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Neurological prognostication after cardiac arrest and targeted temperature management 33°C versus 36°C: Results from a randomized controlled clinical trial
Abstract
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.
We calculated sensitivity and false positive rate for Glasgow Coma Scale motor score (GCSM), 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.
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%.
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.
Copyright © 2015. Published by Elsevier Ireland Ltd.
... The GCS motor scores less than three at three days after ROSC in PCAS patients not treated with TTM strongly predict poor outcomes (false positive rate 0-3%) [2]. On the other hand, in PCAS patients treated with TTM, the GCS motor scores less than three at three days after normothermia or five days after ROSC may not always predict poor outcomes (false positive rate 19%) [11,12]. The GCS motor scores more than three before initiation of TTM strongly predict good outcomes [13]. ...
... The absence of PLR three days after ROSC in PCAS patients not treated with TTM strongly predicts poor outcomes (false positive rate 0-3%) [2]. On the other hand, in PCAS patients treated with TTM, the absence of PLR at three days after normothermia or five days after ROSC remains predictive for poor outcomes with a 2.1% false-positive rate [11,14]. Thus, early absent PLR after ROSC before initiation of TTM may not always predict poor outcomes [15]. ...
... The absence of bilateral corneal reflex three days after ROSC in PCAS patients not treated with TTM strongly predicts poor outcomes (false positive rate 0-3%) [2]. On the other hand, in PCAS patients treated with TTM, the absence of bilateral corneal reflex at three days after normothermia or five days after ROSC remains predictive for poor outcomes with a 2.2% false-positive rate [11]. ...
After resuscitation from cardiac arrest, a combination of the complex patho-physiologic process, known as post-cardiac arrest syndrome (PCAS), is attributed to multiple organ damage. Global ischemic cascade occurs in the brain due to generalized ischemia during cardiac arrest and the reperfusion process after the return of spontaneous circulation (ROSC), leading to hypoxic/ ischemic brain injury. Targeted temperature management (TTM) is a well-known neuroprotective therapy for ischemic/hypoxic brain injury. This global brain injury is a significant cause of death in PCAS. The implementation of TTM for PCAS leads to a reduction in mortality and better clinical outcomes among survivors. Prognostication is an essential part of post-resuscitation care. Before the TTM era, physicians relied on the algorithm for prognostication in comatose patients released by the American Academy of Neurology in 2006. However, TTM also announced more significant uncertainty during prognostication. During this TTM era, prognostication should not rely on just a solitary parameter. The trend of prognostication turns into a mul-timodal strategy integrating physical examination with supplementary methods, consisting of electrophysiology such as somatosensory evoked potential (SSEP) and electroencephalography (EEG), blood biomarkers, particularly serum neuron-specific enolase (NSE), and neuro-radiography including brain imaging with CT/ MRI, to enhance prognostic accuracy.
... A continuous, normal voltage and reactive EEG background are benign features whereas a burst-suppression pattern or a suppressed background without reactivity are features related to worse prognosis [181,199]. Early onset (< 24 h) of electrographic seizures, before the recovery of a continuous background is associated with worse prognosis [197,202,203]. In these patients, the EEG is often affected by the ongoing treatment. ...
... SSEPs may be depressed by barbiturate coma but are preserved with other sedative drugs such as propofol and midazolam [357]. A bilateral absence of the short-latency N20-potentials over the sensory cortex is a reliable sign of a poor prognosis after cardiac arrest with high specificity and limited sensitivity both early and late after cardiac arrest [201,202,302,310,331,335,337,338,340,342,343,350,352,[358][359][360][361][362][363][364][365][366]. Occasional false positive predictions were reported [367]. ...
... In most patients, awakening from coma following cardiac arrest occurs within 3-4 days from ROSC [202,305]. However, patients who are initially unconscious following cardiac arrest are usually treated with sedatives and neuromuscular blocking drugs to enable targeted temperature management (TTM), and to facilitate mechanical ventilation and other life support measures. ...
The European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM) have collaborated to produce these post-resuscitation care guidelines for adults, which are based on the 2020 International Consensus on Cardiopulmonary Resuscitation Science with Treatment Recommendations. The topics covered include the post-cardiac arrest syndrome, diagnosis of cause of cardiac arrest, control of oxygenation and ventilation, coronary reperfusion, haemodynamic monitoring and management, control of seizures, temperature control, general intensive care management, prognostication, long-term outcome, rehabilitation and organ donation.
... However, in two small studies, FPR of this sign was 50% [62] at 24-48 h and 25% at 24-72 h [94]. In a multicentre study on 201 patients [95], one false-positive result was observed (FPR 2.6%). ...
... In both of these studies, only a few patients were assessed with SSEP, which may have amplified the observed false positive rate. Nevertheless, false-positive predictions have occasionally been reported in other studies included in both this [95,96] and in previous reviews [5,143]. In some cases, the cause of a false-positive result was an incorrect reading of the SSEP record [143]. ...
... However, they can be affected by a self-fulfilling prophecy bias. Indeed, in several studies we included in our review [68,93,95,96,99,106], SSEPs were part of the criteria for WLST. In two of these studies, the rate of WLST based on bilaterally absent SSEP was 50% [64] and 82% [95]. ...
Purpose:
To assess the ability of clinical examination, blood biomarkers, electrophysiology, or neuroimaging assessed within 7 days from return of spontaneous circulation (ROSC) to predict poor neurological outcome, defined as death, vegetative state, or severe disability (CPC 3-5) at hospital discharge/1 month or later, in comatose adult survivors from cardiac arrest (CA).
Methods:
PubMed, EMBASE, Web of Science, and the Cochrane Database of Systematic Reviews (January 2013-April 2020) were searched. Sensitivity and false-positive rate (FPR) for each predictor were calculated. Due to heterogeneities in recording times, predictor thresholds, and definition of some predictors, meta-analysis was not performed.
Results:
Ninety-four studies (30,200 patients) were included. Bilaterally absent pupillary or corneal reflexes after day 4 from ROSC, high blood values of neuron-specific enolase from 24 h after ROSC, absent N20 waves of short-latency somatosensory-evoked potentials (SSEPs) or unequivocal seizures on electroencephalogram (EEG) from the day of ROSC, EEG background suppression or burst-suppression from 24 h after ROSC, diffuse cerebral oedema on brain CT from 2 h after ROSC, or reduced diffusion on brain MRI at 2-5 days after ROSC had 0% FPR for poor outcome in most studies. Risk of bias assessed using the QUIPS tool was high for all predictors.
Conclusion:
In comatose resuscitated patients, clinical, biochemical, neurophysiological, and radiological tests have a potential to predict poor neurological outcome with no false-positive predictions within the first week after CA. Guidelines should consider the methodological concerns and limited sensitivity for individual modalities. (PROSPERO CRD42019141169).
... Ethical consent was obtained in each participating country [10]. The TTM-database contains information on clinical data, patient demographics, neurological prognostication, withdrawal of life-sustaining-therapy (WLST) and follow-up at 6 months after CA [11,12]. Poor neurological outcome was defined as Cerebral Performance Category Scale (CPC) 3-5 (severe cerebral disability, vegetative state or brain death) [13]. ...
... Poor neurological outcome was defined as Cerebral Performance Category Scale (CPC) 3-5 (severe cerebral disability, vegetative state or brain death) [13]. GCS-M and clinical seizures were evaluated daily; brain stem reflexes were registered at formal neurological prognostication ≥ 108 h post-arrest [10,11,14]. In this study, we used GCS-M on day 4 (72-96 h post-arrest), since this is closest to guideline recommendations [1,2]. ...
... The ERC/ESICM algorithm permits unimodal prognostication using SSEP, whilst the TTM-trial protocol permitted unimodal prognostication for patients fulfilling specific SSEP or EEG criteria [1,11]. Applying a stricter In c, any ≥ 2 pathological findings in Steps 2 and 3 combined are considered indicative of poor outcome (as in the TTM2 and TAME Trials [39,40], but we here used the ERC/ ESICM definitions of pathological EEG [41] as stated in the methods section). ...
PurposeTo 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.ResultsThe 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.
... Initial research in this area had focused on reduction of brain injury secondary to cardiac arrest, in an attempt to improve functional outcomes in survivors [9]. These efforts led to the addition of therapeutic hypothermia in the international post-cardiac arrest guidelines since 2005 [10]. ...
... Further, metabolism of these drugs is changed by lowered body temperature, further altering time to wake [22]. Studies have shown that use of the Glasgow Coma Scale Motor Response (GCS-M) 72 h after ROSC has a false positive rate (FPR) of 20% in prediction of poor outcome, defined as GCS-M ≤ 2. Absent pupillary light reflexes at 72 h from ROSC have an FPR of 2% for prediction of poor neurological outcome [9]. Conversely, the presence of bilateral pupillary reflexes lacked sensitivity in predicting favorable (positive) outcome, defined by Cerebral Performance Category (CPC) 1-2, Glasgow Outcome Score (GOS) of 4-5, or Modified Rankin Scale of 0-3 [22]. ...
... Bilateral absence of this N20 peak has been regarded as a reliable tool to predict poor neurological outcome after cardiac arrest [24,33,48]. Recent studies have declared absent N20 peaks to be an early predictor of neurological outcome even during hypothermia [9,34]. ...
