Clinical examination for the prediction of poor neurological outcome after return of circulation following pediatric cardiac arrest: PLS 4220.02 TF SR

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors declared an intellectual conflict of interest, and this was acknowledged and managed by the Task Force Chairs/vice chair and Conflict of Interest committees: Scholefield, B, Topjian A were authors and investigator in pediatric post-cardiac arrest neuro-prognostication studies. Data extraction and risk of bias were conducted by other members of the writing group.

CoSTR Citation

Scholefield BR, Tijssen J, Ganesan S, Topjian A, Bittencourt Couto T, Atkins D, Acworth J Guerguerian AM on behalf of the International Liaison Committee on Resuscitation Pediatric Life Support Task Force. Biomarkers for the prediction of survival with poor neurological outcome after return of circulation following pediatric cardiac arrest Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Pediatric Life Support Task Force, 2025 XXXX. Available from: http://ilcor.org

Methodological Preamble and Link to Published Systematic Review

The continuous evidence evaluation process for the production of Consensus on Science with Treatment Recommendations (CoSTR) started with a systematic review of tests for predicting good neurological outcome after pediatric cardiac arrest (Scholefield, 2021, PROSPERO CRD42021279221) conducted by the members of the PLS TF with involvement of clinical content experts. This review has been updated and reevaluated for the current systematic review on poor neurological outcome. Evidence for pediatric literature was sought and considered by the Pediatric Life Support Task Force. Additional scientific literature was published after the completion of the systematic review and identified by the Pediatric Task Force, and is described before the justifications and evidence to decision highlights section of this CoSTR. These data were taken into account when formulating the Treatment Recommendations.

Systematic Review

Scholefield BR et al. Clinical examination for the prediction of survival with poor neurological outcome after return of circulation following pediatric cardiac arrest (in preparation)

PICOST

The PICOST

Population: This review is studying children (<18 years) who achieve a return of spontaneous or mechanical circulation (ROC) after resuscitation from in-hospital cardiac arrest (IHCA) and out-of-hospital (OHCA), from any cause.

Intervention:

Clinical examination: Includes every part of a bedside neurological clinical examination, including pupillary response (assessed using manual light reflex or automated pupillometry), level of coma (eg, Glasgow Coma Scale score or Full Outline of Unresponsiveness [FOUR]) score), and brainstem reflexes.

Index prognostic tests, recorded less than 12 hours, 12 to <24 hours, 24 to <48 hours, 48 to <72 hours, 72 hours to <7 days, and/or 7 to 10 days after cardiac arrest.

Comparators: There was no control group for intervention/exposure. The accuracy of the prognostic index test was assessed by comparing the predicted outcome with the final outcome, which represents the comparator.

Outcomes: Primary outcome of interest is survival with poor neurological outcome is defined as a Pediatric Cerebral Performance Category (PCPC) score of >3, or Vineland Adaptive Behavioural scale-II <70. PCPC score ranges 1 (normal), 2 (mild disability), 3 (moderate disability), 4 (severe disability), 5 (coma), and 6 (brain death). We also report studies defining poor neurological outcomes with other assessment tools, or as a PCPC score >2, or change in PCPC score from baseline >2.

Study Designs: RCTs and nonrandomized studies (nonrandomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies) were eligible for inclusion. Case series were considered if greater than 5 cases were reported. Unpublished studies (eg, conference abstracts, trial protocols) and animal studies were excluded. We selected studies where the sensitivity and FPR of the prognostic (index) test were reported.

Timeframe: All years and all languages were included as long as there was an English abstract. Literature search updated to Aug 24^th 2024.

PROSPERO Registration CRD42021279221

Consensus on Science

Introduction

There is no universal consensus on what the acceptable limits for imprecision should be in prediction for infants and children after cardiac arrest. We defined poor neurological outcome prediction as imprecise when the false positive rate (FPR) was >1%. However, there is no universal consensus on what the acceptable limits for precision or imprecision should be for clinicians in prediction for infants and children after cardiac arrest. We defined the reliability of the evidence as reliable if the FPR was <1% and the upper 95% confidence intervals <10% and moderately reliable if FPR was <1% with without a restriction on width of 95% confidence interval.

A low false positive rate means that a low proportion of patients, predicted to have a poor outcome will have a falsely pessimistic prediction (test predicted a poor outcome, but patient went on to have a good outcome). The task force felt that when focused on accuracy of predicting a poor outcome - a low false positive rate (e.g. <1%) is more desirable to avoid falsely pessimistic prediction than a high sensitivity. The cut off of FPR <1% (equivalent to 99% specificity) was chosen as the consequences of false pessimism is substantial and may result in discontinuation of life sustaining therapy in a patient who will eventually have a good outcome.

Results

The overall quality of evidence for individual tests was rated as very low for all outcomes primarily due to a very serious risk of bias, assessed using the QUIPS tool. The studies were all at a moderate to high risk of bias due to confounding. Because of this and a high degree of heterogeneity, no meta-analyses could be performed.

