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Editorial |

To Sleep, Perhaps to Dream: Sedatives and the Uncertainties Surrounding Therapeutic Choices in Critical Care FREE TO VIEW

Yoanna Skrobik, MD, FCCP
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

CORRESPONDENCE TO: Yoanna Skrobik, MD, FCCP, McGill University Health Centre, Medicine Desk D05.5133, 1001 Blvd Décarie, Montreal, QC H4A 3J1, Canada


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;149(6):1355-1356. doi:10.1016/j.chest.2016.03.033
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Published online

Intensivists ubiquitously administer sedatives to palliate their patients’ discomfort. However, sedative-associated unresponsiveness confers significant risk and worsens outcomes., Sedative-associated morbid consequences are more likely to occur, given critically ill patients’ unique pharmacokinetics. Protocols mandating sedative titration benefit patients, but the persistence of oversedation,, despite these protocols, suggest that drug–drug interaction and metabolite accumulation may contribute to this iatrogenic complication., Some class-specific pharmacologic characteristics explain the association described between sedative exposure and untoward effects. Overall, the incidence, severity, and cost of sedation-associated problems appear to be rising.

FOR RELATED ARTICLE SEE PAGE 1373

In this issue of CHEST, Klompas et al extracted sedative administration information from electronic chart data in critically ill patients admitted between 2006 and 2013, and ventilated ≥ 3 days, in a single US center. Sedative exposure was considered as a dichotomous variable for benzodiazepine, propofol, and/or dexmedetomidine exposure. Hazard ratios were reported for each targeted outcome: infection-related ventilator-associated complications, time to extubation and hospital discharge, and death. Hazard ratios for these outcomes were exposure-modeled for each sedative, and they were adjusted for illness severity and individual predicted probability of death, using models from this center’s database.

Nearly one-half of the patients were administered two sedatives (a benzodiazepine and propofol) simultaneously. Only 12% received dexmedetomidine for at least 1 day; most were cardiac surgery patients. In 9603 “episodes” of ≥ 3 ventilation days, benzodiazepines and propofol were associated with more purported ventilator-associated complications; dexmedetomidine was not. Further comparisons suggest shorter time to extubation for propofol than with a benzodiazepine; the hazard ratio for dexmedetomidine was higher still compared with both the benzodiazepines and propofol. Mortality and hospital length of stay were similar in all groups.

Klompas et al are to be commended for this description of a large, pragmatic observational trial. Their data speak to what many clinicians believe to be their clinical sedative administration experience. Methodologic limitations (eg, how few patients received dexmedetomidine, suggesting selection bias) weaken their conclusions. It was impossible to determine whether drug class or sedation level (or both) drove the hazard ratio results; indeed, sedation levels were not documented concomitantly with sedative administration. In “risk of bias terms,” which “exposure” drove outcomes is unclear.

Sedation level and drug class are not necessarily linked. However, sedation depth (ie, unresponsiveness) is what has most been associated with harm and increased mortality., The conclusions of Klompas et al—that the effect is related to drug, without addressing unresponsiveness—invites caution. Moreover, although variables such as duration of mechanical ventilation, hospitalization duration, or death, were probably documented accurately, chart extraction imprecision muddles clinical diagnosis variables, such as reported infection outcomes. Finally, confounders for drug administration (eg, alcohol or substance withdrawal) may have skewed the results.

The benefits of avoiding deep sedation have led the Society of Critical Care Medicine to issue guidelines emphatically supporting this approach as the preferred sedation strategy. However, trials in which deep sedation duration (for hours or days) is associated with dramatic outcome differences (mortality or cost) should provoke questions about biological mechanisms. Sedatives may affect immunity, mobilization, heart rate and respiratory rate variability, and other ICU patient outcome drivers. We understand little, yet should be compelled to explore, why such easily prescribed pharmacologic interventions are associated with such dramatically worse outcomes.

Sedatives remain the most ubiquitously administered pharmacologic agents in critical care. The current publication describing the effects associated with three drugs is provocative. Was it the drug used, or its sedative effect? Studies such as this one highlight the need to ask these basic pharmacologic questions.

References

The Australian and New Zealand Intensive Care Society Clinical Outcome and Resource Evaluation 2010 Annual Report.  2011;:- [PubMed] Australia: Australian and New Zealand Intensive Care Society Melbournejournal
 
Shehabi Y. .Bellomo R. .Reade M.C. . Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators; ANZICS Clinical Trials Groupet al Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012;186:724-731 [PubMed]journal. [CrossRef] [PubMed]
 
Ouimet S. .Kavanagh B.P. .Gottfried S.B. .Skrobik Y. . Incidence, risk factors and consequences of ICU delirium. Intensive Care Med. 2007;33:66-73 [PubMed]journal. [CrossRef] [PubMed]
 
Kopp B.J. .Mrsan M. .Erstad B.L. .Duby J.J. . Cost implications of and potential adverse events prevented by interventions of a critical care pharmacist. Am J Health Syst Pharm. 2007;64:2483-2487 [PubMed]journal. [CrossRef] [PubMed]
 
