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Opioid Withdrawal in Critically Ill AdultsA Retrospective Study to Identify at Risk PatientsPrimary Investigator: Raymond Melika, PharmD, RPhSupervisor: Lisa Burry, BScPharm, PharmD, FCCP, FCCM Collaborators:Alexandra Cheung, BSc, BScPharm, PharmD, RPhJennifer Korman, BScPharm, ACPR, RPhMay Musing, BScPharm, RPhAcknowledgementsI would like to acknowledge the truly tireless hard work of Andrew Wyllie, Christinne Duclos, Winnie Seto and Virginia Fernandes; a team which, without, I could not have overcome the obstacles presented by this study.TABLE OF CONTENTS TOC \o "1-3" \h \z \u 1: Abbreviations PAGEREF _Toc4449888 \h 42: Abstract PAGEREF _Toc4449889 \h 53: Background PAGEREF _Toc4449890 \h 74: Methods PAGEREF _Toc4449891 \h 94.1: Design PAGEREF _Toc4449892 \h 94.2: Patients PAGEREF _Toc4449893 \h 94.3: Procedures PAGEREF _Toc4449894 \h 104.4: Statistical Analysis PAGEREF _Toc4449895 \h 115: Results PAGEREF _Toc4449896 \h 115.1: Population PAGEREF _Toc4449897 \h 125.2: Outcomes PAGEREF _Toc4449898 \h 126: Discussion PAGEREF _Toc4449899 \h 137: Conclusion PAGEREF _Toc4449900 \h 178: References PAGEREF _Toc4449901 \h 199: Figures PAGEREF _Toc4449902 \h 239.1: Figure 1: Study Flowchart PAGEREF _Toc4449903 \h 239.2: Figure 2: Schematic of Patient Chart Assessment PAGEREF _Toc4449904 \h 249.3: Figure 3: Symptom Documentation Frequency PAGEREF _Toc4449905 \h 259.4: Figure 4: Daily Clonidine, Dexmedetomidine, and Propranolol Administration PAGEREF _Toc4449906 \h 269.5: Figure 5: Daily Acetaminophen, NSAID, and Antipsychotic Administration PAGEREF _Toc4449907 \h 279.6: Figure 6: Daily Benzodiazepine and Propofol Administration PAGEREF _Toc4449908 \h 2810: Tables PAGEREF _Toc4449909 \h 2910.1: Table 1: Baseline Patient Demographics PAGEREF _Toc4449910 \h 2910.2: Table 2: Daily Opioid Dose Changes PAGEREF _Toc4449911 \h 3010.3: Table 3: Symptom Documentation Frequency on Each Day PAGEREF _Toc4449912 \h 3111: Appendix PAGEREF _Toc4449913 \h 3211.1: Protocol for the Collection of Data PAGEREF _Toc4449914 \h 3211.2: Comparison of Opioid Withdrawal Assessments PAGEREF _Toc4449915 \h 3411.3: Opioid and Benzodiazepine Dosing Equivalence PAGEREF _Toc4449916 \h 351: AbbreviationsCOWS: Clinical Opiate Withdrawal ScaleCPOT: Critical Pain Observation ToolDSM: Diagnostic and Statistical Manual of Mental Disorders GCS: Glasgow Coma ScaleICU: Intensive Care UnitIOWS: Iatrogenic Opioid Withdrawal SyndromeLOS: Length of StayNRS: Numerical Rating ScaleOBWS: Opioid and Benzodiazepine Withdrawal ScorePTSD: Post-Traumatic Stress DisorderSAS: Riker Sedation-Agitation ScaleSOS: Sophia Observation and Withdrawal Symptoms ScaleWAT-1: Withdrawal Assessment Tool – Version 12: AbstractBackground: The incidence of opioid withdrawal and associated symptoms in critically ill adults has not been adequately studied. The lack of dedicated scales for the detection of iatrogenic opioid withdrawal syndrome (IOWS) in critically ill adults represents a gap in the literature. Objectives: To 1) determine the feasibility of identifying patients at risk of IOWS for a future study evaluating IOWS in critically ill adults 2) determine the frequency of documentation of potential signs and symptoms of IOWS; 3) determine patterns of opioid doses used in critically ill adults.Methods: A retrospective chart review of critically ill adults (aged ≥ 18 years) who received regularly administered opioids for at least 72 hours in the ICU. Patient charts were reviewed for documentation of signs and symptoms of opioid withdrawal using a checklist of 17 symptoms developed from a review of the literature. Feasibility was defined as the ability to include 20 subjects in 1 year. Results: One thousand, one hundred and eighteen subjects were screened between December 2016 and December 2017. Twenty-eight subjects were included. The median age was 65 years. Male sex comprised 61% of subjects. The most common reason for exclusion was not receiving scheduled opioids in ICU for ≥ 72 hours (91.7%.) The most commonly documented symptom was a ≥ 15% variance in respiratory rate (92.5% frequency of documentation). Documentation of the absence of symptoms was rare (< 1%). The symptoms least commonly documented were piloerection and lacrimation (0% frequency of documentation, respectively). Median daily opioid dose changes were + 13%, - 5%, -19% and -22% on days 2, 3, 4 and 5, respectively. The most frequently used opioids were IV Fentanyl, IV Hydromorphone, and Oral Hydromorphone, representing 70.1%, 42.5%, and 21.6% of patient days, respectively.Conclusions: In identifying 28 patients at risk of IOWS, our findings demonstrate the feasibility identifying patients at risk of IOWS for a future study evaluating IOWS in critically ill adults. Data on the frequency of documentation of 17 symptoms suggest a wide range of documentation frequency and may inform the choice of symptoms assessed in future studies of IOWS. Our data identified 20% dose reductions beginning on day 4, which informs a standardized dose reduction to be tested in an interventional study.3: BackgroundCritically ill patients often require analgesia with opioids to manage the pain associated with procedures and the use of supportive care devices. Beyond patient comfort, analgesia-first strategies (as opposed to sedation-first) are increasingly important in the prevention of negative patient outcomes, including PTSD, agitation and delirium. 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Wesley"}],"issued":{"date-parts":[["2007",9]]}}}],"schema":""} 4 Once patients become tolerant to opioids and physiologic dependence is exhibited, Iatrogenic Opioid Withdrawal Syndrome (IOWS) can be precipitated with either abrupt discontinuation of therapy or active reversal with opioid receptor antagonists or partial agonists. 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The summed score of the eleven items can be used to assess a patient's level of opiate withdrawal and to make inferences about their level of physical dependence on opioids. With increasing use of opioids for treatment of pain and the availability of sublingual buprenorphine in the United States for treatment of opioid dependence, clinical assessment of opiate withdrawal intensity has received renewed interest. Buprenorphine, a partial opiate agonist at the mu receptor, can precipitate opiate withdrawal in patients with a high level of opioid dependence who are not experiencing opioid withdrawal. Since development of the first opiate withdrawal scale in the mid-1930s, many different opioid withdrawal scales have been used in clinical and research settings. This article reviews the history of opiate withdrawal scales and the context of their initial use. A template version of the COWS that can be copied and used clinically is appended. PDF formatted versions of the COWS are also available from the websites of the American Society of Addiction Medicine, the California Society of Addiction Medicine, the UCLA Integrated Substance Abuse Programs, and .","DOI":"10.1080/02791072.2003.10400007","ISSN":"0279-1072","note":"PMID: 12924748","journalAbbreviation":"J Psychoactive Drugs","language":"eng","author":[{"family":"Wesson","given":"Donald R."},{"family":"Ling","given":"Walter"}],"issued":{"date-parts":[["2003",6]]}}}],"schema":""} 11 Several scales have been validated to assess the severity of IOWS in children and non-critically ill adults, including CINA ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5eHMEC2b","properties":{"formattedCitation":"\\super 8\\nosupersub{}","plainCitation":"8","noteIndex":0},"citationItems":[{"id":18,"uris":[""],"uri":[""],"itemData":{"id":18,"type":"article-journal","title":"Assessment of Opioid Dependence with Naloxone","container-title":"Addiction","page":"193-201","volume":"83","issue":"2","source":"Crossref","DOI":"10.1111/j.1360-0443.1988.tb03981.x","ISSN":"0965-2140, 1360-0443","language":"en","author":[{"family":"Peachey","given":"J. 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The summed score of the eleven items can be used to assess a patient's level of opiate withdrawal and to make inferences about their level of physical dependence on opioids. With increasing use of opioids for treatment of pain and the availability of sublingual buprenorphine in the United States for treatment of opioid dependence, clinical assessment of opiate withdrawal intensity has received renewed interest. Buprenorphine, a partial opiate agonist at the mu receptor, can precipitate opiate withdrawal in patients with a high level of opioid dependence who are not experiencing opioid withdrawal. Since development of the first opiate withdrawal scale in the mid-1930s, many different opioid withdrawal scales have been used in clinical and research settings. This article reviews the history of opiate withdrawal scales and the context of their initial use. A template version of the COWS that can be copied and used clinically is appended. PDF formatted versions of the COWS are also available from the websites of the American Society of Addiction Medicine, the California Society of Addiction Medicine, the UCLA Integrated Substance Abuse Programs, and .","DOI":"10.1080/02791072.2003.10400007","ISSN":"0279-1072","note":"PMID: 12924748","journalAbbreviation":"J Psychoactive Drugs","language":"eng","author":[{"family":"Wesson","given":"Donald R."