E SPECIAL ARTICLE Society for Obstetric and Perinatology Consensus Statement: Recommendations for Prevention and Detection of Respiratory Depression Associated With Administration of Neuraxial for Cesarean Delivery Analgesia

Jeanette R. Bauchat, MD, MS, Carolyn F. Weiniger, MBChB, Pervez Sultan, MBChB, FRCA, MD, Ashraf S. Habib, MBBCh, MSc, MHSc, FRCA, Kazuo Ando, MD, PhD,║ John J.* Kowalczyk, MD, Rie Kato, MD,† DPhil, Ronald B. George, MD, FRCPC, Craig‡ M. Palmer, MD, and Brendan Carvalho, §MBBCh, FRCA ¶ # ** †† ‡‡ The majority of women undergoing cesarean delivery in the United States receive neuraxial morphine, the most effective form of postoperative analgesia for this surgery. Current American Society of Anesthesiologists (ASA) and American Society of Regional Anesthesia and Pain Medicine (ASRA) recommend respiratory monitoring standards following neuraxial morphine administration in the general surgical population that may be too frequent and intensive when applied to the healthy obstetric population receiving a single dose of neuraxial morphine at the time of surgery. There is limited evidence to support or guide the optimal modality, frequency, and duration of respiratory monitoring in the postoperative cesarean delivery patient receiving a single dose of neuraxial morphine. Consistent with the mission of the Society for Obstetric Anesthesia and Perinatology (SOAP) to improve outcomes in pregnancy for women and neo- nates, the purpose of this consensus statement is to encourage the use of this highly effective technique while promoting safe practice and patient-centered care. The document aims to reduce unnecessary interruptions from respiratory monitoring in healthy mothers while focusing vigilance on monitoring in those women at highest risk for respiratory depression fol- lowing neuraxial morphine administration. This consensus statement promotes the use of low- dose neuraxial morphine and multimodal analgesia after cesarean delivery, gives perspective on the safety of this analgesic technique in healthy women, and promotes patient risk stratifica- tion and perioperative risk assessment to determine and adjust the intensity, frequency, and duration of respiratory monitoring. (Anesth Analg XXX;XXX:00–00)

PURPOSE OF THIS CONSENSUS STATEMENT women receiving neuraxial morphine for postoperative Cesarean delivery is the most commonly performed inpa- analgesia. The purpose of this document is to provide expert tient procedure in the United States with the majority of consensus recommendations on the monitoring of obstetric patients following neuraxial morphine administration. The From the Department of , Vanderbilt University Medical primary aims of this document are as follows: Center, Nashville, Tennessee; Division of Anesthesiology & Critical Care & Pain, Sourasky* Medical Center, Tel Aviv, Israel; Department of Anaesthesia 1. Support the mission of the Society for Obstetric and Perioperative Medicine, University† College London Hospital, London, United Kingdom; Department of Anesthesiology,‡ Duke University School Anesthesia and Perinatology (SOAP) to improve of Medicine, Durham, North Carolina; ║Department of Anesthesiology, pregnancy-related outcomes for women and Aichi Medical University,§ Aichi, Japan; Department of Anaesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard neonates; Medical School, Boston, Massachusetts;¶ Division of Anesthesiology, 2. Encourage the use of a highly effective analgesic Kitasato University School of Medicine, Kanagawa, Japan; Department technique following cesarean delivery by reduc- of Anaesthesia, Pain Management and Perioperative# Medicine, Dalhousie University, IWK Health Centre, Halifax, Nova Scotia, Canada; **Department ing resource burden for unnecessary respiratory of Anesthesiology, University of Arizona College of Medicine, Tucson, monitoring; Arizona; and Department of Anesthesiology, Perioperative†† and Pain 3. Promote patient-centered care by reducing the bur- Medicine, Stanford University School of Medicine, Stanford, California. ‡‡ den of excessive respiratory monitoring in healthy Accepted for publication March 21, 2019. mothers recovering from cesarean delivery; and Funding: None. The authors declare no conflicts of interest. 4. Focus clinical vigilance and intensive respiratory Supplemental digital content is available for this article. Direct URL citations monitoring on those women at high risk for respi- appear in the printed text and are provided in the HTML and PDF versions of ratory depression following neuraxial morphine this article on the journal’s website (www.anesthesia-analgesia.org). administration. Reprints will not be available from the authors. Address correspondence to Jeanette R. Bauchat, MD, MS, Obstetric An- This writing group was appointed and selected by the esthesiology Division, Vanderbilt University Medical Center, Room 4202 SOAP board and comprised a representative group of clini- VUH (7580), 1211 Medical Center Dr, Nashville, TN 37232. Address e-mail to [email protected]. cal experts in obstetric anesthesiology who conduct research Copyright © 2019 International Anesthesia Research Society or have a special interest in respiratory monitoring or neur- DOI: 10.1213/ANE.0000000000004195 axial administration. The writing group consisted of

XXX 2019 • Volume XXX • Number XXX www.anesthesia-analgesia.org 1 Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. EE Special Article

7 members: Jeanette R. Bauchat, Carolyn F. Weiniger, Pervez Box 1. Considerations for Use of Neuraxial Opioid Sultan, Ashraf S. Habib, Rie Kato, Ronald B. George, and Analgesia in a Low-Resource Environment Brendan Carvalho (chair). Craig M. Palmer provided valu- A physician anesthesiologist in the low-resource environment must able input into the document, and Kazuo Ando and John evaluate the appropriateness of neuraxial opioid use in their setting J. Kowalczyk conducted the SOAP member survey and including provided valuable input into the document. This statement Availability of medical providers who can evaluate underlying represents the consensus of the writing committee and was patient comorbidities and risk factors that may increase the approved by the SOAP board of directors. In generating its likelihood of respiratory depression consensus, several committee members conducted a sys- System to ensure reliable and accurate administration of 1 nonopioid multimodal medication tematic review. Selected articles from this review and any Availability of postpartum nurses who can detect respiratory additional articles identified by committee members were depression then selected based on relevance for this consensus state- Emergency response team in the event of unexpected respiratory ment. The committee reviewed systematic reviews, meta- depression, which may result from undiagnosed comorbidities analyses, randomized controlled trials, retrospective trials, and/or drug error and case reports primarily in the obstetric patient popula- tion. For topics where there are no data specific to the obstet- stratification, dosing of intrathecal or epidural morphine, as ric population, the writing group referenced best available well as modality, duration, and frequency of perioperative literature collected in nonobstetric populations. respiratory monitoring.

DERIVATION OF THIS CONSENSUS DOCUMENT What Other Statements or Guidelines Are In writing a consensus document, it is recognized that Available Regarding This Topic? consensus recommendation does not mean that there was The ASA/ASRA have developed Practice Guidelines complete agreement among all writing group members. for the Prevention, Detection and Management of Email surveys and personal meetings of the entire writ- Respiratory Depression Associated with Neuraxial Opioid ing group were used to identify areas of consensus. The Administration for all surgical patients.3 These guidelines American College of Cardiology and American Heart codify recommendations to identify patients at risk for Association Clinical Practice Guideline Recommendation respiratory depression and to prevent, detect, and manage Classification System was used for classes of recommenda- respiratory depression associated with neuraxial in 2 tion and strength of evidence (See details of the classifica- the general surgical population.3 However, the guidelines tion system in Supplemental Digital Content 1, Document, do not distinguish between the obstetric population receiv- http://links.lww.com/AA/C801). Authors used the class ing single-shot neuraxial morphine for postcesarean deliv- of recommendation and strength of evidence as agreed on ery analgesia and the general surgery population receiving by greater than or equal to two-third (5 of 7 members) of the neuraxial morphine for postoperative analgesia. Task Force writing group. If the class recommendation was not agreed on by greater than or equal to two-third, then we Why Was This Consensus Statement Developed? moved to a lower class of recommendation and strength of This consensus statement was developed by SOAP to pro- evidence until greater than or equal to two-third agreement vide recommendations for strategies surrounding the pre- was obtained by the Task Force writing group. vention and detection of respiratory depression associated APPROPRIATE USE OF THE CONSENSUS with neuraxial morphine specifically in the obstetric popula- DOCUMENT tion following cesarean delivery. Opioid-induced ventilatory 4 The ultimate judgment regarding care of an individual impairment is under scrutiny at a national level. The ASA/ patient must be made by the physician anesthesiologist ASRA guidelines for postoperative monitoring following and other health care providers in conjunction with the neuraxial opioid administration were perceived by many to patient. Construction of the optimal postpartum analgesic be overly rigorous for the healthy obstetric population, given plan should incorporate the patient’s medical condition and the low risk of respiratory depression utilizing contemporary preferences, the institutional management options available neuraxial morphine dosing strategies.3 Moreover, the ASA/ (which may be limited in low-resource environments), and ASRA guidelines may inadvertently reduce the utilization of the relative risks and benefits of available analgesic options. intrathecal morphine, a highly effective postcesarean deliv- The physician anesthesiologist working in a low-resource ery analgesic, due to high resource requirements imposed by environment must consider the capabilities and limitations the included recommendations for respiratory monitoring.5,6 of their setting before implementation of neuraxial opioid The ASA/ASRA guidelines recommend frequent and pro- analgesia (Box 1). This document focuses on the manage- longed duration of postoperative assessments for respiratory ment of obstetric patients who are receiving low-dose intra- monitoring without differentiation for populations at risk.3 thecal or epidural morphine for postoperative analgesia as Healthy obstetric patients who receive low doses of neuraxial part of a multimodal analgesic regimen following cesarean morphine have a reduced risk of respiratory depression when delivery. The writing committee expanded the American compared with older patients and other vulnerable popula- Society of Anesthesiologists (ASA) and American Society tions. Moreover, breastfeeding already interrupts sleep, so of Regional Anesthesia and Pain Medicine (ASRA) recom- the necessity of monitoring should be considered against the mendations for respiratory monitoring following neuraxial risk of further sleep disruption and impact on maternal and opioid administration,3 specifically addressing patient risk neonatal welfare. Finally, the requirement for unnecessary

2 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. Respiratory Monitoring After Neuraxial Morphine

respiratory monitoring for all postcesarean patients may RECOMMENDATIONS detract from monitoring vigilance for those patients at high SOAP Task Force Recommendations for risk of respiratory depression. Frequency and Modality of Respiratory Monitoring Following Neuraxial Morphine How Does This Consensus Statement Differ From Administration for Postoperative Analgesia After Existing Guidelines? Cesarean Delivery This statement interprets and applies aspects of the recom- mendations from the ASA/ASRA Practice Guidelines that 1. Scientific literature findings: frequency and modality were updated in 2016 as they relate to postcesarean delivery of respiratory monitoring analgesia in the obstetric population.3 The ASA/ASRA guide- lines considered all forms of neuraxial opioid administration a. The literature is insufficient to assess whether any (single shot, intrathecal, epidural, continuous, patient con- monitoring interval or duration of monitoring is trolled), all doses, and all patients as equivalent.3 Unlike the optimal for detecting respiratory depression or ASA/ASRA guidelines, this consensus statement does not reducing risks associated with respiratory depres- address all modes of neuraxial drug administration (ie, contin- sion (level C-EO). uous, patient-controlled epidural analgesia) or cover neuraxial b. The literature is insufficient to assess whether any lipophilic opioids (eg, or sufentanil). This consensus modality of respiratory monitoring is optimal for document bases its recommendations on obstetric women detecting clinically relevant respiratory depres- undergoing cesarean delivery who are generally younger, not sion (level C-EO). sedated and have fewer comorbidities than other surgical pop- 2. Recommendation ulations, and receive a neuraxial technique using a low-dose “single-shot” administration of neuraxial morphine. a. The Task Force members agree that frequency and modality of respiratory monitoring should be SUMMARY POINTS based on patient risk stratification, neuraxial mor- SOAP Task Force Summary Points Based on phine dose administered, and clinical setting (see Literature Review Table 1; Figure). 1. Neuraxial opioids have been safely administered to millions of women for cesarean delivery for sev- SOAP Task Force Recommendations for eral decades. Reports in the literature or registries of Respiratory Monitoring Based on Neuraxial severe morbidity or mortality in the healthy obstetric Morphine Dose population due to respiratory depression from neur- axial morphine administration are exceedingly rare. 1. When using ultra–low-dose intrathecal morphine 2. There is limited evidence to support or guide the (≤0.05 mg) or epidural morphine (≤1 mg) in low-risk, optimal modality, frequency, and duration of respi- healthy parturients: The Task Force members agree ratory monitoring required to detect or prevent that it is reasonable to have no additional respiratory adverse respiratory events after cesarean delivery in monitoring beyond routine institutional postoperative women receiving neuraxial morphine. cesarean delivery monitoring (clinical decision tool in 3. Monitoring should be appropriately adjusted for Table 1; class 2A). (Ultra–low-dose of neuraxial mor- high-risk patients with comorbidities or with risk phine may provide less optimal analgesia when com- factors predisposing them to respiratory depres- pared to higher doses. If ultra–low-dose morphine is sion. Monitoring for respiratory depression can be used in combination with a nonopioid multimodal intrusive, disturb sleep, increase nursing workload, analgesic regimen, this approach may be a reasonable interfere with newborn care, and increase health care option in low resource settings with limited postopera- cost. Overly aggressive monitoring for respiratory tive respiratory monitoring but must be evaluated in depression in the setting of low-dose neuraxial mor- the context of all potential limitations of a low resource phine in low-risk parturients may impact resource environment [Box 1].) allocation and patient-centered postcesarean deliv- 2. When using low-dose intrathecal morphine (>0.05 to ery care without improving safety. ≤0.15 mg) or epidural morphine (>1 mg to ≤3 mg) in low- 4. Neuraxial morphine provides superior analgesia risk, healthy parturients: The Task Force members agree compared to systemically administered opioids and that in addition to routine institutional postoperative should be utilized preferentially for postoperative cesarean delivery monitoring, it is reasonable to monitor analgesia after cesarean delivery. Neuraxial opioids with respiratory rate and sedation measurement every 2 do not increase the risk of respiratory depression com- hours for 12 hours postoperatively (class 2A). pared to systemic opioids after cesarean delivery with 3. When using higher doses of intrathecal morphine neuraxial anesthesia. Low-dose neuraxial morphine (>0.15 mg) or epidural morphine (>3 mg) in low-risk, combined with multimodal (eg, nonsteroi- healthy parturients: The Task Force members agree dal anti-inflammatory drugs [NSAIDs], acetamino- that it is reasonable to monitor based on ASA/ASRA phen) provides effective analgesia while minimizing Practice Guidelines for the Prevention, Detection, and the risk for side effects such as pruritus, nausea/vom- Management of Respiratory Depression Associated iting, and possibly respiratory depression. with Neuraxial Opioid Administration3 (class 2A).