Improved understanding of post-cardiac arrest syndrome and clinical practices such as targeted temperature management have led to improved mortality in this cohort. Attention has now been placed on development of tools to aid in predicting functional outcome in comatose cardiac arrest survivors. Current practice uses a multimodal approach including physical examination, neuroimaging, and electrophysiologic data, with a primary utility in predicting poor functional outcome. These modalities remain confounded by self-fulfilling prophecy and the withdrawal of life-sustaining therapies. To date, a reliable measure to predict good functional outcome has not been established or validated, but the use of quantitative somatosensory evoked potential (SSEP) shows potential for this use. MEDLINE and EMBASE search using words "Cardiac Arrest" and "SSEP," "Somato sensory evoked potentials," "qSSEP," "quantitative SSEP," "targeted temperature management in cardiac arrest" was conducted. Relevant recent studies on targeted temperature management in cardiac arrest, plus studies on SSEP in cardiac arrest in the setting of hypothermia and without hypothermia, were included. In addition, animal studies evaluating the role of different components of SSEP in cardiac arrest were reviewed. SSEP is a specific indicator of poor outcomes in post-cardiac arrest patients but lacks sensitivity and has not clinically been established to foresee good outcomes. Novel methods of analyzing quantitative SSEP (qSSEP) signals have shown potential to predict good outcomes in animal and human studies. In addition, qSSEP has potential to track cerebral recovery and guide treatment strategy in post-cardiac arrest patients. Lying beyond the current clinical practice of dichotomized absent/present N20 peaks, qSSEP has the potential to emerge as one of the earliest predictors of good outcome in comatose post-cardiac arrest patients. Validation of qSSEP markers in prospective studies to predict good and poor outcomes in the cardiac arrest population in the setting of hypothermia could advance care in cardiac arrest. It has the prospect to guide allocation of health care resources and reduce self-fulfilling prophecy.
... 19 Detailed information on neurological prognostication and decisions on level-of-care have been previously reported. [21][22][23] Neurological outcome was assessed at 6 months post-arrest according to the Cerebral Performance Category Scale (CPC). Poor outcome was defined as CPC 3-5 (severe cerebral disability, vegetative state, or death). ...
... 34,35 In analogy with brainstem reflexes, a continuous background may recover later than 24 hours post-arrest despite extensive brain injury and is therefore not automatically predictive of good outcome. 4,23 At relatively long latency after arrest, this pattern could still be associated with severe histopathologic brain damage. 29 Whether the patients in our cohort restored a continuous background late cannot be determined, since continuous EEG-monitoring was not used. ...
Background and objectives:
Electroencephalography (EEG) is widely used for prediction of neurological outcome after cardiac arrest. To better understand the relationship between EEG and neuronal injury, we explore the association between EEG and neurofilament light (NFL) as a marker of neuroaxonal injury. We evaluate whether highly malignant EEG patterns are reflected by high NFL levels. Additionally, we explore the association of EEG backgrounds and EEG discharges with NFL.
Methods:
Post-hoc analysis of the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Routine EEGs were prospectively performed after the temperature intervention ≥36 hours post-arrest. Patients who awoke or died prior to 36 hours post-arrest were excluded. EEG-experts blinded to clinical information classified EEG background, amount of discharges and highly malignant EEG patterns according to the standardized American Clinical Neurophysiology Society terminology. Prospectively collected serum samples were analyzed for NFL after trial completion. The highest available concentration at 48 or 72-hours post-arrest was used.
Results:
262/939 patients with EEG and NFL data were included. Patients with highly malignant EEG patterns had 2.9 times higher NFL levels than patients with malignant patterns and NFL levels were 13 times higher in patients with malignant patterns than those with benign patterns (95% CI: 1.4-6.1 and 6.5-26.2 respectively, effect size 0.47, p<0.001). Both background and the amount of discharges were independently strongly associated with NFL levels (p<0.001). The EEG background had a stronger association with NFL levels than EEG discharges (R2=0.30 and R2=0.10, respectively). NFL levels in patients with a continuous background were lower than for any other background (95% CI for discontinuous, burst-suppression and suppression, respectively: 2.26-18.06, 3.91-41.71 and 5.74-41.74, effect size 0.30 and p<0.001 for all). NFL levels did not differ between suppression and burst-suppression. Superimposed discharges were only associated with higher NFL levels if the EEG background was continuous.
Discussion:
Benign, malignant, and highly malignant EEG patterns reflect the extent of brain injury as measured by NFL in serum. The extent of brain injury is more strongly related to the EEG background than superimposed discharges. Combining EEG and NFL may be useful to better identify patients misclassified by single methods.
Clinical trials registration number:
clinicaltrials.gov, NCT01020916.
... Several indicators of good outcome exist; an early recovery of a normal voltage, continuous and reactive EEG-background within 12-24 h post arrest, a normal MRI scan or a Glasgow Coma Scale motor score ≥ 3 have been reported to predict good outcome in 53-100% of patients [10][11][12][13][14][15][16]. The presence of brain stem reflexes, somatosensory-evoked cortical potentials or a normal computed tomography is less predictive of a good prognosis [5,13,14,17,18]. Blood biomarkers of brain injury are quantifiable and objective, and low blood levels may help identify patients with little or no brain injury to optimize allocation of resources and avoid pessimistic predictions in patients still affected by potent confounders such as remaining sedation. ...
... Original EEGs were evaluated centrally after trial completion by investigators blinded to clinical information, neuroimaging and SSEP were evaluated at the patients local hospital as published [5,17,18,[33][34][35][36][37]. Neurological outcome was dichotomized according the Cerebral Performance Category Scale as good (CPC 1-2, no to moderate cerebral disability) or poor (CPC 3-5, severe cerebral disability, vegetative state or death) at 6 months. ...
PurposeThe majority of unconscious patients after cardiac arrest (CA) do not fulfill guideline criteria for a likely poor outcome, their prognosis is considered “indeterminate”. We compared brain injury markers in blood for prediction of good outcome and for identifying false positive predictions of poor outcome as recommended by guidelines.Methods
Retrospective analysis of prospectively collected serum samples at 24, 48 and 72 h post arrest within the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Clinically available markers neuron-specific enolase (NSE) and S100B, and novel markers neurofilament light chain (NFL), total tau, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were analysed. Normal levels with a priori cutoffs specified by reference laboratories or defined from literature were used to predict good outcome (no to moderate disability, Cerebral Performance Category scale 1–2) at 6 months.ResultsSeven hundred and seventeen patients were included. Normal NFL, tau and GFAP had the highest sensitivities (97.2–98% of poor outcome patients had abnormal serum levels) and NPV (normal levels predicted good outcome in 87–95% of patients). Normal S100B and NSE predicted good outcome with NPV 76–82.2%. Normal NSE correctly identified 67/190 (35.3%) patients with good outcome among those classified as “indeterminate outcome” by guidelines. Five patients with single pathological prognostic findings despite normal biomarkers had good outcome.Conclusion
Low levels of brain injury markers in blood are associated with good neurological outcome after CA. Incorporating biomarkers into neuroprognostication may help prevent premature withdrawal of life-sustaining therapy.
... Eine kontinuierliche, normale Spannung und reaktive Grundaktivität im EEG sind prognostisch günstige Kriterien, während ein Burst-Supression-Muster oder eine spannungsarme Grundaktivität ohne Reaktivität mit einer ungünstigen Prognose assoziiert sind [184,202]. Das frühzeitige Einsetzen (<24 h) elektrographischer Anfälle vor der Rückkehr einer kontinuierlichen Grundaktivität ist mit einer schlechteren Prognose verbunden [200,205,206] Die hochdosierte Behandlung mit Sedativa und konventionellen Antiepileptika kann das Aufwachen verzögern sowie die Dauer der mechanischen Beatmung und die Verweildauer auf der Intensivstation verlängern [207]. Es gilt zu bedenken, dass ein generalisierter Myoklonus in Kombination mit epileptiformen Entladungen ein frühes Zeichen eines Lance-Adams-Syndroms sein kann, welches mit einem guten neurologischen Ergebnis vereinbar ist [184,187]. ...
... SSEP können durch Barbituratkoma un-terdrückt werden, bleiben jedoch mit anderen Sedativa wie Propofol und Midazolam erhalten [360]. Ein bilaterales Fehlen der N20-Potenziale mit kurzer Latenz über dem sensorischen Kortex ist ein zuverlässiges Zeichen für eine schlechte Prognose nach Kreislaufstillstand mit hoher Spezifität und begrenzter Sensitivität sowohl früh als auch spät nach Kreislaufstillstand [204,205,305,313,334,338,340,341,343,345,346,353,355,[361][362][363][364][365][366][367][368][369]. Gelegentlich wurden falsch-positive Vorhersagen berichtet [370]. ...
The European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM) have collaborated to produce these post-resuscitation phase guidelines for adults, which are based on the 2020 International Liaison Committee on Resuscitation consensus on cardiopulmonary resuscitation.The topics covered include post-cardiac arrest syndrome, the differential diagnosis of the causes of cardiac arrest, control of oxygenation and ventilation, coronary reperfusion, haemodynamic monitoring and management, control of seizures, temperature control, general intensive care management, prognostication, long-term outcome, rehabilitation and organ donation.
... 181,199 Early onset (<24 h) of electrographic seizures, before the recovery of a continuous background is associated with worse prognosis. 197,202,203 In these patients, the EEG is often affected by the ongoing treatment. It is therefore suggested that additional information is obtained on the severity of brain injury from methods not significantly affected by sedative and anti-epileptic drugs such as somatosensory evoked potentials, serum NSE and neuroradiological investigations (preferably MRI). ...
... 406 In most patients, awakening from coma following cardiac arrest occurs within 3À4 days from ROSC. 202,305 However, patients who are initially unconscious following cardiac arrest are usually treated with sedatives and neuromuscular blocking drugs to enable targeted temperature management (TTM), and to facilitate mechanical ventilation and other life support measures. Therefore, to enable a reliable clinical examination, these drugs should be stopped for sufficient time to avoid interference from their effects. ...
The European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM) have collaborated to produce these post-resuscitation care guidelines for adults, which are based on the 2020 International Consensus on Cardiopulmonary Resuscitation Science with Treatment Recommendations. The topics covered include the post-cardiac arrest syndrome, diagnosis of cause of cardiac arrest, control of oxygenation and ventilation, coronary reperfusion, haemodynamic monitoring and management, control of seizures, temperature control, general intensive care management, prognostication, long-term outcome, rehabilitation, and organ donation.
... The rst neurological examinations were performed at a median of 80 min (IQR, 46−173) from ROSC. Of the 291 patients, 22.3% showed good neurological status on day 7, 23.0% at hospital discharge, and 17.0% at 12 months. The proportion of patients with good neurological status did not signi cantly increase from day 7 to hospital admission (p = 0.88), showed a statistically nonsigni cant decrease between hospital discharge and 6 months (p = 0.08), and remained stationary between 6 months and 12 months (p = 0.97). ...
