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Variation in diurnal sedation in mechanically ventilated patients who are managed with a sedation protocol… Mehta, Sangeeta; Meade, Maureen; Burry, Lisa; Mallick, Ranjeeta; Katsios, Christina; Fergusson, Dean; Dodek, Peter; Burns, Karen; Herridge, Margaret; Devlin, John W; Tanios, Maged; Fowler, Robert; Jacka, Michael; Skrobik, Yoanna; Olafson, Kendiss; Cook, Deborah Aug 1, 2016

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RESEARCH Open AccessVariation in diurnal sedation inmechanically ventilated patients who aremanaged with a sedation protocol alone ora sedation protocol and daily interruptionSangeeta Mehta1,17*, Maureen Meade2, Lisa Burry3, Ranjeeta Mallick4, Christina Katsios5, Dean Fergusson4,Peter Dodek6, Karen Burns5,7,8, Margaret Herridge9, John W. Devlin10, Maged Tanios11, Robert Fowler5,12,Michael Jacka13, Yoanna Skrobik14, Kendiss Olafson15, Deborah Cook16 and for the SLEAP Investigators and theCanadian Critical Care Trials GroupAbstractBackground: Mechanically ventilated patients may receive more sedation during the night than during the day,potentially delaying extubation. We compared nighttime and daytime benzodiazepine and opioid administration inadult patients enrolled in a multicenter sedation trial comparing protocolized sedation alone or protocolizedsedation combined with daily sedation interruption; and we evaluated whether nighttime and daytime doses wereassociated with liberation from mechanical ventilation.Methods: This is a secondary analysis of a randomized trial which was conducted in 16 North American medical-surgical ICUs. In all 423 patients, nurses applied a validated sedation scale hourly to titrate benzodiazepine andopioid infusions to achieve a light level of sedation. Using fentanyl equivalents and midazolam equivalents, wecompared dosages administered during night (19:00 to 07:00) and day (07:00 to 19:00) shifts. Using multivariablelogistic regression we evaluated the association between nighttime and daytime opioid and sedative doses, andspontaneous breathing trial (SBT) conduct, SBT success, and extubation.Results: Nighttime benzodiazepine and opioid doses were significantly higher than daytime doses (meandifference midazolam equivalents 23.3 mg, 95 % CI 12.9, 33.8, p < 0.0001; mean difference fentanyl equivalents 356mcg, 95 % CI 130, 582, p = 0.0021). Mean Sedation Agitation Scale score was similar between night and day, andwas at target (3.2 vs 3.3, 95 % CI −0.05, 0.02, p = 0.35). Self-reported nurse workload was similar during the nightand day. Patients were more often restrained during day shifts (76.3 % vs 73.7 %, p < 0.0001), and there were moreunintentional device removals during the day compared with night (15.9 % vs 9.1 %, p < 0.0001). Increases innighttime drug doses were independently associated with failure to meet SBT screening criteria, SBT failure, and thedecision not to extubate the patient despite successful SBT.Conclusion: Patients received higher doses of opioids and benzodiazepines at night. Higher nighttime doses wereassociated with SBT failure and delayed extubation.(Continued on next page)* Correspondence: Geeta.mehta@utoronto.ca1Department of Medicine and Interdepartmental Division of Critical CareMedicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario,Canada17Mount Sinai Hospital, Suite 18-216, 600 University Ave., Toronto M5G 1X5,CanadaFull list of author information is available at the end of the article© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Mehta et al. Critical Care  (2016) 20:233 DOI 10.1186/s13054-016-1405-3(Continued from previous page)Trial registration: ClinicalTrials.gov NCT00675363. Registered 7 May 2008.Keywords: Sedation, Opioids, Mechanical ventilation, Protocols, Weaning, Diurnal rhythm, Intensive care unitBackgroundAnalgesia and sedation are a ubiquitous and essentialcomponent of care for critically ill patients. However, deepsedation is associated with prolonged mechanical ventila-tion (MV), longer intensive care unit (ICU) stay [1, 2], andhigher mortality [3, 4]. Mechanically ventilated patientsmay receive more sedation during the night comparedwith the day [5], potentially delaying extubation [6]. Diur-nal variation in sedation in critically ill patients is import-ant to elucidate as it may affect weaning from mechanicalventilation, impair