Impact of oversedation prevention in ventilated critically ill patients: a randomized trial-the AWARE study
SRLF Trial Group, Bernard de Jonghe, Jérôme Aboab, Nadia Aissaoui, Djillali Annane, Corinne Audoin, Jean-Luc Baudel, Florence Brouard, Alexandre Cambonie, Isabelle Camilatto, Karim Chergui, Vincent Das, Daniel da Silva, Nicolas Devos, Nicolas Deye, Stephan Ehrmann, Frédérique Ganster, Bruno Giraudeau, David Grimaldi, Emmanuelle Gourdin, Antoine Gros, Olfa Hamzaoui, Frédéric Jacobs, Antoine Kimmoun, Jean-Claude Lacherade, Bernard Lambermont, Pierre-François Laterre, Julie Leger, Stéphane Legriel, Lucas Liaudet, Charles-Edouard Luyt, Philippe Michel, Jean-Paul Mira, Xavier Monnet, Grégoire Muller, Michael Piagnerelli, Gaëtan Plantefeve, Jean Reignier, Jean-Damien Ricard, François Vincent, Jugurtha Aliane, Fabienne Plouvier, Alain Mercat, Mohebbi Amoli Abolfazl, Gaëtan Plantefeve, Cédric Cleophax, Karim Chergui, Guillaume Carteaux, Jérôme Aboab, Jean Reignier, Gilles Troche, Laurent Guerin, Patrick Girardie, Emmanuel Vivier, Romain Hernu, Philippe Obbee, Laurence Donetti, Thierry Jacques, Aurélie Cravoisy-Popovic, Thierry Boulain, Qin Lu, Danielle Reuter, Elie Azoulay, Hervé Clavier, Walter Picard, René Robert, Renaud Chouquer, Christophe Girault, Daniel da Silva, Stéphane Merat, Charlotte Quentin, Jean-François Hicter, Maleka Schenck, Sandie Dauriac, Jean-Luc Desmaretz, Hervé Hyvernat, Alexis Soumer, Annabelle Stoclin, Jean-Philippe Rigaud, Alexandre Duguet, Laetitia Bodet-Contentin, Siu-Ming Au, Sébastien Ena, SRLF Trial Group, Bernard de Jonghe, Jérôme Aboab, Nadia Aissaoui, Djillali Annane, Corinne Audoin, Jean-Luc Baudel, Florence Brouard, Alexandre Cambonie, Isabelle Camilatto, Karim Chergui, Vincent Das, Daniel da Silva, Nicolas Devos, Nicolas Deye, Stephan Ehrmann, Frédérique Ganster, Bruno Giraudeau, David Grimaldi, Emmanuelle Gourdin, Antoine Gros, Olfa Hamzaoui, Frédéric Jacobs, Antoine Kimmoun, Jean-Claude Lacherade, Bernard Lambermont, Pierre-François Laterre, Julie Leger, Stéphane Legriel, Lucas Liaudet, Charles-Edouard Luyt, Philippe Michel, Jean-Paul Mira, Xavier Monnet, Grégoire Muller, Michael Piagnerelli, Gaëtan Plantefeve, Jean Reignier, Jean-Damien Ricard, François Vincent, Jugurtha Aliane, Fabienne Plouvier, Alain Mercat, Mohebbi Amoli Abolfazl, Gaëtan Plantefeve, Cédric Cleophax, Karim Chergui, Guillaume Carteaux, Jérôme Aboab, Jean Reignier, Gilles Troche, Laurent Guerin, Patrick Girardie, Emmanuel Vivier, Romain Hernu, Philippe Obbee, Laurence Donetti, Thierry Jacques, Aurélie Cravoisy-Popovic, Thierry Boulain, Qin Lu, Danielle Reuter, Elie Azoulay, Hervé Clavier, Walter Picard, René Robert, Renaud Chouquer, Christophe Girault, Daniel da Silva, Stéphane Merat, Charlotte Quentin, Jean-François Hicter, Maleka Schenck, Sandie Dauriac, Jean-Luc Desmaretz, Hervé Hyvernat, Alexis Soumer, Annabelle Stoclin, Jean-Philippe Rigaud, Alexandre Duguet, Laetitia Bodet-Contentin, Siu-Ming Au, Sébastien Ena
Abstract
Background: Although oversedation has been associated with increased morbidity in ventilated critically ill patients, it is unclear whether prevention of oversedation improves mortality. We aimed to assess 90-day mortality in patients receiving a bundle of interventions to prevent oversedation as compared to usual care.