... Previous studies have shown that therapy limitation is the most common cause of death for patients resuscitated from cardiac arrest and critically ill patients [10,22]. However, the current practice on therapy limitation is not based on strong scienti c evidence because it is unethical to conduct a randomized controlled trial on therapy limitations in cardiac arrest survivors. ...
Background: The precise neurological profiles after in-hospital cardiac arrest (IHCA) are yet to be elucidated. We aimed to evaluate the neurological profiles of patients with IHCA from early time to long-term follow-up and the changes in their neurological outcomes after implementing legislation on the cessation of life-sustaining treatments.
Methods: A national legislation allowing the withdrawal of life-sustaining treatments was implemented in South Korea on February 4, 2018. For this prospective cohort study, we established a neurological rapid response team on March 21, 2017, and serially evaluated the neurological status of patients with IHCA from the initial resuscitation to 12 months after the onset of IHCA. The primary outcome was good neurological status defined as a Clinical Performance Category score (range from 1 to 5, with higher scores indicating greater disability) of 1−2 at 12 months after IHCA. The secondary outcomes were the awakening and neurological recovery during the first week and the survival at 12 months. The outcomes were also compared between before and after the implementation of the legislation.
Results: Of 291 adult patients with IHCA, 144 were included in the Before Period, and 147 were included in the After Period. Physician Orders for Life-Sustaining Treatments were made in 63 (42.9%) patients in the After Period. On the first day and during the first week after IHCA, the awakening was achieved in 21.0% and 40.9%, respectively, and neurological recovery in 4.1% and 15.8%, respectively. The proportion of patients with good neurological status at 12 months was not significantly different between the Before Period (19.0%) and the After Period (15.1%; p = 0.37). Awakening (40.0% vs. 42.2%; p = 0.65) and neurological recovery (16.7% vs. 15.0%; p = 0 .69) during the first week as well as survival at 12 months (25.0% vs. 18.4%; p = 0.17) also did not show significant differences between the two periods.
Conclusion: Awakening and neurological recovery were remarkable throughout the first week. In the current study, implementating the legislation allowing the cessation of life-sustaining treatments did not significantly affect the neurological and survival outcomes after IHCA.
Trial registration: This study was registered in clinical-trial.gov (NCT03006484) in December 2016.
... F ollowing cardiac arrest (CA), the severity of hypoxicischemic encephalopathy (HIE) determines neurologic outcome. In patients with suspected HIE, current guidelines recommend multimodal neuroprognostication. 1,2 Bilaterally absent cortical somatosensory-evoked potentials (SSEPs), [3][4][5][6][7] serum neuron-specific enolase (NSE) concentration above a critical threshold, 8,9 highly malignant electroencephalographic (EEG) patterns, 10-13 and a gray-white matter ratio (GWR) based on brain computed tomographic (CT) imaging findings below a critical threshold 14-18 reliably estimate poor outcome. Neuroprognostication studies are susceptible to a self-fulfilling prophecy, as the findings shown with investigated prognostic parameters frequently influence decisions regarding withdrawal of life-sustaining therapy. ...
... All 21 patients with bilaterally absent SSEPs showed severe HIE, with 79% of those showing near-complete neuronal death in the hippocampus, supporting findings from clinical studies. [3][4][5][6][7]25 The lowest cortical SSEP amplitude in a patient with no/mild HIE was 0.5 μV, in line with studies on CA survivors. 5,26-28 Amorim et al 29 stated that the false-positive rate of SSEP for predicting poor outcome may be as high as 7%. ...
Importance
Neuroprognostication studies are potentially susceptible to a self-fulfilling prophecy as investigated prognostic parameters may affect withdrawal of life-sustaining therapy.
Objective
To compare the results of prognostic parameters after cardiac arrest (CA) with the histopathologically determined severity of hypoxic-ischemic encephalopathy (HIE) obtained from autopsy results.
Design, Setting, and Participants
In a retrospective, 3-center cohort study of all patients who died following cardiac arrest during their intensive care unit stay and underwent autopsy between 2003 and 2015, postmortem brain histopathologic findings were compared with post-CA brain computed tomographic imaging, electroencephalographic (EEG) findings, somatosensory-evoked potentials, and serum neuron-specific enolase levels obtained during the intensive care unit stay. Data analysis was conducted from 2015 to 2020.
Main Outcomes and Measures
The severity of HIE was evaluated according to the selective eosinophilic neuronal death (SEND) classification and patients were dichotomized into categories of histopathologically severe and no/mild HIE.
Results
Of 187 included patients, 117 were men (63%) and median age was 65 (interquartile range, 58-74) years. Severe HIE was found in 114 patients (61%) and no/mild HIE was identified in 73 patients (39%). Severe HIE was found in all 21 patients with bilaterally absent somatosensory-evoked potentials, all 15 patients with gray-white matter ratio less than 1.10 on brain computed tomographic imaging, all 9 patients with suppressed EEG, 15 of 16 patients with burst-suppression EEG, and all 29 patients with neuron-specific enolase levels greater than 67 μg/L more than 48 hours after CA without confounders. Three of 7 patients with generalized periodic discharges on suppressed background and 1 patient with burst-suppression EEG had a SEND 1 score (<30% dead neurons) in the cerebral cortex, but higher SEND scores (>30% dead neurons) in other oxygen-sensitive brain regions.
Conclusions and Relevance
In this study, histopathologic findings suggested severe HIE after cardiac arrest in patients with bilaterally absent cortical somatosensory-evoked potentials, gray-white matter ratio less than 1.10, highly malignant EEG, and serum neuron-specific enolase concentration greater than 67 μg/L.
... Another major limitation is that validated outcome measures such as the cerebral performance category (CPC) score or cognitive tests were not available in the eICU database. We devised a surrogate outcome based on mGCS and discharge location, however neither of these captures the functional state information that is encompassed in scores like the CPC [15][16][17]. Finally, it should be recognized that the performance of our models, while rivaling those of scores derived at later time points (> 72 h), will need to be significantly increased in order for them to be considered in clinical decision-making. ...
Background
There is an unmet need for timely and reliable prediction of post-cardiac arrest (CA) clinical trajectories. We hypothesized that physiological time series (PTS) data recorded on the first day of intensive care would contribute significantly to discrimination of outcomes at discharge.
Patients and methods
Adult patients in the multicenter eICU database who were mechanically ventilated after resuscitation from out-of-hospital CA were included. Outcomes of interest were survival, neurological status based on Glasgow motor subscore (mGCS) and surrogate functional status based on discharge location (DL), at hospital discharge. Three machine learning predictive models were trained, one with features from the electronic health records (EHR), the second using features derived from PTS collected in the first 24 hours after ICU admission (PTS24), and the third combining PTS24 and EHR. Model performances were compared, and the best performing model was externally validated in the MIMIC-III dataset.
Results
Data from 2,216 admissions were included in the analysis. Discrimination of prediction models combining EHR and PTS24 features was higher than models using either EHR or PTS24 for prediction of survival (AUROC 0.83, 0.82 and 0.79 respectively), neurological outcome (0.87, 0.86 and 0.79 respectively), and DL (0.80, 0.78 and 0.76 respectively). External validation in MIMIC-III (n = 86) produced similar model performance. Feature analysis suggested prognostic significance of previously unknown EHR and PTS24 variables.
Conclusion
These results indicate that physiological data recorded in the early phase after CA resuscitation contain signatures that are linked to post-CA outcome. Additionally, they attest to the effectiveness of ML for post-CA predictive modeling.
... Absent or extensor response to pain at ≥ 72 h after ROSC predicts a poor outcome neurologically, with a 70-80% sensitivity and 72% specificity in one study [41]. Absence of bilateral pupillary reflexes at ≥ 72 h also indicates poor neurologic outcome, with a sensitivity of 82% and specificity of 100% [42,43]. Because there may be some subjectivity associated with assessment of pupils, use of automated infrared pupillometry should be considered to obtain objective measurements of pupillary size and constriction velocity [44]. ...
Purpose of review
This review summarizes current and emerging treatments for hypoxic-ischemic brain injury (HIBI). Guidance on neuroprognostication after HIBI is also presented.
Recent findings
After two 2002 studies demonstrated cooling improved neurologic outcome after HIBI, a 2013 trial found targeting 36 °C was non-inferior to targeting 33 °C. Research is ongoing, but there is no other definitive human data on therapies to prevent secondary brain injury after HIBI.
Summary
Guideline-recommended treatment of HIBI includes early, optimal cardiopulmonary resuscitation to prevent primary brain injury, and targeted temperature management to mitigate secondary brain injury. Multiple novel treatment options, including anti-inflammatory agents, anesthetics, and neuroprotective cocktails, are currently being investigated. Additionally, neurostimulants may help promote wakefulness after HIBI. Neuroprognostication after HIBI requires a multimodal approach using the neurologic exam, electroencephalography, somatosensory evoked potentials, neuroimaging, and serum biomarkers. It is important to avoid premature prognostication and nihilism.
... The neurologic examination remains the cornerstone of assessing prognosis in patients resuscitated from CA. Specifically, pupillary light reflexes, corneal reflexes, and motor response were widely considered to be "critically important, " whereas clinical myoclonus was also perceived as important. However, high falsepositive rates have been demonstrated using motor response as a prognostic indicator (11)(12)(13)(14)(15). Similarly, myoclonus has been observed in patients who achieve a good recovery (14,15) and is not recommended as a sole predictor of poor outcome (16). ...
End-of-life care and decisions on withdrawal of life-sustaining therapies vary across countries, which may affect the feasibility of future multicenter cardiac arrest trials. In Brazil, withdrawal of life-sustaining therapy is reportedly uncommon, allowing the natural history of postcardiac arrest hypoxic-ischemic brain injury to present itself. We aimed to characterize approaches to neuroprognostication of cardiac arrest survivors among physicians in Brazil.