cognition, and worsen sleep [7].SLEAP was a multicenter trial that randomized mech-anically ventilated adult patients to protocolized sedation(PS) alone (control), or protocolized sedation combinedwith daily interruption (DI) of sedation [8]. There wasno difference between the two groups in the primaryoutcome of time to extubation (hazard ratio (HR) 1.08,95 % CI 0.86, 1.35, p = 0.52), nor in secondary outcomesof ICU and hospital length of stay [9]. However, the DIgroup received higher doses of opioids and benzodiaze-pines, potentially reflecting nurse apprehension about pa-tient discomfort or the risk of adverse events during DI.The objective of this study was to describe daytime andnighttime doses of sedatives and opioids, and to identify as-sociations between these doses and conduct of spontaneousbreathing trials (SBTs), success of SBTs, and extubation, inpatients enrolled in the SLEAP Trial. We hypothesized thatpatients received more opioids and sedatives at night thanduring the day, regardless of randomization group, and thathigher nighttime doses would be associated with delays inthe extubation process.MethodsThis was a secondary analysis of the multicenter random-ized SLEAP trial [8]. We included critically ill adults whowere expected to require mechanical ventilation for longerthan 48 hours and were receiving continuous infusions ofopioids and/or benzodiazepines. Patients admitted to theICU after cardiac arrest or traumatic brain injury, patientsreceiving neuromuscular blockade, or patients without acommitment to maximal therapy were excluded. The Re-search Ethics board at each participating site approved thestudy, and written informed consent was obtained fromsubstitute decision makers.In both study arms the Sedation Agitation Scale (SAS)or Richmond Agitation Sedation Scale (RASS) were re-corded hourly, and nurses titrated opioid and sedativeinfusions to achieve a target SAS score of 3 to 4, orRASS score of −3 to 0. In the DI arm nurses interruptedbenzodiazepine and opioid infusions daily; if ongoinginfusions were necessary they were resumed at half theprevious dose(s). If infusions were no longer necessary pa-tients were managed with intermittent doses of opioidsand sedatives. Mechanical ventilation was weaned at thediscretion of the ICU team. As previously described [2],patients in both arms were screened daily by respiratorytherapists for eligibility to have an SBT; information aboutsuccessful SBTs was communicated to the ICU team witha view to extubation. Decisions on extubation were at thediscretion of the ICU team.We recorded total doses of sedatives and opioidsadministered to patients during mechanical ventilation, asinfusions and intermittent bolus doses. We calculatedtotal medication doses and number of bolus doses admin-istered during night shifts and day shifts. Night shifts weredefined as 12 hours from 19:00 to 07:00 hours, and dayshifts were defined as 12 hours from 07:00 to 19:00 hours.Twice daily at the end of each shift, bedside nurses re-corded their perceived additional clinical workload relatedto trial procedures, using a 10-point visual analog scale(VAS), with 1 corresponding to “very easy” and 10 corre-sponding to “difficult”. Daily, we recorded physical restraintuse and unintentional device removal during each shift.Statistical analysisDescriptive data are presented as percentages for categor-ical data, means with standard deviations for normally dis-tributed variables, and medians with interquartile rangesfor non-normally distributed variables. For the analysis,opioid doses were converted to fentanyl equivalents (10mg morphine = 2 mg hydromorphone = 0.1 mg fentanyl)and benzodiazepine doses were converted to midazolamequivalents (1 mg midazolam = 0.5 mg lorazepam) [8].RASS scores were converted to an SAS equivalent [8](Additional file 1, Table 1).Using multivariable logistic regression with generalizedestimating equations (GEE) to account for repeated mea-surements within patients, we evaluated the associationbetween the nighttime and daytime opioid and sedativedoses on the previous study day with three different out-comes: 1) meeting criteria to have an SBT; 2) passingthe SBT; and 3) not being extubated despite passing theSBT. The baseline covariates included in our model wererandomization group, age, sex, and medical vs surgicaldiagnosis. In order to account for