Clinical examination for the prediction of survival with good neurological outcome after return of circulation following pediatric cardiac arrest: PLS TFSR

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 were recused from the discussion as they declared a conflict of interest: (none applicable)

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 and Conflict of Interest committees:

Dr Topjian was an author and investigator in pediatric post-cardiac arrest neuro-prognostication studies.

Dr Scholefield was an author and investigator in pediatric post-cardiac arrest neuro-prognostication studies and received UK NIHR funding for research into post-cardiac arrest neuro-prognostication research.

Dr Rodriguez-Nunez was an author and investigator in pediatric post-cardiac arrest neuro-prognostication studies.

CoSTR Citation

Barnaby R Scholefield, Janice Tijssen, Saptharishi Lalgudi Ganesan, Mirjam Kool, Alexis Topjian, Thomaz Bittencourt Couto, Anne-Marie Guerguerian on behalf of the International Liaison Committee on Resuscitation Pediatric Life Support Task Force.

Clinical examination for the prediction of survival with good 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, 2022 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 (Scholefield, 2021, PROSPERO CRD42021279221) conducted by the members of the PLS TF with involvement of clinical content experts. 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

Webmaster to insert the Systematic Review citation and link to Pubmed using this format when it is available if published

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

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

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

Studies which include newly born infants or patients in hypoxic coma from causes without a cardiac arrest (e.g., respiratory arrest, toxidromes, drowning, hanging) will be excluded, except when a subpopulation of cardiac arrest patients can be evaluated separately.

Intervention: Index prognostic tests, recorded less than 12 hours, 12 to <24 hours, 24 to <48 hours, 48 to <72 hours, 72hrs to <7 days, and/or 7 to 10 days after cardiac arrest and will include:

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 (e.g. Glasgow Coma Scale score or FOUR score) and brainstem reflexes.

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

Outcomes: Primary outcome of interest is survival with good neurological outcome*.

*Good neurological outcome is defined as a Pediatric Cerebral Performance Category (PCPC) score of 1, 2 or 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 will also report separately studies defining good neurological outcome with other assessment tools, or as a PCPC score 1 or 2, or change in PCPC score from baseline ≤ 2.

Outcome time point(s) will include hospital discharge, 30 days, 60 days, 180 days and/or 1 year.

Study Designs: Randomized controlled trials (RCTs) and non-randomized studies (non-randomized 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 reported. Unpublished studies (e.g., conference abstracts, trial protocols*) and animal studies were excluded. We selected studies where the sensitivity and false-positive rate (FPR) of the prognostic (index) test are reported.

*please note that the search for unpublished trials was limited to a comprehensive search of three clinical trial registries for unpublished completed trials.

1. International Clinical Trials Registry Platform (www.who.int/ictrp/en/)

2. US clinical trials registry (www.ClinicalTrials.gov)

3. Cochrane CENTRAL (http://www.cochranelibrary.com/about/central-landing-page.html)

Timeframe: All years and all languages were included as long as there was an English abstract; unpublished studies (e.g., conference abstracts, trial protocols) were excluded. Literature search updated to Feb 17^th 2022.

PROSPERO Registration CRD42021279221

Consensus on Science

Introduction

We defined good neurological outcome prediction as imprecise when the false positive rate (FPR) was above 30%. However, there is no universal consensus on what the acceptable limits for imprecision should be in prediction for infants and children after cardiac arrest.

A low false positive rate means that a low proportion of patients, predicted to have a good outcome will have a falsely optimistic prediction (test predicted a good outcome, but patient went on to have a bad outcome). The task force felt that when focused on accurate good outcome prediction - a low false positive rate (eg <30%) is more desirable to avoid falsely optimistic prediction than a high sensitivity. The cut off of 30% FPR (equivalent to 70% specificity) was chosen as the consequences of false optimism were felt by the task force to be less critical than false pessimism. False optimism may result in continued life sustaining therapy in a patient who will eventually have a poor outcome. This will involve increased resources and treatment; however, will allow more time for further prognostic evaluation. Also reasons for not achieving a very low false positive rate may be non-neurological causes of poor outcome or death, not attributable to the index test assessment.