Design:
Cross-sectional study.
Setting:
Between August 2, 2019, and July 31, 2020, we distributed a web-based survey to physicians practicing in Brazil.
Subjects:
Physicians practicing in Brazil and members of the Brazilian Association of Neurointensive Care, who care for patients resuscitated following cardiac arrest.
Interventions:
Not applicable.
Measurements and main results:
Responses from 185 physicians were obtained. Pupillary reflexes, corneal reflexes, and motor responses were considered critical to prognostication, whereas neuroimaging and electroencephalography were also regarded as important. For patients without targeted temperature management, absent pupillary and corneal reflexes at 24 hours postarrest were considered strongly predictive of poor neurologic outcome by 31.8% and 33.0%, respectively. For targeted temperature management-treated patients, absent pupillary and corneal reflexes at 24-hour postrewarming were considered prognostic by 22.9% and 20.0%, respectively. Physicians felt comfortable making definitive prognostic recommendations at day 6 postarrest or later (34.2%) for nontargeted temperature management-treated patients, and at day 6 postrewarming (20.4%) for targeted temperature management-treated patients. Over 90% believed that improving neuroprognostic accuracy would affect end-of-life decision-making.
Conclusions:
There is significant variability in neuroprognostic approaches to postcardiac arrest patients and timing of prognostic studies among Brazilian physicians, with practices frequently deviating from current guidelines, underscoring a need for greater neuroprognostic accuracy. Nearly all physicians believed that improving neuroprognostication will impact end-of-life decision-making. Given the tendency to delay prognostic recommendations while using similar neuroprognostic tools, Brazil offers a unique cohort in which to examine the natural history of hypoxic-ischemic brain injury in future studies.
... In a multicentre study, among 39 patients with good neurological outcome at six months, one had a bilaterally absent N20 SSEP wave (FPR 2.6%). 5 . In another multicentre study, three false positive SSEP results were reported (FPR 3[1À7]%). ...
Background
bilaterally absent pupillary light reflexes (PLR) or N20 waves of short-latency evoked potentials (SSEPs) are recommended by the 2015 ERC-ESICM guidelines as robust, first-line predictors of poor neurological outcome after cardiac arrest. However, recent evidence shows that the false positive rates (FPRs) of these tests may be higher than previously reported. We investigated if testing accuracy is improved when combining PLR/SSEPs with malignant electroencephalogram (EEG), oedema on brain computed tomography (CT), or early status myoclonus (SM).
Methods
post-hoc analysis of ProNeCA multicentre prognostication study. We compared the prognostic accuracy of the ERC-ESICM prognostication strategy vs. that of a new strategy combining ≥2 abnormal results from any of PLR, SSEPs, EEG, CT and SM. We also investigated if using alternative classifications for abnormal SSEPs (absent-pathological vs. bilaterally-absent N20) or malignant EEG (ACNS-defined suppression or burst-suppression vs. unreactive burst-suppression or status epilepticus) improved test sensitivity.
Results
we assessed 210 adult comatose resuscitated patients of whom 164 (78%) had poor neurological outcome (CPC 3-5) at six months. FPRs and sensitivities of the ≥2 abnormal test strategy vs. the ERC-ESICM algorithm were 0[0-8]% vs. 7 [1–18]% and 49[41-57]% vs. 63[56-71]%, respectively (p < .0001). Using alternative SSEP/EEG definitions increased the number of patients with ≥2 concordant test results and the sensitivity of both strategies (67[59-74]% and 54[46-61]% respectively), with no loss of specificity.
Conclusions
in comatose resuscitated patients, a prognostication strategy combining ≥2 among PLR, SSEPs, EEG, CT and SM was more specific than the 2015 ERC-ESICM prognostication algorithm for predicting 6-month poor neurological outcome.
... OHCA is a leading cause of death in high-to-middle income countries [2]. Despite improvements in resuscitation and postcardiac arrest care, the rates of mortality and permanent brain damage in OHCA patients remain high [3,4]. ...
Background:
To evaluate the associations between glycated hemoglobin (HbA1c) at admission and 6-month mortality and outcomes after out-of-hospital cardiac arrest (OHCA) treated by hypothermic targeted temperature management (TTM).
Methods:
This single-center retrospective cohort study included adult OHCA survivors who underwent hypothermic TTM from December 2011 to December 2019. High HbA1c at admission was defined as a level higher than 6%. Poor neurological outcomes were defined as cerebral performance category scores of 3-5. The primary outcome was 6-month mortality. The secondary outcome was the 6-month neurological outcome. Descriptive statistics, log-rank tests, and multivariable regression modeling were used for data analysis.
Results:
Of the 302 patients included in the final analysis, 102 patients (33.8%) had HbA1c levels higher than 6%. The high HbA1c group had significantly worse 6-month survival (12.7% vs. 37.5%, p < 0.001) and 6-month outcomes (89.2% vs. 73.0%, p = 0.001) than the non-high HbA1c group. Kaplan-Meier analysis and the log-rank test showed that the survival time was significantly shorter in the patients with HbA1c > 6% than in those with HbA1c ≤6%. In the multivariable logistic regression analysis, HbA1c > 6% was independently associated with 6-month mortality (OR 5.85, 95% CI 2.26-15.12, p < 0.001) and poor outcomes (OR 4.18, 95% CI 1.41-12.40, p < 0.001).
Conclusions:
This study showed that HbA1c higher than 6% at admission was associated with increased 6-month mortality and poor outcomes in OHCA survivors treated with hypothermic TTM. Poor long-term glycemic management may have prognostic significance after cardiac arrest.
... OHCA is a leading cause of death in high-to-middle income countries [2]. Despite improvements in resuscitation and postcardiac arrest care, the rates of mortality and permanent brain damage in OHCA patients remain high [3,4]. ...
Background: To evaluate the associations between glycated hemoglobin (HbA1c) at admission and 6-month mortality and outcomes after out-of-hospital cardiac arrest (OHCA) treated by hypothermic targeted temperature management (TTM).
Methods: This single-center retrospective cohort study included adult OHCA survivors who underwent hypothermic TTM from December 2011 to December 2019. High HbA1c at admission was defined as a level higher than 6%. Poor neurological outcomes were defined as cerebral performance category scores of 3-5. The primary outcome was 6-month mortality. The secondary outcome was the 6-month neurological outcome. Descriptive statistics, log-rank tests, and multivariable regression modeling were used for data analysis.
Results: Of the 302 patients included in the final analysis, 102 patients (33.8%) had HbA1c levels higher than 6%. The high HbA1c group had significantly worse 6-month survival (12.7% vs. 37.5%, p < 0.001) and 6-month outcomes (89.2% vs. 73.0%, p = 0.001) than the non-high HbA1c group. Kaplan-Meier analysis and the log-rank test showed that the survival time was significantly shorter in the patients with HbA1c >6% than in those with HbA1c ≤6%. In the multivariable logistic regression analysis, HbA1c >6% was independently associated with 6-month mortality (OR 5.85, 95% CI 2.26-15.12, p < 0.001) and poor outcomes (OR 4.18, 95% CI 1.41-12.40, p < 0.001).
Conclusions: This study showed that HbA1c higher than 6% at admission was associated with increased 6-month mortality and poor outcomes in OHCA survivors treated with hypothermic TTM. Poor long-term glycemic management may have prognostic significance after cardiac arrest.
... OHCA is a leading cause of death in high-to-middle income countries [2]. Despite improvements in resuscitation and postcardiac arrest care, the mortality and permanent brain damage rates of OHCA patients remain high [3,4]. ...
Background: To evaluate the associations between glycated hemoglobin (HbA1c) at admission and 6-month mortality and outcomes after out-of-cardiac arrest (OHCA) treated by hypothermic targeted temperature management (TTM).
Methods: This single-center retrospective cohort study included adult OHCA survivors who underwent hypothermic TTM from December 2011 to December 2019. High HbA1c at admission was defined as a level higher than 6%. Poor neurological outcomes were defined as cerebral performance category scores of 3-5. The primary outcome was 6-month mortality. The secondary outcome was the 6-month neurological outcome. Descriptive statistics, log-rank tests, and multivariable regression modelling were used for data analysis.
Results: Of the 302 patients included in the final analysis, 102 patients (33.8%) had HbA1c levels higher than 6%. The high HbA1c group had significantly worse 6-month survival (12.7% vs. 37.5%, p < 0.001) and 6-month outcomes (89.2% vs. 73.0%, p = 0.001) compared to the non-high HbA1c group. Kaplan-Meier analysis and the log-rank test showed that the survival time was significantly shorter in the patients with HbA1c >6% than in those with HbA1c ≤6%. In the multivariable logistic regression analysis, HbA1c >6% was independently associated with 6-month mortality (OR 5.85, 95% CI 2.26-15.12, p < 0.001) and poor outcomes (OR 4.18, 95% CI 1.41-12.40, p < 0.001).
Conclusions: This study showed that HbA1c higher than 6% at admission was associated with increased 6-month mortality and poor outcomes in OHCA survivors treated with hypothermic TTM. Poor long-term glycemic management may have prognostic significance after cardiac arrest.
... [4][5][6] Most of the patients with unfavorable neurological outcome eventually died or were in a vegetative state. 7,8 At present, related studies had shown that electroencephalogram, short-delay somatosensory evoked potential (SSEEP), neuron-specific enolase (NSE), S-100B, microRNAs (miRNAs), near-infrared spectroscopy (NIRS), and so forth may be used as a predictor of neurological function for patients with successful CPR. 9,10 The prediction of outcomes at 24 hours after ROSC may be clinically less important since patients after CPR. ...
Background
Cardiac arrest is still a global public health problem at present. The neurological outcome is the core indicator of the prognosis of cardiac arrest. However, there is no effective means or tools to predict the neurological outcome of patients with coma and survived 24 hours after successful cardiopulmonary resuscitation (CPR).
Hypothesis
Therefore, we expect to construct a prediction model to predict the neurological outcome for patients with coma and survived 24 hours after successful CPR.
