Clinical paperTime to awakening after cardiac arrest and the association with target temperature management☆
Introduction
At cardiac arrest the brain suffers a period of diminished blood flow with subsequent immediate loss of consciousness. After successful resuscitation most survivors will remain comatose due to ischaemic brain injury. Current guidelines recommend treating these patients with target temperature management (TTM) at 32–36 °C ≥24 h as a neuroprotective strategy [[1], [2]]. In order for the patient to tolerate a lowered body temperature and to reduce shivering, sedation is required for the duration of TTM.
Drug metabolism is slower and more variable in the critically ill as compared to healthy volunteers [3] and a lowering of the body temperature decreases drug elimination [[4], [5]]. Hence, sedation may linger after rewarming from TTM and discontinuation of sedation, and possibly delay awakening.
Previous studies performed before the introduction of TTM showed that awakening generally occurs within three days of cardiac arrest [[6], [7], [8]]. Subsequent studies on TTM-treated patients have reported longer times until awakening [[9], [10], [11], [12]], with reported awakening as late as several weeks after cardiac arrest [13]. These studies were all small, retrospective and lacked comparable control groups.
Previous studies were equivocal regarding the association between early awakening and better neurological outcome, but all agree that good outcomes frequently occur after late awakening [[10], [11], [14], [15], [16], [17]]. One study measured neurological outcome at 90 days post-arrest [10], the remainder at ICU or hospital discharge when neurological recovery is unlikely to be complete. Importantly, all but one [14] published studies on time until awakening after cardiac arrest lacked protocols for withdrawal of life sustaining therapy (WLST), increasing the risk of premature WLST leading to poor outcome, the so-called self-fulfilling prophecy [18].
This post hoc analysis of the Target Temperature Management trial (TTM-trial) [19] was predefined before the randomisation code was broken. It reports time until awakening after cardiac arrest and its correlation with long-term neurological outcome in the two intervention arms (TTM33 °C and TTM36 °C). Our pre-defined hypotheses were that time until awakening would not be affected by level of TTM and that time until awakening would correlate with long-term neurological outcome. In addition we decided to investigate whether predictors of time until awakening can be identified already at ICU admission, as suggested in recent publications [[11], [14]].
Section snippets
Study population
The TTM-trial was an international, randomized, parallel group, assessor-blinded trial designed to evaluate outcome after temperature management at either 33 °C (TTM33) or 36 °C (TTM36) in unconscious patients after out-of-hospital cardiac arrest of presumed cardiac origin [19]. It enrolled 950 adult (≥18 years) patients in 26 months 2010–2013. The modified intention to treat group included 473 patients at 33 °C and 476 at 36 °C. Trial data were obtained from 36 intensive care units in Europe
Pre-randomisation characteristics
A total number of 539 patients awoke (262 managed at TTM33 and 277 at TTM36), of whom 496 patients had registered day of awakening in the primary ICU (235 managed at TTM33 and 261 at TTM36). Forty-three patients awoke after discharge from the primary ICU according to the CPC scale, with no exact day of awakening available. There were no significant differences in the pre-randomisation characteristics between the intervention arms, with the exception of body mass index (BMI), which was higher in
Discussion
This post-hoc analysis of the TTM-trial is to our knowledge the largest prospective study on awakening after cardiac arrest and TTM. Late awakening was common and compatible with good long-term neurological outcome. Awakening occurred later in TTM33 than in TTM36, with no differences in long-term neurological outcome between intervention groups. There were no differences in administered sedative drugs between TTM33 and TTM36 during the first 48 h. Lower level of consciousness on admission,
Conclusion
Late awakening is common and patients often have a good long-term neurological outcome. Time to awakening was longer in TTM33 than in TTM36, this difference could not be attributed to differences in sedative drugs administered during the first 48 h after cardiac arrest. TTM33, level of consciousness on admission and presence of clinical seizures were independent predictors of late awakening.
Conflicts of interest
Anna Lybeck, Anders Aneman, Christian Hassager, Jan Hovdenes, Jesper Kjærgaard, Michael Kuiper, Michael Wanscher, Pascal Stammet, Susann Ullén, and Tobias Cronberg have none to declare. Matthew Wise served on the advisory board for Bard Medical in 2010. Hans Friberg, Janneke Horn and Niklas Nielsen report lecture fees from Bard Medical. Hans Friberg is a scientific advisor for QuickCool. Niklas Nielsen serves on the advisory board for BrainCool.
Authors’ contributions
AL, HF and TC designed the study and wrote the first draft of the manuscript. AA, CH, JHorn, JHovdenes, JK, MK, MW, PS and MW were principal investigators in the TTM trial. NN was the chief-investigator of the TTM trial and participated in the design and development of the present study. SU was study statistician. All authors of the manuscript were involved in the analysis and interpretation of the data, reviewed and edited the manuscript. All authors read and approved the final version of the
Funding
The TTM-trial and the present study was funded by independent research grants from the non-profit or governmental agencies: Swedish Heart Lung Foundation (grant no. 20090275); AFA-Insurance Foundation (grant no. 100001); The Swedish Research Council (grant nos. 134281, 296161, 286321); Regional research support, Region Skane; Governmental funding of clinical research within the Swedish NHS (National Health Services) (grant nos. M2010/1837, M2010/1641, 353301); Skane University Hospital, Sweden;
Ethics and patient consent
Australia: Health Ethics Review Committee Protocol No X11-0150 & HREC/11/RPAH/216 – “GI-CCT886. Czeck Republic: Ethics committee of the General University Hospital of Prague, c/j 193-11S 17.2.2011. Denmark: De vitenskabsetiske Komiteer i Region Hovedstaden, H-1-2010-059. Italy: Comitato Etico Indipendente, Hospedaliera S Maria degli Angeli Pordenone, No 9. Luxembourg: Comité National d’Ethique de Recherche CNER No 201007/05 Ver 1.0. The Netherlands: Medisch Etische Toetsingscommissie MEC 10/107
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A Spanish translated version of the abstract of this article appears as Appendix in the final online version at https://doi.org/10.1016/j.resuscitation.2018.01.027.