Methods: In this randomized multicentre trial, all adult patients requiring mechanical ventilation for more than 48 h were included. Two groups were compared: patients managed according to usual sedation practices (control), and patients receiving sedation according to an algorithm which provided a gradual multilevel response to pain, agitation, and ventilator dyssynchrony with no specific target to alter consciousness and no use of sedation scale and promoted the use of alternatives to continuous infusion of midazolam or propofol (intervention).
Results: Inclusions were stopped before reaching the planned enrolment. Between 2012 and 2014, 584 patients were included in the intervention group and 590 in the control group. Baseline characteristics were well balanced between groups. Although the use of midazolam and propofol was significantly lower in the intervention group, 90-day mortality was not significantly lower (39.4 vs. 44.2% in the control group, p = 0.09). There were no significant differences in 1-year mortality between the two groups. The time to first spontaneous breathing trial and time to successful extubation were significantly shorter in the intervention group than in the control group. These last results should be interpreted with precaution regarding the several limitations of the trial including the early termination.
Conclusions: This underpowered study of severely ill patients was unable to show that a strategy to prevent oversedation could significantly reduce mortality. Trial registration NCT01617265.
Keywords: Intensive care units; Mechanical ventilation; Mortality; Sedation; Weaning.
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References
- Patel SB, Kress JP. Sedation and analgesia in the mechanically ventilated patient. Am J Respir Crit Care Med. 2012;185:486–497. doi: 10.1164/rccm.201102-0273CI.
- Jackson DL, Proudfoot CW, Cann KF, Walsh TS. The incidence of sub-optimal sedation in the ICU: a systematic review. Crit Care. 2009;13:R204. doi: 10.1186/cc8212.
- Kress J, Pohlman A, O’Connor M, Hall J. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med. 2000;342:1471–1477. doi: 10.1056/NEJM200005183422002.
- Brook AD, Ahrens TS, Schaiff R, Prentice D, Sherman G, Shannon W, Kollef MH. Effect of a nursing-implemented sedation protocol on the duration of mechanical ventilation. Crit Care Med. 1999;27:2609–2615. doi: 10.1097/00003246-199912000-00001.
- De Jonghe B, Bastuji-Garin S, Fangio P, Lacherade JC, Jabot J, Appere-De-Vecchi C, Rocha N, Outin H. Sedation algorithm in critically ill patients without acute brain injury. Crit Care Med. 2005;33:120–127. doi: 10.1097/01.CCM.0000150268.04228.68.
- Quenot JP, Ladoire S, Devoucoux F, Doise JM, Cailliod R, Cunin N, Aube H, Blettery B, Charles PE. Effect of a nurse-implemented sedation protocol on the incidence of ventilator-associated pneumonia. Crit Care Med. 2007;35:2031–2036. doi: 10.1097/01.ccm.0000282733.83089.4d.
- Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B, McArthur C, Murray L, Seppelt IM, Webb S, Weisbrodt L. Early goal-directed sedation versus standard sedation in mechanically ventilated critically ill patients: a pilot study*. Crit Care Med. 2013;41:1983–1991. doi: 10.1097/CCM.0b013e31828a437d.
- Strom T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Lancet. 2010;375:475–480. doi: 10.1016/S0140-6736(09)62072-9.
- Breen D, Karabinis A, Malbrain M, Morais R, Albrecht S, Jarnvig IL, Parkinson P, Kirkham AJ. Decreased duration of mechanical ventilation when comparing analgesia-based sedation using remifentanil with standard hypnotic-based sedation for up to 10 days in intensive care unit patients: a randomised trial. Crit Care. 2005;9:R200–R210. doi: 10.1186/cc3495.
- Treggiari MM, Romand JA, Yanez ND, Deem SA, Goldberg J, Hudson L, Heidegger CP, Weiss NS. Randomized trial of light versus deep sedation on mental health after critical illness. Crit Care Med. 2009;37:2527–2534. doi: 10.1097/CCM.0b013e3181a5689f.
- Shehabi Y, Bellomo R, Reade MC, Bailey M, Bass F, Howe B, McArthur CJ, Seppelt IM, Webb SA, Weisbrodt L. Early intensive care sedation predicts long-term mortality in ventilated critically ill patients. Am J Respir Crit Care Med. 2012;186:724–731. doi: 10.1164/rccm.201203-0522OC.
- Balzer F, Weiss B, Kumpf O, Treskatsch S, Spies C, Wernecke KD, Krannich A, Kastrup M. Early deep sedation is associated with decreased in-hospital and two-year follow-up survival. Crit Care. 2015;19:197. doi: 10.1186/s13054-015-0929-2.