the time-dependent na-ture of sedative exposure, our model accounted for theMehta et al. Critical Care  (2016) 20:233 Page 2 of 7daytime benzodiazepine dose on the previous study day,the difference between nighttime and daytime benzodiazep-ine dose, daytime opioid dose, and difference betweennighttime and daytime opioid dose, for every patient. Allstatistical tests were two sided, with a p value <0.05 consid-ered statistically significant. All statistical analysis was doneusing SAS 9.3 (SAS Institute Inc., Cary, NC, USA).ResultsAmong 423 patients enrolled in the SLEAP study, patientcharacteristics were similar between the DI and controlgroups. The mean APACHE II scores were 24 and 23, re-spectively (Table 1), 84 % had medical diagnoses and, atenrollment, patients had been mechanically ventilated fora median of 2 days.Nighttime and daytime benzodiazepine and opioid dosingAmong all 423 patients, nighttime benzodiazepine andopioid doses were significantly higher than daytimedoses (mean difference midazolam equivalents 23.3 mg,95 % confidence interval (CI) 12.9, 33.8, p < 0.0001; meandifference fentanyl equivalents 356 mcg, 95 % CI 130, 582,p = 0.0021) (Fig. 1 and Table 2). Although patients receivedmore opioid bolus doses during the day than during thenight, there was no difference in the number of benzodi-azepine bolus doses administered during night and dayshifts.Nighttime and daytime dosing in the daily interruptionversus control groupsWe compared benzodiazepine and opioid doses adminis-tered to the DI and control groups (Additional file 1,Table 2). Compared with the control group, the DI groupreceived higher benzodiazepine doses during both day(mean difference 9 mg, 95 % CI 0.1, 18.0, p = 0.047) andnight (mean difference 12 mg, 95 % CI 2.7, 21.1, p = 0.01)shifts, and higher opioid doses during both day (mean dif-ference 336 mcg, 95 % CI 236, 436, p < 0.0001) and night(mean difference 405 mcg, 95% CI −48, 1636, p < 0.0001)shifts. In terms of bolus dosing, the DI group also receivedmore opioid boluses during both day and night shifts, andmore benzodiazepine boluses at night.We further compared the total doses (infusion andbolus) administered during the night and day withineach randomization group (Additional file 1, Table 3). Inthe DI group, mean total opioid and benzodiazepinedoses administered per shift were higher at night thanduring the day. The control group also received more ben-zodiazepines and opioids at night than during the day. Pa-tients in the DI group received more opioid bolusesduring the daytime compared with nighttime.SAS scores, nurse workload, device removal, and use ofphysical restraintMean reported SAS scores did not differ between nightand day shifts, and were within the target range (3.2 vs 3.3,respectively, mean difference −0.02, 95 % CI −0.05, 0.02,p = 0.35) (Table 3). Self-reported nurse workload usinga VAS (score 1–10) was similar during the night andday (3.9 vs 4.0, mean difference −0.04, 95 % CI −0.05,0.12, p = 0.38). There were more unintentional deviceremovals (self-extubation, removal of venous access)during the day compared with the night (15.9 % vs 9.1 %,p < 0.0001). The majority of patients (78 %) were re-strained at least once during the study, more often duringday shifts than during night shifts.Multivariable analysesFactors independently associated with a patient meetingthe criteria for an SBT (Table 4) were: lower daytime mid-azolam dose (odds ratio (OR) 0.9930, 95 % CI 0.9892,0.9969, p = 0.0004), smaller difference between nighttimeand daytime midazolam dose (OR 0.9938, 95 % CI 0.9896,Table 1 Baseline characteristics of patientsCharacteristic Protocolized sedationand daily interruptionProtocolizedsedationn = 214 n = 209Age, years, median (IQR) 57 (46–70) 60 (49–70)Female sex, n (%) 93 (44) 92 (44)Type of admission, n (%)Medical 175 (82) 179 (86)Surgical 30 (14) 22 (11)Trauma 8 (4) 6 (3)Body mass index, median (IQR) 28.2 (23.8–34.2) 28.6 (25.0–33.2)APACHE II, median (IQR) 24 (18–28) 23 (19–29)Mechanical ventilation days,median (IQR)2 (1–4) 2 (1–4)Pre ICU conditions, n (%)Alcohol use 49 (23.0) 44 (21.2)Tobacco use 48 (22.5) 40 (19.3)Any psychiatric condition 42 (19.6) 29 (14.4)Any neurologic condition 33 (15.4) 36 (17.2)Respiratory disease 17 (8.0) 26 (12.4)Renal dysfunction 20 (9.4) 16 (7.7)Habitual drug use 14 (6.6) 10 (4.8)Liver disease 12 (5.6) 11 (5.3)Baseline