Khan B.A. .Fadel W.F. .Tricker J.L. .et al Effectiveness of implementing a wake up and breathe program on sedation and delirium in the ICU. Crit Care Med. 2014;42:e791-e795 [PubMed]journal. [CrossRef] [PubMed]
 
Mehta S. .Burry L. .Cook D. . for the SLEAP Investigators and the Canadian Critical Care Trials Groupet al Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized trial. JAMA. 2012;308:1985-1992 [PubMed]journal. [CrossRef] [PubMed]
 
Skrobik Y. .Leger C. .Cossette M. .Michaud V. .Turgeon J. . factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors. Crit Care Med. 2013;41:999-1008 [PubMed]journal. [CrossRef] [PubMed]
 
Devlin J.W. . The pharmacology of over sedation in mechanically ventilated adults. Curr Opin Crit Care. 2008;14:403-407 [PubMed]journal. [CrossRef] [PubMed]
 
Rewa O. .Bagshaw S.M. . Acute kidney injury—epidemiology, outcomes and economics. Nat Rev Nephrol. 2014;10:193-207 [PubMed]journal. [CrossRef] [PubMed]
 
Wunsch H. .Kahn J.M. .Kramer A.A. .Rubenfeld G.D. . Use of intravenous infusion sedation among mechanically ventilated patients in the United States. Crit Care Med. 2009;37:3031-3039 [PubMed]journal. [CrossRef] [PubMed]
 
Klompas M. .Li L. .Szumita P. .Kleinman K. .Murphy M.V. . Associations between different sedatives and ventilator-associated events, length of stay, and mortality in patients who were mechanically ventilated. Chest. 2016;149:1373-1379 [PubMed]journal
 
Bradley B.D. .Green G. .Ramsay T. .Seely A.J. . Impact of sedation and organ failure on continuous heart and respiratory rate variability monitoring in critically ill patients: a pilot study. Crit Care Med. 2013;41:433-444 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

The Australian and New Zealand Intensive Care Society Clinical Outcome and Resource Evaluation 2010 Annual Report.  2011;:- [PubMed] Australia: Australian and New Zealand Intensive Care Society Melbournejournal
 
Shehabi Y. .Bellomo R. .Reade M.C. . Sedation Practice in Intensive Care Evaluation (SPICE) Study Investigators; ANZICS Clinical Trials Groupet al Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012;186:724-731 [PubMed]journal. [CrossRef] [PubMed]
 
Ouimet S. .Kavanagh B.P. .Gottfried S.B. .Skrobik Y. . Incidence, risk factors and consequences of ICU delirium. Intensive Care Med. 2007;33:66-73 [PubMed]journal. [CrossRef] [PubMed]
 
Kopp B.J. .Mrsan M. .Erstad B.L. .Duby J.J. . Cost implications of and potential adverse events prevented by interventions of a critical care pharmacist. Am J Health Syst Pharm. 2007;64:2483-2487 [PubMed]journal. [CrossRef] [PubMed]
 
Khan B.A. .Fadel W.F. .Tricker J.L. .et al Effectiveness of implementing a wake up and breathe program on sedation and delirium in the ICU. Crit Care Med. 2014;42:e791-e795 [PubMed]journal. [CrossRef] [PubMed]
 
Mehta S. .Burry L. .Cook D. . for the SLEAP Investigators and the Canadian Critical Care Trials Groupet al Daily sedation interruption in mechanically ventilated critically ill patients cared for with a sedation protocol: a randomized trial. JAMA. 2012;308:1985-1992 [PubMed]journal. [CrossRef] [PubMed]
 
Skrobik Y. .Leger C. .Cossette M. .Michaud V. .Turgeon J. . factors predisposing to coma and delirium: fentanyl and midazolam exposure; CYP3A5, ABCB1, and ABCG2 genetic polymorphisms; and inflammatory factors. Crit Care Med. 2013;41:999-1008 [PubMed]journal. [CrossRef] [PubMed]
 
Devlin J.W. . The pharmacology of over sedation in mechanically ventilated adults. Curr Opin Crit Care. 2008;14:403-407 [PubMed]journal. [CrossRef] [PubMed]
 
Rewa O. .Bagshaw S.M. . Acute kidney injury—epidemiology, outcomes and economics. Nat Rev Nephrol. 2014;10:193-207 [PubMed]journal. [CrossRef] [PubMed]
 
Wunsch H. .Kahn J.M. .Kramer A.A. .Rubenfeld G.D. . Use of intravenous infusion sedation among mechanically ventilated patients in the United States. Crit Care Med. 2009;37:3031-3039 [PubMed]journal. [CrossRef] [PubMed]
 
Klompas M. .Li L. .Szumita P. .Kleinman K. .Murphy M.V. . Associations between different sedatives and ventilator-associated events, length of stay, and mortality in patients who were mechanically ventilated. Chest. 2016;149:1373-1379 [PubMed]journal
 
Bradley B.D. .Green G. .Ramsay T. .Seely A.J. . Impact of sedation and organ failure on continuous heart and respiratory rate variability monitoring in critically ill patients: a pilot study. Crit Care Med. 2013;41:433-444 [PubMed]journal. [CrossRef] [PubMed]
 
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