Performance of a guideline-recommended algorithm for prognostication of poor neurological outcome after cardiac arrest.

PURPOSE: To assess the performance of a 4-step algorithm for neurological prognostication after cardiac arrest recommended by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM). METHODS: Retrospective descriptive analysis with data from the Target Temperature Management (TTM) Trial. Associations between predicted and actual neurological outcome were investigated for each step of the algorithm with results from clinical neurological examinations, neuroradiology (CT or MRI), neurophysiology (EEG and SSEP) and serum neuron-specific enolase. Patients examined with Glasgow Coma Scale Motor Score (GCS-M) on day 4 (72-96 h) post-arrest and available 6-month outcome were included. Poor outcome was defined as Cerebral Performance Category 3-5. Variations of the ERC/ESICM algorithm were explored within the same cohort. RESULTS: The ERC/ESICM algorithm identified poor outcome patients with 38.7% sensitivity (95% CI 33.1-44.7) and 100% specificity (95% CI 98.8-100) in a cohort of 585 patients. An alternative cut-off for serum neuron-specific enolase, an alternative EEG-classification and variations of the GCS-M had minor effects on the sensitivity without causing false positive predictions. The highest overall sensitivity, 42.5% (95% CI 36.7-48.5), was achieved when prognosticating patients irrespective of GCS-M score, with 100% specificity (95% CI 98.8-100) remaining. CONCLUSION: The ERC/ESICM algorithm and all exploratory multimodal variations thereof investigated in this study predicted poor outcome without false positive predictions and with sensitivities 34.6-42.5%. Our results should be validated prospectively, preferably in patients where withdrawal of life-sustaining therapy is uncommon to exclude any confounding from self-fulfilling prophecies.

Serum GFAP and UCH-L1 for the prediction of neurological outcome in comatose cardiac arrest patients.

OBJECTIVE: Neurological outcome prediction is crucial early after cardiac arrest. Serum biomarkers released from brain cells after hypoxic-ischaemic injury may aid in outcome prediction. The only serum biomarker presently recommended in the European Resuscitation Council prognostication guidelines is neuron-specific enolase (NSE), but NSE has limitations. In this study, we therefore analyzed the outcome predictive accuracy of the serum biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in patients after cardiac arrest. METHODS: Serum GFAP and UCH-L1 were collected at 24, 48 and 72 h after cardiac arrest. The primary outcome was neurological function at 6-month follow-up assessed by the cerebral performance category scale (CPC), dichotomized into good (CPC1-2) and poor (CPC3-5). Prognostic accuracies were tested with receiver-operating characteristics by calculating the area under the receiver-operating curve (AUROC) and compared to the AUROC of NSE. RESULTS: 717 patients were included in the study. GFAP and UCH-L1 discriminated between good and poor neurological outcome at all time-points when used alone (AUROC GFAP 0.88-0.89; UCH-L1 0.85-0.87) or in combination (AUROC 0.90-0.91). The combined model was superior to GFAP and UCH-L1 separately and NSE (AUROC 0.75-0.85) at all time-points. At specificities ≥95%, the combined model predicted poor outcome with a higher sensitivity than NSE at 24 h and with similar sensitivities at 48 and 72 h. CONCLUSION: GFAP and UCH-L1 predicted poor neurological outcome with high accuracy. Their combination may be of special interest for early prognostication after cardiac arrest where it performed significantly better than the currently recommended biomarker NSE.

Serum Neurofilament Light Chain for Prognosis of Outcome After Cardiac Arrest.

