Background
Analgesia and sedation are a ubiquitous and essential component of care for critically ill patients. However, deep sedation is associated with prolonged mechanical ventilation (MV), longer intensive care unit (ICU) stay [
1,
2], and higher mortality [
3,
4]. Mechanically ventilated patients may receive more sedation during the night compared with the day [
5], potentially delaying extubation [
6]. Diurnal variation in sedation in critically ill patients is important to elucidate as it may affect weaning from mechanical ventilation, impair cognition, and worsen sleep [
7].
SLEAP was a multicenter trial that randomized mechanically ventilated adult patients to protocolized sedation (PS) alone (control), or protocolized sedation combined with daily interruption (DI) of sedation [
8]. There was no difference between the two groups in the primary outcome of time to extubation (hazard ratio (HR) 1.08, 95 % CI 0.86, 1.35,
p = 0.52), nor in secondary outcomes of ICU and hospital length of stay [
9]. However, the DI group received higher doses of opioids and benzodiazepines, potentially reflecting nurse apprehension about patient discomfort or the risk of adverse events during DI.
The objective of this study was to describe daytime and nighttime doses of sedatives and opioids, and to identify associations between these doses and conduct of spontaneous breathing trials (SBTs), success of SBTs, and extubation, in patients enrolled in the SLEAP Trial. We hypothesized that patients received more opioids and sedatives at night than during the day, regardless of randomization group, and that higher nighttime doses would be associated with delays in the extubation process.
Methods
This was a secondary analysis of the multicenter randomized SLEAP trial [
8]. We included critically ill adults who were expected to require mechanical ventilation for longer than 48 hours and were receiving continuous infusions of opioids and/or benzodiazepines. Patients admitted to the ICU after cardiac arrest or traumatic brain injury, patients receiving neuromuscular blockade, or patients without a commitment to maximal therapy were excluded. The Research Ethics board at each participating site approved the study, and written informed consent was obtained from substitute decision makers.
In both study arms the Sedation Agitation Scale (SAS) or Richmond Agitation Sedation Scale (RASS) were recorded hourly, and nurses titrated opioid and sedative infusions to achieve a target SAS score of 3 to 4, or RASS score of −3 to 0. In the DI arm nurses interrupted benzodiazepine and opioid infusions daily; if ongoing infusions were necessary they were resumed at half the previous dose(s). If infusions were no longer necessary patients were managed with intermittent doses of opioids and sedatives. Mechanical ventilation was weaned at the discretion of the ICU team. As previously described [
2], patients in both arms were screened daily by respiratory therapists for eligibility to have an SBT; information about successful SBTs was communicated to the ICU team with a view to extubation. Decisions on extubation were at the discretion of the ICU team.
We recorded total doses of sedatives and opioids administered to patients during mechanical ventilation, as infusions and intermittent bolus doses. We calculated total medication doses and number of bolus doses administered during night shifts and day shifts. Night shifts were defined as 12 hours from 19:00 to 07:00 hours, and day shifts were defined as 12 hours from 07:00 to 19:00 hours.
Twice daily at the end of each shift, bedside nurses recorded their perceived additional clinical workload related to trial procedures, using a 10-point visual analog scale (VAS), with 1 corresponding to “very easy” and 10 corresponding to “difficult”. Daily, we recorded physical restraint use and unintentional device removal during each shift.
Statistical analysis
Descriptive data are presented as percentages for categorical data, means with standard deviations for normally distributed variables, and medians with interquartile ranges for non-normally distributed variables. For the analysis, opioid doses were converted to fentanyl equivalents (10 mg morphine = 2 mg hydromorphone = 0.1 mg fentanyl) and benzodiazepine doses were converted to midazolam equivalents (1 mg midazolam = 0.5 mg lorazepam) [
8]. RASS scores were converted to an SAS equivalent [
8] (Additional file
1, Table 1).
Table 1
Baseline characteristics of patients
Age, 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) |
Using multivariable logistic regression with generalized estimating equations (GEE) to account for repeated measurements within patients, we evaluated the association between the nighttime and daytime opioid and sedative doses on the previous study day with three different outcomes: 1) meeting criteria to have an SBT; 2) passing the SBT; and 3) not being extubated despite passing the SBT. The baseline covariates included in our model were randomization group, age, sex, and medical vs surgical diagnosis. In order to account for the time-dependent nature of sedative exposure, our model accounted for the daytime benzodiazepine dose on the previous study day, the difference between nighttime and daytime benzodiazepine dose, daytime opioid dose, and difference between nighttime and daytime opioid dose, for every patient. All statistical tests were two sided, with a p value <0.05 considered statistically significant. All statistical analysis was done using SAS 9.3 (SAS Institute Inc., Cary, NC, USA).
Discussion
In the SLEAP study, mechanically ventilated adult patients in both arms of the trial received more opioids and benzodiazepines during the night compared with during the day. Increased nocturnal sedation was independently associated with failure to meet criteria for an SBT, failure to pass the SBT, and delayed extubation after passing an SBT.
