severe intracranial lesion. Her temperature was ening hyperthermia, rigidity starting in methemoglobinemia(9) and identifying the 101° F. (38.3° C.) the lower extremities, coma, rhabdomy- parathyroid glands during thyroid and The anesthesiologist who called olysis, and disseminated intravascular parathyroid surgery, intravenous methy- the hotline was evaluating the patient in coagulation. Rigidity may progress with lene blue has been used to identify the the recovery room and had not taken care development of jaw muscle or truncal ureteral orifices during cystoscopy and of her in the OR. The patient was reintu- rigidity which may impair ventilation; to treat vasoplegia -- low blood pressure bated because of increased blood carbon 6) Severe serotonin toxicity is nearly with impaired response to commonly used dioxide and decreased oxygen saturation always associated with the combina- vasopressors -- associated with cardiac as well as agitation. The striking finding tion of an SRI with an MAO-A inhibitor surgery or drug overdose. In patients on of severe lower extremity rigidity rapidly or nonselective monoamine oxidase pre-anesthetic SRI therapy, this has re- resolved following complete relaxation inhibitor (MAOI) (1). sulted in acute serotonin toxicity observed with vecuronium; this excluded MH as the after emergence from anesthesia(10-11). cause of her rigidity. In MH, muscle rigid- I suggested the diagnosis of serotonin Unlike MH, serotonin toxicity has not been ity will persist despite full relaxation with toxicity because the patient was taking observed during the maintenance phase a non-depolarizing muscle relaxant; the sertraline – an SRI – preoperatively and of inhalational general anesthesia. pathologic process is “downstream” from postoperatively rapidly manifested agita- continued on page 9 9 continued from page 8 Dantrolene, while delaying increase in temperature, does not prevent mortality When Regulatory in an animal model of severe serotonin Deaths due to severe serotonin toxicity toxicity; 5-HT antagonists prevented Agencies Come Calling have been reported following methylene 2A mortality. No cooling measures or oth- blue administration to patients on pre- (12) er supportive therapy were described in Don’t Get Caught anesthetic SRI’s . this study(19). Without the Revised 4) In addition to supportive therapy, the Principles of diagnosis and treatment serotonin antagonist cyproheptadine of serotonin toxicity include: Emergency Therapy has been successfully used to treat 1) Review of the patient’s chronic medica- signs of serotonin toxicity. There is no for MH Poster tions, history of substance abuse, and parenteral formulation. In patients un- medications given perioperatively to The Malignant Hyperthermia Associa- able to take oral medication, cyprohep- identify a combination of medications tion of the United States (MHAUS) tadine must be given via oro- or naso- with SRI or serotonin-releasing activ- gastric tube, with doses of 8-16 mg up is pleased to announce the newly ity (e.g. Ecstasy or “bath salts”) with to a daily maximum of 32 mg. revised 2018 Emergency Therapy an MAO inhibitor. Ongoing selective for Malignant Hyperthermia Poster serotonin re-uptake inhibitor (SSRI) Boddy et al described the successful use and Pocket Card are now available. treatment attenuates serotonin release (13) of sublingual olanzapine, a potent 5-HT2A Additional information has been added with Ecstasy . Of the tricyclic anti- antagonist, to treat acute serotonin toxic- to the diagnosis, acute phase treat- depressants, only clomipramine and ity in a series of 10 patients who had ment, and post acute phase treatment high-doses of imipramine have resulted taken overdoses of SSRI’s. Patients were in severe serotonin toxicity when sections. The revised poster sells for given 10 mg sublingual olanzapine, with combined with an MAO inhibitor. The only $35.00, or $24.50 for members. a 10 mg dose repeated after two hours following opioids or analgesics have Now is the time to replace in two patients(20). In the United States, SRI activity: tramadol, methadone, your old 2015 posters with a newly olanzapine is available in a short-acting meperidine (Demerol or pethidine), revised version (effective October parenteral form for intramuscular ad- tapentadol, and the cough suppressant 2018). More than likely the regulatory ministration. Chlorpromazine has also dextromethorphan. Fentanyl, while agency surveyors will be looking for been successfully used to treat severe without demonstrated SRI activity, does them – so make sure you have yours! serotonin toxicity. Gillman described bind to 5-hydroxytryptamine 2 (5-HT ) 2 a patient with serotonin