Resuscitation 102 (2016) A3–A4
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Editorial
Does early withdrawal of life-sustaining treatment increase mortality after cardiac arrest?
Keywords: Cardiac arrest Prognosis Hypoxia–ischaemia Brain
The majority of patients who are admitted to the hospital after a successful resuscitation from out-of-hospital cardiac arrest (OHCA) die before hospital discharge. Most of these deaths are due to severe hypoxic–ischaemic brain injury1 and occur after withdrawal of life sustaining treatment (WLST),2,3 because a poor neurological prognosis is expected. When prognosticating a poor neurological outcome in patients who are unconscious after resuscitation from cardiac arrest the risk of a falsely pessimistic prediction should be minimised in order to avoid an inappropriate WLST. Since even the most robust predictors of poor neurological outcome are not 100% specific (e.g. some false positive may be expected), an integrated approach using multiple prognostic tests is recommended.4,5 In addition, international guidelines recommend that prognostication should not be made before 72 h after return of spontaneous circulation (ROSC). In fact, in patients treated with targeted temperature management (TTM) the presence of low body temperature and the use of sedation and paralysis used to maintain it may interfere with clinical examination during the first 36 h after ROSC; even in patients not treated with TTM, predictors based on clinical examination perform best at 72 h of more after ROSC.6 Finally, the majority of patients who eventually recover consciousness after cardiac arrest awake spontaneously within 72–96 h after ROSC.7,8 Despite these findings, however, a premature prognostication (during or immediately after TTM) has been documented in up to 57% of comatose survivors of cardiac arrest and may result in an early WLST.9 In their study published in this issue of Resuscitation, Elmer et al.10 investigated whether withdrawal of life-sustaining therapy based on neurological criteria before 72 h (WLST-N < 72) was associated with increased – and potentially avoidable – mortality in patients resuscitated from OHCA. The authors performed a retrospective analysis of the ROC-PRIMED (Resuscitation Outcomes Consortium Prehospital Resuscitation Impedance Valve and Early Versus Delayed Analysis) trial database. This trial included 16,875 adult OHCA patients treated by the emergency medical services in the United States, who were randomized into two different http://dx.doi.org/10.1016/j.resuscitation.2016.02.007 0300-9572/© 2016 Elsevier Ireland Ltd. All rights reserved.
strategies to improve the quality of resuscitation (impedance threshold device vs. control) and to evaluate the optimal timing for defibrillation (early vs. late).11 In the present study, the authors included only the subgroup of patients who were admitted to hospital after ROSC and who survived at least one hour and matched patients exposed to WLST before 72 h (WLST-N < 72) with those unexposed using a propensity score. Adjusted logistic regression models were fit to predict the odds of survival and functionally favourable survival in the unexposed cohort and these models were used to predict the outcomes in the WLST-N < 72 cohort. Among the 4265 patients included in the study, 2775 died before hospital discharge. WLST-N was the most common cause of death (n = 1626; 59%). A total of 919 subjects (one third of non-survivors) underwent WLST-N < 72, mostly within the first day after ROSC. All these subjects died. The logistic regression model derived from the unexposed cohort predicted that 237/919 (26%) exposed subjects would have survived and 16% would had functionally favourable survival if WLST-N < 72 did not occur. By extrapolating these results to a national level, the authors estimated that WLST-N < 72 is associated with death in approximately 2300 US citizens every year of whom nearly 1500 (64%) might have had a functional recovery. The results of this provocative study are of great interest and show that early WLST based on neurological criteria is not only common, but it may also be associated with an attributable mortality. Although the observational design precludes any definitive conclusion about the causal nature of this association, the large sample size allowed the use of complex statistical modelling to mitigate the selection bias due to a non-random assignment of WLST-N < 72. A major limitation of this study is that the odds of functionally favourable survival in the unexposed cohort, used to assess the excess mortality associated to WLST-N < 72, were calculated on regression models that by definition excluded neurological variables, which were not included in the propensity score. It would have been interesting to know what predictors of poor neurological outcome were present in patients who underwent WLST-N < 72. Unfortunately, this information is not included in the study, because it was not required for inclusion in the ROC-PRIMED trial database. In addition, the trial was focused to the interventions made in the pre-hospital setting and did not standardise postresuscitation care. The authors therefore could not assess whether patient care in this phase may have been influenced by the treating