XXX 2019 • Volume XXX • Number XXX www.anesthesia-analgesia.org 3 Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. EE Special Article

Figure. Respiratory monitoring algorithm following neuraxial morphine administration for postcesarean delivery analgesia. BMI indicates body mass index; EPI, epidural; IT, intrathecal; Mg, magnesium; NSAIDs, nonsteroidal anti-inflammatory drugs; OSA, obstructive sleep apnea; PACU, postoperative anesthesia care unit; Q, every; RR, respiratory rate.

Table 1. Suggested Clinical Decision Tool for Risk Stratification Using Neuraxial Morphine Neuraxial Morphine Dose Risk Factors Intrathecal Epidural Postoperative Respiratory Monitoring Recommendation None (healthy, normal BMI) ≤0.05 mg ≤1 mg No further respiratory monitoring needed in addition to institutional guidelines for postoperative monitoring in this patient population >0.05 and ≤0.15 mg >1 and Q 2 h for 12 h RR and sedation checks ≤3 mg >0.15 mg >3 mg Follow ASA/ASRA guidelines3: 1. RR and sedation assessments for Q 1 h for first 12 h; Q 2 h for 12–24 h 2. Consider additional monitoring modalities (eg, pulse oximetry, ); continuous versus continual intermittent monitoring as indicated Patient risk factors examples ≤0.05 mg ≤1 mg No further respiratory monitoring needed in addition to Cardiopulmonary/neurological comorbidity institutional guidelines for postoperative monitoring in Class III obesity (BMI ≥40 kg/m2) this patient population Known or suspected OSAa Chronic opioid use Hypertension Peri/postoperative risk factors examples General anesthesia Supplemental IV opioid Concomitant sedating medicationsb Magnesium administration Desaturation >0.05 mg >1 mg Follow ASA/ASRA guidelines3: event in the PACU 1. RR and sedation assessments for Q 1 h for first 12 h; Q 2 h for 12–24 h 2. Consider additional monitoring modalities (eg, pulse oximetry, capnography); continuous versus continual intermittent monitoring as indicated Abbreviations: ASA, American Society of Anesthesiologists; ASRA, American Society of Regional Anesthesia and Pain Medicine; BMI, body mass index; OSA, obstructive sleep apnea; PACU, postanesthesia care unit; Q, every; RR, respiratory rate; EPI, epidural; IV, intravenous. aAll patients with risk factors for OSA (ie, obesity > 30 kg/m2, hypertension, etc) should be screened using any or a combination of STOP, STOP-BANG, the ASA checklist, Flemons Index Berlin, or the Epworth Sleepiness Scale.7–12 Additionally consider these OSA screening questions: BMI > 35 kg/m2, falling asleep while talking with someone, and history of treatment for hypertension.13,14 bExamples include general anesthetics, benzodiazepines, and sedating antiemetics.

4 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. Respiratory Monitoring After Neuraxial Morphine

SOAP Task Force Recommendation for Patient Risk Stratification for Postoperative Respiratory Box 2. Examples of Patient and Postoperative Risk Factors for Respiratory Depression in the Obstetric Depression After Cesarean Delivery Population 1. Scientific literature findings: Patients may have Perioperative General anesthesia Desaturation event in PACU comorbidities or postoperative circumstances Coadministration of intravenous opioid that increase their risk of developing respiratory Coadministration of sedatives (intra/postoperative) depression: Coadministration of magnesium Patient Cardiopulmonary or neurological comorbidities a. Risk factors in the nonobstetric population that Class III obesity (BMI ≥ 40 kg/m2) are relevant to the obstetric population include Obstructive sleep apnea obesity, known or suspected obstructive sleep Chronic opioid use apnea (OSA), chronic opioid use or abuse, addi- Hypertension tional sedative medications (eg, benzodiazepines, Abbreviations: BMI, body mass index; PACU, postanesthesia care unit. antihistamines), concomitant systemic opioid use, significant respiratory, cardiac or surgical comor- bidities, and detection of an adverse respiratory ASRA Practice Guidelines for the Prevention, event after opioid administration intraoperatively Detection, and Management of Respiratory or in the postanesthesia care unit (PACU) (level Depression Associated with Neuraxial Opioid B-NR). Administration. b. Additional risk factors in the obstetric population may include preeclampsia and administration of SOAP Task Force Recommendation for Neuraxial magnesium sulfate (level C-EO). Compared to Systemic Morphine Administration

2. Recommendation based on risk stratification (Table 1): 1. Scientific literature findings: neuraxial morphine compared to systematic administration: a. Elective and nonurgent clinical situations: Task Force Members strongly agree that it is reason- a. Numerous studies demonstrate the superior anal- able to evaluate women with a focused history gesic efficacy of neuraxial (epidural or intrathe- and physical examination for identification of cal) opioid analgesia compared to systemic opioid those who may be at increased risk of respira- administration (eg, intravenous [clinician bolus tory depression for neuraxial morphine admin- or patient controlled], oral or intramuscular anal- istration (class 2A). Members agree that women gesia) for postcesarean delivery analgesia (level undergoing cesarean delivery may require opioid B-R). analgesia via any route during the perioperative b. Studies demonstrate the superior analgesic period, and therefore, all women who present for efficacy of neuraxial (epidural or intrathecal) opioid analgesia compared to cesarean delivery, irrespective of whether intra- techniques (eg, transversus abdominis plane thecal morphine will be administered, should be block or wound infiltration) for postcesarean assessed and screened for respiratory depression analgesia (level B-R). risk factors (class 2A). c. Respiratory depression with neuraxial opioids is b. Urgent clinical situations: Task Force members no greater than with systemic opioids in the gen- strongly agree that when the urgency of a cesarean eral surgery population (level B-R). delivery may not allow for patient risk stratifica- tion before neuraxial morphine administration, a 2. Recommendations: The SOAP Task Force members focused history and physical examination is rea- strongly agree that neuraxial morphine should be the sonable in the postoperative period for evaluation preferred method for postcesarean delivery analgesia of appropriate respiratory monitoring (class 2A). in healthy women (class 1). These recommendations c. The Task Force members agree that in low-risk are in accordance with the ASA Practice Guidelines women, with no risk factors for respiratory for Obstetric Anesthesia recommendations.15 depression, for routine cesarean delivery, it is rea- sonable for neuraxial morphine dose to guide the frequency, duration, and modality of respiratory SOAP Task Force Recommendations for monitoring (class 2A). Neuraxial Morphine Dosing for Postcesarean d. The Task Force Members agree that in higher- Delivery Analgesia risk women with ≥1 comorbidities and other 1. Scientific literature findings: neuraxial (intrathecal perioperative circumstances that place them at and epidural) morphine dose selection for postcesar- higher risk of respiratory depression (Box 2), it ean delivery analgesia: is reasonable for the frequency, duration, and modality of respiratory monitoring to be guided a. An analgesic dose–response ceiling exists for by clinical judgment of the physician anesthesi- neuraxial morphine for postcesarean analgesia ologist, institutional guidelines, and/or the ASA/ (level A [intrathecal] and B-R [epidural]).

XXX 2019 • Volume XXX • Number XXX www.anesthesia-analgesia.org 5 Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. EE Special Article

b. Increasing doses of neuraxial morphine can guidelines were just right. The majority (60%) agreed or increase the duration of analgesia (level A). were neutral with the first draft recommendations from c. Increasing doses of neuraxial morphine increase this consensus statement that healthy women receiving the risk of opioid-related side effects (eg, pruritus, low-dose morphine (>0.05 to ≤0.15 mg) should be nausea, vomiting) (level A). monitored with sedation scores and RRs every 3 hours for d. Higher neuraxial morphine doses increase the 12 hours. Of those who disagreed, the majority (81%) felt risk of respiratory depression (level C-LD). our initial recommendations of every 3 hours were too long e. Nonopioid multimodal analgesic regimens allow an interval between respiratory monitoring. In response for both reduction in neuraxial dosing and systemic to the SOAP member survey and the SOAP comment opioid use in the perioperative setting (level A). period, the Task Force writing group voted to change the initial recommendation of respiratory monitoring every 2. Recommendations: 3 hours for 12 hours to every 2 hours for 12 hours. Two- a. The Task Force members strongly agree that low- thirds of respondents also agreed or were neutral that dose intrathecal morphine and epidural mor- ultra–low-dose intrathecal morphine (≤0.05 mg) should phine should be used to minimize opioid-related require no additional monitoring. In their current practice, side effects (class 2A). the majority (64%) of respondents increased the frequency b. The Task Force members agree that a multimodal and/or intensity of respiratory monitoring in women with nonopioid analgesic approach is beneficial to use risk factors for respiratory depression such as obesity and in addition to neuraxial morphine (class 2A). sleep apnea.

Survey of International Experts. An international Surveys of SOAP Membership and International experts’ survey was designed to assess their opinions Experts on Respiratory Monitoring Following on the recommendations presented in this consensus Neuraxial Morphine in the Obstetric Population statement and determine potential implications on SOAP members (Supplemental Digital Content 2, Appendix postcesarean analgesic practices in their respective 1, http://links.lww.com/AA/C802) and an international countries (Supplemental Digital Content 3, Appendix 2, group of experts (Supplemental Digital Content 3, Appendix http://links.lww.com/AA/C803). International experts 2, http://links.lww.com/AA/C803) were surveyed to were selected based on their leadership involvement in understand current practices nationally and internation- international societies in obstetric anesthesia and their ally for neuraxial morphine administration and respiratory research publications in obstetric anesthesia. Diversity in monitoring practices. country representation was considered in selection of these experts. International experts were sent a nonvalidated Survey of SOAP Members. A SOAP member survey was nested structure survey, designed by this consensus group designed to determine membership opinions regarding that was sent via email link in September 2017. Thirty current ASA/ASRA guideline recommendations for experts from outside the United States were surveyed, with monitoring following neuraxial morphine as applied to a 93% response rate (28/30). Over 90% of experts reported the obstetric population (Supplemental Digital Content using neuraxial techniques for cesarean delivery but only 2, Appendix 1, http://links.lww.com/AA/C802).3 In 43% used neuraxial morphine routinely. The majority addition, members were queried on a first draft proposal of international practitioners (54%) felt that current of these consensus statement recommendations so their ASA/ASRA guidelines were overly conservative with feedback could be used for consideration in the final respiratory monitoring in healthy women receiving low- consensus statement. A nonvalidated nested structure dose neuraxial morphine. Seventy-three percent agreed survey designed by this consensus group was sent via an that no additional respiratory monitoring beyond routine emailed link in February 2017 to all SOAP members with postoperative care should be required with ultra–low-dose 2 subsequent reminders sent 1 week apart to complete intrathecal (≤0.05 mg) or epidural (≤1 mg) morphine. Most the survey. The response rate to the SOAP member respondents (63%) agreed or were neutral with our initial survey was 59%, with 339 of 571 members responding. recommendations from this consensus statement that This SOAP member survey demonstrated that almost healthy women receiving low-dose morphine (>0.05 to all responding members (91%) routinely use intrathecal ≤0.15 mg) should be monitored with sedation scores and morphine for postcesarean delivery analgesia. This rate of RRs every 3 hours for 12 hours. The majority (89%) also use of intrathecal morphine is higher than the previously agreed that respiratory monitoring frequency intervals reported survey from 2009, where 77% of SOAP members should be performed at a minimum according to ASA/ used intrathecal morphine.16 The majority of SOAP ASRA recommendations in women with comorbidities members (67%) use low-dose (stated as ≤0.15 mg in the and risk factors for development of respiratory survey) intrathecal morphine in their practice. Almost depression.3 Barriers to using neuraxial morphine in two-thirds of respondents (64%) follow current ASA/ respondents’ practice included hospital policy, inability ASRA guidelines (ie, respiratory rate [RR] and sedation to monitor postoperatively, and lack of drug availability. monitoring every 1 hour for the first 12 hours and 2 hours The majority (69%) felt the SOAP consensus statement for the next 12 hours) for healthy obstetric patients.3 Thirty- recommendations had the potential to increase utilization seven percent felt the ASA/ASRA guidelines are too strict of neuraxial morphine for postcesarean delivery analgesia for low-risk parturients, though 55% of member felt the in their respective countries.