toxicity due to and 5-HT receptors at high concentra- 1 clomipramine and tranylcypromine who Also now available is the tions, such as might be seen after rapid revised MH Crisis Protocol Kit. (14- responded well after 50 mg intramuscular administration of 50 micrograms/kg 15) chlorpromazine following unsuccess- Included in the kit: . A case report by Noble describes q ful treatment with 16 mg cyprohepta- One MH Laminated Crisis Poster lethal serotonin toxicity in a patient on dine; in 1999 he reviewed all reported “Emergency Therapy for MH” a preoperative MAOI who underwent cases treated with either drug(21). Though q One 8½” x 11” Mini MH Laminated cardiac surgery and received a total of (16) chlorpromazine or olanzapine may be 7,000 micrograms of fentanyl . Drugs Crisis Poster “Emergency Therapy associated with hypotension, their 5HT2A given for treatment of migraine head- for MH” antagonism may benefit the patient with q aches that are selective 5-HT1B and One MH Crisis Pocket Card “Emer- severe serotonin toxicity, particularly 5-HT1D agonists and antiemetics that gency Therapy for MH” when the patient is deteriorating despite are 5-HT3 antagonists do not result in (17-18) intense supportive therapy. Given that it serotonin toxicity . This MH Crisis Protocol Kit (CPK) has no dopamine antagonism, cyprohep- 2) Not giving additional SRI or MAO is a kit for healthcare profession- tadine may be preferable to chlorproma- inhibiting medication. Mild-to-moderate als to display in any area where an zine or olanzapine in cases where there serotonin toxicity usually responds to MH Crisis can occur. The kit sells for is diagnostic uncertainty between severe discontinuing medications with 5-HT2A serotonin toxicity or neuroleptic malignant only $45.00, or $31.50 for members. agonist activity and giving benzodiaz- syndrome. Please note that the 8½” x 11” Mini epines to treat agitation. MH Laminated Crisis Poster “Emer- 3) Supportive therapy, including sedation, Alternatives to methylene blue gency Therapy for MH” is not sold endotracheal intubation when indicat- 1. For identification of the ureteral orifices separately and is only available in this ed, cooling measures for hyperthermia, during cystoscopy, preoperative oral kit. MHAUS strongly recommends, and assessment and treatment for hy- phenazopyridine or intraoperative povolemia or secondary cardiac failure. in an MH event, referring only to intravenous fluorescein have been Truncal rigidity may impair ventilation. the easy to read 16” x 24” poster to administered. More recently, Grimes et Non-depolarizing muscle relaxants may assure an appropriate action plan is al demonstrated that instillation of man- be employed to treat rigidity, aid cool- followed. nitol into the bladder was superior to ing, and prevent further rhabdomyolysis You can order these new either fluorescein or phenazopyridine in (skeletal muscle damage). While dan- products and learn about our other visually assessing ureteral patency(22). trolene may also be used to treat rigid- products to help you manage an MH 2. Spiess and Shah have described the ity and aid cooling, there is no evidence crisis by visiting the MHAUS online use of hydroxycobalamin, a form of of its superiority to non-depolarizing store at: https://my.mhaus.org/store/ vitamin B12, to treat vasoplegia associ muscle relaxants in sedated, intubated Together we can save a life! patients with severe serotonin toxicity(1). continued on page 10 10

estimated 10% of adults in North America 2014;72:179–81 continued from page 9 13. Liechti ME, Vollenweider FX. The serotonin uptake inhibi- take an SRI(27), this safeguard would help ated with cardiac surgery. Hydroxyco- tor citalopram reduces acute cardiovascular and vegeta- prevent administration of methylene blue tive effects of 3,4-methylenedioxymethamphetamine balamin is supplied as a 5 gram vial to a patient taking an SRI antidepressant. (‘ecstasy’) in healthy volunteers. J Psychopharmacol for treatment of cyanide poisoning, 2000;14:269-74. and Spiess and Shah used 5 grams 14. Rickli A, Liakoni E, Hoener MC, et al. Opioid-induced in- References hibition of the human 5-HT and noradrenaline transport- given iv over 10-15 minutes to treat 1. Buckley N, Dawson AH, Isbister GK. Serotonin syndrome. ers in vitro: link to clinical reports of serotonin syndrome. vasoplegia; treatment was not always BMJ 2014 Feb 19; 348: g1626 Br J Pharmacol 2018; 175: 523-543. 