Importance: Prognostication of neurologic outcome after cardiac arrest is an important but challenging aspect of patient therapy management in critical care units. Objective: To determine whether serum neurofilament light chain (NFL) levels can be used for prognostication of neurologic outcome after cardiac arrest. Design, Setting and Participants: Prospective clinical biobank study of data from the randomized Target Temperature Management After Cardiac Arrest trial, an international, multicenter study with 29 participating sites. Patients were included between November 11, 2010, and January 10, 2013. Serum NFL levels were analyzed between August 1 and August 23, 2017, after trial completion. A total of 782 unconscious patients with out-of-hospital cardiac arrest of presumed cardiac origin were eligible. Exposures: Serum NFL concentrations analyzed at 24, 48, and 72 hours after cardiac arrest with an ultrasensitive immunoassay. Main Outcomes and Measures: Poor neurologic outcome at 6-month follow-up, defined according to the Cerebral Performance Category Scale as cerebral performance category 3 (severe cerebral disability), 4 (coma), or 5 (brain death). Results: Of 782 eligible patients, 65 patients (8.3%) were excluded because of issues with aliquoting, missing sampling, missing outcome, or transport problems of samples. Of the 717 patients included (91.7%), 580 were men (80.9%) and median (interquartile range [IQR]) age was 65 (56-73) years. A total of 360 patients (50.2%) had poor neurologic outcome at 6 months. Median (IQR) serum NFL level was significantly increased in the patients with poor outcome vs good outcome at 24 hours (1426 [299-3577] vs 37 [20-70] pg/mL), 48 hours (3240 [623-8271] vs 46 [26-101] pg/mL), and 72 hours (3344 [845-7838] vs 54 [30-122] pg/mL) (P < .001 at all time points), with high overall performance (area under the curve, 0.94-0.95) and high sensitivities at high specificities (eg, 69% sensitivity with 98% specificity at 24 hours). Serum NFL levels had significantly greater performance than the other biochemical serum markers (ie, tau, neuron-specific enolase, and S100). At comparable specificities, serum NFL levels had greater sensitivity for poor outcome compared with routine electroencephalogram, somatosensory-evoked potentials, head computed tomography, and both pupillary and corneal reflexes (ranging from 29.2% to 49.0% greater for serum NFL level). Conclusions and Relevance: Findings from this study suggest that the serum NFL level is a highly predictive marker of long-term poor neurologic outcome at 24 hours after cardiac arrest and may be a useful complement to currently available neurologic prognostication methods.

Head computed tomography for prognostication of poor outcome in comatose patients after cardiac arrest and targeted temperature management.

INTRODUCTION: A multimodal approach to prognostication of outcome after cardiac arrest (CA) is recommended. Evidence for combinations of methods is low. In this post-hoc analysis we described findings on head computed tomography (CT) after CA. We also examined whether generalised oedema on CT alone or together with the biomarker Neuron-specific enolase (NSE) could predict poor outcome. METHODS: Patients participating in the Target Temperature Management after out-of-hospital-cardiac-arrest-trial underwent CT based on clinical indications. Findings were divided into pre-specified categories according to local radiologists descriptions. Generalised oedema alone and in combination with peak NSE at either 48h or 72h was correlated with poor outcome at 6 months follow-up using the Cerebral Performance Category (CPC 3-5). RESULTS: 356/939 (37.9%) of patients underwent head CT. Initial CT≤24h after CA was normal in 174/218 (79.8%), whilst generalised oedema was diagnosed in 21/218 (9.6%). Between days 1-7, generalised oedema was seen in 65/143 (45.5%), acute/subacute infarction in 27/143 (18.9%) and bleeding in 9/143 (6.3%). Overall, generalised oedema predicted poor outcome with 33.6% sensitivity (95%CI:28.1-39.5) and 98.4% specificity (95%CI:94.3-99.6), whilst peak NSE demonstrated sensitivities of 61.5-64.8% and specificity 95.7% (95%CI:89.5-98.4). The combination of peak NSE>38ng/l and generalised oedema on CT predicted poor outcome with 46.0% sensitivity (95%CI:36.5-55.8) with no false positives. NSE was significantly higher in patients with generalised oedema. CONCLUSION: In this study, generalised oedema was more common >24h≤7d after CA. The combination of CT and NSE improved sensitivity and specificity compared to CT alone, with no false positives in this limited population.

Protocol-driven neurological prognostication and withdrawal of life-sustaining therapy after cardiac arrest and targeted temperature management.

BACKGROUND: Brain injury is reportedly the main cause of death for patients resuscitated after out-of-hospital cardiac arrest (OHCA). However, the majority may actually die following withdrawal of life-sustaining therapy (WLST) with a presumption of poor neurological recovery. We investigated how the protocol for neurological prognostication was used and how related treatment recommendations might have affected WLST decision-making and outcome after OHCA in the targeted temperature management (TTM) trial. METHODS: Analyses of prospectively recorded data: details of neurological prognostication; recommended level-of-care; WLST decisions; presumed cause of death; and cerebral performance category (CPC) 6 months following randomization. RESULTS: Of 939 patients, 452 (48%) woke and 139 (15%) died, mostly for non-neurological reasons, before a scheduled time point for neurological prognostication (72h after the end of TTM). Three hundred and thirteen (33%) unconscious patients underwent prognostication at a median 117 (IQR 93-137) hours after arrest. Thirty-three (3%) unconscious patients were not neurologically prognosticated and for 2 patients (1%) data were missing. Related care recommendations were: continue in 117 (37%); not escalate in 55 (18%); and withdraw in 141 (45%). WLST eventually occurred in 196 (63%) at median day 6 (IQR 5-8). At 6 months, only 2 patients with WLST were alive and 248 (79%) of prognosticated patients had died. There were significant differences in time to WLST and death after the different recommendations (log rank <0.001). CONCLUSION: Delayed prognostication was relevant for a minority of patients and related to subsequent decisions on level-of-care with effects on ICU length-of-stay, survival time and outcome.