},{"family":"Ling","given":"Walter"}],"issued":{"date-parts":[["2003",6]]}}}],"schema":""} 11. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM V) indicates that 3 or more of the following symptoms must be present to diagnose opioid withdrawal syndrome: dysphoric mood, nausea or vomiting, muscle aches, lacrimation or rhinorrhea, pupillary dilation, piloerection, or sweating, diarrhea, yawning, fever, insomnia. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6aBbIAdi","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":10,"uris":[""],"uri":[""],"itemData":{"id":10,"type":"book","title":"Diagnostic and Statistical Manual of Mental Disorders","publisher":"American Psychiatric Association","edition":"Fifth Edition","source":"Crossref","URL":"","ISBN":"978-0-89042-555-8","note":"DOI: 10.1176/appi.books.9780890425596","language":"en","author":[{"literal":"American Psychiatric Association"}],"issued":{"date-parts":[["2013",5,22]]},"accessed":{"date-parts":[["2018",10,29]]}}}],"schema":""} 6 These symptoms have not, however, been integrated into a validated tool for assessment of IOWS in the adult ICU. Given the ubiquity of therapeutic and pathological sedation and paralysis in the ICU, the reliance on subjective patient-reported symptoms in these scales limits the utility of these tools in the ICU. In critically ill children two tools have been specifically developed and validated to assess opioid withdrawal: WAT-1 ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6hucGPst","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":23,"uris":[""],"uri":[""],"itemData":{"id":23,"type":"article-journal","title":"The Withdrawal Assessment Tool–1 (WAT–1): An assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients*:","container-title":"Pediatric Critical Care Medicine","page":"573-580","volume":"9","issue":"6","source":"Crossref","DOI":"10.1097/PCC.0b013e31818c8328","ISSN":"1529-7535","shortTitle":"The Withdrawal Assessment Tool–1 (WAT–1)","language":"en","author":[{"family":"Franck","given":"Linda S."},{"family":"Harris","given":"Sion Kim"},{"family":"Soetenga","given":"Deborah J."},{"family":"Amling","given":"June K."},{"family":"Curley","given":"Martha A. 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A recent assessment of the applicability of the WAT-1 in critically ill adults found a specificity of 0.7, and a sensitivity of only 0.5. 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Q."}],"issued":{"date-parts":[["2008",11]]}}}],"schema":""} 12 and duration of mechanical ventilation ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"pa9b1xX5","properties":{"formattedCitation":"\\super 15\\nosupersub{}","plainCitation":"15","noteIndex":0},"citationItems":[{"id":13,"uris":[""],"uri":[""],"itemData":{"id":13,"type":"article-journal","title":"Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics: A first evaluation*:","container-title":"Critical Care Medicine","page":"2427-2432","volume":"36","issue":"8","source":"Crossref","DOI":"10.1097/CCM.0b013e318181600d","ISSN":"0090-3493","shortTitle":"Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics","language":"en","author":[{"family":"Ista","given":"Erwin"},{"family":"Dijk","given":"Monique","non-dropping-particle":"van"},{"family":"Gamel","given":"Claudia"},{"family":"Tibboel","given":"Dick"},{"family":"Hoog","given":"Matthijs","non-dropping-particle":"de"}],"issued":{"date-parts":[["2008",8]]}}}],"schema":""} 15) the risk factors for, and incidence of, IOWS in the adult critically ill population have not been well described. Despite the presence of dedicated scales in both the pediatric ICU population and the non-critically ill adult population, the lack of dedicated scales for the detection of IOWS in critically ill adults is a gap in the literature. We conducted a literature review to identify symptoms used in the assessment of opioid withdrawal in the pediatric ICU (SOS ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"C5HW1soG","properties":{"formattedCitation":"\\super 13\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":25,"uris":[""],"uri":[""],"itemData":{"id":25,"type":"article-journal","title":"Construction of the Sophia Observation withdrawal Symptoms-scale (SOS) for critically ill children","container-title":"Intensive Care Medicine","page":"1075-1081","volume":"35","issue":"6","source":"Crossref","DOI":"10.1007/s00134-009-1487-3","ISSN":"0342-4642, 1432-1238","language":"en","author":[{"family":"Ista","given":"Erwin"},{"family":"Dijk","given":"Monique","non-dropping-particle":"van"},{"family":"Hoog","given":"Matthijs","non-dropping-particle":"de"},{"family":"Tibboel","given":"Dick"},{"family":"Duivenvoorden","given":"Hugo J."}],"issued":{"date-parts":[["2009",6]]}}}],"schema":""} 13, WAT-1 ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sr0eU8WY","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":23,"uris":[""],"uri":[""],"itemData":{"id":23,"type":"article-journal","title":"The Withdrawal Assessment Tool–1 (WAT–1): An assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients*:","container-title":"Pediatric Critical Care Medicine","page":"573-580","volume":"9","issue":"6","source":"Crossref","DOI":"10.1097/PCC.0b013e31818c8328","ISSN":"1529-7535","shortTitle":"The Withdrawal Assessment Tool–1 (WAT–1)","language":"en","author":[{"family":"Franck","given":"Linda S."},{"family":"Harris","given":"Sion Kim"},{"family":"Soetenga","given":"Deborah J."},{"family":"Amling","given":"June K."},{"family":"Curley","given":"Martha A. Q."}],"issued":{"date-parts":[["2008",11]]}}}],"schema":""} 12) and adult non-ICU population (DSM-V ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"9daUo2zc","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":10,"uris":[""],"uri":[""],"itemData":{"id":10,"type":"book","title":"Diagnostic and Statistical Manual of Mental Disorders","publisher":"American Psychiatric Association","edition":"Fifth Edition","source":"Crossref","URL":"","ISBN":"978-0-89042-555-8","note":"DOI: 10.1176/appi.books.9780890425596","language":"en","author":[{"literal":"American Psychiatric Association"}],"issued":{"date-parts":[["2013",5,22]]},"accessed":{"date-parts":[["2018",10,29]]}}}],"schema":""} 6, and COWS ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"5ivfhatx","properties":{"formattedCitation":"\\super 11\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":21,"uris":[""],"uri":[""],"itemData":{"id":21,"type":"article-journal","title":"The Clinical Opiate Withdrawal Scale (COWS)","container-title":"Journal of Psychoactive Drugs","page":"253-259","volume":"35","issue":"2","source":"PubMed","abstract":"The clinical opiate withdrawal scale (COWS) is a clinician-administered, pen and paper instrument that rates eleven common opiate withdrawal signs or symptoms. The summed score of the eleven items can be used to assess a patient's level of opiate withdrawal and to make inferences about their level of physical dependence on opioids. With increasing use of opioids for treatment of pain and the availability of sublingual buprenorphine in the United States for treatment of opioid dependence, clinical assessment of opiate withdrawal intensity has received renewed interest. Buprenorphine, a partial opiate agonist at the mu receptor, can precipitate opiate withdrawal in patients with a high level of opioid dependence who are not experiencing opioid withdrawal. Since development of the first opiate withdrawal scale in the mid-1930s, many different opioid withdrawal scales have been used in clinical and research settings. This article reviews the history of opiate withdrawal scales and the context of their initial use. A template version of the COWS that can be copied and used clinically is appended. PDF formatted versions of the COWS are also available from the websites of the American Society of Addiction Medicine, the California Society of Addiction Medicine, the UCLA Integrated Substance Abuse Programs, and .","DOI":"10.1080/02791072.2003.10400007","ISSN":"0279-1072","note":"PMID: 12924748","journalAbbreviation":"J Psychoactive Drugs","language":"eng","author":[{"family":"Wesson","given":"Donald R."},{"family":"Ling","given":"Walter"}],"issued":{"date-parts":[["2003",6]]}}}],"schema":""} 11). We identified 17 symptoms (Appendix 11.2). Our objectives of this study are to 1) determine the feasibility of identifying patients at risk of IOWS for a future study evaluating IOWS in critically ill adults 2) determine the frequency of documentation of potential signs and symptoms of IOWS; 3) determine patterns of opioid doses used in critically ill adults.4: Methods4.1: DesignWe conducted a retrospective chart review in the medical-surgical ICU of Mount Sinai Hospital, Sinai Health System. Patient enrollment occurred between December 2016 and December 2017. The study protocol was reviewed and approved by the Research Ethics Board of the hospital (MSH REB #18-0038-C). 