Methods
A retrospective cohort study was used to construct a prediction model of the neurological function for patients with coma and survived 24 hours after successful CPR. From January 2007 to December 2015, a total of 262 patients met the inclusion and exclusion criteria.
Results
The predictive model was developed using preselected variables by a systematic review of the literature. Finally, we get five sets of models (three sets of construction models and two sets of internal verification models) which with similar predictive value. The stepwise model, which including seven variables (age, noncardiac etiology, nonshockable rhythm, bystander CPR, total epinephrine dose, APTT, and SOFA score), was the simplest model, so we choose it as our final predictive model. The area under the ROC curve (AUC), specificity, and sensitivity of the stepwise model were respectively 0.82 (0.77, 0.87), 0.72and 0.82. The AUC, specificity, and sensitivity of the bootstrap stepwise (BS stepwise) model were respectively 0.82 (0.77, 0.87), 0.71, and 0.82.
Conclusion
This new and validated predictive model may provide individualized estimates of neurological function for patients with coma and survived 24 hours after successful CPR using readily obtained clinical risk factors. External validation studies are required further to demonstrate the model's accuracy in diverse patient populations.
... According to a recent systematic review, the bilateral absence of N20 had good predictive value for poor neurologic outcomes, with a false positive rate (FPR) of 0.7% (10). However, the sensitivity of bilateral N20 absence is approximately 40%, and many patients fail to recover even though they have a preserved N20 peak (10)(11)(12). Recently, the assessment of the N20-P25/30 amplitude was presented as a promising predictive tool with high sensitivity for predicting poor outcomes (13,14). ...
Objectives:
The aim of this study was to evaluate the prognostic performance of the peak amplitude of P25/30 cortical somatosensory evoked potentials in predicting nonawakening in targeted temperature management-treated cardiac arrest patients.
Design:
Prospective analysis.
Setting:
Four academic tertiary care hospitals.
Patients:
Eighty-seven cardiac arrest survivors after targeted temperature management.
Interventions:
Analysis of the amplitude of P25/30.
Measurements and main results:
In all participants, somatosensory evoked potentials were recorded after rewarming, and bilaterally absent pupillary and corneal reflexes were evaluated at 72 hours after the return of spontaneous circulation. We analyzed the amplitudes of the N20 and P25/30 peaks and the N20-P25/30 complex in cortical somatosensory evoked potentials. Upon hospital discharge, 87 patients were dichotomized into the awakening and nonawakening groups. The lowest amplitudes of N20, P25/30, and N20-P25/30 in the awakening patients were 0.17, 0.45, and 0.73 μV, respectively, and these thresholds showed a sensitivity of 70.5% (95% CI, 54.8-83.2%), 86.4% (95% CI, 72.7-94.8%), and 75.0% (95% CI, 59.7-86.8%), respectively, for nonawakening. The area under the curve of the P25/30 amplitude was significantly higher than that of the N20 amplitude (0.955 [95% CI, 0.912-0.998] vs 0.894 [95% CI, 0.819-0.969]; p = 0.036) and was comparable with that of the N20-P25/30 amplitude (0.931 [95% CI, 0.873-0.989]). Additionally, adding resuscitation variables or an absent brainstem reflex to the P25/30 amplitude showed a trend toward improving prognostic performance compared with the use of other somatosensory evoked potential amplitudes (area under the curve, 0.958; 95% CI, 0.917-0.999 and area under the curve, 0.974; 95% CI, 0.914-0.996, respectively).
Conclusions:
Our results provide evidence that the absence of the P25/30 peak and a reduction in the P25/30 amplitude may be considered prognostic indicators in these patients.
... Loss of pupillary light reactivity is a recognised indicator of poor prognosis during and after cardiopulmonary resuscitation, even though it can be impaired in mild hypothermia, low cardiac output and modified by resuscitation drugs (21). Despite a high specificity for predicting a poor neurological outcome, its sensitivity is low (27)(28)(29). Consequently, pupillary light reactivity alone is not sufficiently accurate to determine the prognosis and the decision making (30)(31)(32). ...
Objective:
The objective of this study was to assess the association of early pupil evaluation with death occurrence on Day 28 in patients with refractory out-of-hospital cardiac arrest (ROHCA) admitted to the intensive care unit (ICU) and treated by extra-corporeal cardiopulmonary resuscitation (eCPR).
Methods:
The pupil size (miosis, intermediary or mydriasis) and bilateral pupillary light reactivity (present or absent) were monitored in sedated and paralysed patients treated by eCPR. Mortality was assessed on Day 28.
Results:
A total of 46 consecutive patients with ROHCA were included in the study. Thirty (65%) patients died on Day 28. Twenty-seven (90%) patients had pupils non-reactive to light, and 18 (60%) had mydriasis at the ICU admission. Using logistic regression, including age, gender, no flow, low-flow, size and pupil reactivity to light, only the pupillary reactivity to light remained associated with death on Day 28 (Odds ratio=0.12, 95%CI=[0.01-0.96]).
Conclusion:
Pupils not reacting to light at the ICU admission were associated with mortality on Day 28 in patients with ROHCA. Pupillary light reactivity is a simple and easy tool that can be used to early detect a poor outcome in patients with ROHCA treated by eCPR.
Background
The objective of this study is to describe incidence and factors associated with early withdrawal of life-sustaining therapies based on presumed poor neurologic prognosis (WLST-N) and practices around multimodal prognostication after out-of-hospital cardiac arrest (OHCA).Methods
We performed a subanalysis of a randomized controlled trial assessing prehospital therapeutic hypothermia in adult patients admitted to nine hospitals in King County with nontraumatic OHCA between 2007 and 2012. Patients who underwent tracheal intubation and were unconscious following return of spontaneous circulation were included. Our outcomes were (1) incidence of early WLST-N (WLST-N within < 72 h from return of spontaneous circulation), (2) factors associated with early WLST-N compared with patients who remained comatose at 72 h without WLST-N, (3) institutional variation in early WLST-N, (4) use of multimodal prognostication, and (5) use of sedative medications in patients with early WLST-N. Analysis included descriptive statistics and multivariable logistic regression.ResultsWe included 1,040 patients (mean age was 65 years, 37% were female, 41% were White, and 44% presented with arrest due to ventricular fibrillation) admitted to nine hospitals. Early WLST-N accounted for 24% (n = 154) of patient deaths and occurred in half (51%) of patients with WLST-N. Factors associated with early WLST-N in multivariate regressions were older age (odds ratio [OR] 1.02, 95% confidence interval [CI]: 1.01–1.03), preexisting do-not-attempt-resuscitation orders (OR 4.67, 95% CI: 1.55–14.01), bilateral absent pupillary reflexes (OR 2.4, 95% CI: 1.42–4.10), and lack of neurological consultation (OR 2.60, 95% CI: 1.52–4.46). The proportion of patients with early WLST-N among all OHCA admissions ranged from 19–60% between institutions. A head computed tomography scan was obtained in 54% (n = 84) of patients with early WLST-N; 22% (n = 34) and 5% (n = 8) underwent ≥ 1 and ≥ 2 additional prognostic tests, respectively. Prognostic tests were more frequently performed when neurological consultation occurred. Most patients received sedating medications (90%) within 24 h before early WLST-N; the median time from last sedation to early WLST-N was 4.2 h (interquartile range 0.4–15).Conclusions
Nearly one quarter of deaths after OHCA were due to early WLST-N. The presence of concerning neurological examination findings appeared to impact early WLST-N decisions, even though these are not fully reliable in this time frame. Lack of neurological consultation was associated with early WLST-N and resulted in underuse of guideline-concordant multimodal prognostication. Sedating medications were often coadministered prior to early WLST-N and may have further confounded the neurological examination. Standardizing prognostication, restricting early WLST-N, and a multidisciplinary approach including neurological consultation might improve outcomes after OHCA.
Cardiac arrest is a leading cause of mortality and morbidity. The prognosis of patients that survive to intensive care unit admission largely depends on the severity of the neurological injury. Prevention of secondary brain injury is the mainstay of treatment in the intensive care unit. This chapter describes the temporal course of the cerebral perfusion and autoregulation of post-cardiac arrest patients during treatment in the intensive care unit. Knowledge of the cerebral pathophysiological processes after cardiac arrest is essential for adequate treatment of these patients.
Background
Science continues to search for a neuroprotective drug therapy to improve outcomes after cardiac arrest (CA). The use of glibenclamide (GBC) has shown promise in preclinical studies, but its effects on neuroprognostication tools are not well understood. We aimed to investigate the effect of GBC on somatosensory evoked potential (SSEP) waveform recovery post CA and how this relates to the early prediction of functional outcome, with close attention to arousal and somatosensory recovery, in a rodent model of CA.Methods
Sixteen male Wistar rats were subjected to 8-min asphyxia CA and assigned to GBC treatment (n = 8) or control (n = 8) groups. GBC was administered as a loading dose of 10 μg/kg intraperitoneally 10 min after the return of spontaneous circulation, followed by a maintenance dosage of 1.6 μg/kg every 8 h for 24 h. SSEPs were recorded from baseline until 150 min following CA. Coma recovery, arousal, and brainstem function, measured by subsets of the neurological deficit score (NDS), were compared between both groups. SSEP N10 amplitudes were compared between the two groups at 30, 60, 90, and 120 min post CA.ResultsRats treated with GBC had higher sub-NDS scores post CA, with improved arousal and brainstem function recovery (P = 0.007). Both groups showed a gradual improvement of SSEP N10 amplitude over time, from 30 to 120 min post CA. Rats treated with GBC showed significantly better SSEP recovery at every time point (P < 0.001 for 30, 60, and 90 min; P = 0.003 for 120 min). In the GBC group, the N10 amplitude recovered to baseline by 120 min post CA. Quantified Cresyl violet staining revealed a significantly greater percentage of damage in the control group compared with the GBC treatment group (P = 0.004).Conclusions
Glibenclamide improves coma recovery, arousal, and brainstem function after CA with decreased number of ischemic neurons in a rat model. GBC improves SSEP recovery post CA, with N10 amplitude reaching the baseline value by 120 min, suggesting early electrophysiologic recovery with this treatment. This medication warrants further exploration as a potential drug therapy to improve functional outcomes in patients after CA.