15. Murkin JM, Moldenauer CC, Hug CC Jr., et al. Absence successful. Hydroxycobalamin directly 2. Martindale SJ, Stedeford JC. Neurological sequelae following methylene blue injection for parathyroidectomy. of seizures during induction of anesthesia with high-dose binds of nitric oxide and inhibits nitric Anaesthesia 2003; 58: 1041–2. fentanyl. Anesth Analg 1984; 63: 489-494. oxide synthase and soluble guanylate 3. Wegener G, Volke V, Rosenberg R. Endogenous nitric 16. Noble WH, Baker A. MAO inhibitors and cardiac surgery: (23-24) oxide decreases hippocampal levels of serotonin and a patient death. Can J Anaesth 1992; 39: 1061-1066. cyclase . dopamine in vivo. Br J Pharmacol 2000; 130: 575-80. 17. Rojas-Fernandez C. Can 5-HT3 antagonists really 3. For treatment of severe methemoglo- 4. Naylor GJ, Martin B, Hopwood SE, et al. A two-year contribute to serotonin toxicity? A call for clarity and binemia with methemoglobin levels double-blind crossover trial of the prophylactic effect pharmacological law and order. Drugs—Real World of methylene blue in manic-depressive psychosis. Biol Outcomes 2014;1:3–5 >30% or signs of severely impaired Psychiatry 1986; 21: 915-20. 18. Gillman PK. Triptans, serotonin agonists, and serotonin oxygen delivery, alternative treatments 5. Gillman PK. Methylene blue implicated in potentially fatal syndrome (serotonin toxicity): a review. Headache 2010;50:264–72 to methylene blue with rapid effects serotonin toxicity. Anaesthesia 2006; 61: 1013-1014. 6. Ramsay RR, Dunford C, Gillman PK. Methylene blue and 19. Nisijima K, Yoshino T, Yui K, et al. Potent serotonin include hyperbaric oxygen therapy or serotonin toxicity: inhibition of monoamine oxidase A (5-HT)2A receptor antagonists completely prevent the exchange transfusion. High-dose intra- (MAO A) confirms a theoretical prediction. Br J Pharmacol development of hyperthermia in an animal model of the 2007;152:946–51 5-HT syndrome. Brain Research 2001; 890: 23-31. venous ascorbic acid has also been 7. Petzer A, Harvey BH, Wegener G, et al. Azure B, a me- 20. Boddy R, Dowsett RP, Jeganathan D. Sublingual used as a treatment for methemoglo- tabolite of methylene blue, is a high-potency, reversible olanzapine for the treatment of serotonin syndrome. J Toxicol Clin Toxicol 2006; abstract 45, pp. 439-440. binemia(25). I am unaware of any cur- inhibitor of monoamine oxidase. Toxicol Appl Pharmacol 258:403-409, 2012 21. Gillman PK. Serotonin syndrome and its treatment. J rently available analogs of methylene 8. Gillman PK. CNS toxicity involving methylene blue: the ex- Psychopharmacol 1999; 13: 100-109. blue that do not inhibit MAO-A which emplar for understanding and predicting drug interactions 22. Grimes CL, Patankar S, Ryntz T, et al. Evaluating ure- that precipitate serotonin toxicity. J Psychopharmacol teral patency in the post-indigo carmine era: a random- could be used to treat vasoplegia or 2011; 25:429–36 ized controlled trial. Am J Obstet Gynecol 2017;217:601. severe methemoglobinemia. 9. link: https://www.uptodate.com/contents/clinical- e1-10. features-diagnosis-and-treatment-of-methemo- 23. Roderique JD, VanDyck K, Holman B, et al. The use of globinemia?search=methemoglobinemia%20 high-dose hydroxycobalamin for vasoplegic syndrome. Prevention treatment§ionRank=2&usage_type=default&anchor= Ann Thorac Surg 2014; 97: 1785-1786. The key to preventing severe serotonin H25&source=machineLearning&selectedTitle=1~150&dis 24. Shah PR, Reynolds PS, Pal N, et al. Hydroxocobalamin for the treatment of cardiac surgery-associated vasople- toxicity is reviewing the patient’s medica- play_rank=1#H25 10. Adler AR, Charnin JA, Quraishi SA. Serotonin syndrome: gia: a case series. Can J Anesth 2018; 65: 560-568. tions and avoiding methylene blue in pa- the potential for a severe reaction between common peri- 25. Park S-Y, Lee K-W, Kang T-S. High-dose vitamin C tients taking preoperative SRI medication. operative medications and selective serotonin reuptake management in dapsone-induced methemoglobinemia. inhibitors. A A Case Rep 2015;5:156–9 Am J Emerg Med 2014; 32: 684. e1-e3. Ken Gillman and I strongly recommend 11. Martino EA, Winterton D, Nardelli P, et al. The Blue 26. Rosenbaum HK, Gillman PK. Patient safety and methy- that a “timeout” take place prior to order- Coma: The role of methylene blue in unexplained coma lene blue-associated severe serotonin toxicity. Anesth Analg Case Rep. 2016; 7:1. ing and/or administering methylene blue after cardiac surgery. J. Cardiothor and Vasc Anesth 2016; 30 (2): 423-427. 