4.2: PatientsPatients were included if they were admitted to the ICU, aged at least 18 years old, and received scheduled opioids for at least 72 hours in the ICU. We used 72 hours as the cut-off due to a previous study describing IOWS after as little as three days of exposure. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"P77xBF4V","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":4,"uris":[""],"uri":[""],"itemData":{"id":4,"type":"article-journal","title":"Opioid-associated iatrogenic withdrawal in critically ill adult patients: a multicenter prospective observational study","container-title":"Annals of Intensive Care","volume":"7","issue":"1","source":"Crossref","URL":"","DOI":"10.1186/s13613-017-0310-5","ISSN":"2110-5820","shortTitle":"Opioid-associated iatrogenic withdrawal in critically ill adult patients","language":"en","author":[{"family":"Wang","given":"Pan Pan"},{"family":"Huang","given":"Elaine"},{"family":"Feng","given":"Xue"},{"family":"Bray","given":"Charles-André"},{"family":"Perreault","given":"Marc M."},{"family":"Rico","given":"Philippe"},{"family":"Bellemare","given":"Patrick"},{"family":"Murgoi","given":"Paul"},{"family":"Gélinas","given":"Céline"},{"family":"Lecavalier","given":"Annie"},{"family":"Jayaraman","given":"Dev"},{"family":"Frenette","given":"Anne Julie"},{"family":"Williamson","given":"David"}],"issued":{"date-parts":[["2017",12]]},"accessed":{"date-parts":[["2018",10,29]]}}}],"schema":""} 2 We also included patients ordered “as-needed” doses who received more than half of the daily permitted doses. A convenience benchmark “half of the daily permitted doses” was used, following a previous study ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"6XDSF1oA","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":4,"uris":[""],"uri":[""],"itemData":{"id":4,"type":"article-journal","title":"Opioid-associated iatrogenic withdrawal in critically ill adult patients: a multicenter prospective observational study","container-title":"Annals of Intensive Care","volume":"7","issue":"1","source":"Crossref","URL":"","DOI":"10.1186/s13613-017-0310-5","ISSN":"2110-5820","shortTitle":"Opioid-associated iatrogenic withdrawal in critically ill adult patients","language":"en","author":[{"family":"Wang","given":"Pan Pan"},{"family":"Huang","given":"Elaine"},{"family":"Feng","given":"Xue"},{"family":"Bray","given":"Charles-André"},{"family":"Perreault","given":"Marc M."},{"family":"Rico","given":"Philippe"},{"family":"Bellemare","given":"Patrick"},{"family":"Murgoi","given":"Paul"},{"family":"Gélinas","given":"Céline"},{"family":"Lecavalier","given":"Annie"},{"family":"Jayaraman","given":"Dev"},{"family":"Frenette","given":"Anne Julie"},{"family":"Williamson","given":"David"}],"issued":{"date-parts":[["2017",12]]},"accessed":{"date-parts":[["2018",10,29]]}}}],"schema":""} 2, and in order to capture a larger sample size.We excluded the following patients: self-reported exposure to opioids in the 90 days prior to admission (determined from outpatient medication list); receiving opioids in the ICU administered exclusively spinally; severe brain injury (defined as GCS of 8 or less on admission to the ICU); palliative on ICU admission; admission to the ICU with substance overdose or acute alcohol withdrawal syndrome. Given the sample sizes used in studies for the development of withdrawal scales in the pediatric ICU such as OBWS ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gDHxgfHh","properties":{"formattedCitation":"\\super 16\\nosupersub{}","plainCitation":"16","noteIndex":0},"citationItems":[{"id":29,"uris":[""],"uri":[""],"itemData":{"id":29,"type":"article-journal","title":"Franck LS, Naughton I, Winter I. Opioid and benzodiazepine withdrawal symptoms in paediatric intensive care patients. Intensive Crit Care Nurs. 2004;20:344-351. doi:10.1016/j. iccn.2004.07.008"}}],"schema":""} 16 (n=15), SOS ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"XdHEmhCN","properties":{"formattedCitation":"\\super 13\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":25,"uris":[""],"uri":[""],"itemData":{"id":25,"type":"article-journal","title":"Construction of the Sophia Observation withdrawal Symptoms-scale (SOS) for critically ill children","container-title":"Intensive Care Medicine","page":"1075-1081","volume":"35","issue":"6","source":"Crossref","DOI":"10.1007/s00134-009-1487-3","ISSN":"0342-4642, 1432-1238","language":"en","author":[{"family":"Ista","given":"Erwin"},{"family":"Dijk","given":"Monique","non-dropping-particle":"van"},{"family":"Hoog","given":"Matthijs","non-dropping-particle":"de"},{"family":"Tibboel","given":"Dick"},{"family":"Duivenvoorden","given":"Hugo J."}],"issued":{"date-parts":[["2009",6]]}}}],"schema":""} 13 (n=79), and WAT-1 ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2QVbfpfi","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":23,"uris":[""],"uri":[""],"itemData":{"id":23,"type":"article-journal","title":"The Withdrawal Assessment Tool–1 (WAT–1): An assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients*:","container-title":"Pediatric Critical Care Medicine","page":"573-580","volume":"9","issue":"6","source":"Crossref","DOI":"10.1097/PCC.0b013e31818c8328","ISSN":"1529-7535","shortTitle":"The Withdrawal Assessment Tool–1 (WAT–1)","language":"en","author":[{"family":"Franck","given":"Linda S."},{"family":"Harris","given":"Sion Kim"},{"family":"Soetenga","given":"Deborah J."},{"family":"Amling","given":"June K."},{"family":"Curley","given":"Martha A. Q."}],"issued":{"date-parts":[["2008",11]]}}}],"schema":""} 12 (n=83), and considering a study by Perrault et al. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"A6Tice52","properties":{"formattedCitation":"\\super 17\\nosupersub{}","plainCitation":"17","noteIndex":0},"citationItems":[{"id":33,"uris":[""],"uri":[""],"itemData":{"id":33,"type":"article-journal","title":"Perreault M, Martone A, Sandu PR, et al. Withdrawal assessment in adult ICU patients: validation of the WAT-1 scale. 37th International Symposium on Intensive Care and Emergency Medicine. Crit Care. 2017;21(suppl 1):56, [abstract] P277."}}],"schema":""} 17 which included 54 adult patients from two ICUs over an enrollment period of eight months, we defined feasibility as the ability to include a convenience sample 20 subjects from one site in one year. 4.3: ProceduresPatients meeting the above-mentioned inclusion, and not meeting the exclusion criteria, were then assessed against the 17 symptoms derived from a review of the literature (Appendix 11.2) to determine the frequency of the documentation of these symptoms in the population of interest. Once patients were enrolled, demographic information was collected using a standardized case report form in Microsoft Excel (Microsoft Office 365 [2016], Version 1810, Build 11001.20108). Baseline data collected included: age, sex, height, weight, date of hospital and ICU admission and discharge, reason for ICU admission, mechanical ventilation (% of patients mechanically ventilated and duration of mechanical ventilation), alcohol abuse (defined as ≥2 drinks per day and/or ≥14 drinks per week in men and ≥9 drinks per week for women ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"LqZBJ1TC","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":4,"uris":[""],"uri":[""],"itemData":{"id":4,"type":"article-journal","title":"Opioid-associated iatrogenic withdrawal in critically ill adult patients: a multicenter prospective observational study","container-title":"Annals of Intensive Care","volume":"7","issue":"1","source":"Crossref","URL":"","DOI":"10.1186/s13613-017-0310-5","ISSN":"2110-5820","shortTitle":"Opioid-associated iatrogenic withdrawal in critically ill adult patients","language":"en","author":[{"family":"Wang","given":"Pan Pan"},{"family":"Huang","given":"Elaine"},{"family":"Feng","given":"Xue"},{"family":"Bray","given":"Charles-André"},{"family":"Perreault","given":"Marc M."