6 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. Respiratory Monitoring After Neuraxial Morphine

LITERATURE BACKGROUND SUPPORTING SOAP cesarean delivery reported between 2004 and 2009 among TASK FORCE RECOMMENDATIONS these institutions, and the vast majority of women received Mechanism of Respiratory Depression neuraxial morphine. There were no reported cases of respi- Neuraxial opioids can cause respiratory depression by both ratory arrest secondary to neuraxial opioid administration. direct and indirect mechanisms, and the timing of respira- The American Society of Anesthesiologists Closed Claims tory depression onset can be biphasic, early, and late.17–20 Project database that analyzed claims related to anesthesia Early-onset respiratory depression, specifically, reduced administration between 1990 and 2009 found only 1 case of brainstem ventilatory response to hypoxia, could occur respiratory depression after cesarean delivery.30 The patient between 30 and 90 minutes after injection due to rapid vas- received a continuous epidural infusion (CEI) of bupiva- cular uptake of the opioid, but this is unlikely with low doses caine and fentanyl for analgesia, not neuraxial morphine. of neuraxial morphine used in modern practice.21 Delayed Additionally, there is no evidence that the ASA/ASRA depression of the ventilatory drive, 6 to 18 hours after neur- Practice Guidelines for the Prevention, Detection, and axial morphine injection,22 may occur due to rostral spread Management of Respiratory Depression Associated with through the cerebrospinal fluid (CSF) and penetration of Neuraxial Opioid Administration, first published in 2009, the brainstem, with maximum depression occurring 6.5–7.5 have reduced the incidence of respiratory depression or hours after morphine administration.23,24 Although uptake improved safety. into the CSF is slower when morphine is administered A 2009 survey evaluated intrathecal opioid use for elec- epidurally rather than intrathecally approximately 60–90 tive cesarean delivery in the United Kingdom.31 At that minutes, rostral spread also occurs with epidural adminis- time, 90% (183/203) of units in the United Kingdom admin- tration that can lead to delayed respiratory depression.25–27 istered neuraxial diamorphine and the other 10% used The clinical data on timing of respiratory depression after neuraxial morphine. Diamorphine is a lipid-soluble drug, neuraxial morphine administration were conducted in a but its active metabolite is morphine. One hundred fourteen small sample of male subjects (N = 10 per group) who did (56%) units had departmental guidelines for postoperative not undergo surgical procedures and who received higher monitoring of patients, but only 34 (30%) were compliant doses of neuraxial morphine (0.3 mg intrathecal morphine with the National Institute for Health and Care Excellence and 10 mg epidural morphine) than are used clinically in (NICE) recommendations (hourly RR, sedation, and pain obstetrics.22,23 Hydrophilic opioids (eg, morphine) are asso- scores for 12 hours after neuraxial diamorphine and for 24 ciated with delayed respiratory depression after epidural or hours after neuraxial morphine).31,32 Only a minority of units intrathecal injection. Due to the hydrophilic nature of mor- were aware of the existence of the NICE guidelines. As a phine, the opioid remains in the aqueous CSF much longer testament to the safety profile of these 2 intrathecal opioids, than other, more hydrophobic opioids (eg, fentanyl). This none of the units surveyed and led by consultants reported feature of morphine greatly improves its bioavailability, any documented cases of respiratory depression following thus producing the desired prolonged analgesia after lum- neuraxial opioids in obstetrics, despite its frequent use.31 In bar neuraxial morphine administration.17 the latest 2015 Mothers and Babies: Reducing Risk through Audits and Confidential Enquiries (MBRACE-UK) report Safety of Neuraxial Morphine for Postcesarean of 2,305,920 pregnancies (national collaborative to moni- Analgesia tor maternal deaths) and previous triennial Confidential The 2015 US National Vital Statistics Report noted 3,977,745 Enquiry into Maternal and Child Health/Center for births nationally, of which 32% of births were via cesarean Maternal and Child Enquires (CEMACH/CEMACE) delivery.28 The majority of anesthesiologists who special- reports, none of the reported maternal deaths were attrib- ize in obstetric anesthesiology, for at least the past decade, utable to maternal neuraxial opioid administration.33 There have been using neuraxial morphine for analgesia follow- were also no reported intensive care unit (ICU) admissions ing cesarean delivery16 (Supplemental Digital Content attributed to neuraxial opioid-induced respiratory depres- 2, Appendix 1, http://links.lww.com/AA/C802). There sion in the summary of Intensive Care National Audit and are no studies that report the precise number of cesarean Research Center (ICNARC) data from 200734,35 to 2009 to deliveries performed using neuraxial morphine, but data 2012 admissions.36,37 obtained from 2009 indicated the majority of women in aca- demic centers in the United States likely received neuraxial Incidence of Respiratory Depression After morphine for postcesarean analgesia.16 Neuraxial Morphine for Postcesarean Analgesia The safety profile of modern low-dose intrathecal and The true incidence of respiratory depression following epidural morphine to treat pain postcesarean delivery has neuraxial morphine administration for cesarean delivery been demonstrated both through research and clinical use is unknown, due in part to the lack of a standard defini- over an extended time. The widespread use of neuraxial tion for respiratory depression.38 RR, pulse oximetry oxy-

morphine in the United States suggests that cases of death gen saturation (Spo2), and hypercarbia have each been used and disability would be anticipated and reported if respi- at various numerical “cutoffs” as indicators of respiratory ratory depression was a significant clinical problem in the depression in obstetric studies, along with consciousness setting of cesarean delivery. The Serious Complication levels or sedation scores, depressed ventilatory response Repository (SCORE) systematically tracked complications to hypoxia or hypercarbia, and clinical interventions (eg, related to obstetric anesthesia in academic centers over a naloxone requirement, oxygen administration, bag-mask 5-year period.29 There were 90,795 neuraxial anesthetics for ventilation).38 Retrospective, observational studies likely

XXX 2019 • Volume XXX • Number XXX www.anesthesia-analgesia.org 7 Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. EE Special Article

underestimate the true incidence of respiratory depression, among the studies likely reflect heterogeneity in definitions, while prospective research studies that utilize continuous monitoring techniques for respiratory depression, dosing monitoring techniques (eg, transcutaneous carbon dioxide regimens, and surgical populations.49,50 Importantly, higher

(CO2) measurements, capnography, Spo2) likely overesti- morphine doses, above 0.25 mg, may be associated with mate the incidence, as events that meet the definitions of frequencies of respiratory depression that do not necessarily respiratory depression are not associated with clinically rel- reflect current risks using ultra–low-dose (≤0.05 mg) or low- evant events.39–41 Finally, the heterogeneity of administered dose (0.05 to ≤0.15 mg) neuraxial morphine. neuraxial morphine doses hampers efforts to obtain a true incidence of respiratory depression. RESPIRATORY MONITORING TECHNIQUES AFTER In the obstetric population, the incidence of respiratory CESAREAN DELIVERY depression following neuraxial morphine has been reported Respiratory monitoring techniques for patients should ide- to range between 0% and 1.3% when using bradypnea as ally be noninvasive, reliable, and inexpensive. Continuous a clinical measure of respiratory depression.42–46 One large monitoring should capture intermittent and delayed respi- retrospective study (N = 5036) in women who received ratory events.23,39,40,49,51 Hypercapnia and desaturation occur intrathecal (0.05–0.25 mg) or epidural (1–5 mg) morphine concurrently in the healthy lung, with desaturation occur- for cesarean delivery aimed to capture clinically relevant ring soon after hypercapnia ensues.15 Oxygen supplemen- episodes of respiratory depression (defined as either requir- tation can modify this relationship, normalizing RRs and ing naloxone administration or a rapid response team call) oxygen saturation in the presence of significant hypercap- 47 found no instances of respiratory depression. A systematic nia.39,52–54 Hypoxemia induced by intrathecal morphine may literature review performed by a subset of authors from this not manifest as decreased RR,55 rather as an irregular breath- consensus statement aimed to determine the incidence of ing pattern before opioid-induced apnea.56,57 Somnolence “clinically significant” respiratory depression after cesar- is often observed before clinically important respiratory ean delivery in women receiving neuraxial morphine or depression occurs.30 RR may be less important than depth 1 diamorphine. The systematic review included 78 articles of respiration, presence of upper airway obstruction, work (randomized controlled trials, prospective observational, of breathing, and other qualitative measures of breathing.58 retrospective studies, and case reports), with a total of The ASA and ASRA guidelines3 propose hourly respiratory 18,455 women who received neuraxial morphine or dia- monitoring through nurse assessments of RR and sedation morphine for postoperative analgesia after elective and for 24 hours in postcesarean patients following single-shot emergency cesarean delivery. Clinically significant respira- neuraxial morphine administration. There are no studies or tory depression was defined as requirement for (1) airway any evidence demonstrating that the ASA and ASRA guide- intervention, (2) oxygen therapy for hypoxia (Spo2 < 90%) lines3 have reduced morbidity or mortality associated with or bradypnea (RR < 8/min), (3) pharmacological therapy to respiratory depression in the obstetric population. As pre- reverse opioid narcosis, or (4) documented excessive seda- viously reported, the incidence of respiratory depression tion requiring more than verbal stimulation. Sixteen cases is low, and studies reporting respiratory depression in the of clinically significant respiratory depression were iden- obstetric population are presented in Table 2. tified among 18,452 patients. Three cases were considered by authors to be definitely/probably/possibly due to the NURSING ASSESSMENTS morphine (administered in low doses: intrathecal mor- Intermittent RR counting, usually by clinical staff, is the phine ≤150 µg and epidural morphine ≤3 mg) after cesarean most commonly utilized respiratory assessment after cesar- delivery. The incidence of clinically significant respiratory ean delivery.16 As this requires physical presence of staff, it depression from published studies in this systematic review is not performed continuously. It is unclear how intermittent was estimated to be 1.63 per 10,000 (95% confidence inter- rate counts compare to electronic monitoring in terms of staff val [CI], 00.62–8.77) women. There were 2 cases considered workload and cost burden, in preventing the rare occurrence by the authors to be definitely caused by low-dose neur- of respiratory depression following neuraxial morphine axial morphine resulting in clinically significant respiratory 59 depression, indicating an incidence of 1.08 per 10,000 (95% administration. Nursing assessment of RR is challenging CI, 00.24–7.22).1 Thus, the risk of morbidity or mortality in and time-consuming to perform leading to inconsistent mea- a healthy obstetric patient following administration of low- surement. Nursing assessment of RR has not been shown dose of neuraxial morphine appears extremely low. Among to correlate with hypercapnic events or apnea alert events nonobstetric patients receiving neuraxial opioids, underly- measured by transcutaneous CO2 measurements and cap- 5,39,41,60 ing comorbidities are associated with increased likelihood nography. In addition, nurses may elevate the impor- of respiratory depression.48 tance of RR over somnolence to identify pending respiratory depression.30,36 Multiple studies assessing nurse compliance Mixed Obstetric and Nonobstetric Study Populations. with respiratory monitoring report that assessment of level of Retrospective and prospective database analyses of mixed sedation is the parameter with the lowest likelihood of accu- 5,58 populations (including a total of 8927 obstetric and 12,434 rate measurement and documentation. nonobstetric patients) indicate a wide range of incidences for respiratory depression: between 0.26% and 3% for intrathecal CONTINUOUS RESPIRATION MONITORS morphine (dose ranges from 0.15 to 0.8 mg) and between Pulse Oximetry 0% and 2.8% for epidural morphine (dose ranges from 2 to 5 A 2009 Cochrane review by Pedersen et al61 included 5 mg).49 Differences in the incidence of respiratory depression randomized controlled trials with 22,992 postoperative

8 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. Respiratory Monitoring After Neuraxial Morphine