- Tanaka LM, Azevedo LC, Park M, Schettino G, Nassar AP, Rea-Neto A, Tannous L, de Souza-Dantas VC, Torelly A, Lisboa T, Piras C, Carvalho FB, Maia Mde O, Giannini FP, Machado FR, Dal-Pizzol F, de Carvalho AG, dos Santos RB, Tierno PF, Soares M, Salluh JI. Early sedation and clinical outcomes of mechanically ventilated patients: a prospective multicenter cohort study. Crit Care. 2014;18:R156. doi: 10.1186/cc13995.
- The SRLF Trial Group Sedation in French intensive care units: a survey of clinical practice. Ann Intensive Care. 2013;3:24. doi: 10.1186/2110-5820-3-24.
- Boles JM, Bion J, Connors A, et al. Weaning from mechanical ventilation. Eur Respir J. 2007;29:1933–1956. doi: 10.1183/09031936.00010206.
- Eldridge S, Kerry S, Torgerson DJ. Bias in identifying and recruiting participants in cluster randomised trials: What can be done? BMJ. 2009;339:b4006. doi: 10.1136/bmj.b4006.
- Giraudeau B, Ravaud P. Preventing bias in cluster randomised trials. PLoS Med. 2009;6:e1000065. doi: 10.1371/journal.pmed.1000065.
- Torgerson DJ. Contamination in trials: Is cluster randomisation the answer? BMJ. 2001;322:355–357. doi: 10.1136/bmj.322.7282.355.
- Savovic J, Jones HE, Altman DG, Harris RJ, Juni P, Pildal J, Als-Nielsen B, Balk EM, Gluud C, Gluud LL, Ioannidis JP, Schulz KF, Beynon R, Welton NJ, Wood L, Moher D, Deeks JJ, Sterne JA. Influence of reported study design characteristics on intervention effect estimates from randomized, controlled trials. Ann Intern Med. 2012;157:429–438. doi: 10.7326/0003-4819-157-6-201209180-00537.
- Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509. doi: 10.1080/01621459.1999.10474144.
- R-Core-Team. R: a language and environment for statistical computing. 2015. . Accessed 17 Sept 2018.
- Wunsch H, Kahn JM, Kramer AA, Rubenfeld GD. Use of intravenous infusion sedation among mechanically ventilated patients in the United States. Crit Care Med. 2009;37:3031–3039. doi: 10.1097/CCM.0b013e3181b02eff.
- Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, Shintani AK, Thompson JL, Jackson JC, Deppen SA, Stiles RA, Dittus RS, Bernard GR, Ely EW. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007;298:2644–2653. doi: 10.1001/jama.298.22.2644.
- Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, Whitten P, Margolis BD, Byrne DW, Ely EW, Rocha MG. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301:489–499. doi: 10.1001/jama.2009.56.
- Jakob SM, Ruokonen E, Grounds RM, Sarapohja T, Garratt C, Pocock SJ, Bratty JR, Takala J. Dexmedetomidine vs. midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012;307:1151–1160. doi: 10.1001/jama.2012.304.
- Chanques G, Jaber S, Barbotte E, Violet S, Sebbane M, Perrigault PF, Mann C, Lefrant JY, Eledjam JJ. Impact of systematic evaluation of pain and agitation in an intensive care unit. Crit Care Med. 2006;34:1691–1699. doi: 10.1097/01.CCM.0000218416.62457.56.
- Boles JM, Bion J, Connors A, Herridge M, Marsh B, Melot C, Pearl R, Silverman H, Stanchina M, Vieillard-Baron A, Welte T. Weaning from mechanical ventilation. Eur Respir J. 2007;29:1033–1056. doi: 10.1183/09031936.00010206.
- 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, Bernard GR, Ely EW. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008;371:126–134. doi: 10.1016/S0140-6736(08)60105-1.
- Elliott R, McKinley S, Aitken LM, Hendrikz J. The effect of an algorithm-based sedation guideline on the duration of mechanical ventilation in an Australian intensive care unit. Intensive Care Med. 2006;32:1506–1514. doi: 10.1007/s00134-006-0309-0.
- Eldridge S, Kerry S, Torgerson DJ. Bias in identifying and recruiting participants in cluster randomised trials: What can be done? BMJ. 2009;339:b4006. doi: 10.1136/bmj.b4006.
- Giraudeau B, Ravaud P. Preventing bias in cluster randomised trials. PLoS Med. 2009;6:e1000065. doi: 10.1371/journal.pmed.1000065.
- Torgerson DJ. Contamination in trials: Is cluster randomisation the answer? BMJ. 2001;322:355–357. doi: 10.1136/bmj.322.7282.355.
Source: PubMed