Electroencephalographic characteristics of status epilepticus after cardiac arrest.

OBJECTIVE: To describe the electrophysiological characteristics and pathophysiological significance of electrographic status epilepticus (ESE) after cardiac arrest and specifically compare patients with unequivocal ESE to patients with rhythmic or periodic borderline patterns defined as possible ESE. METHODS: Retrospective cohort study of consecutive patients treated with targeted temperature management and monitored with simplified continuous EEG. Patients with ESE were identified and electrographically characterised until 72h after ESE start using the standardised terminology of the American Clinical Neurophysiology Society. RESULTS: ESE occurred in 41 of 127 patients and 22 fulfilled the criteria for unequivocal ESE, which typically appeared early and transiently. Three of the four survivors had unequivocal ESE, starting after rewarming from a continuous background. There were no differences between the groups of unequivocal ESE and possible ESE regarding outcome, neuron-specific enolase levels or prevalence of reported clinical convulsions. CONCLUSION: ESE is common after cardiac arrest. The distinction between unequivocal and possible ESE patterns was not reflected by differences in clinical features or survival. SIGNIFICANCE: A favourable outcome is seen infrequently in patients with ESE, regardless of using strict or liberal ESE definitions.

The rate of brain death and organ donation in patients resuscitated from cardiac arrest: a systematic review and meta-analysis.

BACKGROUND: The occurrence of brain death in patients with hypoxic-ischaemic brain injury after resuscitation from cardiac arrest creates opportunities for organ donation. However, its prevalence is currently unknown. METHODS: Systematic review. MEDLINE via PubMed, ISI Web of Science and the Cochrane Database of Systematic Reviews were searched for eligible studies (2002-2016). The prevalence of brain death in adult patients resuscitated from cardiac arrest and the rate of organ donation among brain dead patients were summarised using a random effect model with double-arcsine transformation. The quality of evidence (QOE) was evaluated according to the GRADE guidelines. RESULTS: 26 studies [16 on conventional cardiopulmonary resuscitation (c-CPR), 10 on extracorporeal CPR (e-CPR)] included a total of 23,388 patients, 1830 of whom developed brain death at a mean time of 3.2 ± 0.4 days after recovery of circulation. The overall prevalence of brain death among patients who died before hospital discharge was 12.6 [10.2-15.2] %. Prevalence was significantly higher in e-CPR vs. c-CPR patients (27.9 [19.7-36.6] vs. 8.3 [6.5-10.4] %; p < 0.0001). The overall rate of organ donation among brain dead patients was 41.8 [20.2-51.0] % (9/26 studies, 1264 patients; range 0-100 %). The QOE was very low for both outcomes. CONCLUSIONS: In patients with hypoxic-ischaemic brain injury following CPR, more than 10 % of deaths were due to brain death. More than 40 % of brain-dead patients could donate organs. Patients who are unconscious after resuscitation from cardiac arrest, especially when resuscitated using e-CPR, should be carefully screened for signs of brain death.

Outcome following postanoxic status epilepticus in patients with targeted temperature management after cardiac arrest.