A high sensitivity means the majority of patients who have the good outcome tested positive and therefore a low proportion will have a falsely pessimistic prediction (test predicted a poor outcome, but patient went on to have a good outcome). When considering accurate poor outcome prediction, then a high sensitivity (with a corresponding low rate of falsely pessimistic prediction) is more desirable than a low false positive rate. Our cut off threshold for considering precise sensitivity was higher (>95%), as the consequences of false pessimism may be a decision to limit or withdraw life sustaining therapy in a patient who will have a good neurological outcome and therefore greater precision in prognostic accuracy is required.

Results

The overall quality of evidence was rated as very low for all outcomes primarily due to a very serious risk of bias, assessed using the QUIPS tool. The individual 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 presence of pupil reactivity to classify good neurological outcome was evaluated in 8 studies [Abend 2012 32, Anton-Martin 2020 607, Brooks 2018 324, Ducharme-Crevier 2017 452, Fink 2014 664, Topjian 2021 282, Nishisaki 2007 10, Lin 2020 534], in 402 patients, within 1 hour, 6-12 h, 24h, and 72 h post-resuscitation. Most studies had a sensitivity greater than 82% at all assessment time points with the exception of Lin 2020 (50%) and Anton-Martin 2020 (40%) and corresponding FPR ranged from 3.2% to 67%. Within 12 hours of ROC the FPR was less than 33% in 3 out of 4 studies reporting this time period [Anton-Martin 2020 607, Brooks 2018 324, Lin 2020 534]. FPR increased (38-68%) at 24-72 hours and corresponding sensitivity for predicting good neurological outcome was 100% at 48-72 hrs following ROC [Abend 2012 32, Fink 2014 664]. No studies evaluated automated pupillometer monitoring devices.

Coma level

The relationship between coma assessment using the Glasgow Coma Score (GCS) motor score alone, or total GCS and good neurological outcome at intensive care unit or hospital discharge and 6 months, were evaluated in 3 studies [Nishisaki 2007 10, Lin 2013 285, Lin 2020 534] in 296 patients. In one study, GCS motor score ≥4 within 1 hour and at 4-6 hours post ROC, for predicting good neurological outcome at 6 months, had a sensitivity of 17 and 50% with a corresponding FPR of 6 and 7%, respectively [Lin 2020 534]. Using total GCS measured at resuscitation or within 1 hour, a score of ≥5 predicted good neurological outcome with a low sensitivity of 30% and a FPR of 14% [Lin 2013 285]. Whereas, using a total GCS score ≥8 had a slightly higher sensitivity of 31% with a low FPR of 6% [Nishisaki 2007 10]. However, only one study was available to assess each test using total GCS or GCS motor score cut off, or at each testing time point.

Motor response

The presence of a motor response to any stimulus was evaluated in 1 study [Abend 2012 32] at <1h, 48, and 72 hours post return of circulation with up to 27 patients. Sensitivity and FPR improved for time since return of circulation, where if performed at <1h post ROC the sensitivity was 38% and FPR was 30%, whereas at 72h the sensitivity was 100% and the FPR was 23%.

Brainstem reflex

The presence of brain stem reflexes to predict good neurological outcome at intensive care unit or hospital discharge were evaluated in 2 studies [Brooks 2018 324, Topjian 2021 282] which included 118 patients. Evoked response to pain, gag reflex, and cough reflex were assessed at 6-12 hours, and 24h. Predictive sensitivity of presence of pain response at 6-12 hours was 100% with a FPR of 67% [Brooks 2018 324]. A present gag and cough reflex at 24h both predicted a good neurological outcome with a sensitivity of 40% and FPR of 32- 35%, respectively [Topjian 2021 282].

Treatment Recommendations

• All evaluated tests were used in combination with other tests by clinicians in these studies. Although the predictive accuracy of tests were evaluated individually, we recommend that no single test should be used in isolation for prediction of good neurological outcome (good practice statement).

• We suggest using pupillary light reflex within 12 hours after ROC for predicting good neurological outcome in children after cardiac arrest (weak recommendation, very-low-certainty evidence).

• We cannot make a recommendation for or against using total GCS, GCS motor score or motor response after ROC for predicting good neurological outcome in children after cardiac arrest (weak recommendation, very-low-certainty evidence).

