Brain Imaging for the prediction of poor neurological outcome after return of circulation following pediatric cardiac arrest: PLS 4220.04 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. Brain Imaging 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 poor 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 B et al. Brain Imaging 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.

Studies which include newborn infants or patients in hypoxic coma from causes other than cardiac arrest (e.g., respiratory arrest, toxidromes, drowning, hanging) were excluded, except when a subpopulation of cardiac arrest patients can be evaluated separately.

Intervention: Imaging: Neuroimaging modalities which included head computed tomography (CT) and brain magnetic resonance imaging (MRI).

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 precision or imprecision should be for clinicians 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%. 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 pediatric task force considered 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 <1% FPR (equivalent to 99% specificity) was chosen as the consequences of false pessimism is substantial and may result in advising 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.

Computed Tomography (CT) Imaging

Head CT was evaluated in three studies and reported the relationship to poor neurological outcome (PCPC >3) in 173 patients. (Fink 2014 664-674, Starling 2015 542-548, Yang 2019 223) The majority of CT imaging was acquired at 24 h or 48 h after the cardiac arrest. Neurological outcome was assessed on discharge from the intensive care unit or hospital in two studies (Fink 2014 664-674, Starling 2015 542-548) and at six months in one.(Yang 2019 223)

The absence of GWM (gray-white matter) differentiation was reported in one study with a FPR 0% (95%CI 0-12%) and sensitivity 65% for poor outcome prediction. Presence of reversal sign on CT at 24 hours was reported in two studies with a range of FPR of 0% to 36%,and corresponding sensitivity of 20 to 30% for poor outcome prediction.(Starling 2015 542-548, Yang 2019 223) Presence of effacement of sulci or basal cisterns at 24 hours predicted poor neurological outcome with a low FPR (0-7%; range of 95% CI 0-30%).(Starling 2015 542-548, Yang 2019 223) Presence of CT lesions, oedema, or intracranial hemorrhage predicted poor neurological outcome with a FPR 7-17%; however, sensitivity ranged 11 to 68%. Clinicians were not blinded to the CT results in any study. CT reported GWM differentiation at 24 hours was a moderately reliable test, but only reported in a single study. All other CT reported tests at 24 and 48 hours were unreliable for poor neurological outcome prediction.

Magnetic Resonance Imaging (MRI)

MRI imaging was reported in five studies, including 305 patients, to predict poor neurological outcomes. (Bach 2024 e209134, Fink 2013 31-40, Fink 2020 185-194, Kirschen 2021 e719-e731, Yacoub 2019 103-109) Median time from ROC to MRI ranged 3 to 6 days across all studies with inclusion of patients MRI up to 14 days reported in three studies. (Fink 2013 31-40, Kirschen 2021 e719-e731, Yacoub 2019 103-109)

An ADC (apparent diffusion coefficient) threshold <650x10^-6 mm²/s in ≥10% of brain volume (indicating high ischemic burden), at a median of 4 days after ROC, predicted poor neurological outcome with a sensitivity of 49-52% and FPR 0-6% (95% 1-21%) in 3 studies.(Bach 2024 e209134, Kirschen 2021 e719-e731, Yacoub 2019 103-109) One study using ADC thresholds to identify high ischemic burden fulfilled the low FPR <1% with moderate reliability for poor neurological outcome prediction.(Yacoub 2019 103-109)

Any region of abnormality on restricted diffusion, at a median of 4 days after ROC, predicted poor neurological outcome with a range of FPR 12% to 58% and corresponding sensitivity of 98% to 100%. (Kirschen 2021 e719-e731, Oualha 2013 1306-1312) An abnormal MRI by qualitative reporting of presence of hypoxic ischemic injury, predicted a poor neurological outcome at 6 months with a FPR of 19% and sensitivity of 90%.(Yacoub 2019 103-109)

Three studies reported up to 14 different individual regions of the brain, at 4-6 days post ROC with DWI, T1 and T2 weighted imaging.(Fink 2013 31-40, Fink 2020 185-194, Oualha 2013 1306-1312) FPR for outcome prediction was predominately 0-10% but upper limits of the 95% CI ranged widely from 20-50%.

Overall, only one study using ADC thresholds fulfilled the low FPR <1% with moderate reliability for poor neurological outcome prediction.