Background
Status myoclonus (SM) after cardiac arrest (CA) may signify devastating brain injury. We hypothesized that SM correlates with severe neurologic and systemic post-cardiac-arrest syndrome (PCAS).Methods
Charts of patients admitted with CA to Mayo Clinic Saint Marys Hospital between 2005 and 2019 were retrospectively reviewed. Data included the neurologic examination, ancillary neurologic tests, and systemic markers of PCAS. Nonsustained myoclonus was clinically differentiated from SM. The cerebral performance category score at discharge was assessed; poor outcome was a cerebral performance category score > 2 prior to withdrawal of life-sustaining therapies or death.ResultsOf 296 patients included, 276 (93.2%) had out-of-hospital arrest and 202 (68.5%) had a shockable rhythm; the mean time to return of spontaneous circulation was 32 ± 19 min. One hundred seventy-six (59.5%) patients had a poor outcome. One hundred one (34.1%) patients had myoclonus, and 74 (73.2%) had SM. Neurologic predictors of poor outcome were extensor or absent motor response to noxious stimulus (p = 0.02, odds ratio [OR] 3.8, confidence interval [CI] 1.2–12.4), SM (p = 0.01, OR 10.3, CI 1.5–205.4), and burst suppression on EEG (p = 0.01, OR 4.6, CI 1.4–17.4). Of 74 patients with SM, 73 (98.6%) had a poor outcome. A nonshockable rhythm (p < 0.001, OR 4.5, CI 2.6–7.9), respiratory arrest (p < 0.001, OR 3.5, CI 1.7–7.2), chronic kidney disease (p < 0.001, OR 3.1, CI 1.6–6.0), and a pressor requirement (p < 0.001, OR 4.4, CI 1.8–10.6) were associated with SM. No patients with SM, anoxic-ischemic magnetic resonance imaging findings, and absent electroencephalographic reactivity had a good outcome.Conclusions
Sustained status myoclonus after CPR is observed in patients with other reliable indicators of severe acute brain injury and systemic PCAS. These clinical determinants should be incorporated as part of a comprehensive approach to prognostication after CA.
As more people are surviving cardiac arrest, focus needs to shift towards improving neurological outcomes and quality of life in survivors. Brain injury after resuscitation, a common sequela following cardiac arrest, ranges in severity from mild impairment to devastating brain injury and brainstem death. Effective strategies to minimise brain injury after resuscitation include early intervention with cardiopulmonary resuscitation and defibrillation, restoration of normal physiology, and targeted temperature management. It is important to identify people who might have a poor outcome, to enable informed choices about continuation or withdrawal of life-sustaining treatments. Multimodal prediction guidelines seek to avoid premature withdrawal in those who might survive with a good neurological outcome, or prolonging treatment that might result in survival with severe disability. Approximately one in three admitted to intensive care will survive, many of whom will need intensive, tailored rehabilitation after discharge to have the best outcomes.
Post-cardiac arrest syndrome is an extremely complex nosology, characterized by high mortality and the development of severe neurological disorders. Predicting the neurological outcome in this pathology is an urgent problem, since it allows determining the tactics of patient management and optimizing the scope of medical care, as well as preparing the patient's family members for expected results of treatment. Currently, clinical, laboratory and instrumental data are used as predictors of an unfavorable neurological outcome (e.g., pupillary responses, neuron-specific enolase levels, electroencephalography). There is no single criterion with high sensitivity and specificity for predicting neurological disorders; therefore, a multimodal approach is required. This article discusses several factors, the combination of which allows predicting the outcome of post-cardiac arrest syndrome with the greatest degree of reliability.
Purpose
Cardiopulmonary resuscitation guidelines recommend multimodal neuro-prognostication after cardiac arrest using neurological examination, electroencephalography, biomarkers, and brain imaging. The Patient State Index (PSI) and suppression ratio (SR) represent the depth and degree of sedation, respectively. We evaluated the predictive ability of PSI and SR for neuro-prognostication of post-cardiac arrest patients who underwent targeted temperature management.
Methods
This prospective observational study was conducted between January 2017 and August 2020 and enrolled adult patients in an intensive care unit (ICU) with non-traumatic out-of-hospital cardiac arrest with return of spontaneous circulation (ROSC). PSI and SR were monitored continuously during ICU stay, and their maximum, mean, and minimum cutoff values 24 h after ROSC were analyzed to predict poor neurologic outcome and long-term survival.
Results
The final analysis included 103 patients. A mean PSI ≤ 14.53 and mean SR > 36.6 showed high diagnostic accuracy as single prognostic factors. Multimodal prediction using the mean PSI and mean SR showed the highest area-under-the-curve value of 0.965 (95% confidence interval 0.909–0.991). Patients with mean PSI ≤ 14.53 and mean SR > 36.6 had relatively higher long-term mortality rates than those of patients with values >14.53 and ≤ 36.6, respectively.
Conclusions
The PSI and SR are good predictors for early neuro-prognostication in post-cardiac arrest patients.
Objectives:
An automated infrared pupillometer measures quantitative pupillary light reflex using a calibrated light stimulus. We examined whether the timing of performing quantitative pupillary light reflex or standard pupillary light reflex may impact its neuroprognostic performance in postcardiac arrest comatose patients and whether quantitative pupillary light reflex may outperform standard pupillary light reflex in early postresuscitation phase.
Data sources:
PubMed and Embase databases from their inception to July 2020.
Study selection:
We selected studies providing sufficient data of prognostic values of standard pupillary light reflex or quantitative pupillary light reflex to predict neurologic outcomes in adult postcardiac arrest comatose patients.
Data extraction:
Quantitative data required for building a 2 × 2 contingency table were extracted, and study quality was assessed using standard criteria.
Data synthesis:
We used the bivariate random-effects model to estimate the pooled sensitivity and specificity of standard pupillary light reflex or quantitative pupillary light reflex in predicting poor neurologic outcome during early (< 72 hr), middle (between 72 and 144 hr), and late (≧ 145 hr) postresuscitation periods, respectively. We included 39 studies involving 17,179 patients. For quantitative pupillary light reflex, the cut off points used in included studies to define absent pupillary light reflex ranged from 0% to 13% (median: 7%) and from zero to 2 (median: 2) for pupillary light reflex amplitude and Neurologic Pupil index, respectively. Late standard pupillary light reflex had the highest area under the receiver operating characteristic curve (0.98, 95% CI [CI], 0.97-0.99). For early standard pupillary light reflex, the area under the receiver operating characteristic curve was 0.80 (95% CI, 0.76-0.83), with a specificity of 0.91 (95% CI, 0.85-0.95). For early quantitative pupillary light reflex, the area under the receiver operating characteristic curve was 0.83 (95% CI, 0.79-0.86), with a specificity of 0.99 (95% CI, 0.91-1.00).
Conclusions:
Timing of pupillary light reflex examination may impact neuroprognostic accuracy. The highest prognostic performance was achieved with late standard pupillary light reflex. Early quantitative pupillary light reflex had a similar specificity to late standard pupillary light reflex and had better specificity than early standard pupillary light reflex. For postresuscitation comatose patients, early quantitative pupillary light reflex may substitute for early standard pupillary light reflex in the neurologic prognostication algorithm.
Despite advances in the management of cardiac arrest, mortality remains very high and persistence of coma often leads to withdrawal of life support. Accurate prediction of neurologic outcome early after resuscitation is important for directing goals of medical care. This chapter reviews the pathophysiology of hypoxic-ischemic brain injury and the clinical, biochemical, radiographic, and electrophysiologic tests used to predict neurologic outcome following cardiac arrest as well as the ethical issues that can arise during prognostication.
Aim
We aimed to evaluate neurological profiles of patients with in-hospital cardiac arrest (IHCA) from early time points to long-term follow-up periods.
Methods
For this prospective cohort study, we established a neurological rapid response team, and serially evaluated the neurological status of patients with IHCA from the initial resuscitation to 12 months after the onset of IHCA. The primary outcome was good neurological status defined as a Clinical Performance Category score of 1 − 2 at 12 months after IHCA. The secondary outcomes were the awakening and neurological recovery during the first week, the survival and neurological status at hospital discharge, and the survival at 12 months.
Results
A total of 291 adult patients with IHCA were included. On the first day and during the first week after IHCA, the awakening was achieved in 61 (21.0%) and 119 patients (40.9%), respectively; and neurological recovery in 12 (4.1%) and 46 patients (15.8%), respectively. Epileptic seizures developed in 9.7% following restoration of spontaneous circulation. At hospital discharge, 106 patients (36.4%) had survived; among them, 63.2% showed good neurological status. At 12 months, 63 (21.6 %) patients survived; among them, 81.7% showed good neurological status (17.0% among all patients with IHCA). Of patients without awakening during the first 3 and 7 days, 2.7% and 1.2% showed good neurological status at 12 months, respectively.
Conclusions
Among patients with IHCA, awakening and neurological recovery were remarkable throughout the first week. Survival and good neurological status were substantial at 12 months after IHCA.
Objective
To measure inter- and intra-rater agreement in the interpretation of cortical somatosensory evoked potential (SSEP) components following paediatric cardiac arrest (CA) in multi-professional neurophysiology teams.
Methods
Thirteen professionals blinded to patient outcome interpreted 96 SSEPs in paediatric patients 24-/48-/72-hours following CA. Of these, 34 were duplicates used to assess intra-rater agreement. Consistent interpretations (absent/present/indeterminate) between scientists (who record/identify SSEP components) and neurophysiologists (who provide prognostic SSEP interpretation) were expressed as percentages. Rates of agreement were calculated using Fleiss’ kappa coefficient (K).
