Elsevier

Resuscitation

Volume 84, Issue 10, October 2013, Pages 1324-1338
Resuscitation

Review article
Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: A systematic review and meta-analysis. Part 2: Patients treated with therapeutic hypothermia

https://doi.org/10.1016/j.resuscitation.2013.06.020Get rights and content

Abstract

Aims and methods

To systematically review the accuracy of early (≤7 days) predictors of poor outcome, defined as death or vegetative state (Cerebral Performance Categories [CPC] 4–5) or death, vegetative state or severe disability (CPC 3–5), in comatose adult survivors from cardiac arrest (CA) treated using therapeutic hypothermia (TH). Electronic databases were searched for eligible studies. Sensitivity, specificity, and false positive rates (FPR) for each predictor were calculated. Quality of evidence (QOE) was evaluated according to the GRADE guidelines.

Results

37 studies (2403 patients) were included. A bilaterally absent N20 SSEP wave during TH (4 studies; QOE: Moderate) or after rewarming (5 studies; QOE: Low), a nonreactive EEG background (3 studies; QOE: Low) after rewarming, a combination of absent pupillary light and corneal reflexes plus a motor response no better than extension (M  2) (1 study; QOE: Very low) after rewarming predicted CPC 3–5 with 0% FPR and narrow (<10%) 95% confidence intervals. No consistent threshold for 0% FPR could be identified for blood levels of biomarkers. In 6/8 studies on SSEP, in 1/3 studies on EEG reactivity and in the single study on clinical examination the investigated predictor was used for decisions to withdraw treatment, causing the risk of a self-fulfilling prophecy.

Conclusions

in the first 7 days after CA, a bilaterally absent N20 SSEP wave anytime, a nonreactive EEG after rewarming or a combination of absent ocular reflexes and M  2 after rewarming predicted CPC 3–5 with 0% FPR and narrow 95% CIs, but with a high risk of bias.

Introduction

Mortality after resuscitation from cardiac arrest is high. Two thirds of initially resuscitated patients die before hospital discharge.1 Many of these deaths are due to post cardiac arrest brain dysfunction2 and in more than one-fourth of those who survive to hospital discharge brain hypoxia-ischaemia results in severe neurological impairment.3

Prediction of neurological outcome is an important component of the management of comatose resuscitated patients. In 2006, the Quality Standards Subcommittee of the American Academy of Neurology (AAN) published a review on available evidence. The document concluded that the presence of myoclonus status epilepticus on day 1, the bilateral absence of the N20 wave of somatosensory evoked potentials (SSEPs) or a blood concentration of neuron specific enolase (NSE) above 33 mcg/L at days 1–3, and absent pupillary and corneal reflexes or a motor response no better than extension (M1 -2) at day 3 accurately predicted poor outcome, defined as death or unconsciousness after 1 month or unconsciousness or severe disability after 6 months. However, that review was based on evidence derived from patients not treated with therapeutic hypothermia (TH), which currently represents the standard for the treatment of comatose patients resuscitated from out-of-hospital cardiac arrest.4 Evidence showing that AAN recommendations may not apply to TH-treated patients has been accumulating in the last years. Moreover, this and previous reviews did not comply with the currently recommended guidelines for data reporting in systematic reviews and meta-analysis, such as PRISMA,5 and did not adequately address some important limitations of the included studies, such as the risk of ‘self-fulfilling prophecy’, which is a bias present in most studies on prognostication after cardiac arrest wherein the treating physicians are not blinded to the results of the outcome predictor and use it to make a decision to withdraw treatment.6, 7

The aim of the current work is to perform a new systematic review that, in comparison with previous reviews: (a) incorporates any missed studies or studies published more recently; (b) implements an improved approach for the evaluation of main sources of bias and statistical heterogeneity; (c) complies with the most recognised standards for evidence evaluation and data reporting; and, finally (d) addresses prognostication both in patients who have not been treated with TH and in TH-treated patients. In the first part of this review we addressed prognostication in patients who have not been treated with TH.8 The present study deals with the predictors of neurological outcome in resuscitated comatose patient treated with TH.

We reviewed the evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines,9 in order to provide grounds for future recommendations, as part of a staged approach.

Section snippets

Materials and methods

This is a systematic review and aggregate data meta-analysis of prognostic accuracy studies. Data reporting is consistent with the recommendations included in the PRISMA statement.10 According to the PICOS template, the review question was formulated as follows: “In adult patients who are comatose following resuscitation from cardiac arrest and who have been treated with TH (P), does the use of predictors based on clinical examination, electrophysiology, serum biomarkers or neuroimaging (I)

Study selection (Fig. 1)

The initial search produced 977 records from PubMed, 392 records from Scopus and 11 records from the Cochrane Database of Systematic Reviews. Thirty-seven additional records were identified through forward search. After duplicate removal and abstract screening, 200 studies were considered for full-text analysis. Among them, 163 were excluded because they did not fulfil inclusion criteria. The remaining 37 studies were included in our review. Excluded studies with reasons for their exclusion are

Brainstem reflexes and motor response

In almost all studies included in our review, predictors based on clinical examination were recorded either on admission or at 36 h or more from cardiac arrest, after the end of TH. Use of clinical examination in patients undergoing therapeutic hypothermia is hampered by the interference from hypothermia itself and from sedatives or muscle relaxants used to maintain it. However, even when performed after TH, clinical examination could have been still affected by sedation, firstly because

Conclusions

Our analysis identified a series of early predictors of poor neurological outcome with 100% specificity and narrow CIs in comatose patients resuscitated from cardiac arrest and treated using TH. For poor outcome defined as CPC 4–5 these included presence of either burst-suppression or electrographic status epilepticus evolving from a burst-suppression anytime (QOE: Low). However, these predictors were described in a small number of patients in a single study, which severely limits the relevance

Author contributions

Study design: Claudio Sandroni, Fabio Cavallaro, Jerry Nolan.

Data search and collection, grading: Matteo Biancone, Clifton Callaway, Fabio Cavallaro, Sonia D’Arrigo, Michael Kuiper, Claudio Sandroni, Tommaso Sanna.

Drafting of the manuscript: Claudio Sandroni, Fabio Cavallaro, Jerry Nolan (Manuscript's body text); Matteo Biancone, Sonia D’Arrigo, Giacomo Della Marca (Tables).

Revision of the manuscript: Clifton Callaway, Giacomo Della Marca, Michael Kuiper.

Data analysis: Fabio Cavallaro, Claudio

Conflict of interest statement

Claudio Sandroni, Fabio Cavallaro, Clifton Callaway, Sonia D’Arrigo, Tommaso Sanna, Michael Kuiper, Matteo Biancone Giacomo Della Marca and Alessio Farcomeni have no conflicts of interest to declare.

Jerry Nolan is Editor-in-Chief of Resuscitation.

Acknowledgements

We gratefully thank the following investigators for having provided original data from their studies:

  • 1.

    Dr. Amy Z. Crepeau, Department of Neurology, Mayo Clinic, Rochester, MN;

  • 2.

    Dr. Stephane Legriel, Intensive Care Department, CH Versailles – Site André Mignot, Le Chesnay, France;

  • 3.

    Dr. Pascal Stammet, Department of Anaesthesia and Intensive Care, Centre Hospitalier, Luxembourg;

  • 4.

    Dr. Michael Mlynash, Stanford Stroke Center, Department of Neurology and Neurological Sciences, Stanford University, Palo

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