demographic data for patients randomized to each arm of the SLEAPstudy. There were no significant differences between the two groups. Pre ICUconditions: neurological condition defined as stroke, seizure disorder, dementia,neuromuscular disease, Parkinson’s disease, or other neurological condition;psychiatric condition includes depression, bipolar disorder, schizophrenia, anxietydisorder, or other psychiatric condition; respiratory disease defined as homeoxygen, CO2 retention at baseline, or home ventilation; renal dysfunction definedas chronic renal failure with creatinine >180 umol/L, or chronic dialysis; habitualdrug use other than tobacco or alcohol; liver disease defined as Child Pugh gradeC or known esophageal varices. IQR interquartile range, APACHE II AcutePhysiology and Chronic Health Evaluation II.Mehta et al. Critical Care  (2016) 20:233 Page 3 of 70.9980, p = 0.0004), and lower daytime fentanyl dose(OR 0.9402, 95 % CI 0.9071, 0.9746, p = 0.0008).Passing an SBT (Table 5) was independently associatedwith lower daytime fentanyl dose (OR 0.9602, 95 % CI0.9347, 0.9864, p = 0.003), and a smaller difference be-tween nighttime and daytime fentanyl dose (OR 0.9729,95 % CI 0.9524, 0.9937, p = 0.01).The only factor independently associated with a pa-tient not being extubated after passing an SBT (Table 6)was a larger difference between nighttime and daytimemidazolam dose (OR 1.0145, 95 % CI 1.0039, 1.0253,p = 0.007), with more midazolam given at night thanduring the day.DiscussionIn the SLEAP study, mechanically ventilated adult pa-tients in both arms of the trial received more opioidsand benzodiazepines during the night compared withTable 2 Nighttime vs daytime benzodiazepine and opioid administration in all 423 patientsNighttime Daytime Mean Difference (95 % CI) P valueMidazolam equivalentsTotal dose/pt (mg)a 547 (2220) 523 (2236) 23.3 (12.9, 33.8) <0.0001Total dose/pt, infusion (mg) 543 (2216) 519 (2231) 23.8 (13.1, 34.5) <0.0001Total dose/pt, bolus (mg) 4.0 (16.4) 4.5 (16.4) −0.5 (−1.5, 0.6) 0.37Number of bolusesb 1.2 (4.0) 1.2 (3.9) 0.02 (−0.2, 0.2) 0.81Bolus dose (mg) 0.39 (1.4) 0.43 (1.5) −0.04 (−0.1, 0.1) 0.41Fentanyl equivalentsTotal dose/pt (mcg)a 8379 (22754) 8024 (23083) 356 (130, 582) 0.002Total dose/pt, infusion (mcg) 7846 (22270) 7387 (22539) 459 (236, 682) <0.0001Total dose/pt, bolus (mcg) 534 (914) 637 (1082) −103 (−150, −55) <0.0001Number of bolusesb 11.0 (14.8) 12.1 (15.9) −1.2 (−1.8, −0.5) 0.0001Bolus dose (mcg) 51.4 (71.6) 52.4 (59.9) −1.0 (−6.7, 4.7) 0.73Benzodiazepine (midazolam equivalents) and opioid (fentanyl equivalents) administration for all patients during night (19:00–07:00 hours) and day (07:00–19:00hours) shifts. All data are presented as mean (SD). Mean difference is presented for total dose/patient (Total dose/pt), and all routes of administration includingboluses and infusions. aTotal dose received over the duration of the study. bTotal number of boluses received over the duration of the studyFig. 1 Daily benzodiazepine and opioid doses during night and day shifts. Mean benzodiazepine (midazolam equivalents, mg) and mean opioid(fentanyl equivalents, mcg) administration for all patients during night (N, blue bars, 19:00–07:00 hours) and day (D, red bars, 07:00–19:00 hours)shifts. Total dose/patient represents doses received for the duration of the study; Total dose/patient as infusion represents total doses receivedthrough intravenous infusion, excluding bolus doses, for the duration of the study. P < 0.005 for all four comparisons of nighttime versusdaytime dosesMehta et al. Critical Care  (2016) 20:233 Page 4 of 7during the day. Increased nocturnal sedation was inde-pendently associated with failure to meet criteria for anSBT, failure to pass the SBT, and delayed extubationafter passing an SBT.Greater daytime patient wakefulness is also suggestedby more unintentional device removals (self-extubation,removal of venous access) and more use of physical re-straint during day shifts compared with night shifts. It isunclear why mechanically ventilated patients who wereenrolled in the SLEAP trial received more sedation atnight. It is unlikely that the higher nighttime dosesreflect more patient distress or agitation, given the simi-lar mean SAS scores and nurse workload during day andnight shifts, less use of physical restraint at night, andno increase in adverse events