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Editorial / Resuscitation 102 (2016) A3–A4
team’s own expectations, based for example on the neurological status on admission. Finally, in order to put the findings of this study in the correct historical perspective, it should be considered that this patient cohort was enrolled between June 2007 and October 2009. At that time, the only available guidelines for neuroprognostication were those published by the American Academy of Neurology in 2006.12 These guidelines were based on evidence in patients treated in the pre-hypothermia era and supported an unimodal approach to WLST-N < 72 based on clinical, electrophysiological, or biochemical criteria that is no more recommended. In conclusion, the paper from Elmer et al. represents the largest available study on WLST-N after resuscitation from cardiac arrest. Its findings not only confirm that WLST-N is the commonest cause of death in comatose survivors of cardiac arrest, but also show that, when performed before the recommended timing for neuroprognostication, WLST-N may be associated to a significant risk of excess mortality. Prospective cohort studies investigating the natural course of neurological recovery after cardiac arrest in patients treated according to current recommendations are warranted to confirm these findings. Conflict of interest statement The authors declare they have no conflicts of interest. Funding None. References 1. Laver S, Farrow C, Turner D, Nolan J. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med 2004;30:2126–8. 2. Lemiale V, Dumas F, Mongardon N, et al. Intensive care unit mortality after cardiac arrest: the relative contribution of shock and brain injury in a large cohort. Intensive Care Med 2013;39:1972–80. 3. Dragancea I, Rundgren M, Englund E, Friberg H, Cronberg T. The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest. Resuscitation 2013;84:337–42.
4. Sandroni C, Cariou A, Cavallaro F, et al. Prognostication in comatose survivors of cardiac arrest: an advisory statement from the European Resuscitation Council and the European Society of Intensive Care Medicine. Resuscitation 2014;85:1779–89. 5. Nolan JP, Soar J, Cariou A, et al. European Resuscitation Council and European Society of Intensive Care Medicine Guidelines for Post-resuscitation Care 2015: Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015. Resuscitation 2015;95:202–22. 6. Sandroni C, Cavallaro F, Callaway CW, et al. Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: a systematic review and meta-analysis. Part 1: Patients not treated with therapeutic hypothermia. Resuscitation 2013;84:1310–23. 7. Cronberg T, Rundgren M, Westhall E, et al. Neuron-specific enolase correlates with other prognostic markers after cardiac arrest. Neurology 2011;77: 623–30. 8. Zandbergen EGJ, de Haan RJ, Reitsma JB, Hijdra A. Survival and recovery of consciousness in anoxic–ischemic coma after cardiopulmonary resuscitation. Int J Equity Health 2003;29:1911–5. 9. Perman SM, Kirkpatrick JN, Reitsma AM, et al. Timing of neuroprognostication in postcardiac arrest therapeutic hypothermia. Crit Care Med 2012;40: 719–24. 10. Elmer J, Torres C, Aufderheide TP, et al. Association of early withdrawal of lifesustaining therapy for perceived neurological prognosis with mortality after cardiac arrest. Resuscitation 2016;102:127–35. 11. Stiell IG, Nichol G, Leroux BG, et al. Early versus later rhythm analysis in patients with out-of-hospital cardiac arrest. N Engl J Med 2011;365:787–97. 12. Wijdicks EF, Hijdra A, Young GB, Bassetti CL, Wiebe S. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2006;67:203–10.
Claudio Sandroni a,∗ Fabio Silvio Taccone b a Department of Anaesthesiology and Intensive Care—Catholic University School of Medicine, Largo Gemelli, 8, 00168 Rome, Italy b Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles (ULB), Route de Lennik, 808, Brussels 1070, Belgium ∗ Corresponding
author. Fax: +39 0 63013450. E-mail address:
[email protected] (C. Sandroni)