• We cannot make a recommendation for or against the use of brainstem tests after ROC for predicting good neurological outcomes in children after cardiac arrest (weak recommendation, very-low-certainty evidence).

Justification and Evidence to Decision Framework Highlights

• The Task Force considered the use of individual clinical examination tests to help the clinician in predicting a good neurological outcome. This assessment is different to predicting a poor neurological outcome, which may involve consideration of withdrawal of life sustaining therapies. Recommendations for or against tests to predict good neurological outcomes cannot be transferred to recommendations for poor outcome prediction.

• 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 specificity for prediction of good neurological outcome was highest within 12 hours of ROC after cardiac arrest. There was increased sensitivity (up to 100%) for predicting good outcomes at 48 to 72 hours; however, the point estimates had wide 95% confidence intervals. Pupillary light reflex at 48-72 should be evaluated for use for predicting poor neurological outcome at these time points.

• For all clinical examination modalities in accuracy 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, even if the withdrawal of life-sustaining therapy based on clinical examination has not been documented in any of the studies included in our review.

• The studies inconsistently reported the co-intervention of temperature targeted management on the clinical assessments.

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

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 multi-modal prognostication, 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.

Attachments:

Clinical exam pupillary light reflex ETD

Clinical exam motor response ETD

Clinical exam comascore ETD

Clinical exam brainstem reflex ETD

References

ABEND, N. S., TOPJIAN, A. A., KESSLER, S. K., GUTIERREZ-COLINA, A. M., BERG, R. A., NADKARNI, V., DLUGOS, D. J., CLANCY, R. R. & ICHORD, R. N. 2012. 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, 13, 32.

ANTON-MARTIN, P., MOREIRA, A., KANG, P. & GREEN, M. L. 2020. Outcomes of paediatric cardiac patients after 30 minutes of cardiopulmonary resuscitation prior to extracorporeal support. Cardiology in the Young, 30, 607.

BROOKS, G. A. & PARK, J. T. 2018. Clinical and Electroencephalographic Correlates in Pediatric Cardiac Arrest: Experience at a Tertiary Care Center. Neuropediatrics, 49, 324.

DUCHARME-CREVIER, L., PRESS, C. A., KURZ, J. E., MILLS, M. G., GOLDSTEIN, J. L. & WAINWRIGHT, M. S. 2017. Early presence of sleep spindles on electroencephalography is associated with good outcome after pediatric cardiac arrest. Pediatric Critical Care Medicine, 18, 452.

FINK, E. L., BERGER, R. P., CLARK, R. S. B., WATSON, R. S., ANGUS, D. C., RICHICHI, R., PANIGRAHY, A., CALLAWAY, C. W., BELL, M. J. & KOCHANEK, P. M. 2014. Serum biomarkers of brain injury to classify outcome after pediatric Cardiac Arrest*. Critical Care Medicine, 42, 664.

LIN, J. J., HSIA, S. H., WANG, H. S., CHIANG, M. C. & LIN, K. L. 2013. Therapeutic hypothermia associated with increased survival after resuscitation in children. Pediatric Neurology, 48, 285.

LIN, J. J., LIN, Y. J., HSIA, S. H., KUO, H. C., WANG, H. S., HSU, M. H., CHIANG, M. C., LIN, C. Y. & LIN, K. L. 2020. Early Clinical Predictors of Neurological Outcome in Children With Asphyxial Out-of-Hospital Cardiac Arrest Treated With Therapeutic Hypothermia. Frontiers in Pediatrics, 7, 534.

NISHISAKI, A., SULLIVAN, J., 3RD, STEGER, B., BAYER, C. R., DLUGOS, D., LIN, R., ICHORD, R., HELFAER, M. A. & NADKARNI, V. 2007. Retrospective analysis of the prognostic value of electroencephalography patterns obtained in pediatric in-hospital cardiac arrest survivors during three years. Pediatr Crit Care Med, 8, 10.

TOPJIAN, A. A., ZHANG, B., XIAO, R., FUNG, F. W., BERG, R. A., GRAHAM, K. & ABEND, N. S. 2021. Multimodal monitoring including early EEG improves stratification of brain injury severity after pediatric cardiac arrest. Resuscitation, 167, 282.