Pupil Reactivity

The predictive ability of absence of pupillary light reflex to classify poor neurological outcome was evaluated in 9 studies (Abend 2012 32-8, Anton-Martin 2020 607-616, Brooks 2018 324-329, Ducharme-Crevier 2017 452-460, Fink 2014 664-674, Lin 2020 534, Nishisaki 2007 10-7, Oualha 2013 1306-12, Topjian 2021 282-288) in 402 patients within 1 hour, 6 to 12 hours, 24 hours, and 72 hours after resuscitation. Between <1 hour and 24 hours, 6/7 studies reported FPR >10% up to 60% for predicting poor neurological outcome. (Abend 2012 32-8, Ducharme-Crevier 2017 452-460, Fink 2014 664-674, Lin 2020 534, Nishisaki 2007 10-7, Topjian 2021 282-288) At 48 and 72 hours after ROC, FPR was less than 1% threshold but with wide confidence interval (95% CI 0-40%) and corresponding sensitivity for predicting poor outcome was 12-46%. (Abend 2012 32-8, Fink 2014 664-674, Oualha 2013 1306-12) No studies evaluated information from automated pupillometer monitoring devices. Pupil reactivity prior to 24 hours was not a reliable prognostic test. At 48 and 72 hours post ROC, pupil reactivity was a moderately reliable test for poor neurological outcome prediction.

Coma Level

The relationship between coma assessment using the GCS motor score alone or total GCS and poor neurological outcome was evaluated in 3 studies(Lin 2020 534, Lin 2013 439-47, Nishisaki 2007 10-7) including 296 patients. Outcomes were assessed at intensive care unit discharge, hospital discharge, and 6 months. GCS motor score of less than 4 within 1 hour and at 4 to 6 hours after ROC had a sensitivity of 94% and 93% for predicting poor neurological outcome at 6 months, with a high corresponding FPR of 83% and 50% respectively.(Lin 2020 534) Using total GCS measured at resuscitation or within 1 hour, a score of 4 or less predicted poor neurological outcome with a high sensitivity of 86% and an FPR of 70%.(Lin 2013 439-47) A total GCS score of 7 or less had a slightly higher sensitivity of 92%, with a FPR of 69%.(Nishisaki 2007 10-7) However, only 1 study was available to assess each test using total GCS or GCS motor score cutoff or at each testing time point. GCS was an unreliable test for poor outcome prediction.

Motor Response

The absence of a motor response to any stimulus was evaluated in 1 study.(Abend 2012 32-8) Sensitivity for prediction was 70%, 73% and 61% at <1 hour, 48 hours, and 72 hours after ROC with up to 27 patients. FPR only reached <1% (95% CI 0-28%) at 72 hours testing timepoint. Motor response was moderately reliable in only one study at 72 hours.

Brainstem Reflex

The presence of brainstem reflexes to predict poor neurological outcome at intensive care unit or hospital discharge was evaluated in 3 studies(Brooks 2018 324-329, Oualha 2013 1306-12, Topjian 2021 282-288) including 118 patients. Evoked responses to pain, gag reflex, and cough reflex were assessed at 6 to 12 hours, 24 hours and 72 hours. Predictive sensitivity of absence of pain response at 6 to 12 hours was 33% with an FPR of 0% (95%CI 0-15%).(Brooks 2018 324-329) The absence of a gag and cough reflex at 24 hours both predicted a poor neurological outcome with a sensitivity of 65-68% and FPR of 60% respectively.(Topjian 2021 282-288) Brainstem reflex was moderately reliable in only one test at 6-12 hours.

Treatment Recommendations

• We recommend that no single clinical examination test be used in isolation to predict poor neurological outcome in children after cardiac arrest at any time point (strong recommendation, very-low certainty evidence).
• Clinicians should consider using multiple tests in combination for poor neurological outcome prediction (good practice statement).
• The absence of pupil reactivity to light at 48 and 72 hours after ROC may be considered as part of multi-modal testing to predict poor neurological outcome in children after cardiac arrest (good practice statement).
• We suggest against using absence of pupil reactivity to light within 24 hours after ROC to predict poor neurological outcome in children after cardiac arrest (weak recommendation, low-certainty evidence).
• We suggest against using GCS within 24 hours after ROC to predict poor neurological outcome in children after cardiac arrest (weak recommendation, low-certainty evidence).
• There is insufficient evidence to make a recommendation for or against the use of other brainstem or motor response tests to predict poor neurological outcome in children after cardiac arrest at any time point.

Justification and Evidence to Decision Framework Highlights

• The available scientific evidence had a high risk of bias based on high heterogeneity across studies, small number of studies and small number of patients included in addition to lack of blinding, variation in test assessment and performance, and variability in outcome measurement. Therefore, no meta-analysis was performed. Overall assessment of test performance was based on visual assessment of forest plots.