Table 2. Obstetric Studies With Incidence Data for Respiratory Depression Secondary to Neuraxial Morphine Cohort Retrospective/ Definition of Respiratory IT Dose EPI Dose Incidence Author, Year Size Prospective Depression (mg) (mg) Other Opioids (%) Kato et al,43 2008 1915 Retrospective Bradypnea = RR < 10/min 0.15 Y Bradypnea: 0.26 Severe RD = Naloxone Severe RD: 0.052 44 Abouleish et al, 1991 856 Prospective Spo2 ≤ 85% or RR ≤ 10/min 0.2 Y 0.9 Fuller et al, 45 1990 4880 Retrospective RR < 10/min 2–5 Y 0.25 Kotelko et al,46 1984 276 Prospective RR < 10/min 5 Y 0 Crowgey et al,47 2013 5036 Retrospective Need for naloxone or rapid 0.15 3 Y 0 response team for respiratory events Bauchat et al,39 2017 120 Prospective Hypercapnic episode 0.15 Y 32 > 50 mm Hg for 2 min Ladha et al,40 2017 721 Prospective Hypoxemia 0.15 N Mild RD: 23

Mild Spo2 < 90% Severe RD: 4

Severe Spo2 < 85% for 30 s 41 Weiniger et al, 2018 74 Prospective “Apnea alert event” (Etco2 < 5 0.15 Y 53% had apnea alert mm Hg for 30–120 s) event

Abbreviations: Etco2, end-tidal carbon dioxide, using capnography; EPI, epidural; IT, intrathecal; N, no; RD, respiratory depression; RR, respiratory rate; Spo2, oxygen saturation; Y, yes.

patients, monitored with or without continuous pulse breathing and the monitor is bothersome to postpartum oximetry. Pulse oximetry improved early detection and women.41

treatment of hypoventilation and hypoxemia. Monitoring Studies utilizing transcutaneous CO2 and capnography

changed patient management more frequently and reduced show significant increases in arterial CO2 levels and poten- unplanned respiratory admissions to the ICU, decreased the tial apneic events following intrathecal morphine admin- length of ICU readmission or both, however, did not reduce istration in the obstetric population.39,41,67 One prospective overall morbidity and mortality in the perioperative period. study of 120 women receiving 0.15 mg intrathecal morphine

One significant concern was the false alarms that likely for cesarean delivery used continuous transcutaneous CO2 inflated the reported incidence of postoperative desatura- measurements and demonstrated a 32% incidence of hyper- tion.62 In addition, false alarms may lead to alarm fatigue as capnia, defined by sustained hypercapnia >50 mm Hg for

demonstrated by the American Society of Anesthesiologists 2 minutes. Patients with higher baseline CO2 levels were at Closed Claims Project database for opioid-related respira- higher risk of hypercapnic episodes.39 Another prospective tory depression, where 33% of patients who experienced study of postcesarean delivery women receiving 0.15 mg morbidity were being monitored via continuous pulse intrathecal morphine utilized continuous capnography and oximetry.30 Two studies in the obstetric population utiliz- found a 53% incidence of apnea alert events.41 However, ing continuous pulse oximetry demonstrated low rates despite sustained hypercapnia and apnea alert events, no

of desaturation events (Spo2 < 85%) of 0.1% and 4%, but obstetric patients in either of these trials required naloxone patients who desaturated were more likely to be obese or administration or experienced clinically significant sedation have a positive Berlin questionnaire (sleep apnea screening or an adverse respiratory event.39,41 Additionally, in both questionnaire).40,44 False alarms also led to decreased patient studies, all nurse assessments of hourly RRs were recorded satisfaction and continuous monitoring restricted mobility,44 ≥14 breaths per minute and no sedation assessment param-

and alarms may be particularly problematic in postpartum eters correlated with the transcutaneous CO2 or capnogra- sleep-deprived patients and their newborns. phy measures indicative of respiratory depression. Thus, although 0.15 mg intrathecal morphine after cesarean deliv-

CO2 Monitors ery affects the peripartum ventilatory drive as reflected by Hypercapnia may be an early sign of respiratory depression, episodes of hypercapnia or hypoxemia, it does not appear

which can be detected using arterial CO2 measurements, to cause clinically significant respiratory depression. The

transcutaneous CO2 measurements, and capnography. relationship between subclinical hypercapnia and clinically

Arterial blood gas measurements of oxygen and CO2 are relevant respiratory events requires further study. considered the gold standard for measurements of arterial oxygenation and hypercapnia, however, are invasive, inter- Additional Monitors mittently measured, and not routinely used. Transcutaneous Thoracic impedance, acoustic plethysmography, and photo-

CO2 measurements are continuous, more accurate than end- plethysmography have been described as continuous meth-

tidal CO2 measurements, and within 0–6 mm Hg of arterial ods of RR monitoring. Thoracic impedance monitoring can

blood gas CO2 measurements. However, RR and depth of only occur with the use of electrocardiography monitoring. 63–66 breathing are not measured, and transcutaneous CO2 Acoustic plethysmography and photoplethysmography monitoring is a newer technology that is expensive and are newer and more expensive than thoracic impedance not widely available. Capnography is a continuous moni- monitoring.68–70 Acoustic monitoring is more accurate

tor providing a RR and quantitative measure of CO2; how- than thoracic impedance and well tolerated by patients in ever, its accuracy is dependent on tidal volumes and nasal the PACU.68–70 Photoplethysmography overestimates RR

XXX 2019 • Volume XXX • Number XXX www.anesthesia-analgesia.org 9 Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. EE Special Article

when airway obstruction is present. With this technique, morphine administration in the obstetric patient popula- oxygen saturation is monitored simultaneously via digit tion at clinically relevant doses without confounding clinical pulse oximetry, which is prone to inaccuracies during finger factors, such as concomitant systemic opioid administra- movement. A respiratory volume monitor utilizing a sensor tion, wrong route administration, or patient risk factors.1 that detects impedance to calculate minute ventilation, tidal Duration of monitoring for respiratory depression should volume, and RR is a potentially useful continuous monitor- reflect the expected duration of respiratory depression after ing technology. It is more sensitive at detecting respiratory neuraxial morphine. At contemporary doses, respiratory changes than capnometry alone and has been shown to pre- depression is extremely unlikely to occur after 12 hours. dict respiratory depression in patients using patient-con- trolled analgesia (PCA) with intravenous morphine in the PATIENT AND PERIOPERATIVE RISK FACTORS PACU.71–73 None of these technologies have been studied in INCREASING THE LIKELIHOOD TO DEVELOP the obstetric population. RESPIRATORY DEPRESSION FOLLOWING In conclusion, the ideal modality and frequency of NEURAXIAL MORPHINE respiratory monitoring to prevent adverse respiratory out- The majority of the SOAP members (65%) and interna- comes is unknown. The incidence of bradypnea when RRs tional experts (89%) in the field of obstetric anesthesia agree are monitored intermittently (eg, hourly) by clinical staff that monitoring should be increased in women with risk is exceedingly rare following administration of low doses factors for respiratory depression (Supplemental Digital of intrathecal morphine for cesarean delivery. Continuous Content 2–3, Appendix 1, http://links.lww.com/AA/C802, monitoring technology is the only way to identify adverse Appendix 2, http://links.lww.com/AA/C803). In general respiratory parameters that occur intermittently and unpre- surgical populations, reported risk factors for respiratory dictably. Noninvasive continuous respiratory monitoring depression after systemic and neuraxial opioid administra- such as pulse oximetry, capnography, and transcutane- tion include respiratory, cardiac, and renal comorbidities ous CO2 measurements are not widely applied following (ASA physical status ≥III), OSA, obesity, chronic opioid cesarean delivery.16 The routine use of continuous monitors use, concomitant systemic opioid administration, con- to detect respiratory depression for all women undergo- current sedating medication administration, and hypox- ing cesarean delivery seems excessively conservative, and emia, hypoventilation, or apnea observed in the PACU intensive respiratory monitoring may be better accepted (Box 2).30,51,76–79 In addition, the ASA Closed Claims Project when only applied to higher-risk patients. database confirms that the majority of cases of respiratory depression were associated with patient risk factors such as DURATION OF RESPIRATORY MONITORING obesity, OSA, and increased age.30 FOLLOWING NEURAXIAL MORPHINE There is a paucity of data on risk factors for respiratory ADMINISTRATION depression related to neuraxial morphine administration Recommendations for duration of respiratory monitor- specific to the obstetric population. The prospective stud- ing are frequently based on studies of the pharmacological ies to determine the incidence of respiratory depression properties of neuraxial opioids. One small study measured often exclude obstetric patients with additional risk factors

ventilatory response to CO2 in women undergoing cesar- for respiratory depression. Reports from studies are mixed ean delivery receiving placebo, 0.1 or 0.25 mg of intrathecal as to whether obesity itself increases the risk of respiratory morphine. The ventilatory response to progressive hyper- depression. One retrospective study with 856 patients only capnia was measured intermittently (baseline, 3 hours, 6 demonstrated respiratory depression (pulse oximetry <85% hours, 12 hours,16 hours, and 24 hours) using a modified or RR < 10/min) in obese women (N = 8).44 Another large ret-

Read rebreathing technique that extrapolated CO2 response rospective study including 5036 patients identified no cases curves with a computer-controlled data acquisition system.74 of respiratory depression (naloxone administration or rapid

Intermittent ventilatory responses to CO2 did not differ from response team activation) after administration of spinal mor- baseline CO2 values at 2.5–3 hours or at any other measured phine 0.15 mg or epidural morphine 3 mg. Sixty-three per- time point, after administration of intrathecal morphine. cent of women in this study were obese (mean body mass Although the authors concluded that intrathecal morphine index [BMI] = 34 kg/m2) and 18% had a BMI ≥40 kg/m2.47

did not cause depression of the ventilatory variables, CO2 Many of the risk factors for respiratory depression in response was measured intermittently with patient stimu- the general surgical population can be extrapolated to the lation and only 10–12 women were recruited per study obstetric population, but there are also unique risk factors group. In a small sample of volunteer male subjects who in the obstetric population. These include magnesium sul- received high doses of neuraxial morphine (0.3 mg intrathe- fate administration for preeclampsia and pregnancy-related cal morphine and 10 mg epidural morphine),22–24 maximum hypertension. In a systematic review of the literature to evalu- depression occurred 6.5–7.5 hours after neuraxial morphine ate the side effects of magnesium sulfate for seizure prophy- administration.23,24 The duration of analgesia and side effects laxis in preeclampsia, the incidence of respiratory depression after neuraxial morphine are dose dependent.75 Based on ranged from 0% to 8.2%.80 In the largest prospective random- limited studies, early-onset respiratory depression should ized control trial studying magnesium sulfate for seizure pro- be evident during the immediate period following neuraxial phylaxis in women with preeclampsia, the Eclampsia Trial opioid administration, and late-onset respiratory depres- Collaborative, the incidence of respiratory depression related sion, if it were to occur, would likely be at 6.5–7.5 hours to magnesium administration was 8.2% using an unspecified after administration.23,24 There have been no reported cases definition of respiratory depression.81 Although the exist- of respiratory depression beyond 12 hours after neuraxial ing research poorly defines respiratory depression in this

10 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. Respiratory Monitoring After Neuraxial Morphine