BACKGROUND: Postanoxic electrographic status epilepticus (ESE) is considered a predictor of poor outcome in resuscitated patients after cardiac arrest (CA). Observational data suggest that a subgroup of patients may have a good outcome. This study aimed to describe the prevalence of ESE and potential clinical and electrographic prognostic markers. METHODS: In this retrospective single study, we analyzed consecutive patients who suffered from CA, and who received temperature management and were monitored with simplified continuous EEG (cEEG) during a five-year period. The patients' charts and cEEG data were initially screened to identify patients with clinical seizures or ESE. The cEEG diagnosis of ESE was retrospectively reanalyzed according to strict criteria by a neurophysiologist blinded to patient outcome. The EEG background patterns prior to the onset of ESE, duration of ESE, presence of clinical seizures, and use of antiepileptic drugs were analyzed. The results of somatosensory-evoked potentials (SSEPs) and neuron-specific enolase (NSE) at 48 h after CA were described in all patients with ESE. Antiepileptic treatment strategies were not protocolized. Outcome was evaluated using the Cerebral Performance Category (CPC) scale at 6 months, and good outcome was defined as CPC 1-2. RESULTS: Of 127 patients, 41 (32%) developed ESE. Twenty-five patients had a discontinuous EEG background prior to ESE, and all died without regaining consciousness. Sixteen patients developed a continuous EEG background prior to the start of ESE, four of whom survived, three with CPC 1-2 and one with CPC 3 at 6 months. Among survivors, ESE developed at a median of 46 h after CA. All had preserved N20 peaks on SSEP and NSE values of 18-37 µg/l. CONCLUSION: Electrographic status epilepticus is common among comatose patients after cardiac arrest, with few survivors. A combination of a continuous EEG background prior to ESE, preserved N20 peaks on SSEPs, and low or moderately elevated NSE levels may indicate a good outcome. This article is part of a Special Issue entitled "Status Epilepticus".

Neurological prognostication after cardiac arrest and targeted temperature management 33°C versus 36°C: Results from a randomised controlled clinical trial.

BACKGROUND: The reliability of some methods of neurological prognostication after out-of-hospital cardiac arrest has been questioned since the introduction of induced hypothermia. The aim of this study was to determine whether different treatment temperatures after resuscitation affected the prognostic accuracy of clinical neurological findings and somatosensory evoked potentials (SSEP) in comatose patients. METHODS: We calculated sensitivity and false positive rate for Glasgow Coma Scale motor score (GCS M), pupillary and corneal reflexes and SSEP to predict poor neurological outcome using prospective data from the Target Temperature Management after Out-of-Hospital Cardiac Arrest Trial which randomised 939 comatose survivors to treatment at either 33 °C or 36 °C. Poor outcome was defined as severe disability, vegetative state or death (Cerebral Performance Category scale 3-5) at six months. RESULTS: 313 patients (33%) were prognostically assessed; 168 in the 33 °C, and 145 in the 36 °C group. A GCS M ≤ 2 had a false positive rate of 19.1% to predict poor outcome due to nine false predictions. Bilaterally absent pupillary reflexes had a false positive rate of 2.1% and absent corneal reflexes had a false positive rate of 2.2% due to one false prediction in each group. The false positive rate for bilaterally absent SSEP N20-peaks was 2.6%. CONCLUSIONS: Bilaterally absent pupillary and corneal reflexes and absent SSEP N20-peaks were reliable markers of a poor prognosis after resuscitation from out-of-hospital cardiac arrest but low GCS M score was not. The reliability of the tests was not altered by the treatment temperature.

The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest.

BACKGROUND: Brain injury is considered the main cause of death in patients who are hospitalized after cardiac arrest (CA). Induced hypothermia is recommended as neuroprotective treatment after (CA) but may affect prognostic parameters. We evaluated the effect of delayed neurological prognostication on the mode of death in hypothermia-treated CA-survivors. STUDY DESIGN: Retrospective study at a Swedish university hospital, analyzing all in-hospital and out-of-hospital CA-patients treated with hypothermia during a 5-year period. Cause of death was categorized as brain injury, cardiac disorder or other. Multimodal neurological prognostication and decision on level of care was performed in comatose patients 72 h after rewarming. Neurological function was evaluated by Cerebral Performance Categories scale (CPC). RESULTS: Among 162 patients, 76 survived to hospital discharge, 65 of whom had a good neurological outcome (CPC 1-2), and 11 were severely disabled (CPC 3). No patient was in vegetative state. The cause of death was classified as brain injury in 61 patients, cardiac disorder in 14 and other in 11. Four patients were declared brain dead and became organ donors. They were significantly younger (median 40 years) and with long time to ROSC. Active intensive care was withdrawn in 50 patients based on a statement of poor neurological prognosis at least 72 h after rewarming. These patients died, mainly from respiratory complications, at a median 7 days after CA. CONCLUSION: Following induced hypothermia and delayed neurological prognostication, brain injury remains the main cause of death after CA. Most patients with a poor prognosis statement died within 2 weeks.