Results
Unanimous agreement between professionals was present in 40% (95%CI: 28-54%) of the interpreted SSEPs, with a K value of 0.62 (95%CI: 0.55-0.70) based on average agreement. Agreement was similar between neurophysiologists (K=0.67; 95%CI: 0.57-0.77) and scientists (K=0.62; 95%CI: 0.54-0.70) but lower in patients <2 years old (K=0.23; 95%CI: 0.14-0.33) and in those with poor outcome (K=0.21; 95%CI: 0.07-0.35). No SSEP was unanimously interpreted as absent and 92% (95%CI: 89-95%) of duplicate SSEPs were interpreted consistently.
Conclusion
Despite substantial agreement when interpreting prognostic SSEPs, this was significantly lower in children with poor outcome and of younger age.
Significance
Clinicians using SSEPs in the intensive care unit should be aware of the inter-rater variability when interpreting SSEPs as absent.
This 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations for advanced life support includes updates on multiple advanced life support topics addressed with 3 different types of reviews. Topics were prioritized on the basis of both recent interest within the resuscitation community and the amount of new evidence available since any previous review. Systematic reviews addressed higher-priority topics, and included double-sequential defibrillation, intravenous versus intraosseous route for drug administration during cardiac arrest, point-of-care echocardiography for intra-arrest prognostication, cardiac arrest caused by pulmonary embolism, postresuscitation oxygenation and ventilation, prophylactic antibiotics after resuscitation, postresuscitation seizure prophylaxis and treatment, and neuroprognostication. New or updated treatment recommendations on these topics are presented. Scoping reviews were conducted for anticipatory charging and monitoring of physiological parameters during cardiopulmonary resuscitation. Topics for which systematic reviews and new Consensuses on Science With Treatment Recommendations were completed since 2015 are also summarized here. All remaining topics reviewed were addressed with evidence updates to identify any new evidence and to help determine which topics should be the highest priority for systematic reviews in the next 1 to 2 years.
This 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations for advanced life support includes updates on multiple advanced life support topics addressed with 3 different types of reviews. Topics were prioritized on the basis of both recent interest within the resuscitation community and the amount of new evidence available since any previous review. Systematic reviews addressed higher-priority topics, and included double-sequential defibrillation, intravenous versus intraosseous route for drug administration during cardiac arrest, point-of-care echocardiography for intra-arrest prognostication, cardiac arrest caused by pulmonary embolism, postresuscitation oxygenation and ventilation, prophylactic antibiotics after resuscitation, postresuscitation seizure prophylaxis and treatment, and neuroprognostication. New or updated treatment recommendations on these topics are presented. Scoping reviews were conducted for anticipatory charging and monitoring of physiological parameters during cardiopulmonary resuscitation. Topics for which systematic reviews and new Consensuses on Science With Treatment Recommendations were completed since 2015 are also summarized here. All remaining topics reviewed were addressed with evidence updates to identify any new evidence and to help determine which topics should be the highest priority for systematic reviews in the next 1 to 2 years.
Background
The assessment of the neurological prognosis after cardiac arrest should be made using a multimodal approach involving clinical, physical and laboratory findings. Here, biomarkers are of high importance. The reliable prognostication has far-reaching consequences for the patient on the further course of therapy and rehabilitation.Objectives
Which biomarkers help in prognosis estimation and therapy target definition and are currently used in daily clinical practice?Materials and methodsPresentation of the multimodal approach for prognosis generation in patients after resuscitation with hypoxic-ischemic encephalopathy with special consideration and discussion of various biomarkers.Results and conclusionNeuron-specific enolase (NSE) is the best-established predictive biomarker in patients with hypoxic-ischemic encephalopathy after cardiac arrest. In combination with other methods (clinical examination, physical testing) and considering possible interfering factors (hemolysis, tumor diseases), NSE is used after 48–72 h with a cutoff value of 90 ng/ml. Most other biomarkers have so far only been studied in smaller groups or individual studies and thus cannot currently be routinely used outside of studies.
Background:
The gray-white-matter ratio (GWR) measured on cerebral non-contrasted computed tomography (NCCT) has been reported to help the prognostication of mortality or comatose status of out-of-hospital cardiac arrest (OHCA) victims. Since the etiologies and resuscitative process differ significantly between patients with OHCA and in-hospital cardiac arrest (IHCA), the predictive ability of GWR in IHCA survivors remains unclear.
Methods:
This retrospective observational study conducted in a single tertiary medical center in Taiwan enrolled all the non-traumatic IHCA adults with sustained return of spontaneous circulation (ROSC) and had received cerebral NCCT examination within 24 hours following cardiac arrest. The GWR of survivor and non-survivor as well as good and poor neurological outcome were analyzed.
Results:
A total of 79 IHCA patients with 68.4% in male gender and mean age of 66-year-old were enrolled in the current study. 34 patients (43.0%) survived to hospital discharge and 20 patients (25.3%) were discharged with good neurological outcome. The median GWR of patients with good and poor outcomes in either aspect of survival or neurological function did not show significant difference. The area under the plotted receiver of characteristic curves of each GWR also did not show satisfactory predictive performance.
Conclusions:
The use of GWR for outcome prognosis of patients in emergency department whom progressed to circulatory failure did not show promising result.
Aim:
We presented the cut-off value of a diffusion-weighted image (DWI) scoring system to predict poor neurologic outcome using DWI taken 72-96 h after out-of-hospital cardiac arrest (OHCA) patients underwent target temperature management (TTM).
Methods:
This was a prospective single-centre observational study, conducted from March 2018 to April 2020 in OHCA patients after TTM. Neurological status was assessed 6 months after return of spontaneous circulation (ROSC) using the Glasgow-Pittsburgh cerebral performance categories (CPC) scale. CPC of 1-2 demonstrated good neurologic outcomes whilst a CPC of 3-5 was related to poor neurologic outcomes. The receiver operating characteristic curves and DeLong method were used to evaluate the cut-off value of the DWI scoring system to predict poor neurologic outcome.
Results:
The good and poor neurologic outcome groups consisted of 38 (54.3%) and 32 (45.7%) patients, respectively. The area under the receiver operating characteristic curve (AUROC) of the overall, cortex, deep grey nuclei, and cortex plus deep grey nuclei scores, white matter, brainstem, and cerebellum measured 72-96 h after ROSC were 0.96, 0.96, 0.97, 0.96, 0.95, 0.95, and 0.93 respectively. For 100.0% specificity to predict poor neurologic outcome, the overall scores of the DWI scoring system measured 72-96 h after ROSC with a cut-off value of 52 had a sensitivity of 81.3% (95% CI: 63.6∼92.8).
Conclusion:
This study demonstrated that the DWI scoring systems measured between 72 and 96 h after ROSC were valuable tools to predict poor neurologic outcome in post-OHCA patients treated with TTM.
The human brain is dependent upon the delivery of oxygen and glucose and the removal of waste products for normal activity with the interruption of this cycle resulting in tissue injury. A reduction of oxygen content within the brain parenchyma is the state of anoxia, while the cessation of blood flow is ischemia. There are many different etiologies of anoxia including a reduction in blood flow—stagnant anoxia; lack of oxygenation—hypoxic anoxia; insufficient oxygen transport—anemic anoxia; and a disturbance in the intracellular oxygen transport—histotoxic anoxia. In adults the most common cause is a combined hypoxic and ischemic injury caused by cardiac arrest. For a neurological disease state with such high prevalence, surprisingly little is understood about the precise patterns of impairment or about the natural history of recovery. There are robust early predictors of outcome of anoxic-ischemic coma (Nolan et al., Intensive Care Med 41: 2039–2056, 2015; Wijdicks, Neurology 67: 203–210, 2006), but the outcome has rarely been specified beyond good, poor, and death. This chapter is designed to examine the etiology, pathology, neurological sequelae, treatment, and outcome of patients who survive a cardiac arrest.
Objective
Neurological outcome prediction is crucial early after cardiac arrest. Serum biomarkers released from brain cells after hypoxic-ischemic 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 analysed 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 hours 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 hours and with similar sensitivities at 48 and 72 hours.
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.
After successful cardiopulmonary resuscitation, some out-of-hospital cardiac arrest patients develop a “sepsis-like” syndrome caused by a systemic inflammatory response following whole-body ischemia and reperfusion; this inflammatory response may contribute to multiorgan failure and death. The observed inflammatory response comprises rapid neutrophil and complement activation, followed by an increase in inflammatory cytokines. The inflammatory response is later followed by immunosuppression, which is the body’s way of protecting itself from further tissue damage. This response may also predispose patients to nosocomial infections in the intensive care unit setting. Several inflammatory biomarkers have been studied for their role as outcome predictors in cardiac arrest patients. Most other prognostic biomarkers that are currently in use focus on predicting neurological outcomes; for example, neuron-specific enolase correlates fairly well with the severity of ischemic brain damage. The systemic inflammatory markers, procalcitonin and interleukin-6, also seem to correlate with organ dysfunction as well as worsened 1-year survival. Limited evidence suggests that combining these markers with brain injury markers might improve the accuracy of outcome prediction models. Using admission serum biomarkers as indicators of impending circulatory shock may be one future perspective that enables identification of patients who may potentially benefit from goal-directed hemodynamic optimization. Based on the clear correlation between the inflammatory response’s severity and patient outcomes, several studies have attempted to alleviate the inflammatory response and thereby improve patient prognosis. These studied therapeutic approaches include targeted temperature management, corticosteroid use, and the removal of circulating cytokines using high cutoff venovenous hemodialysis. Thus far, the results have been inconclusive.
This chapter is centred on a case study on brain injury after cardiac arrest. This topic is one of the key challenging areas in critical care medicine and one that all intensive care staff will encounter. The chapter is based on a detailed case history, ensuring clinical relevance, together with relevant images, making this easily relatable to daily practice in the critical care unit. The chapter is punctuated by evidence-based, up-to-date learning points, which highlight key information for the reader. Throughout the chapter, a topic expert provides contextual advice and commentary, adding practical expertise to the standard textbook approach and reinforcing key messages.
Objectives
Patients with bilateral absence of cortical response (N20ABS) to somatosensory evoked potentials (SSEPs) have poor neurological outcome after cardiac arrest (CA). However, SSEPs are not available in all centers. The aim of this study was to identify predictors of N20ABS.