subgroup of patients with preeclampsia, the consensus group monitoring receive postoperative nursing assessments as believes administration of magnesium concomitantly with often as hourly for first 12 hours and every 2 hours for the neuraxial opioid warrants closer respiratory monitoring. next 12 hours.3 This may contribute to numerous distur- Physiological and hormonal changes during pregnancy bances and associated sleep deprivation.15,87 Women under- alter sleep architecture and predispose to development and/ going cesarean delivery report higher levels of exhaustion or worsening of OSA.82,83 A recent meta-analysis84 demon- and average 2 hours less of sleep per night with more strated that sleep apnea screening tools used in the general broken sleep than women who deliver vaginally.88,89 Sleep population (Berlin questionnaire, STOP-BANG, Epworth deprivation after cesarean delivery has adverse associations Sleepiness Scale) have shown modest predictive abilities and including postpartum depression, perineal pain, backache, frequently overestimate sleep apnea in pregnancy. A model headache, incisional pain, altered pain perception, mastitis, incorporating frequent snoring (yes/no), chronic hyperten- and difficulty with breastfeeding.90–93 A best practice sugges- sion (yes/no), age, and BMI (continuous) performed signifi- tion for nursing respiratory assessments states that sleeping cantly better than the Berlin or Epworth assessment tools in patients who have normal respiratory patterns should not pregnancy for predicting OSA.13 Other investigators found be woken for sedation assessments.94 BMI >35 kg/m2, falling asleep while talking with someone, Effective analgesia, such as that provided by neuraxial and history of treatment for hypertension highly predictive morphine, could encourage healthy sleep.95–97 Nonetheless, of OSA in pregnancy.14 Obesity has been shown to predispose overly frequent monitoring for respiratory depression women to desaturation events postcesarean delivery follow- may inadvertently interfere with healthy women’s abil- ing 0.15 and 0.2 mg intrathecal morphine.43,44 While the litera- ity to sleep, with potential untoward negative effects. In ture is sparse, the consensus group does not consider obesity a the healthy, obstetric population, minimizing unnecessary contraindication to neuraxial morphine but associated comor- respiratory monitoring as appropriate will help promote bidities must be assessed; thus, the consensus group chose patient-centered care. the World Health Organization definition of class III obesity (BMI ≥40 kg/m2) to consider increased intensity of respira- BENEFITS OF NEURAXIAL MORPHINE FOR tory monitoring.85 Due to the association of OSA with obe- CESAREAN DELIVERY sity and hypertension, the consensus group agreed it is best Neuraxial morphine provides superior analgesia following practice to screen for OSA in women with class I obesity (BMI cesarean delivery compared to intravenous opioid PCA.95,97 ≥30 kg/m2) and women with existing or pregnancy-induced Numerous meta-analyses and systematic reviews in the hypertension. There are no validated screening tools for OSA obstetric population95,97–99 confirm that local anesthetic and in the pregnant population, so practitioners are encouraged opioid delivered by patient-controlled epidural analgesia to use a combination of aforementioned risk factors, clinical (PCEA) or CEI provide superior postoperative pain relief to judgment, and available general surgical population OSA that provided by intravenous PCA, but single-shot neurax- screening tools when determining appropriate respiratory ial morphine provides independence from infusion pumps, monitoring following neuraxial opioid administration in more uniform analgesia and less work for the patient and pregnant women.86 Obstetric patients undergoing cesarean nursing staff than any of these patient-controlled tech- delivery are surgical patients who may require opioid anal- niques. Neuraxial morphine also provides better analge- gesia via any route during the perioperative period, and the sia than local anesthetic regional blocks (eg, transversus writing group agreed that all women who present for cesar- abdominis plane block).100,101 Most studies demonstrate that ean delivery, irrespective of whether intrathecal morphine epidural morphine administration provides better analge- will be administered, should be assessed and screened for sia than local anesthetic wound infiltration techniques.102,103 risk factors for respiratory depression. Patients’ underlying Local anesthetics administered via transversus abdominis risk factors for respiratory depression should determine respi- plane block or wound infiltration techniques have decreased ratory monitoring in the postoperative setting in accordance systemic opioid requirements when provided as analgesic with institutional guidelines, with neuraxial morphine dose adjuvants when neuraxial opioids are not administered.104 being an additional consideration to maintain or adjust these Neuraxial hydromorphone was utilized when preserva- respiratory monitoring requirements. A suggested “clinical tive-free morphine was unavailable in the United States and decision tool” and checklist for clinicians to use or modify for is a reasonable alternative with similar analgesic benefit and patient risk stratification and sleep apnea screening in women side effect profile.105 The dosing equivalence of neuraxial undergoing cesarean delivery to determine appropriate post- hydromorphone to neuraxial morphine has not been stud- operative respiratory monitoring parameters or order sets are ied extensively. One study by Sviggum et al106 explored the provided in Table 1 and Supplemental Digital Content 4–5, 90% effective dose (ED90), defined as numeric rating scale Appendix 3, http://links.lww.com/AA/C804, Appendix 4, pain scores ≤3 up to 12 hours, using up-down sequential http://links.lww.com/AA/C805, respectively. allocation with a biased-coin design and found a dosing ratio of 2:1 for intrathecal morphine (150 µg) to intrathecal PATIENT-CENTERED MODEL FOR POSTCESAREAN hydromorphone (75 µg) administration. However, neurax- DELIVERY ANALGESIA MANAGEMENT ial morphine’s physicochemical properties suggest a longer The SOAP task force recommends adjusting monitoring duration of action than hydromorphone, hydromorphone practices based on the likelihood of women experienc- has not been studied as thoroughly and lacks the track ing respiratory depression. Women who receive neuraxial record of safety that neuraxial morphine has, and therefore morphine for postcesarean analgesia in institutions that if available, intrathecal morphine is the preferred single- follow the ASA/ASRA Practice Guidelines for respiratory shot intrathecal opioid in this setting.

XXX 2019 • Volume XXX • Number XXX www.anesthesia-analgesia.org 11 Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. EE Special Article

In summary, the literature supports the use of neur- demonstrated analgesic benefit in the setting of neuraxial axial morphine for postcesarean delivery analgesia as this morphine, the relative efficacy of each analgesic medication method provides the most efficacious analgesia and is the and the role of COX-2 inhibitors, dexamethasone, and gaba- easiest to administer when utilizing neuraxial anesthesia for pentinoids for postcesarean delivery analgesia is uncertain. cesarean delivery. Utilizing multimodal analgesia postcesarean delivery may allow for reduction in neuraxial morphine dosing without Respiratory Depression Following Neuraxial compromising analgesia.95,119–122 When choosing a multi- Versus Patient-Controlled Intravenous Morphine modal analgesic regimen in the postpartum period, it is Studies overall demonstrate equivalence in the rates of important to consider the drug safety in this setting with respiratory depression when comparing neuraxial and particular emphasis on compatibility with lactation and patient-controlled intravenous opioids in any given post- breastfeeding.123 Assessment of underlying patient comor- operative patient population. Several comparative obser- bidities and potential side effects of these adjuvant medica- vational studies in the nonobstetric, general surgical tions must be made to select the ideal nonopioid multimodal population have documented the incidence of respiratory regimen for patients receiving neuraxial opioids.114,124,125 depression with intravenous PCA ranging from 0% to 11.5% The consensus group recognizes that neuraxial mor- depending on respiratory monitoring modality and moni- phine in conjunction with nonopioid multimodal analgesia toring frequency and are equivalent to those reported for does not completely mitigate the need for opioid analgesia, neuraxial opioids which range from 0.1% to 15%.53,65,107–112 and the majority of women still require analgesics for break- The American Society of Anesthesiologists Closed Claims through pain. Median opioid consumption does not capture Project database reports similar frequencies of patient injury the individual patient’s analgesic medication needs, and due to neuraxial and intravenous PCA opioid administra- most of the studies find a non-normal distribution of opioid tion.30 Dalchow et al67 demonstrated no difference in hyper- utilization, with the majority of women requiring little to no capnia rates in women receiving intravenous opioid via opioid for breakthrough pain with neuraxial morphine and PCA versus a single 0.3 mg intrathecal diamorphine (0.1 multimodal analgesic regimens, and only a small percent- mg intrathecal morphine equivalence) following cesar- age (10%–20%) of women with high analgesic needs.126 If ean delivery, but used 2 separate hospital populations for opioid pain medications are required, oral opioid medica- comparison. Most of the comparative observational stud- tions have been shown to have similar efficacy to intrave- ies in the general surgical population utilize continuous nous opioids, less side effects, and potential advantages (eg, or patient-controlled epidural opioid dosing in a different lower cost, enhanced mobility) and are therefore preferable and older patient population. Due to the paucity of data to intravenous opioids in both the perioperative and postc- comparing intravenous PCA to single-shot neuraxial mor- esarean delivery settings.127 Intravenous opioids should be phine in the obstetric population, we should be cautious to reserved for severe pain not responsive to oral opioids or extrapolate equivalent risk of respiratory depression with patients not tolerating oral medications. Increased respi- these techniques using the general surgery population data. ratory monitoring should be considered if intravenous opioids are deemed necessary in addition to neuraxial mor- Multimodal Analgesia to Reduce Opioid phine and a nonopioid multimodal analgesic regimen. Consumption Multimodal analgesic strategies should be used to improve OPTIMAL DOSING OF NEURAXIAL MORPHINE TO the analgesic efficacy of neuraxial morphine for postcesar- MAXIMIZE ANALGESIA WHILE MINIMIZING SIDE ean analgesia while minimizing the use of systemic opioids EFFECTS for breakthrough pain.113 Nonopioid multimodal analgesic Neuraxial Morphine Dosing and the Risk of regimens that include medications such as acetaminophen, Respiratory Depression NSAIDs, cyclooxygenase (COX)-2 inhibitors, dexametha- Reducing the dose of neuraxial morphine reduces its respi- sone, gabapentinoids, and local anesthetic techniques may ratory depressant effect.23,128,129 A meta-analysis conducted reduce opioid consumption and improve postoperative by Gehling et al50 of mixed nonobstetric and obstetric pop- pain management in both nonobstetric and obstetric patient ulations (28 studies; n = 790) sought to determine adverse populations.113–118 Meta-analyses and recent studies demon- effects of intrathecal morphine in patients undergoing sur- strate that the majority of women require <30 mg of mor- gery with spinal anesthesia. They found that higher doses phine equivalents in 24 hours following administration of (≥0.3 mg) of intrathecal morphine were associated with low-dose intrathecal or epidural morphine with or without high frequency of respiratory depression, 9% (7/80) com- nonopioid analgesic medications.39,41,75,96 Many of the dose- pared to lower doses 1% (2/247), albeit not a statistically finding studies for both intrathecal and epidural morphine significant difference.50 utilized a variety of multimodal analgesic regimens, mak- A meta-analysis by Sultan et al75 evaluated the respira- ing studies difficult to compare directly. However, studies in tory depressant effects of the most commonly clinically the setting of low-dose intrathecal morphine after cesarean utilized intrathecal morphine doses used in current obstet- delivery almost universally show that NSAIDs and acet- ric anesthesia practice. The investigators evaluated the aminophen reduce pain and need for opioid analgesics, with effects of 0.05–0.1 mg versus higher doses >0.1–0.25 mg of a range of 0–15 mg of morphine equivalence consumed for intrathecal morphine on the RR following elective cesar- breakthrough pain in the first 24 hours.95,119,120 Although acet- ean delivery.75 A total of 8 randomized controlled studies aminophen, NSAIDs, and local anesthetic techniques have investigated the incidence (using a variety of definitions) of

12 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. Respiratory Monitoring After Neuraxial Morphine

maternal respiratory depression up to 24 hours after intra- In summary, the duration of analgesia of intrathecal thecal morphine administration.50,74,130–135 There were no morphine can be prolonged by increasing the dose, without reported episodes of respiratory depression in this meta- reducing pain scores or rescue opioid use at the potential analysis; however, inclusion of only 480 women, relative expense of increasing maternal opioid-related side effects of to other larger studies presented in Table 2, suggests it was pruritus, nausea or vomiting, and respiratory depression. likely underpowered.75 The 2017 SOAP member survey demonstrates that intrathe- Studies investigating neuraxial morphine at low doses cal morphine dosing has decreased since 2009,16 currently have thus far been underpowered to detect differences in the 68% use ≤0.15 mg and 89% use ≤0.2 mg (Supplemental rare complication of respiratory depression. Nonetheless, Digital Content 2, Appendix 1, http://links.lww.com/ neuraxial dosing regimens should aim to administer the AA/C802). The majority (71.5%) of international experts lowest effective dose of morphine to minimize side effects in obstetric anesthesia whose countries use intrathecal and possibly the risk of respiratory depression. morphine utilize ≤0.15 mg with 0.1 mg (53.6%) being the most commonly administered dose (Supplemental Digital Intrathecal Morphine Dosing: Analgesic Duration Content 3, Appendix 2, http://links.lww.com/AA/C803). and Side Effects For the purpose of this consensus statement, the definition Multiple dose–response studies have been conducted to of “low-dose” morphine (>0.05 to ≤0.15 mg intrathecal and elucidate the optimal dosing for intrathecal morphine for >1 to ≤3 mg epidural morphine) and the accompanying cesarean analgesia.134,136,137 Most studies demonstrate mini- respiratory monitoring parameters were based on evidence mal or no additional benefit in pain scores or opioid use from the literature balancing the effects of increasing dose for breakthrough pain using analgesic doses above 0.075 to on both analgesia and side effects with the most common 0.1 mg intrathecal morphine.119,132,134,136–138 Two studies also practices of SOAP members and international experts. demonstrate that in combination with intravenous NSAIDs, ultra low doses such as 0.025 or 0.05 mg can have compara- Epidural Morphine Dosing: Analgesic Duration ble analgesic benefit but of shorter duration than 0.1 or 0.15 and Side Effects mg intrathecal morphine, respectively.119,135 Although some The optimal dose for postcesarean epidural morphine is studies demonstrate additional analgesic benefit of dosing unclear, and dosing has been based on intrathecal morphine above 0.1 mg,139 side effects such as pruritus, nausea, and equivalency studies and dose-finding studies. Equipotent vomiting increase with dosing and mitigate the additional dosing requires use of a conversion ratio of 20:1 to 30:1 analgesic benefits. between epidural and intrathecal administration. Multiple Dahl et al132 performed a meta-analysis comparing studies confirm that intrathecal morphine doses of 0.075, intrathecal morphine (doses 0.05–0.2 mg) versus systemic 0.1, and 0.2 mg are the analgesic and side effect equivalent to opioids after cesarean delivery. This systematic review epidural morphine doses of 2, 3, and 4 mg, respectively.42,141 found median time to first analgesic requirement in the Several studies have compared the postcesarean analgesic intrathecal morphine group to be 27 hours (range, 11–29). efficacy of epidural and intrathecal morphine.42,141,142 One Palmer et al137 found increased pruritus but no differences meta-analysis demonstrated equivalence for analgesic effi- in nausea or vomiting with increasing dose of intrathecal cacy, but recommended intrathecal administration as this morphine (0.025–0.5 mg). Antiemetic use increased in an causes less fetal drug exposure than epidural morphine.142 impact study from 24% when utilizing 0.1 mg intrathecal Similar postcesarean analgesia and adverse effects were morphine to 52% when using 0.2 mg for cesarean deliv- found with 2.5, 3, and 4 mg doses of epidural morphine143; ery.140 Berger et al119 compared 0.05, 0.1, and 0.15 mg intra- however, Rosen et al144 found that 2 mg did not provide thecal morphine among 144 women and found pruritus postcesarean analgesia comparable to 5 and 7.5 mg of epi- was more severe in the 0.1 and 0.15 mg groups when com- dural morphine. The optimal dose was found to be 3 mg in pared with the lowest dose group, but nausea and pruri- a large retrospective study, and 3.75 mg in a dose–response tus treatment were not different among the 3 groups. No study.45,121 respiratory depression or significant sedation occurred in A systematic review by Bonnet et al96 of various epidural any patients. morphine doses after cesarean delivery reported median The meta-analysis by Sultan et al75 also evaluated the time until first request for analgesia of 19.0 hours (range, 5.4– analgesic duration and side effects of the commonly used 29.2 hours). A longer duration of analgesia was found with intrathecal morphine doses for cesarean delivery (0.05–0.1 larger epidural morphine doses (8.9 hours with 2 mg ver- mg versus >0.1–0.25 mg). The mean time to first analgesic sus 26.8 hours with 6 mg).96 In this systematic review, they request (primary outcome) was longer (mean difference, were unable to demonstrate a correlation between epidural 4.49 hours; 95% CI, 1.85–7.13; P = .0008) in the high-dose morphine dose and incidence of pruritus or nausea.96 The group compared to the low-dose group. The range of mean largest randomized controlled study to date exploring epi- times to first analgesic request in the high-dose group was dural morphine dose and analgesic duration demonstrated between 13.8 and 39.5 hours compared to 9.7 and 26.6 hours no significant difference between 1.5 and 3 mg.121 However, in the low-dose group. Heterogeneity in the duration of the study included a multimodal regimen with scheduled analgesia may reflect differences in NSAID administration NSAIDs that may have mitigated analgesic differences intraoperatively and/or postoperatively. Pain scores at 12 between lower and higher epidural morphine dose groups. hours as well as morphine consumption at 24 hours were In summary, increasing doses of epidural morphine not significantly different. The incidence of nausea or vom- prolong analgesia following cesarean delivery, while the iting and pruritus was lower in the low-dose group.75 ideal analgesic dose to maximize analgesia and minimize