at night. It is possible thatnurses or other clinicians perceived that patients, whohad been kept awake during the day for physiotherapy,procedures, tests, visits, and weaning, needed additionalmedications for adequate overnight rest. It is also pos-sible that the expectation of conventional sleep and signsof poor sleep may have prompted nurses to administermore sedative medications at night. An additional possi-bility is perceived patient discomfort related to a changein ventilation settings at night. Finally, the difference be-tween nighttime and daytime doses may reflect moreTable 3 SAS scores, VAS scores and unintentional deviceremoval during night and day shiftsNighttime Daytime P valueSAS score, mean (SD) 3.2 (0.8) 3.3 (0.8) 0.35SAS score, number of values 49437 49264Nurse VAS score, mean (SD) 3.9 (1.4) 4.0 (1.4) 0.38Nurse VAS score, number of values 4179 4471Patients with physical restraint, n (%) 308 (73.7) 321 (76.3) <0.0001Shifts with physical restraint, median (IQR) 3 (0,6) 3 (1,7) <0.0001Unintentional device removal, n (%)At least one 38 (9.1) 67 (15.9) <0.0001Central venous catheter 2 (0.5) 5 (1.2) <0.0001Arterial catheter 10 (2.4) 14 (3.3) <0.0001Endotracheal tube 7 (1.7) 17 (4.0) <0.0001Gastric tube 24 (5.7) 35 (8.3) <0.0001Urinary catheter 6 (1.4) 13 (3.1) <0.0001Peripheral venous catheter 4 (1.0) 9 (2.1) <0.0001The Riker Sedation Agitation Scale (SAS) score and nurse visual analog scale(VAS) score represent workload associated with trial procedures, use ofphysical restraint, and unintentional device removal during night and dayshifts. IQR interquartile rangeTable 4 Variables associated with the patient meeting criteriafor a spontaneous breathing trial, multivariable analysisOdds ratio 95 % CI P valuelower upperSedation protocol and dailyinterruption vs sedationprotocol alone0.956 0.685 1.332 0.79Age (10-year increase) 1.013 0.892 1.151 0.84Gender (male vs female) 1.039 0.734 1.474 0.83Surgical/trauma vs medical 0.799 0.441 1.446 0.46Daytime midazolam dose(1 mg increase)0.993 0.989 0.997 0.0004Midazolam: nighttime-daytimedose (1 mg increase)0.994 0.989 0.998 0.0004Daytime fentanyl dose(100 mcg increase)0.940 0.907 0.975 0.0008Fentanyl: nighttime-daytimedose (100 mcg increase)0.977 0.938 1.018 0.27Table 5 Variables associated with the patient passing thespontaneous breathing trial, multivariable analysisOdds ratio 95 % CI P valuelower upperSedation protocol and dailyinterruption vs sedationprotocol alone1.206 0.828 1.756 0.33Age (10-year increase) 0.949 0.839 1.075 0.42Gender (male vs female) 1.030 0.716 1.483 0.87Surgical/trauma vs medical 1.598 0.884 2.891 0.12Daytime midazolam dose(1 mg increase)0.998 0.994 1.001 0.13Midazolam: nighttime-daytimedose (1 mg increase)0.997 0.992 1.002 0.28Daytime fentanyl dose(100 mcg increase)0.960 0.935 0.986 0.003Fentanyl: nighttime-daytimedose (100 mcg increase)0.973 0.952 0.994 0.01Table 6 Variables associated with the patient not beingliberated from mechanical ventilation despite passing thespontaneous breathing trial, multivariable analysisOdds ratio 95 % CI P valuelower upperSedation protocol and dailyinterruption vs. sedationprotocol alone0.957 0.644 1.421 0.83Age (10-year increase) 1.124 0.987 1.280 0.08Gender (male vs female) 1.420 0.967 2.086 0.07Surgical/trauma vs medical 1.066 0.630 1.804 0.81Daytime midazolam dose(1 mg increase)1.008 0.999 1.017 0.07Midazolam: nighttime-daytimedose (1 mg increase)1.014 1.004 1.025 0.007Daytime fentanyl dose(100 mcg increase)1.012 0.961 1.067 0.64Fentanyl: nighttime-daytimedose (100 mcg increase)0.974 0.906 1.047 0.48Mehta et al. Critical Care  (2016) 20:233 Page 5 of 7aggressive weaning of sedatives during the day, becausesigns of over-sedation were more apparent.Our finding of increased nocturnal sedation likely re-flects general clinical practice, given that SLEAP was apragmatic trial conducted in 16 centers, and sedationwas managed by bedside ICU nurses. Our observationcontributes to a very small body of literature on diurnalvariation in sedative management and its consequences.Only three studies, all single-center, have evaluated diur-nal variation in patient sedation assessment and sedativeadministration in critically ill adults. In a prospectivestudy evaluating the epidemiology of sedative use in 274mechanically ventilated adults, Weinert et al. found thatdaytime nursing staff were more likely to