},{"family":"Rico","given":"Philippe"},{"family":"Bellemare","given":"Patrick"},{"family":"Murgoi","given":"Paul"},{"family":"Gélinas","given":"Céline"},{"family":"Lecavalier","given":"Annie"},{"family":"Jayaraman","given":"Dev"},{"family":"Frenette","given":"Anne Julie"},{"family":"Williamson","given":"David"}],"issued":{"date-parts":[["2017",12]]},"accessed":{"date-parts":[["2018",10,29]]}}}],"schema":""} 2), smoking history, illicit substance history (such as cocaine or non-medicinal marijuana use at the time of admission), medical comorbidities, and ever use of physical restraints during ICU admission. Given the uncertainty/ambiguity of risk factors for, and consequences of IOWS, these data were collected due to their anticipated availability and ubiquity in similar studies and for potential investigation in future studies. Beginning on the first day on which each patient received regular opioids for at least 12 hours of the day [referred to as “Day 1”]) each patient’s archived ICU nursing record was reviewed for documentation daily of the 17 signs and symptoms. Symptoms were scored as present, absent, or not documented (Appendix 11.1). Daily assessment for symptom documentation continued until the patient died, was transferred out of the ICU, or until 5 days of assessment had been completed – whichever came first (Figure 2). A convenience period of 5 days was chosen. Other daily data collected from the daily ICU nursing records included Numerical Rating Scale (NRS) pain scores, Critical Care Pain Observation Tool (CPOT) scores, Riker Sedation-Agitation Scale (SAS) scores, and Intensive Care Delirium Screening Checklist (ICDSC) scores. Daily doses of opioids and benzodiazepines were also collected, both from patient electronic medical records (e-MAR) as well as from the daily ICU nursing flowsheets. All doses of opioids and benzodiazepines were converted to fentanyl and midazolam equivalents, respectively ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"2a0xK7MJ","properties":{"formattedCitation":"\\super 18\\uc0\\u8211{}20\\nosupersub{}","plainCitation":"18–20","noteIndex":0},"citationItems":[{"id":37,"uris":[""],"uri":[""],"itemData":{"id":37,"type":"chapter","title":"Alberta Hospice Palliative Care Resource Manual","publisher":"Division of Palliative Care, University of Alberta","page":"20","edition":"2","URL":"","ISBN":"Alberta Hospice Palliative Care Resource Manual","language":"English","author":[{"literal":"Pereira, Jose"},{"literal":"Otfinowski,Pamela"},{"literal":"Hagen,Neil"},{"literal":"Bruera,Aduardo"},{"literal":"Summers, Nancy"}],"issued":{"date-parts":[["2001"]]}}},{"id":36,"uris":[""],"uri":[""],"itemData":{"id":36,"type":"article-journal","title":"Clinical Handbook of Psychotropic Drugs, 19th Revised Edition Edited by AdilVirani, Kalyna Z.Bezchlibnyk-Butler, J. 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ISBN","language":"en","author":[{"family":"Davies","given":"Simon Jonathan Cheshire"}],"issued":{"date-parts":[["2012",11]]}}},{"id":34,"uris":[""],"uri":[""],"itemData":{"id":34,"type":"article-journal","title":"A double-blind, randomized comparison of i.v. lorazepam versus midazolam for sedation of ICU patients via a pharmacologic model","container-title":"Anesthesiology","page":"286-298","volume":"95","issue":"2","source":"PubMed","abstract":"BACKGROUND: Benzodiazepines, such as lorazepam and midazolam, are frequently administered to surgical intensive care unit (ICU) patients for postoperative sedation. To date, the pharmacology of lorazepam in critically ill patients has not been described. The aim of the current study was to characterize and compare the pharmacokinetics and pharmacodynamics of lorazepam and midazolam administered as continuous intravenous infusions for postoperative sedation of surgical ICU patients.\nMETHODS: With Institutional Review Board approval, 24 consenting adult surgical patients were given either lorazepam or midazolam in a double-blind fashion (together with either intravenous fentanyl or epidural morphine for analgesia) through target-controlled intravenous infusions titrated to maintain a moderate level of sedation for 12-72 h postoperatively. Moderate sedation was defined as a Ramsay Sedation Scale score of 3 or 4. Sedation scores were measured, together with benzodiazepine plasma concentrations. Population pharmacokinetic and pharmacodynamic parameters were estimated using nonlinear mixed-effects modeling.\nRESULTS: A two-compartment model best described the pharmacokinetics of both lorazepam and midazolam. The pharmacodynamic model predicted depth of sedation for both midazolam and lorazepam with 76% accuracy. The estimated sedative potency of lorazepam was twice that of midazolam. The predicted C50,ss (plasma benzodiazepine concentrations where P(Sedation > or = ss) = 50%) values for midazolam (sedation score [SS] > or = n, where n = a Ramsay Sedation Score of 2, 3, ... 6) were 68, 101, 208, 304, and 375 ng/ml. The corresponding predicted C50,ss values for lorazepam were 34, 51, 104, 152, and 188 ng/ml, respectively. Age, fentanyl administration, and the resolving effects of surgery and anesthesia were significant covariates of benzodiazepine sedation. The relative amnestic potency of lorazepam to midazolam was 4 (observed). The predicted emergence times from sedation after a 72-h benzodiazepine infusion for light (SS = 3) and deep (SS = 5) sedation in a typical patient were 3.6 and 14.9 h for midazolam infusions and 11.9 and 31.1 h for lorazepam infusions, respectively.\nCONCLUSIONS: The pharmacology of intravenous infusions of lorazepam differs significantly from that of midazolam in critically ill patients. This results in significant delays in emergence from sedation with lorazepam as compared with midazolam when administered for ICU sedation.","ISSN":"0003-3022","note":"PMID: 11506097","journalAbbreviation":"Anesthesiology","language":"eng","author":[{"family":"Barr","given":"J."},{"family":"Zomorodi","given":"K."},{"family":"Bertaccini","given":"E. J."},{"family":"Shafer","given":"S. L."},{"family":"Geller","given":"E."}],"issued":{"date-parts":[["2001",8]]}}}],"schema":""} 18–20 (Appendix 11.3). Data on the use of co-analgesics (acetaminophen, non-steroidal anti-inflammatory drugs; NSAIDs) and other sedatives (antipsychotics, propofol, dexmedetomidine, clonidine, and propranolol) were also collected. 4.4: Statistical AnalysisDescriptive statistics were applied to the data. Median daily opioid doses were calculated for each day, and the percentage change from one day to the next. Descriptive data are expressed as absolute values and/or percentages. Continuous data are expressed as medians and ranges except where otherwise specified. The frequency of documentation of a symptom is expressed as the proportion of “present,” “absent” and “not documented” designations for each symptom across the total number of patient days included in this study. Listwise deletion (a method in which missing data are omitted from the analysis of the variable of interest ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"dRf7ejKL","properties":{"formattedCitation":"\\super 21\\nosupersub{}","plainCitation":"21","noteIndex":0},"citationItems":[{"id":39,"uris":[""],"uri":[""],"itemData":{"id":39,"type":"book","title":"Missing data","collection-title":"Sage university papers. Quantitative applications in the social sciences","collection-number":"no. 07-136","publisher":"Sage Publications","publisher-place":"Thousand Oaks, Calif","number-of-pages":"93","source":"Library of Congress ISBN","event-place":"Thousand Oaks, Calif","ISBN":"978-0-7619-1672-7","call-number":"QA276 .A55 2002","author":[{"family":"Allison","given":"Paul David"}],"issued":{"date-parts":[["2002"]]}}}],"schema":""} 21) was used for missing data. Statistical analysis was performed by the primary investigator using Microsoft Excel (Microsoft Office 365 [2016], Version 1810, Build 11001.20108).5: Results5.1: PopulationDuring the selected study period there were 1,018 patient admissions. After 30 patients were included in this study, two patients were found to have been included in error. Thus, 28 patients met our predefined inclusion criteria and did not meet exclusion criteria (Figure 1). The main reasons for exclusion were regular administration of opioids in the ICU for less than 72 hours (n = 933), self-reported exposure to opioids in the 90 days prior to admission (n = 26) and severe brain injury on admission (n = 22). The eligibility of seven patients could not be determined due to missing outpatient medication reconciliation data (n=4) and/or patient records explicitly locked against access for research purposes (n=3). Male sex represented 61% of the study population; the median age was 65 years (range 26 – 88) (Table 1). The majority of patients were admitted to the ICU for sepsis or hypoxia or respiratory failure (53.4%, cumulatively). Mechanically ventilated patients represented 83.9% of the study population. The median duration of mechanical ventilation was 7 days (range 1-112 days). Three patients had alcohol use disorder, and one patient had documented history of intravenous cocaine use. 5.2: OutcomesThe symptoms most commonly documented as present were a ≥ 15% variance in respiratory rate between peak and trough rate (92.5% frequency of documentation) and a ≥ 15% variance pulse between peak and trough rate (88.1% frequency of documentation) (Figure 3). While reasons may vary, documentation of the absence of symptoms was rare (< 1%). Piloerection, muscle aches, and persistent yawning were never documented in the charts. The frequency of documentation of symptoms ranged from 0% to 92.5% (Figure 9.3, Table 10.3).Median changes in total daily opioid dose are represented in Table 2, illustrating a roughly 20% decrease on days 4 and 5 of regular opioid administration. Median daily opioid dose changes were + 13%, - 5%, -19% and -22% on days 2, 3, 4 and 5, respectively. The most frequently used opioids were IV fentanyl, IV hydromorphone, and oral hydromorphone, representing 70.1%, 42.5%, and 21.6% of patient days, respectively. The frequency of symptom documentation on each respective day is presented in Table 3. No appreciable increase in the frequency of symptom documentation was demonstrated following dose reductions. Data on the use of dexmedetomidine, clonidine, and propranolol as well as acetaminophen, NSAIDs, and antipsychotics are depicted in Figures 4 and 5, respectively. The number of patients administered benzodiazepines and/or propofol on each day is presented in Figure 6. The number of patients using either of these medications declines with each successive day. 6: DiscussionThis study’s inclusion of 28 patients met our pre-specified criteria for feasibility of identifying patients at risk of IOWS. The main reason for study exclusion was not receiving regular opioids in the ICU for at least 72 hours. This reflects similar findings in a previous study. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"N3mOyOPB","properties":{"formattedCitation":"\\super 2\\nosupersub{}","plainCitation":"2","noteIndex":0},"citationItems":[{"id":4,"uris":[""],"uri":[""],"itemData":{"id":4,"type":"article-journal","title":"Opioid-associated iatrogenic withdrawal in critically ill adult patients: a multicenter prospective observational study","container-title":"Annals of Intensive Care","volume":"7","issue":"1","source":"Crossref","URL":"","DOI":"10.1186/s13613-017-0310-5","ISSN":"2110-5820","shortTitle":"Opioid-associated iatrogenic withdrawal in critically ill adult patients","language":"en","author":[{"family":"Wang","given":"Pan Pan"},{"family":"Huang","given":"Elaine"},{"family":"Feng","given":"Xue"},{"family":"Bray","given":"Charles-André"},{"family":"Perreault","given":"Marc M."},{"family":"Rico","given":"Philippe"},{"family":"Bellemare","given":"Patrick"},{"family":"Murgoi","given":"Paul"},{"family":"Gélinas","given":"Céline"},{"family":"Lecavalier","given":"Annie"},{"family":"Jayaraman","given":"Dev"},{"family":"Frenette","given":"Anne Julie"},{"family":"Williamson","given":"David"}],"issued":{"date-parts":[["2017",12]]},"accessed":{"date-parts":[["2018",10,29]]}}}],"schema":""} 2 A more liberal inclusion of “as needed” opioids would increase the number of patients included in the study, but may have captured a population at a lower risk for IOWS. Given a potential association between higher doses of opioids, and incidence of IOWS ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"spcdNJPq","properties":{"formattedCitation":"\\super 22\\nosupersub{}","plainCitation":"22","noteIndex":0},"citationItems":[{"id":50,"uris":[""],"uri":[""],"itemData":{"id":50,"type":"article-journal","title":"Wang PP, Huang E, Feng X, et al. Iatrogenic withdrawal syndrome due to opioids in critically ill patients: a multicenter prospective observational study. Poster presented at: Critical Care Canada Forum; Oct 30, 2016; Toronto, Canada."}}],"schema":""} 22, future studies may consider identifying patients at risk of IOWS not merely on the basis of frequency of administration of the “as needed” doses, but also on the basis of cumulative daily dose.The second most common reason for exclusion was self-reported exposure to opioids in the 90 days prior to admission. To reduce variability in the sample, patients were excluded if their home medication list made mention of opioids. Future studies should aim to quantify opioid exposure prior to hospitalization. This may require linking hospital data to external databases, the use of provincial/state/federal medication administration records, or directly asking patients. Documentation of IOWS symptoms was variable. Lacrimation, piloerection, muscle aches, tremor, rhinorrhea and persistent yawning were rarely documented. The lack of documentation of these symptoms may represent the ambiguity of their presentation, the difficulty of their assessment, and may reflect a policy (whether formal or informal) to “chart by exception”. If included in an opioid withdrawal checklist, these symptoms may increase nursing workload. Missing data presented difficulty in the analysis of the results. Variable documentation practices obscure the difference between the lack of documentation indicating absence of a symptom or indicating a lack of assessment. Listwise deletion was used for missing symptom data, but no sensitivity analysis was performed on the impact of this deletion. Future studies may consider such an analysis. Symptoms such as hallucination, nausea, vomiting, and diarrhea were difficult to categorize in a retrospective review. While these symptoms were readily documented, the subjective nature of certain symptoms makes documentation difficult in heavily sedated patients. These may not be suitable for inclusion in an opioid withdrawal checklist.The most readily documented symptoms are those with explicit documentation prompts (such as check boxes, temperature recording boxes, etc.) on the standard daily nursing ICU flowchart and which are not sensitive to level of sedation. Frequent daily documentation of SAS, temperature, heart rate and respiratory rate allow for easy data collection. Though tachycardia and tachypnea (as opposed to bradycardia and bradypnea) are the symptoms of interest in IOWS, we did not assess for direction of variance in pulse and respiratory rate. We focussed our efforts on determining whether these existed, before devoting focus to variance. Hallucination and sleep-wake disturbance are components of the ICDSC score and are readily documented given that the ICDSC checklist was completed by the nurse. Question 1 of the ICDSC checklist directs nurses to not complete the ICDSC if the patient can only respond to intense repeated stimulation or if the patient cannot respond to noxious stimulation. Thus, in heavily sedated or paralyzed patients, the ICDSC checklist is not completed by a nurse, limiting its documentation frequency. Since these symptoms are not frequently documented in heavily sedated or paralyzed patients, their inclusion in an IOWS checklist would limit the utility of such a checklist to patients for whom an ICDSC checklist assessment could be completed. Decreases in total mean daily opioid dose were approximately 20% beginning on day 4 of regular intermittent or continuous opioid administration. While there are no evidence-based recommendations for opioid weaning in the adult ICU, this decrease is aligned with common practices in the pediatric ICU. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"sF10L6XT","properties":{"formattedCitation":"\\super 23\\nosupersub{}","plainCitation":"23","noteIndex":0},"citationItems":[{"id":45,"uris":[""],"uri":[""],"itemData":{"id":45,"type":"article-journal","title":"Recognition and Management of Iatrogenically Induced Opioid Dependence and Withdrawal in Children","container-title":"Pediatrics","page":"152-155","volume":"133","issue":"1","source":"Crossref","DOI":"10.1542/peds.2013-3398","ISSN":"0031-4005, 1098-4275","language":"en","author":[{"family":"Galinkin","given":"Jeffrey"},{"family":"Koh","given":"Jeffrey Lee"},{"literal":"COMMITTEE ON DRUGS"},{"literal":"SECTION ON ANESTHESIOLOGY AND PAIN MEDICINE"}],"issued":{"date-parts":[["2014",1]]}}}],"schema":""} 23 Using 72-hours as the of scheduled opioids as the cut-off for inclusion into the study may have limited the ability to detect the emergence of IOWS as the duration of opioid administration that predisposes a patient to IOWS is still unclear. Future studies may benefit from investigation and validation of this 72-hour cut-off. While sedative data was collected (such as benzodiazepine, and propofol), the small sample of patients using these sedatives makes an analysis inappropriate. Future investigators may require a much larger sample size in order to warrant an analysis. A limitation of this study is its retrospective design, leading to uncertainty in categorizing target symptoms into “present”, “absent” and “not documented”. The subjective nature of some symptoms, variable nurse documentation practices, and potential for documentation error decreases the internal validity of the study. In order to standardize the data collection process and to support reproducibility of the results, stringent definitions were followed (Appendix 11.1) for coding of symptoms. It is possible that categorizing these symptoms resulted in oversimplification and may not accurately reflect the spectra of a patient’s clinical presentation. Relying on a twice-daily prompt on the standard daily nursing ICU flowchart to reflect a patient’s clinical presentation over a 24-hour period compromises accuracy. Nevertheless, while this risks inaccurate documentation of symptom presentation, it reflects the nature of clinical practice where an assessment is made as a snapshot and may not accurately reflect the unobserved experiences of the patient. Our data may be sensitive to the inclusion of patients receiving 72 hours of regular opioids, and the use of half of scheduled as-needed doses as the threshold for “regular opioid.” Future studies may consider sensitivity-testing the effect of these thresholds. In order to readily assess exclusion criteria, patients were excluded if their home medication list made mention of opioids. This may have limited the inclusion of patients who used opioids sparingly in the outpatient setting, as opposed to chronic opioid use