XXX 2019 • Volume XXX • Number XXX www.anesthesia-analgesia.org 13 Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. EE Special Article

side effects is between 1.5 and 3 mg of epidural morphine Cardiology/American Heart Association Task Force on clinical in combination with a multimodal analgesic postoperative practice guidelines. J Am Coll Cardiol. 2016;67:1572–1574. 3. American Society of Anesthesiologists Task Force on Neuraxial regimen. E Opioids, Horlocker TT, Burton AW, et al. Practice guidelines for the prevention, detection, and management of respiratory ACKNOWLEDGMENTS depression associated with neuraxial opioid administration: an A list of International Obstetric Anesthesiology Experts is as updated report by the American Society of Anesthesiologists Task follows: Australia: Dr Michael Paech, Dr Surbhi Malhotra; Force on neuraxial opioids and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology. 2009;110:218–230. Austria: Dr Clemens Ortner; Belgium: Dr Marc Van de 4. Greenberg S. Opioid-induced ventilatory impairment: an Velde, Dr Patricia Lavand’homme; Brazil: Dr Monica ongoing APSF initiative. Anesthesia Patient Safety Foundation Siaulys, Dr Carlos Othon Bastos; Canada: Dr Philippe Newsletter. 2018;32:57–59. Richebe, Dr Jose Carvalho; China: Dr Mingjun Xu; Chile: 5. Jungquist CR, Correll DJ, Fleisher LA, et al. Avoiding adverse Dr Hector Lacassie; Columbia: Dr Mauriscio Vasco; Egypt: events secondary to opioid-induced respiratory depression: Dr Mohamed Mohamed Tawfik; France: Dr Frederic implications for nurse executives and patient safety. J Nurs Mercier, Dr Dominique Chassard; Germany: Dr Peter Adm. 2016;46:87–94. Kranke; Iceland: Dr Olof Viktorsdottir; Indonesia: Dr Susilo 6. Orbach-Zinger S, Ioscovich A, Aviram A, et al. National survey of postoperative pain control after cesarean delivery. Isr Med Chandra; Israel: Dr Sharon Einav; Panama: Dr Luis Eduardo Assoc J. 2014;16:153–156. de la Ossa, Dr Rita Tello; Singapore: Dr Alex Sia; South 7. Johns MW. A new method for measuring daytime sleepiness: Africa: Dr Sean Chetty, Dr Robert Dyer; Spain: Dr Emilia the Epworth sleepiness scale. Sleep. 1991;14:540–545. Guasch; Switzerland: Dr Thierry Girard, Dr Christian Kern; 8. Finkel KJ, Searleman AC, Tymkew H, et al. Prevalence of undi- and United Kingdom: Dr Nuala Lucas. agnosed obstructive sleep apnea among adult surgical patients in an academic medical center. Sleep Med. 2009;10:753–758. 9. Chung F, Yegneswaran B, Liao P, et al. Validation of the Berlin DISCLOSURES questionnaire and American Society of Anesthesiologists Name: Jeanette R. Bauchat, MD, MS. checklist as screening tools for obstructive sleep apnea in surgi- Contribution: This author helped provide the literature review and cal patients. Anesthesiology. 2008;108:822–830. expert opinion as part of the consensus group and draft and revise 10. Ahmadi N, Chung SA, Gibbs A, Shapiro CM. The Berlin ques- the manuscript. tionnaire for sleep apnea in a sleep clinic population: rela- Name: Carolyn F. Weiniger, MBChB. tionship to polysomnographic measurement of respiratory Contribution: This author helped provide literature review and disturbance. Sleep Breath. 2008;12:39–45. expert opinion as part of the consensus group and revise the 11. Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire: a tool manuscript. to screen patients for obstructive sleep apnea. Anesthesiology. Name: Pervez Sultan, MBChB, FRCA, MD. 2008;108:812–821. Contribution: This author helped provide the literature review 12. Chung F, Subramanyam R, Liao P, Sasaki E, Shapiro C, Sun Y. and expert opinion as part of the consensus group and revise the High STOP-Bang score indicates a high probability of obstruc- manuscript. tive sleep apnoea. Br J Anaesth. 2012;108:768–775. Name: Ashraf S. Habib, MBBCh, MSc, MHSc, FRCA. 13. Facco FL, Ouyang DW, Zee PC, Grobman WA. Development of Contribution: This author helped provide the literature review a pregnancy-specific screening tool for sleep apnea.J Clin Sleep and expert opinion as part of the consensus group and revise the Med. 2012;8:389–394. manuscript. 14. Lockhart EM, Ben Abdallah A, Tuuli MG, Leighton BL. Name: Kazuo Ando, MD, PhD. Obstructive sleep apnea in pregnancy: assessment of current Contribution: This author helped provide the survey data and screening tools. Obstet Gynecol. 2015;126:93–102. expert opinion as part of the consensus group and revise the 15. Petersson J GR. Gas exchange and ventilation-perfusion rela- manuscript. tionships in Practice guidelines for obstetric anesthesia: an Name: John J. Kowalczyk, MD. updated report by the American Society of Anesthesiologists Contribution: This author helped provide the survey data and Task Force on Obstetric Anesthesia and the Society for obstetric expert opinion as part of the consensus group and revise the anesthesia and perinatology. Anesthesiology. 2016;124:270–300. manuscript. 16. Aiono-Le Tagaloa L, Butwick AJ, Carvalho B. A survey of peri- Name: Rie Kato, MD, DPhil. operative and postoperative anesthetic practices for cesarean Contribution: This author helped provide the expert opinion as delivery. Anesthesiol Res Pract. 2009;2009:510642. part of the consensus group and revise the manuscript. 17. Chestnut D, Wong CA, Tsen LC, et al. Postoperative analgesia. Name: Ronald B. George, MD, FRCPC. In: Chestnut's Obstetric Anesthesia: Principles and Practice. 6th ed. Contribution: This author helped provide the expert opinion as Philadelphia, PA: Elsevier; 2014:627–669. part of the consensus group and revise the manuscript. 18. Carvalho B. Respiratory depression after neuraxial opioids in Name: Craig M. Palmer, MD. the obstetric setting. Anesth Analg. 2008;107:956–961. Contribution: This author helped provide the expert opinion as 19. Bernards CM, Shen DD, Sterling ES, et al. Epidural, cerebro- part of the consensus group and revise the manuscript. spinal fluid, and plasma pharmacokinetics of epidural opioids Name: Brendan Carvalho, MBBCH, FRCA. (part 2): effect of epinephrine. Anesthesiology. 2003;99:466–475. Contribution: This author helped provide the survey data, 20. Eisenach JC. Lipid soluble opioids do move in cerebrospinal literature review, and expert opinion as chair of the consen- fluid. Reg Anesth Pain Med. 2001;26:296–297. 21. Cousins MJ, Mather LE. Intrathecal and epidural administra- sus group and draft and revise the manuscript. tion of opioids. Anesthesiology. 1984;61:276–310. This manuscript was handled by: Jill M. Mhyre, MD. 22. Bromage PR, Camporesi EM, Durant PA, Nielsen CH. Rostral spread of epidural morphine. Anesthesiology. 1982;56:431–436. REFERENCES 23. Bailey PL, Lu JK, Pace NL, et al. Effects of intrathecal mor- 1. Sharawi N, Carvalho B, Habib AS, Blake L, Mhyre JM, Sultan phine on the ventilatory response to hypoxia. N Engl J Med. P. A systematic review evaluating neuraxial morphine and 2000;343:1228–1234. diamorphine-associated respiratory depression after cesarean 24. Abboud TK, Moore M, Zhu J, et al. Epidural butorphanol or delivery. Anesth Analg. 2018;127:1385–1395. morphine for the relief of post-cesarean section pain: ventilatory 2. Halperin JL, Levine GN, Al-Khatib SM, et al. Further evolu- responses to carbon dioxide. Anesth Analg. 1987;66:887–893. tion of the ACC/AHA clinical practice guideline recommenda- 25. Bellanca L, Latteri MT, Latteri S, Montalbano L, Papa G, tion classification system: a report of the American College of Sansone A. Plasma and CSF morphine concentrations after

14 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. Respiratory Monitoring After Neuraxial Morphine