judge patientsas “oversedated” compared to their nighttime counterparts,despite only small differences in both sedative dosing andpatient behavior [10]. In a study of 140 patients enrolled inthe ABC trial [2] Seymour and colleagues observed thatbenzodiazepine and propofol doses were increased at nighton 40 % and 41 % of patient-days, respectively; and an in-crease in nighttime sedative doses was associated withfailed SBTs, coma and delirium [6]. Pisani and colleaguesexamined dosing patterns of fentanyl, lorazepam and halo-peridol in a cohort of 309 patients 60 years and older, andfound that doses of lorazepam and haloperidol were higherduring the evening shifts (16:00 hours to midnight) thanduring the day or night shifts [5].The strengths of our study include protocolizedsedation management, multicenter representation, hourlydocumentation of SAS/RASS and opioid/sedative admin-istration, and self-reported nursing workload assessment.Sedation management in the SLEAP study was pragmatic;the research team did not guide the ICU staff in sedativepractices [11]. “Usual care” was assumed, and may vary toa significant degree based on prevailing practice patternsand local culture in different institutions, and the type ofICU (medical vs surgical). These institutional and patientvariables may contribute to the increased use of sedativesat night.Limitations of this study include the observationaldesign of this secondary analysis, and the possibilityof omitting important covariates. The generalizabilityof our findings to shorter-acting sedative agents, suchas dexmedetomidine or propofol, may be limited. Ourresults may not apply to patients experiencing drugwithdrawal, which we did not record, or to patientsreceiving psychotropic medications, used predominantlyat night, which have sedative properties of their own.No formal pain scale was used, and sedative/opioidmanagement was guided by patient assessment andSAS or RASS. Finally, the similar SAS scores during theday and night may reflect inaccurate nighttime SAS scor-ing or reporting by nurses, if they were reluctant to awakenpatients. Another possible explanation is insensitivity ofthe mean SAS score to express small but clinically import-ant differences.Our findings underscore the need for frequent re-assessment of the patient’s sedative and analgesic needs,even during the night. Patients and clinicians wouldbenefit from further research exploring the diurnal vari-ation in sedation, including the reasons for increases innighttime sedation and barriers to minimizing nighttimesedation.ConclusionsPatients enrolled in the SLEAP trial received more opioidsand benzodiazepines at night than during the day. Thereasons for this remain unclear, and factors such as poorpatient sleep, changes in medical personnel, and nighttimechanges in ventilator settings may contribute to diurnalsedative variation. Increased nocturnal sedation hasimportant adverse patient consequences, as we found itwas independently associated with delayed extubation.Our findings highlight the importance of minimizingsedation at night, as well as during the day.Key messages In the SLEAP trial, a randomized controlled trialconducted in 16 North American medical-surgicalICUs, mechanically ventilated adults received higherdoses of benzodiazepines and opioids at nightcompared with daytime doses Increases in nighttime drug doses were independentlyassociated with failure to meet spontaneous breathingtrial (SBT) screening criteria, SBT failure, and thedecision not to extubate the patient despite asuccessful SBTAdditional fileAdditional file 1: Variation in diurnal sedation in mechanicallyventilated patients who are managed with a sedation protocol alone or asedation protocol and daily interruption. (DOC 74 kb)AbbreviationsDI, daily interruption; ICU, intensive care unit; OR, odds ratio; PS, protocolizedsedation; RASS, Richmond Agitation Sedation Scale; SBT, spontaneousbreathing trial; SAS, Sedation Agitation Scale; VAS, visual analogue scaleAcknowledgementsWe are grateful to the Canadian Critical Care Trials Group for their key rolein this work. We are indebted to David Williamson B.Pharm, M.Sc., Ph.D forcritical review of this article.FundingThis research was supported, in part by the Canadian Institutes of HealthResearch, and the Mount Sinai Hospital Department of Medicine.Authors’ contributionsStudy concept