only. Future prospective studies may benefit from quantifying the amount of opioid use prior to admission or using a sensitivity analysis to assess the effect of excluding these patients. Data is also sensitive to nursing documentation practices. For instance, sweating was assumed to be documented absent if “diaphoretic” was not checked off, whether or not the nurse checked off the box for “skin dry.” Future studies may consider a sensitivity analysis to determine the effect of this and other such assumptions (Appendix 11.1). In our study we noted variable documentation practices and were challenged to properly interpret missing data.? Patients who were sedated due to their condition or therapeutically sedated could not express or be monitored for some symptoms, reducing the opportunity to record symptoms such as nausea and hallucinations.? These observations should direct future researchers to isolate indicators of withdrawal which can be reliably collected – either through prospective collection, or by mandatory documentation at regular intervals, and manifest irrespective of the level of sedation of the patient.? This will ensure that a complete and accurate set of indicators be available for scoring.? With their availability, the strength of association to exposure to opioids can be determined and assessed for appropriateness in a tool for predicting opioid withdrawal. This study was also illuminating on documentation practices, interpretation of documentation, and construction of clinical predictive tools. Specifically, in attempting to isolate symptoms for a predictive tool, the study highlights the importance of consistent documentation practices, impaired ability of the ICU patient to communicate symptoms, limited ability of the staff to observe subjective patient experiences, and failing those, the limited ability to determine the influence of confounding factors on the presence or absence of symptoms. The use of a prospective design in future studies exploring IOWS may support more robust execution of exclusion criteria, as well as standardized nursing documentation practices, and prompted assessment of the symptoms of interest. 7: ConclusionOur findings demonstrate the feasibility of identifying patients at risk of IOWS for a future study assessing IOWS in critically ill adults. Data on the frequency of documentation of 17 symptoms suggest a wide variability of obtainability and frequency and may inform the choice of symptoms assessed in future larger prospective studies of IOWS. Median daily opioid dose changes were + 13%, - 5%, -19% and -22% on days 2, 3, 4 and 5, respectively. The most frequently used opioids were IV fentanyl, IV hydromorphone, and oral hydromorphone, representing 70.1%, 42.5%, and 21.6% of patient days, respectively.8: References ADDIN ZOTERO_BIBL {"uncited":[],"omitted":[],"custom":[]} CSL_BIBLIOGRAPHY 1. Barr J, Fraser GL, Puntillo K, Ely EW, Gélinas C, Dasta JF, et al. Clinical Practice Guidelines for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit: Crit Care Med. 2013 Jan;41(1):263–306. 2. Wang PP, Huang E, Feng X, Bray C-A, Perreault MM, Rico P, et al. Opioid-associated iatrogenic withdrawal in critically ill adult patients: a multicenter prospective observational study. Ann Intensive Care [Internet]. 2017 Dec [cited 2018 Oct 29];7(1). Available from: . Burry LD, Williamson DR, Perreault MM, Rose L, Cook DJ, Ferguson ND, et al. Analgesic, sedative, antipsychotic, and neuromuscular blocker use in Canadian intensive care units: a prospective, multicentre, observational study. Can J Anesth Can Anesth. 2014 Jul;61(7):619–30. 4. Masica AL, Girard TD, Wilkinson GR, Thomason JWW, Truman Pun B, Nair UB, et al. Clinical sedation scores as indicators of sedative and analgesic drug exposure in intensive care unit patients. Am J Geriatr Pharmacother. 2007 Sep;5(3):218–31. 5. Best KM, Boullata JI, Curley MAQ. Risk Factors Associated With Iatrogenic Opioid and Benzodiazepine Withdrawal in Critically Ill Pediatric Patients: A Systematic Review and Conceptual Model*. Pediatr Crit Care Med. 2015 Feb;16(2):175–83. 6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders [Internet]. Fifth Edition. American Psychiatric Association; 2013 [cited 2018 Oct 29]. Available from: . Tetrault JM, O’Connor PG. Substance Abuse and Withdrawal in the Critical Care Setting. Crit Care Clin. 2008 Oct;24(4):767–88. 8. Peachey JE, Lei H. Assessment of Opioid Dependence with Naloxone. Addiction. 1988 Feb;83(2):193–201. 9. Bradley BP, Gossop M, Phillips GT, Legarda JJ. The Development of an Opiate Withdrawal Scale (OWS). Addiction. 1987 Oct;82(10):1139–42. 10. Vernon MK, Reinders S, Mannix S, Gullo K, Gorodetzky CW, Clinch T. Psychometric evaluation of the 10-item Short Opiate Withdrawal Scale-Gossop (SOWS-Gossop) in patients undergoing opioid detoxification. Addict Behav. 2016 Sep;60:109–16. 11. Wesson DR, Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoactive Drugs. 2003 Jun;35(2):253–9. 12. Franck LS, Harris SK, Soetenga DJ, Amling JK, Curley MAQ. The Withdrawal Assessment Tool–1 (WAT–1): An assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients*: Pediatr Crit Care Med. 2008 Nov;9(6):573–80. 13. Ista E, van Dijk M, de Hoog M, Tibboel D, Duivenvoorden HJ. Construction of the Sophia Observation withdrawal Symptoms-scale (SOS) for critically ill children. Intensive Care Med. 2009 Jun;35(6):1075–81. 14. Chiu AW, Contreras S, Mehta S, Korman J, Perreault MM, Williamson DR, et al. Iatrogenic Opioid Withdrawal in Critically Ill Patients: A Review of Assessment Tools and Management. Ann Pharmacother. 2017 Dec;51(12):1099–111. 15. Ista E, van Dijk M, Gamel C, Tibboel D, de Hoog M. Withdrawal symptoms in critically ill children after long-term administration of sedatives and/or analgesics: A first evaluation*: Crit Care Med. 2008 Aug;36(8):2427–32. 16. Franck LS, Naughton I, Winter I. Opioid and benzodiazepine withdrawal symptoms in paediatric intensive care patients. Intensive Crit Care Nurs. 2004;20:344-351. doi:10.1016/j. iccn.2004.07.008. 17. Perreault M, Martone A, Sandu PR, et al. Withdrawal assessment in adult ICU patients: validation of the WAT-1 scale. 37th International Symposium on Intensive Care and Emergency Medicine. Crit Care. 2017;21(suppl 1):56, [abstract] P277. 18. Pereira, Jose, Otfinowski,Pamela, Hagen,Neil, Bruera,Aduardo, Summers, Nancy. Alberta Hospice Palliative Care Resource Manual. In: 2nd ed. Division of Palliative Care, University of Alberta; 2001. p. 20. Available from: . Davies SJC. Clinical Handbook of Psychotropic Drugs, 19th Revised Edition Edited by AdilVirani, Kalyna Z.Bezchlibnyk-Butler, J. JoelJeffries, Ric M.Procyshyn, Hogrefe Publishing, G?ttingen. Price ?53.96, pp 362 + pp 50 printable PDF patient information sheets. ISBN: Hum Psychopharmacol Clin Exp. 2012 Nov;27(6):632–632. 20. Barr J, Zomorodi K, Bertaccini EJ, Shafer SL, Geller E. A double-blind, randomized comparison of i.v. lorazepam versus midazolam for sedation of ICU patients via a pharmacologic model. Anesthesiology. 2001 Aug;95(2):286–98. 21. Allison PD. Missing data. Thousand Oaks, Calif: Sage Publications; 2002. 93 p. (Sage university papers. Quantitative applications in the social sciences). 22. Wang PP, Huang E, Feng X, et al. Iatrogenic withdrawal syndrome due to opioids in critically ill patients: a multicenter prospective observational study. Poster presented at: Critical Care Canada Forum; Oct 30, 2016; Toronto, Canada. 23. Galinkin J, Koh JL, COMMITTEE ON DRUGS, SECTION ON ANESTHESIOLOGY AND PAIN MEDICINE. Recognition and Management of Iatrogenically Induced Opioid Dependence and Withdrawal in Children. Pediatrics. 2014 Jan;133(1):152–5. 9: Figures 9.1: Figure 1: Study Flowchart-236913399242Patient records screened between 12/01/2016 and 07/31/2017 (n = 1018)933 patient records did not meet inclusion criteria:Patient did not receive regular opioid in ICU for ≥ 72 hours (n = 933)Patient <18 YOA (n = 0)57 patients met exclusion criteria :Severe brain injury (n = 22)Self-reported exposure to opioids in the 90 days prior to admission (n = 26)Deemed palliative on admission (n = 0)Opioid dose exclusively through neuraxial administration (n = 1)Substance overdose or alcohol withdrawal (n = 1)Patients whose inclusion/exclusion criteria could not be ascertained due to locked charts(n = 3) Patients whose inclusion/exclusion criteria could not be ascertained due to incomplete home medication list (n=4)Patient Charts Reviewed (n = 28)0Patient records screened between 12/01/2016 and 07/31/2017 (n = 1018)933 patient records did not meet inclusion criteria:Patient did not receive regular opioid in ICU for ≥ 72 hours (n = 933)Patient <18 YOA (n = 0)57 patients met exclusion criteria :Severe brain injury (n = 22)Self-reported exposure to opioids in the 90 days prior to admission (n = 26)Deemed palliative on admission (n = 0)Opioid dose exclusively through neuraxial administration (n = 1)Substance overdose or alcohol withdrawal (n = 1)Patients whose inclusion/exclusion criteria could not be ascertained due to locked charts(n = 3) Patients whose inclusion/exclusion criteria could not be ascertained