i.m. and . Pharmacol Res Commun. 40. Ladha KS, Kato R, Tsen LC, Bateman BT, Okutomi T. A pro- 1985;17:189–196. spective study of post-cesarean delivery hypoxia after spinal 26. Sjöström S, Hartvig P, Persson MP, Tamsen A. Pharmacokinetics anesthesia with intrathecal morphine 150μg. Int J Obstet Anesth. of epidural morphine and meperidine in humans. Anesthesiology. 2017;32:48–53. 1987;67:877–888. 41. Weiniger CF, Akdagli S, Turvall E, Deutsch L, Carvalho B. 27. Gourlay GK, Cherry DA, Cousins MJ. Cephalad migration of Prospective observational investigation of capnography and morphine in CSF following lumbar epidural administration in pulse oximetry monitoring after cesarean delivery with intra- patients with cancer pain. Pain. 1985;23:317–326. thecal morphine. Anesth Analg. 2019;128:513–522. 28. Martin JA, Osterman MJK, Driscoll AK, Mathews TJ. Division 42. Dualé C, Frey C, Bolandard F, Barrière A, Schoeffler P. Epidural of vital statistics national vital statistics reports. Births: final versus intrathecal morphine for postoperative analgesia after data for 2015. US Department of Health and Human Services, . Br J Anaesth. 2003;91:690–694. Centers for Disease Control and Prevention, National Center 43. Kato R, Shimamoto H, Terui K, Yokota K, Miyao H. Delayed for Health Statistics, National Vital Statistics System report. respiratory depression associated with 0.15 mg intrathecal 2017. Available at: https://www.cdc.gov/nchs/data/nvsr/ morphine for cesarean section: a review of 1915 cases. J Anesth. nvsr66/nvsr66_01.pdf. Accessed April 22, 2019. 2008;22:112–116. 29. D’Angelo R, Smiley RM, Riley ET, Segal S. Serious complica- 44. Abouleish E, Rawal N, Rashad MN. The addition of 0.2 mg tions related to obstetric anesthesia: the serious complication subarachnoid morphine to hyperbaric bupivacaine for cesar- repository project of the Society for Obstetric Anesthesia and ean delivery: a prospective study of 856 cases. Reg Anesth. Perinatology. Anesthesiology. 2014;120:1505–1512. 1991;16:137–140. 30. Lee LA, Caplan RA, Stephens LS, et al. Postoperative opioid- 45. Fuller JG, McMorland GH, Douglas MJ, Palmer L. Epidural induced respiratory depression: a closed claims analysis. morphine for analgesia after caesarean section: a report of 4880 Anesthesiology. 2015;122:659–665. patients. Can J Anaesth. 1990;37:636–640. 31. Campbell JP, Sabharwal A, Harrop-Griffiths W, Malhotra S. 46. Kotelko DM, Dailey PA, Shnider SM, Rosen MA, Hughes SC, Monitoring after neuraxial opioids for cesarean section: a sur- Brizgys RV. Epidural morphine analgesia after cesarean deliv- vey of UK practice. Anaesthesia. 2010;65:94–113. ery. Obstet Gynecol. 1984;63:409–413. 32. Excellence NIfHaC. Caesarean Section: Full Guideline. National 47. Crowgey TR, Dominguez JE, Peterson-Layne C, Allen TK, Muir Institute for Health and Clinical Excellence; 2013. Available at: HA, Habib AS. A retrospective assessment of the incidence https://www.nice.org.uk/guidance/QS32. Accessed April 22, of respiratory depression after neuraxial morphine admin- 2019. istration for postcesarean delivery analgesia. Anesth Analg. 33. Knight M, Tuffnell D, Kenyon S, Shakespeare J, Gray R, 2013;117:1368–1370. Kurinczuk JJ, eds. Saving Lives, Improving Mothers’ Care. 48. Gupta K, Nagappa M, Prasad A, et al. Risk factors for opioid- Surveillance of maternal deaths in the UK 2011–13 and Lessons induced respiratory depression in surgical patients: a system- Learned to Inform Maternity Care from the UK and Ireland Con atic review and meta-analyses. BMJ Open. 2018;8:e024086. dential Enquiries into Maternal Deaths and Morbidity 2009–13. 49. Sultan P, Gutierrez MC, Carvalho B. Neuraxial morphine MBRACE-UK Mothers and babies: Reducing risk through audits and respiratory depression: finding the right balance. Drugs. and confidential enquiries across the UK 2015; 2015. Available 2011;71:1807–1819. at: https://www.npeu.ox.ac.uk/downloads/files/mbrrace- 50. Gehling M, Tryba M. Risks and side-effects of intrathecal uk/reports/Saving%20Lives%20Improving%20Mothers%20 morphine combined with : a meta-analysis. Care%20report%202014%20Full.pdf. Accessed April 22, 2019. Anaesthesia. 2009;64:643–651. 34. Lewis G, ed. The Confidential Enquiry into Maternal and Child Health (CEMACH). Saving Mothers’ Lives: reviewing maternal 51. Weingarten TN, Herasevich V, McGlinch MC, et al. Predictors deaths to make motherhood safer - 2003–2005; The Seventh Report of delayed postoperative respiratory depression assessed from on Confidential Enquiries into Maternal Deaths in the United naloxone administration. Anesth Analg. 2015;121:422–429. Kingdom. London, UK: CEMACH; 2007. Available at: https:// 52. Fu ES, Downs JB, Schweiger JW, Miguel RV, Smith RA. www.publichealth.hscni.net/sites/default/files/Saving%20 Supplemental oxygen impairs detection of hypoventilation by Mothers'%20Lives%202003-05%20.pdf. Accessed April 22, 2019. pulse oximetry. Chest. 2004;126:1552–1558. 35. Cantwell R, Clutton-Brock T, Cooper G, et al. Saving moth- 53. Kopka A, Wallace E, Reilly G, Binning A. Observational study ers’ lives: reviewing maternal deaths to make motherhood of perioperative PtcCO2 and SpO2 in non-ventilated patients safer: 2006–2008. The eighth report of the confidential enqui- receiving epidural infusion or patient-controlled analge- ries into maternal deaths in the United Kingdom. BJOG. sia using a single earlobe monitor (TOSCA). Br J Anaesth. 2011;118:1–203. 2007;99:567–571. 36. Case Mix Programme. Female Admissions (aged 16–50 years) to Adult, 54. Langhan ML, Li FY, Lichtor JL. Respiratory depression detected General Critical Care Units in England, Wales and Northern Ireland by capnography among children in the postanesthesia care unit: Reported as ‘Currently Pregnant’ or ‘Recently Pregnant’. Report from a cross-sectional study. Paediatr Anaesth. 2016;26:1010–1017. the INARC Intensive Care National Audit and Research Centre; 55. Bailey PL, Rhondeau S, Schafer PG, et al. Dose-response 2013. Available at: https://www.oaa-anaes.ac.uk/assets/_man- pharmacology of intrathecal morphine in human volunteers. aged/cms/files/Obstetric%20admissions%20to%20critical%20 Anesthesiology. 1993;79:49–59; discussion 25A. care%202009-2012%20-%20FINAL.pdf. Accessed April 22, 2019. 56. Pattinson KT. Opioids and the control of respiration. Br J 37. Knight MKS, Brocklehurst P, Neilson J, Shakespeare J, Anaesth. 2008;100:747–758. Kurinczuk JJ, eds. on behalf of MBRRACEUK. Saving Lives, 57. Barbour SJ, Vandebeek CA, Ansermino JM. Increased tidal vol- Improving Mothers’ Care - Lessons Learned to Inform Future ume variability in children is a better marker of opioid-induced Maternity Care from the UK and Ireland Confidential Enquiries respiratory depression than decreased respiratory rate. J Clin into Maternal Deaths and Morbidity 2009–12; 2014. Available at: Monit Comput. 2004;18:171–178. http://www.nwcscnsenate.nhs.uk/files/8914/7316/8018/ 58. Jarzyna D, Jungquist CR, Pasero C, et al. American Society for Saving_Lives_Improving_Mothers_Care_report_2014_Full. Pain Management Nursing guidelines on monitoring for opi- pdf. Accessed April 22, 2019. oid-induced sedation and respiratory depression. Pain Manag 38. Ko S, Goldstein DH, VanDenKerkhof EG. Definitions of Nurs. 2011;12:118.e10–145.e10. “respiratory depression” with intrathecal morphine post- 59. Vanhook PM. Cost-utility analysis: a method of quanti- operative analgesia: a review of the literature. Can J Anaesth. fying the value of registered nurses. Online J Issues Nurs. 2003;50:679–688. 2007;12(3):Manuscript 5. 39. Bauchat JR, McCarthy R, Fitzgerald P, Kolb S, Wong CA. 60. Flenady T, Dwyer T, Applegarth J. Rationalising Transgression: Transcutaneous carbon dioxide measurements in women a grounded theory explaining how emergency department reg- receiving intrathecal morphine for cesarean delivery: a pro- istered nurses rationalise erroneous behaviour. Grounded Theor spective observational study. Anesth Analg. 2017;124:872–878. Rev. 2016;15(2).

XXX 2019 • Volume XXX • Number XXX www.anesthesia-analgesia.org 15 Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. EE Special Article

61. Pedersen T, Moller AM, Hovhannisyan K. Pulse oximetry the use of magnesium sulfate for pre-eclampsia and eclampsia for perioperative monitoring. Cochrane Database Syst Rev. management. BMC Pregnancy Childbirth. 2013;13:34. 2014(3):CD002013. 81. Which anticonvulsant for women with eclampsia? Evidence 62. Lewer BM, Larsen PD, Torrance JM, Galletly DC. Artefactual from the Collaborative Eclampsia Trial. Lancet. 1995;345: episodic hypoxaemia during postoperative respiratory moni- 1455–1463. toring. Can J Anaesth. 1998;45:182–185. 82. Izci B, Vennelle M, Liston WA, Dundas KC, Calder AA, Douglas 63. De Oliveira GS Jr, Ahmad S, Fitzgerald PC, McCarthy RJ. NJ. Sleep-disordered breathing and upper airway size in preg- Detection of hypoventilation during deep sedation in patients nancy and post-partum. Eur Respir J. 2006;27:321–327. undergoing ambulatory gynaecological hysteroscopy: a com- 83. Elkus R, Popovich J Jr. Respiratory physiology in pregnancy. parison between transcutaneous and nasal end-tidal carbon Clin Chest Med. 1992;13:555–565. dioxide measurements. Br J Anaesth. 2010;104:774–778. 84. Tantrakul V, Numthavaj P, Guilleminault C, et al. Performance 64. Parker SM, Gibson GJ. Evaluation of a transcutaneous carbon of screening questionnaires for obstructive sleep apnea during dioxide monitor (“TOSCA”) in adult patients in routine respi- pregnancy: a systematic review and meta-analysis. Sleep Med ratory practice. Respir Med. 2007;101:261–264. Rev. 2017;36:96–106. 65. McCormack JG, Kelly KP, Wedgwood J, Lyon R. The effects 85. World Health Organization. Global database on body mass of different analgesic regimens on transcutaneous CO2 after index. BMI classification. Available at: http://www.assess- major surgery. Anaesthesia. 2008;63:814–821. mentpsychology.com/icbmi.htm. Accessed November 2018. 66. Hirabayashi M, Fujiwara C, Ohtani N, Kagawa S, Kamide M. 86. Dominguez JE, Krystal AD, Habib AS. Obstructive sleep apnea Transcutaneous PCO2 monitors are more accurate than end- in pregnant women: a review of pregnancy outcomes and an tidal PCO2 monitors. J Anesth. 2009;23:198–202. approach to management. Anesth Analg. 2018;127:1167–1177. 67. Dalchow S, Lubeigt O, Peters G, Harvey A, Duggan T, Binning 87. Dolan R, Huh J, Tiwari N, Sproat T, Camilleri-Brennan J. A pro- A. Transcutaneous carbon dioxide levels and oxygen saturation spective analysis of sleep deprivation and disturbance in surgi- following caesarean section performed under spinal anaesthe- cal patients. Ann Med Surg (Lond). 2016;6:1–5. sia with intrathecal opioids. Int J Obstet Anesth. 2013;22:217–222. 88. Thompson JF, Roberts CL, Currie M, Ellwood DA. Prevalence 68. Frasca D, Geraud L, Charriere JM, Debaene B, Mimoz O. and persistence of health problems after childbirth: associa- Comparison of acoustic and impedance methods with mask tions with parity and method of birth. Birth. 2002;29:83–94. capnometry to assess respiration rate in obese patients recover- 89. Lee SY, Lee KA. Early postpartum sleep and fatigue for moth- ing from . Anaesthesia. 2015;70:26–31. ers after cesarean delivery compared with vaginal delivery: 69. Ramsay MA, Usman M, Lagow E, Mendoza M, Untalan E, De an exploratory study. J Perinat Neonatal Nurs. 2007;21:109–113. Vol E. The accuracy, precision and reliability of measuring ven- 90. Clout D, Brown R. Sociodemographic, pregnancy, obstetric, tilatory rate and detecting ventilatory pause by rainbow acous- and postnatal predictors of postpartum stress, anxiety and tic monitoring and capnometry. Anesth Analg. 2013;117:69–75. depression in new mothers. J Affect Disord. 2015;188:60–67. 70. Mimoz O, Benard T, Gaucher A, Frasca D, Debaene B. Accuracy 91. Nicklas JM, Miller LJ, Zera CA, Davis RB, Levkoff SE, Seely of respiratory rate monitoring using a non-invasive acoustic EW. Factors associated with depressive symptoms in the early method after general anaesthesia. Br J Anaesth. 2012;108:872–875. postpartum period among women with recent gestational 71. Williams GW 2nd, George CA, Harvey BC, Freeman JE. A diabetes mellitus. Matern Child Health J. 2013;17:1665–1672. comparison of measurements of change in respiratory status 92. Dias CC, Figueiredo B. Breastfeeding and depression: a system- in spontaneously breathing volunteers by the ExSpiron non- atic review of the literature. J Affect Disord. 2015;171:142–154. invasive respiratory volume monitor versus the capnostream 93. Woods AB, Crist B, Kowalewski S, Carroll J, Warren J, capnometer. Anesth Analg. 2017;124:120–126. Robertson J. A cross-sectional analysis of the effect of patient- 72. Voscopoulos C, Theos K, Tillmann Hein HA, George E. A risk controlled epidural analgesia versus patient controlled anal- stratification algorithm using non-invasive respiratory volume gesia on postcesarean pain and breastfeeding. J Obstet Gynecol monitoring to improve safety when using post-operative opi- Neonatal Nurs. 2012;41:339–346. oids in the PACU. J Clin Monit Comput. 2017;31:417–426. 94. Jungquist CR, Pasero C, Tripoli NM, Gorodetsky R, Metersky 73. Galvagno SM Jr, Duke PG, Eversole DS, George EE. Evaluation M, Polomano RC. Instituting best practice for monitoring for of respiratory volume monitoring (RVM) to detect respiratory opioid-induced advancing sedation in hospitalized patients. compromise in advance of pulse oximetry and help minimize Worldviews Evid Based Nurs. 2014;11:350–360. false desaturation alarms. J Trauma Acute Care Surg. 2016;81(5 95. Lim Y, Jha S, Sia AT, Rawal N. Morphine for post-caesarean suppl 2 Proceedings of the 2015 Military Health System section analgesia: intrathecal, epidural or intravenous? Research Symposium):S162–S170. Singapore Med J. 2005;46:392–396. 74. Abboud TK, Dror A, Mosaad P, et al. Mini-dose intrathecal 96. Bonnet MP, Mignon A, Mazoit JX, Ozier Y, Marret E. Analgesic morphine for the relief of post-cesarean section pain: safety, efficacy and adverse effects of epidural morphine compared efficacy, and ventilatory responses to carbon dioxide.Anesth to parenteral opioids after elective caesarean section: a sys- Analg. 1988;67:137–143. tematic review. Eur J Pain. 2010;14:894.e1–894.e9. 75. Sultan P, Halpern SH, Pushpanathan E, Patel S, Carvalho B. 97. Cohen SE, Subak LL, Brose WG, Halpern J. Analgesia after The effect of intrathecal morphine dose on outcomes after cesarean delivery: patient evaluations and costs of five opioid elective cesarean delivery: a meta-analysis. Anesth Analg. techniques. Reg Anesth. 1991;16:141–149. 2016;123:154–164. 98. Harrison DM, Sinatra R, Morgese L, Chung JH. Epidural nar- 76. Overdyk F, Dahan A, Roozekrans M, van der Schrier R, Aarts cotic and patient-controlled analgesia for post-cesarean sec- L, Niesters M. Opioid-induced respiratory depression in the tion pain relief. Anesthesiology. 1988;68:454–457. acute care setting: a compendium of case reports. Pain Manag. 99. Eisenach JC, Grice SC, Dewan DM. Patient-controlled anal- 2014;4:317–325. gesia following cesarean section: a comparison with epidural 77. Ahmad S, Nagle A, McCarthy RJ, Fitzgerald PC, Sullivan JT, and intramuscular narcotics. Anesthesiology. 1988;68:444–448. Prystowsky J. Postoperative hypoxemia in morbidly obese 100. Mishriky BM, George RB, Habib AS. Transversus abdominis patients with and without obstructive sleep apnea undergoing plane block for analgesia after Cesarean delivery: a systematic laparoscopic bariatric surgery. Anesth Analg. 2008;107:138–143. review and meta-analysis. Can J Anaesth. 2012;59:766–778. 78. Weingarten TN, Chong EY, Schroeder DR, Sprung J. Predictors 101. Abdallah FW, Halpern SH, Margarido CB. Transversus abdom- and outcomes following naloxone administration during phase inis plane block for postoperative analgesia after Caesarean I anesthesia recovery. J Anesth. 2016;30:116–122. delivery performed under spinal anaesthesia? A systematic 79. Meisenberg B, Ness J, Rao S, Rhule J, Ley C. Implementation of review and meta-analysis. Br J Anaesth. 2012;109:679–687. solutions to reduce opioid-induced oversedation and respira- 102. Ranta PO, Ala-Kokko TI, Kukkonen JE, et al. Incisional and tory depression. Am J Health Syst Pharm. 2017;74:162–169. epidural analgesia after caesarean delivery: a prospective, 80. Smith JM, Lowe RF, Fullerton J, Currie SM, Harris L, Felker- placebo-controlled, randomised clinical study. Int J Obstet Kantor E. An integrative review of the side effects related to Anesth. 2006;15:189–194.