Greater daytime patient wakefulness is also suggested by more unintentional device removals (self-extubation, removal of venous access) and more use of physical restraint during day shifts compared with night shifts. It is unclear why mechanically ventilated patients who were enrolled in the SLEAP trial received more sedation at night. It is unlikely that the higher nighttime doses reflect more patient distress or agitation, given the similar mean SAS scores and nurse workload during day and night shifts, less use of physical restraint at night, and no increase in adverse events at night. It is possible that nurses or other clinicians perceived that patients, who had been kept awake during the day for physiotherapy, procedures, tests, visits, and weaning, needed additional medications for adequate overnight rest. It is also possible that the expectation of conventional sleep and signs of poor sleep may have prompted nurses to administer more sedative medications at night. An additional possibility is perceived patient discomfort related to a change in ventilation settings at night. Finally, the difference between nighttime and daytime doses may reflect more aggressive weaning of sedatives during the day, because signs of over-sedation were more apparent.
Our finding of increased nocturnal sedation likely reflects general clinical practice, given that SLEAP was a pragmatic trial conducted in 16 centers, and sedation was managed by bedside ICU nurses. Our observation contributes to a very small body of literature on diurnal variation in sedative management and its consequences. Only three studies, all single-center, have evaluated diurnal variation in patient sedation assessment and sedative administration in critically ill adults. In a prospective study evaluating the epidemiology of sedative use in 274 mechanically ventilated adults, Weinert et al. found that daytime nursing staff were more likely to judge patients as “oversedated” compared to their nighttime counterparts, despite only small differences in both sedative dosing and patient behavior [
10]. In a study of 140 patients enrolled in the ABC trial [
2] Seymour and colleagues observed that benzodiazepine and propofol doses were increased at night on 40 % and 41 % of patient-days, respectively; and an increase in nighttime sedative doses was associated with failed SBTs, coma and delirium [
6]. Pisani and colleagues examined dosing patterns of fentanyl, lorazepam and haloperidol in a cohort of 309 patients 60 years and older, and found that doses of lorazepam and haloperidol were higher during the evening shifts (16:00 hours to midnight) than during the day or night shifts [
5].
The strengths of our study include protocolized sedation management, multicenter representation, hourly documentation of SAS/RASS and opioid/sedative administration, and self-reported nursing workload assessment. Sedation management in the SLEAP study was pragmatic; the research team did not guide the ICU staff in sedative practices [
11]. “Usual care” was assumed, and may vary to a significant degree based on prevailing practice patterns and local culture in different institutions, and the type of ICU (medical vs surgical). These institutional and patient variables may contribute to the increased use of sedatives at night.
Limitations of this study include the observational design of this secondary analysis, and the possibility of omitting important covariates. The generalizability of our findings to shorter-acting sedative agents, such as dexmedetomidine or propofol, may be limited. Our results may not apply to patients experiencing drug withdrawal, which we did not record, or to patients receiving psychotropic medications, used predominantly at night, which have sedative properties of their own. No formal pain scale was used, and sedative/opioid management was guided by patient assessment and SAS or RASS. Finally, the similar SAS scores during the day and night may reflect inaccurate nighttime SAS scoring or reporting by nurses, if they were reluctant to awaken patients. Another possible explanation is insensitivity of the mean SAS score to express small but clinically important differences.
Our findings underscore the need for frequent reassessment of the patient’s sedative and analgesic needs, even during the night. Patients and clinicians would benefit from further research exploring the diurnal variation in sedation, including the reasons for increases in nighttime sedation and barriers to minimizing nighttime sedation.
Abbreviations
DI, daily interruption; ICU, intensive care unit; OR, odds ratio; PS, protocolized sedation; RASS, Richmond Agitation Sedation Scale; SBT, spontaneous breathing trial; SAS, Sedation Agitation Scale; VAS, visual analogue scale
Acknowledgements
We are grateful to the Canadian Critical Care Trials Group for their key role in this work. We are indebted to David Williamson B.Pharm, M.Sc., Ph.D for critical review of this article.
Department of Medicine and Interdepartmental Division of Critical Care, Mount Sinai Hospital and University of Toronto, Toronto, Ontario (Dr Mehta and Dr Katsios); Departments of Medicine, Clinical Epidemiology & Biostatistics, McMaster University, Department of Critical Care, Hamilton Health Sciences, Hamilton, Ontario (Dr Meade); Department of Pharmacy and Medicine, Mount Sinai Hospital and University of Toronto, Toronto, Ontario (Dr Burry); Clinical Epidemiology Program, Ottawa Hospital Research Institute and Faculty of Medicine, University of Ottawa, Ottawa, Ontario (Drs Mallick and Fergusson); Division of Critical Care Medicine and Center for Health Evaluation and Outcome Sciences, St. Paul’s Hospital and University of British Columbia, Vancouver, British Columbia (Dr Dodek); Keenan Research Centre and the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Interdepartmental Division of Critical Care Medicine and the Institute of Health Policy Management and Evaluation, University of Toronto, Toronto, Ontario (Dr Burns); Department of Medicine and Interdepartmental Division of 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 Beach Memorial Medical Center, Long Beach, California (Dr Tanios); Departments of Medicine and Critical Care Medicine, Sunnybrook Hospital, Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario (Dr Fowler); Departments of Anesthesiology and Critical Care, University of Alberta 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, McMaster University, St Joseph’s Healthcare, Hamilton, Ontario (Dr Cook).
Ethics approval and consent to participate
Ethics approval was obtained from the Research Ethics Board of the following 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; Hamilton General 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; Royal Columbian Hospital, New Westminster, British Columbia, Canada; Surrey Memorial 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, USA