due to incomplete home medication list (n=4)Patient Charts Reviewed (n = 28)204676778870AbbreviationsICU: Intensive Care UnitYOA: Years of Age4000020000AbbreviationsICU: Intensive Care UnitYOA: Years of Age9.2: Figure 2: Schematic of Patient Chart Assessment9.3: Figure 3: Symptom Documentation Frequency 9.4: Figure 4: Daily Clonidine, Dexmedetomidine, and Propranolol Administration9.5: Figure 5: Daily Acetaminophen, NSAID, and Antipsychotic Administration9.6: Figure 6: Daily Benzodiazepine and Propofol Administration10: Tables10.1: Table 1: Baseline Patient DemographicsCharacteristicAll subjects (n = 28)Male, n (%)17 (60.7)Age (years), median (range)65 (26 – 88)Weight (kg), median (range)76 (58.2 – 117)Admitting Diagnosis, n (%)Sepsis / Hypoxia / Respiratory Failure15 (53.4)Post-Operative6 (21.4)Other7 (25.2)SCr on ICU admission (mmol/L), median (range)84.5 (33 – 597)Hospital Length of Stay (days), median (range)22.5 (5 -371)ICU Length of Stay (days), median (range)12 (3 – 112)Mechanically Ventilated, n (%)25 (89.2)Duration of Mechanical Ventilation (days), median (%)7 (1 – 112)Comorbidities, n (%)Anxiety/Depression6 (21.4)Epilepsy1 (4.7)Asthma/COPD4 (14.2)Heart Failure4 (14.2)Hypertension15 (53.6)Diabetes4 (14.2)Liver Disease1 (4.7)CKD2 (9.5)Ever-use of Physical Restraints, n (%)15 (53.6)Ever-use of neuromuscular blockade during ICU stay, n (%)15 (53.6)Admitted from, n (%)Ward10 (35.7)Surgery5 (17.9)Transfer from another institution7 (25.0)Outpatient6 (21.4)4121154618355AbbreviationsICU: Intensive Care UnitYOA: Years of AgeSCr: Serum CreatinineCOPD: Chronic Obstructive Pulmonary DiseaseCKD: Chronic Kidney Disease00AbbreviationsICU: Intensive Care UnitYOA: Years of AgeSCr: Serum CreatinineCOPD: Chronic Obstructive Pulmonary DiseaseCKD: Chronic Kidney Disease10.2: Table 2: Daily Opioid Dose ChangesDelta between daysRaw Median Change in Total Daily Opioid Dose?Adjusted* Median Change in Total Daily Opioid DoseDays 1 and 2+ 12.5%+ 12.7% *Days 2 and 3- 2.5%- 4.7 % *Days 3 and 4- 19.0 %- 19.0 %Days 4 and 5- 21.9 %- 21.9 %* Adjusted for missing opioid dose for one patient on one day within study period. Patient’s opioid dose on said date was omitted from calculation of median dose change from this interval. ? Change in Opioid doses calculated from change in daily fentanyl equivalents. 10.3: Table 3: Symptom Documentation Frequency on Each Day Documentation Frequency (%)SymptomDay 1 (28 patient-days)Day 2 (27 patient-days)Day 3 (28 patient-days)Day 4 (28 patient-days)Day 5 (23 patient-days)≥ 15% variance in peak and lowest pulse92.910089.382.173.9≥ 15% variance in peak and lowest respiratory rate10088.996.489.387.0Fever (single temperature ≥ 38.0 degrees Celsius)32.128.628.617.917.9Sweating3.67.114.23.67.1Piloerection00000Lacrimation00000Rhinorrhea3.60000Persistent Yawning03.7000Pupil Dilation03.73.600Muscle Aches00000Tremor3.60000Anxiety/Agitation/ Restlessness46.451.942.939.339.1Hallucination10.714.314.317.92.2Sleep-Wake Disturbance57.170.453.646.456.5Nausea10.73.7000Vomiting3.603.600Diarrhea7.2003.68.711: Appendix 11.1: Protocol for the Collection of Data Sign / SymptomHow to collect15% variance in RRDifference between highest and lowest number documented on the hourly chart. If ≥ 15%, mark “Present.” Otherwise, mark “Absent.” If no documentation, mark “Not Documented.”15% variance in HRDifference between highest and lowest number documented on the hourly chart. If ≥ 15%, mark “Present.” Otherwise, mark “Absent.” If no documentation, mark “Not Documented.”FeverHighest number documented on the hourly chart. If ≥ 38.0 degrees Celsius, mark “Present.” Otherwise, mark “Absent.”SweatingIf sweating box is checked, mark “Present.” If the nursing notes state “sweating” and/or “diaphoretic” or variations thereof, mark “Present.” If sweating is not checked and the nursing notes do not state “sweating” and/or “diaphoretic” or variations thereof, mark “Absent.” PiloerectionIf “piloerection” and/or “goosebumps” and/or “gooseflesh” are mentioned in the written notes, mark “Present.” If the absence is explicitly noted in the nursing notes, mark “Absent.” If not mentioned in the nursing notes, mark “Not Documented.”LacrimationIf the nursing notes state “lacrimation” and/or “tears” are, mark “Present.” If the absence is explicitly noted in the nursing notes, mark “Absent.” If not mentioned in the nursing notes, mark “Not Documented.”RhinorrheaIf the nursing notes state “rhinorrhea” and/or “congestion” and/or “runny nose” and/or “nasal mucus” and/or “nasal secretions,” mark “Present.” If the absence is explicitly noted in the nursing notes, mark “Absent.” If it is not mentioned in the nursing notes, mark “Not Documented.”Persistent YawningIf the nursing notes state “yawning,” mark “Present.” If the absence is explicitly noted in the nursing notes, mark “Absent.” If it is not mentioned in the nursing notes, mark “Not Documented.”Pupil DilationIn the pupil measurement box, if any reading measures ≥ 4 mm, and the pupil is not reactive, mark “Present.” Otherwise, mark “Absent.” If no documentation is made regarding pupil size, mark “Not Documented.” Muscle AchesIf the nursing notes state “muscle aches” and/or “muscle pain”, mark “Present.” If the absence is explicitly noted in the nursing notes, mark “Absent.” If it is not mentioned in the nursing notes, mark “Not Documented.”TremorIf the nursing notes state “tremor” and/or “shaking” and/or “trembling” and/or “twitching,” mark “Present.” If the absence is explicitly noted in the nursing notes, mark “Absent.” If it is not mentioned in the nursing notes, mark “Not Documented.”Anxiety/Agitation/Restlessness1) If there is a single SAS reading of 5 or greater, mark “Present.”2) In the ICDSC score, if anxiety or agitation is circled, mark “Present.”3) In the mental status exam box of the twice-daily shift assessment, if agitation is checked off or if the nurse writes (anywhere) the words “agitation” or “anxiety” and/or “restlessness” and/or any variations of those specific verbs, mark “Present.”In the absence of any of the above (and in the written nursing notes), mark “Absent.”HallucinationIn the ICDSC score, so long as a single question is answered after the two preliminary questions (which dictate whether the scale should be completed or not) the ICDSC box seal is considered broken. In such a case, if hallucination is circled, mark “Present.” If hallucination is not circled (and the seal is broken), mark “Absent.”If the nursing notes state “hallucination” mark hallucination as “present.”If the ICDSC seal is not broken, and no mention is made in the written nursing notes, mark hallucination as “Not Documented.” If the patient is neuromuscular blocked and/or sedated to SAS of 1 or 2 for greater than half the day, and there is no positive or negative documentation of hallucination (as above), mark “Not Documented.” Sleep-Wake DisturbanceIn the ICDSC score, so long as a single question is answered after the two preliminary questions (which dictate whether the scale should be completed or not) the ICDSC box seal is considered broken. In such a case, if sleep-wake disturbance is circled, mark “Present.” If sleep-wake disturbance is not circled (and the seal is broken) mark “Absent.” If the seal is not broken, mark “Not Documented.”If the nursing notes state “insomnia” and/or “sleep-wake disturbance,” and/or “not sleeping” mark as “Present.”NauseaIf nausea box is checked, mark “Present.” If nausea is not checked, mark “Absent.” If the patient is administered any antiemetic medication, mark “Present.”If the written nursing notes state “nausea,” mark as present. If the patient is sedated to SAS of 1 or 2 for greater than half the day, and there is no positive or negative documentation of nausea (as above), mark “Not Documented.”VomitingIf vomiting box is checked, mark “Present.” If vomiting is not checked, mark “Absent.” If the written nursing notes state “vomiting” and/or “vomit,” mark “Present”. DiarrheaIf diarrhea box is checked, mark “Present.” If diarrhea is not checked, mark “Absent.” If the written nursing notes state “diarrhea” and/or stools described as “loose” and/or “watery” and/or “frequent,” mark “Present.” 11.2: Comparison of Opioid Withdrawal Assessments Used in Construction of 17-Item ChecklistSymptomSOS ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Biw5lYuM","properties":{"formattedCitation":"\\super 13\\nosupersub{}","plainCitation":"13","noteIndex":0},"citationItems":[{"id":25,"uris":[""],"uri":[""],"itemData":{"id":25,"type":"article-journal","title":"Construction of the Sophia Observation withdrawal Symptoms-scale (SOS) for critically ill children","container-title":"Intensive Care Medicine","page":"1075-1081","volume":"35","issue":"6","source":"Crossref","DOI":"10.1007/s00134-009-1487-3","ISSN":"0342-4642, 1432-1238","language":"en","author":[{"family":"Ista","given":"Erwin"},{"family":"Dijk","given":"Monique","non-dropping-particle":"van"},{"family":"Hoog","given":"Matthijs","non-dropping-particle":"de"},{"family":"Tibboel","given":"Dick"},{"family":"Duivenvoorden","given":"Hugo J."