• For total GCS, GCS motor score and overall motor response, and brain stem test, only one study was available (with small patient sample size) for each test and time point and therefore a suggestion or recommendation could not be made.

• For pupillary light reflex, limited evidence suggests that the FPR for prediction of poor neurological outcome up to 24 hours following ROC after cardiac arrest was high (5/7 studies reported FPR estimates from 10-60%) to recommend against the use of pupillary reactivity in this early stage. At 48 to 72 hours, the FPR was <1% in three studies: however, with wide 95% confidence interval.

• For all clinical examination modalities, the inaccuracy of outcome prediction tests may be due to confounding from the effect of sedatives used for delivery of neuroprotective interventions (e.g. targeted temperature management) or to facilitate ventilation.

• No studies reported any assessment of the confounding influence of medication. None of the included studies specifically excluded the presence of residual sedation at the time clinical examination was assessed.

No studies included blinding of test results from treating clinicians and only one study had blinded outcome assessment (for Pupil Light Reactivity). Lack of blinding is a major limitation of clinical examination tests studies.

• The studies inconsistently reported the co-intervention of temperature targeted management on the clinical assessments that will be affected by hypothermia.

• Despite its limitations, given the ease of conducting a bedside assessment the balance between the costs and benefits, favors benefits for the functional assessment of pupil light reactivity and coma.

Knowledge Gaps

• Clinical examination for prognostication after cardiac arrest appears promising but more research is required in infants and children.

• The evaluation of the impact of residual medication or temperature on pupillary light reflex assessment, coma score and motor response in infants and children is needed.

• No studies evaluated automated pupillometer monitoring devices, research is needed to assess cost and benefits of the use of pupillometry compared to pupillary light reflex assessment.

• Economic cost evaluation and cost-effectiveness studies are required.

• Further research is required on prognostication using multi-modal approaches, timing, definitions of testing, accurate outcome timing and outcome definition.

• We encourage wider research and consultation with patients, children, parents, guardians and caregivers, health care professionals and members of the wider society on understanding survivorship after pediatric cardiac arrest to inform correct definitions and framework of good neurological outcome for prediction research.

ETD summary table:

References

Abend NS, Topjian AA, Kessler SK, Gutierrez-Colina AM, Berg RA, Nadkarni V, et al. Outcome prediction by motor and pupillary responses in children treated with therapeutic hypothermia after cardiac arrest. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2012;13(1)32-8.

Anton-Martin P, Moreira A, Kang P, Green ML. Outcomes of paediatric cardiac patients after 30 minutes of cardiopulmonary resuscitation prior to extracorporeal support. Cardiology in the Young. 2020;30(5)607-616.

Brooks GA, Park JT. Clinical and Electroencephalographic Correlates in Pediatric Cardiac Arrest: Experience at a Tertiary Care Center. Neuropediatrics. 2018;49(5)324-329.

Ducharme-Crevier L, Press CA, Kurz JE, Mills MG, Goldstein JL, Wainwright MS. Early presence of sleep spindles on electroencephalography is associated with good outcome after pediatric cardiac arrest. Pediatric Critical Care Medicine. 2017;18(5)452-460.

Fink EL, Berger RP, Clark RSB, Watson RS, Angus DC, Richichi R, et al. Serum biomarkers of brain injury to classify outcome after pediatric Cardiac Arrest*. Critical Care Medicine. 2014;42(3)664-674.

Lin JJ, Hsu MH, Hsia SH, Lin YJ, Wang HS, Kuo HC, et al. Epileptiform Discharge and Electrographic Seizures during the Hypothermia Phase as Predictors of Rewarming Seizures in Children after Resuscitation. J Clin Med. 2020;9(7)534.

Lin YR, Wu HP, Chen WL, Wu KH, Teng TH, Yang MC, et al. Predictors of survival and neurologic outcomes in children with traumatic out-of-hospital cardiac arrest during the early postresuscitative period. The journal of trauma and acute care surgery. 2013;75(3)439-47.

Nishisaki A, Sullivan J, 3rd, Steger B, Bayer CR, Dlugos D, Lin R, et al. Retrospective analysis of the prognostic value of electroencephalography patterns obtained in pediatric in-hospital cardiac arrest survivors during three years. Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2007;8(1)10-7.

Oualha M, Gatterre P, Boddaert N, Dupic L, De Saint Blanquat L, Hubert P, et al. Early diffusion-weighted magnetic resonance imaging in children after cardiac arrest may provide valuable prognostic information on clinical outcome. Intensive Care Med. 2013;39(7)1306-12.

Topjian AA, Zhang B, Xiao R, Fung FW, Berg RA, Graham K, et al. Multimodal monitoring including early EEG improves stratification of brain injury severity after pediatric cardiac arrest. Resuscitation. 2021;167282-288.