and design: SM, LB, CK, DF, and RM. Acquisition of data:SM, MM, LB, PD, KB, MH, JWD, MT, RF, MJ, MS, KO, and DC. Analysis andMehta et al. Critical Care  (2016) 20:233 Page 6 of 7interpretation of data: SM, MM, RM, CK, DF, and DC. Drafting of themanuscript: SM, MM, LB, CK, and DC. Critical revision of the manuscript forimportant intellectual content: all authors. Statistical analysis: RM and DF.All authors gave final approval for manuscript submission.Authors’ informationDepartment of Medicine and Interdepartmental Division of Critical Care,Mount Sinai Hospital and University of Toronto, Toronto, Ontario (Dr Mehtaand Dr Katsios); Departments of Medicine, Clinical Epidemiology &Biostatistics, McMaster University, Department of Critical Care, HamiltonHealth Sciences, Hamilton, Ontario (Dr Meade); Department of Pharmacy andMedicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario(Dr Burry); Clinical Epidemiology Program, Ottawa Hospital Research Instituteand Faculty of Medicine, University of Ottawa, Ottawa, Ontario (Drs Mallickand Fergusson); Division of Critical Care Medicine and Center for HealthEvaluation and Outcome Sciences, St. Paul’s Hospital and University of BritishColumbia, Vancouver, British Columbia (Dr Dodek); Keenan Research Centreand the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto,Ontario, Interdepartmental Division of Critical Care Medicine and the Instituteof Health Policy Management and Evaluation, University of Toronto, Toronto,Ontario (Dr Burns); Department of Medicine and Interdepartmental Divisionof Critical Care, University Health Network and University of Toronto,Toronto, Ontario (Dr Herridge); School of Pharmacy, Northeastern University,Boston, Massachusetts (Dr Devlin); Department of Medicine, Long BeachMemorial Medical Center, Long Beach, California (Dr Tanios); Departments ofMedicine and Critical Care Medicine, Sunnybrook Hospital, InterdepartmentalDivision of Critical Care Medicine, University of Toronto, Toronto, Ontario(Dr Fowler); Departments of Anesthesiology and Critical Care, University ofAlberta Hospital, Edmonton, Alberta (Dr Jacka); McGill University, Montréal,Québec (Dr Skrobik); Section of Critical Care, Department of Medicine,Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba (Dr Olafson);Departments of Medicine, Clinical Epidemiology & Biostatistics, McMasterUniversity, St Joseph’s Healthcare, Hamilton, Ontario (Dr Cook).Competing interestsThe authors declare that they have no competing interests.Ethics approval and consent to participateEthics approval was obtained from the Research Ethics Board of thefollowing institutions: Mount Sinai Hospital, Toronto, Ontario, Canada;University Health Network, Toronto, Ontario, Canada; St. Michael's Hospital,Toronto, Ontario, Canada; Sunnybrook Health Sciences Centre, Toronto,Ontario, Canada; St. Joseph’s Healthcare, Hamilton, Ontario, Canada; HamiltonGeneral Hospital, Hamilton, Ontario, Canada; St. Paul's Hospital, Vancouver,British Columbia, Canada; Walter C. Mackenzie Health Sciences Centre,Edmonton, Alberta, Canada; Health Sciences Centre, Winnipeg, Manitoba,Canada; Maisonneuve Rosemount Hospital, Montreal, Quebec, Canada; RoyalColumbian Hospital, New Westminster, British Columbia, Canada; SurreyMemorial Hospital, Surrey, British Columbia, Canada; Royal Alexandra Hospital,Edmonton, Alberta, Canada; Tuft’s Medical Centre, Boston, Massachusetts, USA;Long Beach Memorial Medical Centre, Long Beach, California, USAAuthor details1Department of Medicine and Interdepartmental Division of Critical CareMedicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario,Canada. 2Departments of Medicine, Clinical Epidemiology and Biostatistics,McMaster University, Hamilton, Ontario, Canada. 3Department of Pharmacyand Medicine, Mount Sinai Hospital and University of Toronto, Toronto,Ontario, Canada. 4Clinical Epidemiology Program, Ottawa Hospital ResearchInstitute and Faculty of Medicine, University of Ottawa, Ottawa, Ontario,Canada. 5Interdepartmental Division of Critical Care Medicine, University ofToronto, Toronto, Ontario, Canada. 6Division of Critical Care Medicine andCenter for Health Evaluation and Outcome Sciences, St. Paul’s Hospital andUniversity of British Columbia, Vancouver, British Columbia, Canada.7Department of Critical Care, St. Michael’s Hospital, Toronto, Ontario, Canada.8Li Ka Shing Institute, Toronto, Ontario, Canada. 