16 www.anesthesia-analgesia.org ANESTHESIA & ANALGESIA Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited. Respiratory Monitoring After Neuraxial Morphine

103. O’Neill P, Duarte F, Ribeiro I, Centeno MJ, Moreira J. analgesia: a randomized noninferiority trial. Anesth Analg. Ropivacaine continuous wound infusion versus epidural 2013;117:677–685. morphine for postoperative analgesia after cesarean delivery: 123. Martin E, Vickers B, Landau R, Reece-Stremtan S. ABM clini- a randomized controlled trial. Anesth Analg. 2012;114:179–185. cal protocol 28, peripartum analgesia and anesthesia for the 104. Bamigboye AA, Hofmeyr GJ. Local anaesthetic wound infil- breastfeeding mother. Breastfeed Med. 2018;13:164–171. tration and abdominal nerves block during caesarean sec- 124. Lavoie A, Toledo# P. Multimodal postcesarean delivery analge- tion for postoperative pain relief. Cochrane Database Syst Rev. sia. Clin Perinatol. 2013;40:443–455. 2009:CD006954. 125. Carvalho B, Butwick AJ. Postcesarean delivery analgesia. Best 105. Marroquin B, Feng C, Balofsky A, et al. Neuraxial opioids Pract Res Clin Anaesthesiol. 2017;31:69–79. for post-cesarean delivery analgesia: can hydromorphone 126. Komatsu R, Carvalho B, Flood PD. Recovery after nulliparous replace morphine? A retrospective study. Int J Obstet Anesth. birth: a detailed analysis of pain analgesia and recovery of 2017;30:16–22. function. Anesthesiology. 2017;127:684–694. 106. Sviggum HP, Arendt KW, Jacob AK, et al. Intrathecal hydro- 127. Cheung CW, Ching Wong SS, Qiu Q, Wang X. Oral oxycodone morphone and morphine for postcesarean delivery analge- for acute postoperative pain: a review of clinical trials. Pain sia: determination of the ED90 using a sequential allocation Physician. 2017;20:SE33–SE52. biased-coin method. Anesth Analg. 2016;123:690–697. 128. Lanz E, Kehrberger E, Theiss D. Epidural morphine: 107. Gwirtz KH, Young JV, Byers RS, et al. The safety and efficacy a clinical double-blind study of dosage. Anesth Analg. of intrathecal opioid analgesia for acute postoperative pain: 1985;64:786–791. seven years’ experience with 5969 surgical patients at Indiana 129. Rawal N, Wattwil M. Respiratory depression after epidural University Hospital. Anesth Analg. 1999;88:599–604. morphine–an experimental and clinical study. Anesth Analg. 108. Hagle ME, Lehr VT, Brubakken K, Shippee A. Respiratory 1984;63:8–14. depression in adult patients with intravenous patient-con- 130. Jiang CJ, Liu CC, Wu TJ, et al. Mini-dose intrathecal mor- trolled analgesia. Orthop Nurs. 2004;23:18–27; quiz 28. phine for post-cesarean section analgesia. Ma Zui Xue Za Zhi. 109. Siriussawakul A, Mandee S, Thonsontia J, Vitayaburananont 1991;29:683–689. P, Areewatana S, Laonarinthawoot J. Obesity, epidural anal- 131. Girgin NK, Gurbet A, Turker G, Aksu H, Gulhan N. gesia, and subcostal incision are risk factors for postoperative Intrathecal morphine in anesthesia for cesarean delivery: desaturation. Can J Anaesth. 2010;57:415–422. dose-response relationship for combinations of low-dose 110. Pendi A, Acosta FL, Tuchman A, et al. Intrathecal morphine in intrathecal morphine and spinal bupivacaine. J Clin Anesth. spine surgery: a meta-analysis of randomized controlled tri- 2008;20:180–185. als. Spine (Phila Pa 1976). 2017;42:E740–E747. 132. Dahl JB, Jeppesen IS, Jørgensen H, Wetterslev J, Møiniche 111. Cashman JN, Dolin SJ. Respiratory and haemodynamic effects S. Intraoperative and postoperative analgesic efficacy and of acute postoperative pain management: evidence from pub- adverse effects of intrathecal opioids in patients undergo- lished data. Br J Anaesth. 2004;93:212–223. ing cesarean section with spinal anesthesia: a qualitative and 112. Shapiro A1, Zohar E, Zaslansky R, Hoppenstein D, Shabat S, quantitative systematic review of randomized controlled tri- Fredman B. The frequency and timing of respiratory depres- als. Anesthesiology. 1999;91:1919–1927. sion in 1524 postoperative patients treated with systemic or 133. Cohen SE, Desai JB, Ratner EF, Riley ET, Halpern J. Ketorolac neuraxial morphine. J Clin Anesth. 2005;17:537–542. and spinal morphine for postcesarean analgesia. Int J Obstet 113. Lavand’homme P. Postcesarean analgesia: effective strategies Anesth. 1996;5:14–18. and association with chronic pain. Curr Opin Anaesthesiol. 134. Yang T, Breen TW, Archer D, Fick G. Comparison of 0.25 mg 2006;19:244–248. and 0.1 mg intrathecal morphine for analgesia after Cesarean 114. Sutton CD, Carvalho B. Optimal pain management after section. Can J Anaesth. 1999;46:856–860. cesarean delivery. Anesthesiol Clin. 2017;35:107–124. 135. Cardoso MM, Carvalho JC, Amaro AR, Prado AA, Cappelli 115. Elia N, Lysakowski C, Tramèr MR. Does multimodal analgesia EL. Small doses of intrathecal morphine combined with sys- with acetaminophen, nonsteroidal antiinflammatory drugs, temic diclofenac for postoperative pain control after cesarean or selective cyclooxygenase-2 inhibitors and patient-con- delivery. Anesth Analg. 1998;86:538–541. trolled analgesia morphine offer advantages over morphine 136. Milner AR, Bogod DG, Harwood RJ. Intrathecal administra- alone? Meta-analyses of randomized trials. Anesthesiology. tion of morphine for elective Caesarean section. A comparison 2005;103:1296–1304. between 0.1 mg and 0.2 mg. Anaesthesia. 1996;51:871–873. 116. Mathiesen O, Wetterslev J, Kontinen VK, et al; Scandinavian 137. Palmer CM, Emerson S, Volgoropolous D, Alves D. Dose- Postoperative Pain Alliance (ScaPAlli). Adverse effects of response relationship of intrathecal morphine for postcesar- perioperative paracetamol, NSAIDs, glucocorticoids, gaba- ean analgesia. Anesthesiology. 1999;90:437–444. pentinoids and their combinations: a topical review. Acta 138. Uchiyama A, Nakano S, Ueyama H, Nishimura M, Tashiro C. Anaesthesiol Scand. 2014;58:1182–1198. Low dose intrathecal morphine and pain relief following cae- 117. Maund E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott sarean section. Int J Obstet Anesth. 1994;3:87–91. N. Paracetamol and selective and non-selective non-steroidal 139. Gerancher JC, Floyd H, Eisenach J. Determination of an effec- anti-inflammatory drugs for the reduction in morphine- tive dose of intrathecal morphine for pain relief after cesarean related side-effects after major surgery: a systematic review. delivery. Anesth Analg. 1999;88:346–351. Br J Anaesth. 2011;106:292–297. 140. Wong JY, Carvalho B, Riley ET. Intrathecal morphine 100 118. Pavy TJ, Paech MJ, Evans SF. The effect of intravenous ketoro- and 200 μg for post-cesarean delivery analgesia: a trade-off lac on opioid requirement and pain after cesarean delivery. between analgesic efficacy and side effects.Int J Obstet Anesth. Anesth Analg. 2001;92:1010–1014. 2013;22:36–41. 119. Berger JS, Gonzalez A, Hopkins A, et al. Dose-response of intra- 141. Sarvela J, Halonen P, Soikkeli A, Korttila K. A double-blinded, thecal morphine when administered with intravenous ketoro- randomized comparison of intrathecal and epidural morphine lac for post-cesarean analgesia: a two-center, prospective, for elective cesarean delivery. Anesth Analg. 2002;95:436–440. randomized, blinded trial. Int J Obstet Anesth. 2016;28:3–11. 142. Ng K, Parsons J, Cyna AM, Middleton P. Spinal versus epi- 120. Wilson SH, Wolf BJ, Robinson SM, Nelson C, Hebbar L. dural anaesthesia for caesarean section. Cochrane Database Syst Intravenous vs oral acetaminophen for analgesia after cesar- Rev. 2004(2):CD003765. ean delivery: a randomized trial. Pain Med. 2018 [Epub ahead 143. Chumpathong S, Santawat U, Saunya P, Chimpalee R, of print]. Toomtong P. Comparison of different doses of epidural mor- 121. Palmer CM, Nogami WM, Van Maren G, Alves DM. phine for pain relief following cesarean section. J Med Assoc Postcesarean epidural morphine: a dose-response study. Thai. 2002;85(suppl 3):S956–S962. Anesth Analg. 2000;90:887–891. 144. Rosen MA, Hughes SC, Shnider SM, et al. Epidural morphine 122. Singh SI, Rehou S, Marmai KL, Jones PM. The efficacy of for the relief of postoperative pain after cesarean delivery. 2 doses of epidural morphine for postcesarean delivery Anesth Analg. 1983;62:666–672.

XXX 2019 • Volume XXX • Number XXX www.anesthesia-analgesia.org 17 Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.