27. Pratt LA, Brody DJ, Gu Q: Antidepressant use in persons to patients in the operating room or other 12. Top WM, Gillman PK, de Langen CJ, Kooy A. Fatal aged 12 and over: United States, 2005-2008. NCHS critical care settings(26). Given that an methylene blue associated serotonin toxicity. Neth J Med Data Brief 2011; 127:1-8. Did you know? MHAUS offers a lifesaving MH Hotline, free-of-charge, for any healthcare professional who unexpectedly comes face-to-face with a malignant hyperthermia emergency and quickly needs help. The cost per call to MHAUS is $100.00, which includes the contracted service to transfer your call to a consultant and some of the costs associat- ed with the MH Hotline Coordinator who assures there are consultants ready every day on a 24-hour basis for you. Dedicated MH Hotline Consultants, all well-known MH Experts, freely volunteer their time to help their fellow health- care professionals through an intense situation. Consider making at least a $100.00 donation (to cover a single call) specifically to help us maintain this lifesaving tool provided by MHAUS to all healthcare professionals.

Enclosed is my tax-deductible contribution of $______in support of the lifesaving MH Hotline. Please make checks payable to: MHAUS and send to PO Box 1069, Sherburne, NY 13460.

q Visa q MasterCard q Discover q American Express

Name on card:______

Credit Card Number:______Expiration Date______

Signature:______11 continued from page 2 tion of MHAUS has also been quite busy. door to important education and programs Dr. Stanley Caroff, Vice-President – Di- designed specifically to meet the needs Questions are abundant as to whether rector, NMSIS, put together two programs of the end user. Regular updates are there is a connection between those with this year. The first was a competition of shared to provide the latest on products, an MH mutation and their propensity to papers written on the topic of Tardive programs, new publications, and events develop heatstroke in various circum- Dyskinesia and the second was a series available to the public. stances. What is the answer? We don’t of evening symposia on Tardive Dyskine- As we close out 2018, we at know yet, but more and more research sia. We anticipate there will be additional MHAUS wish you a Happy New Year! and case studies are being investigated positive strides made and expect more by many varied experts. Gaining a heat- to come. Check out the NMSIS website Dianne Daugherty stroke thought leader on either our BOD pages. MHAUS Executive Director or PAC is of prime importance to MHAUS Our social media outlets are and will be of great benefit to individuals growing in importance within MHAUS and Learn how MH has changed relying on our educational materials to are developing as a strong conduit for us help manage their patients and to indi- to engage with our members and other lives and share your own viduals dealing with this health concern. groups interested in the topic of MH and story through “Faces of MH” The Neuroleptic Malignant Syn- other heat-related disorders. The website on the MHAUS website. drome Information Service (NMSIS) por- remains the “face of MHAUS” and the

continued from page 5 odology of the testing utilized. However, clinical episode of MH q of genetic analysis. (More information if a causative mutation is discovered, Patient with positive CHCT q is available on the MHAUS web site). family members can be tested for that Patient with MHS relative as deter- Even if your insurance company agrees to specific causative mutation, and if found, mined by positive CHCT q pay for a genetic test, be aware that some the individual is considered MHS and a Patients with relatives with known laboratories may refuse to accept the fee muscle biopsy for contracture testing can causal RYR-1 mutatione. q schedule of the insurance company, and be avoided. Currently, there are 48 known A genetics laboratory equipped to per- will ask you to first pay up front, then sub- MH causative RYR-1 mutations, (listed form specialized genetic analysis. mit your claim to your insurance company on the European MH web site:www. for personal reimbursement. emhg.org). MHAUS recommends Muscle Biopsy (CHCT) Indications: q Understand that neither test is patients work with a genetic counselor Patient with MHS family member (as recommended as a screening tool for and/or their medical professional in order determined by past suspicious MH MH susceptibility for the general public. A to make a decision. The MHAUS office episode, but without a known causative test’s usefulness depends on the pre-test can provide some recommendations for genetic mutation) q probability that the patient is MH-suscep- genetic counselors. Patient with unexplained rhabdomy- tible (MHS). Before any diagnostic testing So, what other factors help de- olysis during or after surgery in the is recommended, an evaluation of your termine which test you and your medical absence of genetic testing q susceptibility to MH should be completed care provider might choose? Patient with exercise-induced