}],"issued":{"date-parts":[["2009",6]]}}}],"schema":""} 13WAT-1 ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KBae5dDW","properties":{"formattedCitation":"\\super 12\\nosupersub{}","plainCitation":"12","noteIndex":0},"citationItems":[{"id":23,"uris":[""],"uri":[""],"itemData":{"id":23,"type":"article-journal","title":"The Withdrawal Assessment Tool–1 (WAT–1): An assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients*:","container-title":"Pediatric Critical Care Medicine","page":"573-580","volume":"9","issue":"6","source":"Crossref","DOI":"10.1097/PCC.0b013e31818c8328","ISSN":"1529-7535","shortTitle":"The Withdrawal Assessment Tool–1 (WAT–1)","language":"en","author":[{"family":"Franck","given":"Linda S."},{"family":"Harris","given":"Sion Kim"},{"family":"Soetenga","given":"Deborah J."},{"family":"Amling","given":"June K."},{"family":"Curley","given":"Martha A. Q."}],"issued":{"date-parts":[["2008",11]]}}}],"schema":""} 12COWS ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"DfcNpi5r","properties":{"formattedCitation":"\\super 11\\nosupersub{}","plainCitation":"11","noteIndex":0},"citationItems":[{"id":21,"uris":[""],"uri":[""],"itemData":{"id":21,"type":"article-journal","title":"The Clinical Opiate Withdrawal Scale (COWS)","container-title":"Journal of Psychoactive Drugs","page":"253-259","volume":"35","issue":"2","source":"PubMed","abstract":"The clinical opiate withdrawal scale (COWS) is a clinician-administered, pen and paper instrument that rates eleven common opiate withdrawal signs or symptoms. The summed score of the eleven items can be used to assess a patient's level of opiate withdrawal and to make inferences about their level of physical dependence on opioids. With increasing use of opioids for treatment of pain and the availability of sublingual buprenorphine in the United States for treatment of opioid dependence, clinical assessment of opiate withdrawal intensity has received renewed interest. Buprenorphine, a partial opiate agonist at the mu receptor, can precipitate opiate withdrawal in patients with a high level of opioid dependence who are not experiencing opioid withdrawal. Since development of the first opiate withdrawal scale in the mid-1930s, many different opioid withdrawal scales have been used in clinical and research settings. This article reviews the history of opiate withdrawal scales and the context of their initial use. A template version of the COWS that can be copied and used clinically is appended. PDF formatted versions of the COWS are also available from the websites of the American Society of Addiction Medicine, the California Society of Addiction Medicine, the UCLA Integrated Substance Abuse Programs, and .","DOI":"10.1080/02791072.2003.10400007","ISSN":"0279-1072","note":"PMID: 12924748","journalAbbreviation":"J Psychoactive Drugs","language":"eng","author":[{"family":"Wesson","given":"Donald R."},{"family":"Ling","given":"Walter"}],"issued":{"date-parts":[["2003",6]]}}}],"schema":""} 11DSM-V ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Hr1OgTrn","properties":{"formattedCitation":"\\super 6\\nosupersub{}","plainCitation":"6","noteIndex":0},"citationItems":[{"id":10,"uris":[""],"uri":[""],"itemData":{"id":10,"type":"book","title":"Diagnostic and Statistical Manual of Mental Disorders","publisher":"American Psychiatric Association","edition":"Fifth Edition","source":"Crossref","URL":"","ISBN":"978-0-89042-555-8","note":"DOI: 10.1176/appi.books.9780890425596","language":"en","author":[{"literal":"American Psychiatric Association"}],"issued":{"date-parts":[["2013",5,22]]},"accessed":{"date-parts":[["2018",10,29]]}}}],"schema":""} 6RestlessnessxxAgitationxxFeverxxxTremorxxxPupil SizexxSleep DisturbancexxStartle to touchxSeizurexHallucinationxGrimacingxInconsolable CryingxxTime to gain calmxYawningxxxTachycardiaxxTachypneaxLacrimationxxRhinorrheaxxSneezingxNauseaxxxxVomitingxxxxDiarrheaxxxxPiloerectionxxSweatingxxxxJoint/bone/Muscle AchesxxUncoordinated MovementxxMuscle Tonexx11.3: Opioid and Benzodiazepine Dosing EquivalenceOpioid ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gsWngEq3","properties":{"formattedCitation":"\\super 18\\nosupersub{}","plainCitation":"18","noteIndex":0},"citationItems":[{"id":37,"uris":[""],"uri":[""],"itemData":{"id":37,"type":"chapter","title":"Alberta Hospice Palliative Care Resource Manual","publisher":"Division of Palliative Care, University of Alberta","page":"20","edition":"2","URL":"","ISBN":"Alberta Hospice Palliative Care Resource Manual","language":"English","author":[{"literal":"Pereira, Jose"},{"literal":"Otfinowski,Pamela"},{"literal":"Hagen,Neil"},{"literal":"Bruera,Aduardo"},{"literal":"Summers, Nancy"}],"issued":{"date-parts":[["2001"]]}}}],"schema":""} 18MorphineHydromorphoneFentanylOral20 mg4 mgN/AIV10 mg2 mg0.1 mgBenzodiazepine ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"IecrlIji","properties":{"formattedCitation":"\\super 19,20\\nosupersub{}","plainCitation":"19,20","noteIndex":0},"citationItems":[{"id":36,"uris":[""],"uri":[""],"itemData":{"id":36,"type":"article-journal","title":"Clinical Handbook of Psychotropic Drugs, 19th Revised Edition Edited by AdilVirani, Kalyna Z.Bezchlibnyk-Butler, J. JoelJeffries, Ric M.Procyshyn, Hogrefe Publishing, G?ttingen. Price ?53.96, pp 362 + pp 50 printable PDF patient information sheets. ISBN:","container-title":"Human Psychopharmacology: Clinical and Experimental","page":"632-632","volume":"27","issue":"6","source":"Crossref","DOI":"10.1002/hup.2231","ISSN":"08856222","shortTitle":"Clinical Handbook of Psychotropic Drugs, 19th Revised Edition Edited by AdilVirani, Kalyna Z.Bezchlibnyk-Butler, J. JoelJeffries, Ric M.Procyshyn, Hogrefe Publishing, G?ttingen. Price ?53.96, pp 362 + pp 50 printable PDF patient information sheets. ISBN","language":"en","author":[{"family":"Davies","given":"Simon Jonathan Cheshire"}],"issued":{"date-parts":[["2012",11]]}}},{"id":34,"uris":[""],"uri":[""],"itemData":{"id":34,"type":"article-journal","title":"A double-blind, randomized comparison of i.v. lorazepam versus midazolam for sedation of ICU patients via a pharmacologic model","container-title":"Anesthesiology","page":"286-298","volume":"95","issue":"2","source":"PubMed","abstract":"BACKGROUND: Benzodiazepines, such as lorazepam and midazolam, are frequently administered to surgical intensive care unit (ICU) patients for postoperative sedation. To date, the pharmacology of lorazepam in critically ill patients has not been described. The aim of the current study was to characterize and compare the pharmacokinetics and pharmacodynamics of lorazepam and midazolam administered as continuous intravenous infusions for postoperative sedation of surgical ICU patients.\nMETHODS: With Institutional Review Board approval, 24 consenting adult surgical patients were given either lorazepam or midazolam in a double-blind fashion (together with either intravenous fentanyl or epidural morphine for analgesia) through target-controlled intravenous infusions titrated to maintain a moderate level of sedation for 12-72 h postoperatively. Moderate sedation was defined as a Ramsay Sedation Scale score of 3 or 4. Sedation scores were measured, together with benzodiazepine plasma concentrations. Population pharmacokinetic and pharmacodynamic parameters were estimated using nonlinear mixed-effects modeling.\nRESULTS: A two-compartment model best described the pharmacokinetics of both lorazepam and midazolam. The pharmacodynamic model predicted depth of sedation for both midazolam and lorazepam with 76% accuracy. The estimated sedative potency of lorazepam was twice that of midazolam. The predicted C50,ss (plasma benzodiazepine concentrations where P(Sedation > or = ss) = 50%) values for midazolam (sedation score [SS] > or = n, where n = a Ramsay Sedation Score of 2, 3, ... 6) were 68, 101, 208, 304, and 375 ng/ml. The corresponding predicted C50,ss values for lorazepam were 34, 51, 104, 152, and 188 ng/ml, respectively. Age, fentanyl administration, and the resolving effects of surgery and anesthesia were significant covariates of benzodiazepine sedation. The relative amnestic potency of lorazepam to midazolam was 4 (observed). The predicted emergence times from sedation after a 72-h benzodiazepine infusion for light (SS = 3) and deep (SS = 5) sedation in a typical patient were 3.6 and 14.9 h for midazolam infusions and 11.9 and 31.1 h for lorazepam infusions, respectively.\nCONCLUSIONS: The pharmacology of intravenous infusions of lorazepam differs significantly from that of midazolam in critically ill patients. This results in significant delays in emergence from sedation with lorazepam as compared with midazolam when administered for ICU sedation.","ISSN":"0003-3022","note":"PMID: 11506097","journalAbbreviation":"Anesthesiology","language":"eng","author":[{"family":"Barr","given":"J."},{"family":"Zomorodi","given":"K."},{"family":"Bertaccini","given":"E. J."},{"family":"Shafer","given":"S. L."},{"family":"Geller","given":"E."}],"issued":{"date-parts":[["2001",8]]}}}],"schema":""} 19,20MidazolamLorazepamDiazepamClonazepamOralN/A1 mg5 mg0.25 mgIV2 mg1 mg5 mg0.25 mg ................
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