Treatment Recommendations

• We recommend no single imaging test be used alone 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).

• An abnormal MRI showing high ischemic burden on ADC mapping at 72 hours and beyond after ROC or CT scan showing loss of GWM Differentiation within 24 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).

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.

• If only one study was available (with small patient sample size) then a suggestion or recommendation could not be made.

• The low false positive rate (high specificity) for abnormal MRI on global assessment for predicting poor neurological outcome reduces the chance of false pessimism if an abnormal MRI predicts a poor neurological outcome. FPR <1% was only recording for one study for global assessment of brain injury. Low FPR was identified during regional brain assessment, however only in a small number of cases, with wide confidence limits on the point estimate.

• The sensitivity of abnormal MRI or CT to predict a poor neurological outcome is moderate to high, but up to 40% may be falsely categorized and a falsely pessimistic prediction made. Therefore, with the very-low certainty of evidence, we cannot make a treatment recommendation for or against the use of abnormal MRI or CT for predicting poor neurological outcomes as single tests. However, we encourage further research in this area as these modalities appear promising.

• The precision of MRI and CT is affected by the timing of the investigation and is at risk of pseudo-normalization.

• The definition of a presence DWI or cut off values for ADC level on MRI, or GWR on CT was inconsistent in the included studies.

• MRI and CT are both expensive tests and require specialist equipment, training, interpretation and most often, patient transport to obtain the information. This may be prohibitive in physiologically unstable patients, or some health care settings.

Knowledge Gaps

• Neuro-imaging for prognostication after cardiac arrest appears promising but more research is required in infants and children.

• A standardization of definitions and assessment of optimal thresholds for GWR calculation on CT, and DWI, ADC thresholds on MRI is needed.

• The optimal timing for prognostication using CT and MRI after cardiac arrest is still unknown. Studies assessing serial imaging after cardiac arrest are desirable.

• The role of assessing regional areas of the brain for predicting outcome, or the use of Magnetic Resonance Spectroscopy requires further research.

• Economic cost evaluation and cost-effectiveness studies are required as CT and MRI are expensive diagnostic and prognostic modalities.

• Further work on multi-modal prognostication, timing, definitions of testing, accurate outcome timing and 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 neurological outcome for prediction research.

ETD summary table: PLS 4220 04 Posr ROC Poor Imaging CTMRI ETD

References

Bach AM, Kirschen MP, Fung FW, Abend NS, Ampah S, Mondal A, et al. Association of EEG Background With Diffusion-Weighted Magnetic Resonance Neuroimaging and Short-Term Outcomes After Pediatric Cardiac Arrest. Neurology. 2024;102(5)e209134.

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.

Fink EL, Panigrahy A, Clark RSB, Fitz CR, sittel D, Kochanek PM, et al. Regional brain injury on conventional and diffusion weighted MRI is associated with outcome after pediatric cardiac arrest. Neurocritical Care. 2013;19(1)31-40.

Fink EL, Wisnowski J, Clark R, Berger RP, Fabio A, Furtado A, et al. Brain MR imaging and spectroscopy for outcome prognostication after pediatric cardiac arrest. Resuscitation. 2020;157185-194.

Kirschen MP, Licht DJ, Faerber J, Mondal A, Graham K, Winters M, et al. Association of MRI brain injury with outcome after pediatric out-of-hospital cardiac arrest. Neurology. 2021;96e719-e731.

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 Medicine. 2013;39(7)1306-1312.

Starling RM, Shekdar K, Licht D, Nadkarni VM, Berg RA, Topjian AA. Early head CT findings are associated with outcomes after pediatric out-of-hospital cardiac arrest. Pediatric Critical Care Medicine. 2015;16(6)542-548.

Yacoub M, Birchansky B, Mlynash M, Berg M, Knight L, Hirsch KG, et al. The prognostic value of quantitative diffusion-weighted MRI after pediatric cardiopulmonary arrest. Resuscitation. 2019;135103-109.

Yang D, Ryoo E, Kim HJ. Combination of early EEG, brain CT, and ammonia level is useful to predict neurologic outcome in children resuscitated from cardiac arrest. Frontiers in Pediatrics. 2019;7223.