9Department of Medicineand Interdepartmental Division of Critical Care Medicine, University HealthNetwork and University of Toronto, Toronto, Ontario, Canada. 10School ofPharmacy, Northeastern University, Boston, Massachusetts, USA.11Department of Medicine, Long Beach Memorial Medical Center, LongBeach, California, USA. 12Departments of Medicine and Critical Care Medicine,Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. 13Departmentof Anesthesiology, University of Alberta Hospitals, Edmonton, Alberta,Canada. 14Department of Medicine, Hôpital Royal Victoria, Montréal, Quebec,Canada. 15Section of Critical Care, Department of Medicine, University ofManitoba, Winnipeg, Manitoba, Canada. 16Departments of Medicine, ClinicalEpidemiology & Biostatistics, McMaster University, St Joseph’s Healthcare,Hamilton, Ontario, Canada. 17Mount Sinai Hospital, Suite 18-216, 600University Ave., Toronto M5G 1X5, Canada.Received: 9 May 2016 Accepted: 12 July 2016References1. Kress JP, Pohlman AS, O’Connor MF, Hall JB. Daily interruption of sedativeinfusions in critically ill patients undergoing mechanical ventilation.N Engl J Med. 2000;342(20):1471–7.2. Girard TD, Kress JP, Fuchs BD, Thomason JW, Schweickert WD, Pun BT,Taichman DB, Dunn JG, Pohlman AS, Kinniry PA, Jackson JC, Canonico AE,Light RW, Shintani AK, Thompson JL, Gordon SM, Hall JB, Dittus RS, BernardGR, Ely EW. Efficacy and safety of a paired sedation and ventilator weaningprotocol for mechanically ventilated patients in intensive care (Awakeningand Breathing Controlled trial): a randomised controlled trial. Lancet. 2008;371(9607):126–34.3. Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B, McArthur C,Seppelt IM, Webb S, Weisbrodt L. Sedation Practice in Intensive CareEvaluation (SPICE) Study Investigators; ANZICS Clinical Trials Group. Earlyintensive care sedation predicts long-term mortality in ventilated critically illpatients. Am J Respir Crit Care Med. 2012;186(8):724–31.4. Shehabi Y, Chan L, Kadiman S, Alias A, Ismail WN, Tan MA, Khoo TM, Ali SB,Saman MA, Shaltut A, Tan CC, Yong CY, Bailey M. Sedation Practice inIntensive Care Evaluation (SPICE) Study Group investigators. Sedationdepth and long-term mortality in mechanically ventilated critically illadults: a prospective longitudinal multicentre cohort study. IntensiveCare Med. 2013;39(5):910–8.5. Pisani MA, Bramley K, Vest MT, Akgün KM, Araujo KL, Murphy TE. Patterns ofopiate, benzodiazepine, and antipsychotic drug dosing in older patients ina medical intensive care unit. Am J Crit Care. 2013;22(5):e62–9.6. Seymour CW, Pandharipande PP, Koestner T, Hudson LD, Thompson JL,Shintani AK, Ely EW, Girard TD. Diurnal sedative changes during intensivecare: impact on liberation from mechanical ventilation and delirium. CritCare Med. 2012;40(10):2788–96.7. Trompeo AC, Vidi Y, Locane MD, Braghiroli A, Mascia L, Bosma K, Ranieri VM.Sleep disturbances in the critically ill patients: role of delirium and sedativeagents. Minerva Anestesiol. 2011;77(6):604–12.8. Mehta S, Burry L, Cook D, Fergusson D, Steinberg M, Granton J, Herridge M,Ferguson N, Devlin J, Tanios M, Dodek P, Fowler R, Burns K, Jacka M,Olafson K, Skrobik Y, Hebert P, Sabri E, Meade M. for the SLEAP Investigatorsand the Canadian Critical Care Trials Group. Daily sedation interruption inmechanically ventilated critically ill patients cared for with a sedationprotocol: a randomized controlled trial. JAMA. 2012;308(19):1985–92.9. Burry L, Rose L, McCullagh I, Ferguson ND, Fergusson D, Mehta S. Dailysedation interruption versus no daily sedation interruption for critically illadult patients requiring invasive mechanical ventilation. Cochrane DatabaseSyst Rev. 2014;7:CD009176.10. Weinert CR, Calvin AD. Epidemiology of sedation and sedation adequacy formechanically ventilated patients in a medical and surgical intensive careunit. Crit Care Med. 2007;35(2):393–401.11. Rose L, Fitzgerald E, Cook D, Kim S, Steinberg M, Devlin JW, Ashley BJ,Dodek P, Smith O, Poretta K, Lee Y, Burns K, Harvey J, Skrobik Y, FergussonD, Meade M, Kraguljac A, Burry L, Mehta S. for the SLEAP Investigators andthe Canadian Critical Care Trials Group. Clinician perspectives on protocolsdesigned to minimize sedation. J Crit Care. 2015;30(2):348–52.Mehta et al. Critical Care  (2016) 20:233 Page 7 of 7


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