rhabdo- using available medical data. Suscepti- myolysis after a negative rhabdomyoly- bility to MH is inherited in an autosomal Genetic Testing Indications: sis workup, which includes a variety of dominant fashion; therefore, evaluation of This is a very complex issue as there laboratory tests. your susceptibility to MH depends upon are factors that depend on the accuracy a careful review of both your and your of the clinical diagnosis, the patient’s Each year, the accuracy, sensitivity and family members’ medical and anesthetic willingness to undergo testing, financial specificity of genetic testing improves, but history. considerations and travel-related issues. there is still a long way to go before the As noted earlier, a genetic test Some MH experts will not recommend test can be recommended routinely. Much may not be conclusive for MH suscep- genetic testing without a muscle biopsy of the information contained in this article tibility. At this point, not all proven MHS contracture test. Others will recommend can be found on the MHAUS website, individuals have been found to harbor a genetic testing first as it is a less invasive along with a list of testing centers and causative mutation in the RYR-1 gene. test. With that said, conditions for genetic helpful forms patients might use when The sensitivity of the genetic test de- testing might include: contacting their insurance company q pends upon several factors, including Patient with a confirmed or highly sus- about testing options. A webinar video on the population selected and the meth- picious personal or family history of a genetic testing is also available. The U.S. and Canada MH Hotline is 1-800-MH-HYPER (1-800-644-9737) Outside the U.S., call 1-209-417-3722 MHAUS Happenings, Events and Notices ❑ THANKS! MHAUS thanks the and consultative services. NMSIS announced in September that the U.S. following State Society of Anesthesi- is entirely supported by contributed Food and Drug Administration has ology – New Jersey, Ohio, and Wis- funds from members and their granted orphan drug designation to consin – for their financial support. families, medical professionals and ARM210 (also known as S48168), a Our appreciation also goes out to the corporations. potential treatment for patients with Association of Nurse Anesthetists, Ryanodine Receptor Type 1 Related Illinois. Call the MHAUS office to ask q Eagle Pharmaceuticals Con- Myopathies (RYR1-RM). Gloria how your group can join their cludes Enrollment of Second ranks. Safety and Efficacy Study at Hajj q EMHG Meeting May 16-18, 2019 to Evaluate RYANODEX for Exer- The 38th Annual Meeting of the Euro- q Congratulations to Promising tional Heat Stroke pean Malignant Hyperthermia Group Scholars Award Winners Eagle Pharmaceuticals, Inc. an- (EMHG) will take place in Potsdam, Congratulations to Dr. Gopalkumar nounced in August the completion Germany from May 16th to 18th, 2019. Rakesh of Duke University and Dr. of enrollment of the Company’s More information is available online at Haitham Salem of the University second clinical study to further www.emhg.org. of Texas Houston for winning the evaluate the safety and efficacy of national 2018 Promising Scholars RYANODEX® (dantrolene sodium q Send Us Your Expired Dantrolene Award for their original papers on for injectable suspension) for the If your medical facility has expired tardive dyskinesia. The Neurolep- treatment of exertional heat stroke dantrolene sodium for injection, please tic Malignant Syndrome Informa- (“EHS”), an investigational new donate it to MHAUS so that we might tion Service (NMSIS) serves as an indication for the product. use it for training purposes. In return, international resource center for MHAUS will provide you a free year’s knowledge on neuroleptic malignant q ARMGO Pharma Receives FDA membership that includes a 30% dis- syndrome in addition to other heat-re- Orphan Drug Designation for count on most MH educational materi- lated disorders and drug side effects ARM210/S48168 for the Treat- als, access to online forums, quizzes, by: developing educational support ment of Ryanodine Receptor webinars and plenty more! When programs; supporting clinical and new Type 1 Related Myopathies shipping, please be sure the vials are product research and development; ARMGO Pharma, Inc., a clinical wrapped properly to eliminate pos- implementing updated web-based stage biopharmaceutical company sible damage. Please ship to: MHAUS, and published materials; and provid- advancing a novel class of small 1 North Main Street, Sherburne, NY ing evidence-based informational molecule drugs known as Rycals®, 13460.

MHAUS P.O. Box 1069 Sherburne, NY 13460-1069 www.mhaus.org