Methods
Retrospective analysis of institutional databases (2008-2015) in three ICUs including all adult admitted comatose patients undergoing SSEPs between 48 and 72 hours after CA. We collected clinical (i.e. absence of pupillary reflexes, PLR, myoclonus and absent or posturing motor response and myoclonus on day 2-3), electroencephalographic (EEG; i.e. unreactive to painful stimuli; presence of a highly malignant patterns, such as burst-suppression or flat tracings) findings during the first 48 hours, and the highest NSE levels on the first 3 days after CA. Unfavorable neurological outcome (UO) was assessed at 3 months using the Cerebral Performance Categories of 3-5.
Results
We studied 532 patients with SSEPs, including 143 (27%) without N20ABS; UO was observed in 334 (63%) patients. Median time to SSEPs was 72 [48-72] hours after CA. No patient with absent PLR and myoclonus during the ICU stay had N20 present; similar results were observed with the combination of absent PLR, myoclonus and any EEG pattern (i.e. unreactive or highly malignant). Similar results were observed in the subgroup of patients where NSE was available (n = 303). In a multivariate logistic regression, non-cardiac etiology of arrest, unreactive EEG to painful stimuli, absence of pupillary reflexes and posturing motor response, were independent predictors of N20ABS. When available, the highest NSE was also an independent predictor of N20ABS.
Conclusions
Clinical and EEG findings predicting patients with N20ABS, confirm that N20ABS reflects a severe and permanent cerebral damage after CA.
Patients resuscitated from cardiac arrest (CA) face a high risk of neurological disability and death, however pragmatic methods are lacking for accurate and reliable prognostication. The aim of this study was to build computational models to predict post-CA outcome by leveraging high-dimensional patient data available early after admission to the intensive care unit (ICU). We hypothesized that model performance could be enhanced by integrating physiological time series (PTS) data and by training machine learning (ML) classifiers. We compared three models integrating features extracted from the electronic health records (EHR) alone, features derived from PTS collected in the first 24hrs after ICU admission (PTS24), and models integrating PTS24 and EHR. Outcomes of interest were survival and neurological outcome at ICU discharge. Combined EHR-PTS24 models had higher discrimination (area under the receiver operating characteristic curve [AUC]) than models which used either EHR or PTS24 alone, for the prediction of survival (AUC 0.85, 0.80 and 0.68 respectively) and neurological outcome (0.87, 0.83 and 0.78). The best ML classifier achieved higher discrimination than the reference logistic regression model (APACHE III) for survival (AUC 0.85 vs 0.70) and neurological outcome prediction (AUC 0.87 vs 0.75). Feature analysis revealed previously unknown factors to be associated with post-CA recovery. Results attest to the effectiveness of ML models for post-CA predictive modeling and suggest that PTS recorded in very early phase after resuscitation encode short-term outcome probabilities.
Les maladies cardiovasculaires (MCV) représentent la première cause de mortalité dans le Monde et en Europe. Le diagnostic et la prédiction de l’évolution des MCV reposent actuellement sur l’utilisation de biomarqueurs protéiques, mais doivent être améliorés pour optimiser la prise en charge des patients. Le transcriptome sanguin comprend l’ensemble des molécules ARN circulantes, qui sont présentes dans les cellules sanguines et libres dans le sang. Parmi elles, les ARN messagers (ARNm) codent pour des protéines alors que de petits ARN non codants, les microARNs (miARNs), répriment l’expression de leurs gènes cibles. Nous avons émis l’hypothèse que le transcriptome sanguin, et en particulier les ARNm et les miARNs, avaient un potentiel de biomarqueur, diagnostique ou pronostique, dans les MCV. En premier lieu, nous avons montré que l’héparine endogène pouvait induire une inhibition de la transcription inverse couplée à la PCR quantitative lors de la mesure des miARNs circulants et que ce paramètre devait être pris en compte lors de l’étude du transcriptome sanguin. Nous avons ensuite montré que 3 transcrits (codants pour les gènes LMNB1, LTBP4, TGFBR1) exprimés dans le sang total, étaient des prédicteurs indépendants de l’altération de la fonction cardiaque à 4 mois post-IM. De plus, l’ajout de ces 3 transcrits dans un modèle de prédiction contenant des variables cliniques augmente la valeur prédictive de ce modèle. Dans une troisième étude, nous avons montré que les niveaux circulants de miR-574-5p étaient capables de discriminer les patients porteurs d’un AAT des personnes saines. De plus, le miR-574-5p est encapsulé dans des vésicules extracellulaires dans le sang, suggérant un rôle paracrine. Au cours des quatrième et cinquième études, nous avons montré que les niveaux circulants de miR-122-5p étaient des prédicteurs indépendants de l’évolution neurologique et de la survie à moyen terme post-AC, et capable d’améliorer les modèles de prédiction existants. Nous avons également identifié le miR-574-5p comme prédicteur indépendant de l’évolution neurologique post-AC, spécifiquement chez les femmes. En conclusion, ce travail de thèse a permis la découverte ou la confirmation de la valeur de biomarqueurs potentiels de transcrits et miARNs dans différentes MCV. Cependant, leur capacité de biomarqueur devra être validée dans d’autres études à grande échelle et à l’aide d’autres techniques avant d’envisager leur utilisation en clinique
Objectives
To review and update the evidence on predictors of poor outcome (death, persistent vegetative state or severe neurological disability) in adult comatose survivors of cardiac arrest, either treated or not treated with controlled temperature, to identify knowledge gaps and to suggest a reliable prognostication strategy.
Methods
GRADE-based systematic review followed by expert consensus achieved using Web-based Delphi methodology, conference calls and face-to-face meetings. Predictors based on clinical examination, electrophysiology, biomarkers and imaging were included.
Results and conclusions
Evidence from a total of 73 studies was reviewed. The quality of evidence was low or very low for almost all studies. In patients who are comatose with absent or extensor motor response at ≥72 h from arrest, either treated or not treated with controlled temperature, bilateral absence of either pupillary and corneal reflexes or N20 wave of short-latency somatosensory evoked potentials were identified as the most robust predictors. Early status myoclonus, elevated values of neuron-specific enolase at 48–72 h from arrest, unreactive malignant EEG patterns after rewarming, and presence of diffuse signs of postanoxic injury on either computed tomography or magnetic resonance imaging were identified as useful but less robust predictors. Prolonged observation and repeated assessments should be considered when results of initial assessment are inconclusive. Although no specific combination of predictors is sufficiently supported by available evidence, a multimodal prognostication approach is recommended in all patients.
Electronic supplementary material
The online version of this article (doi:10.1007/s00134-014-3470-x) contains supplementary material, which is available to authorized users.
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.
Although well characterized in animals, brain damage in humans treated with hypothermia after cardiac arrest has not been systematically explored. In this study we aimed to describe the characteristic trait of selective eosinophilic neuronal death (SEND) and its correlation with time to return of spontaneous circulation (ROSC) in cardiac arrest patients who died after hypothermia treatment and were referred for autopsy.
Brain autopsy microscopic slides and clinical data were gathered from 23 non-survivors of cardiac arrest who were treated with hypothermia. Based on the percentage of eosinophilic neurons, a damage score 0-4 was given in 6 brain regions and a total damage score was calculated. The damage score was correlated with time to ROSC and with neuron-specific enolase (NSE) in peripheral blood at 48h post arrest.
Hippocampus had the highest damage score with a median of 3 (inter-quartile range 2-4) while the brainstem had the lowest median damage score of 0 (0-2). Total damage score showed the best correlation with time to ROSC (Spearman Rho=0.66). Serum NSE values >33μg/L (n=6) was associated with significantly higher mean damage score than NSE <33μg/L (n=9) (p=0.002).
This is the first study to systematically describe regional SEND in patients treated with hypothermia after cardiac arrest. Hippocampus was the most vulnerable region whereas the brainstem was the most resistant. Although not directly compared here, the regional pattern of SEND seems not to be altered by hypothermia treatment, but maintains its profile distinctive for cardiac arrest pathogenesis.
Background:
Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever.
Methods:
In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale.
Results:
In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar.
Conclusions:
In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.).
Animal experimental studies and previous randomized trials suggest an improvement in mortality and neurological function with temperature regulation to hypothermia after cardiac arrest. According to a systematic review, previous trials were small, had a risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management (TTM) strategy is not known. To prevent outcome reporting bias, selective reporting and data-driven results, we present the a priori defined detailed statistical analysis plan as an update to the previously published outline of the design and rationale for the TTM trial.
The TTM trial is an investigator-initiated, multicenter, international, randomized, parallel-group, and assessor-blinded clinical trial of temperature management in 950 adult unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients are randomized to a TTM of either 33[degree sign]C or 36[degree sign]C after return of spontaneous circulation. The primary outcome is all-cause mortality at maximal follow-up (until end of the trial and a minimum of 180 days). The main secondary outcomes are the composite outcome of all-cause mortality and poor neurological function (Cerebral Performance Category (CPC) 3 and 4, and modified Rankin Scale (mRS) 4 and 5) at hospital discharge and at 180 days; and assessment of safety and harm: bleeding, infections, electrolyte and metabolic disorders, seizures, cardiac arrhythmia, and renal replacement therapy.
The TTM trial investigates potential benefit and harm of two target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.Trial registration: ClinicalTrials.gov identifier: NCT01020916.
Brain injury is well established as a cause of early mortality after out-of-hospital cardiac arrest (OHCA), but postresuscitation shock also contributes to these deaths. This study aims to describe the respective incidence, risk factors, and relation to mortality of post-cardiac arrest (CA) shock and brain injury.
Retrospective analysis of an observational cohort.
24-bed medical intensive care unit (ICU) in a French university hospital.
All consecutive patients admitted following OHCA were considered for analysis. Post-CA shock was defined as a need for infusion of vasoactive drugs after resuscitation. Death related to brain injury included brain death and care withdrawal for poor neurological evolution.
None.
Between 2000 and 2009, 1,152 patients were admitted after OHCA. Post-CA shock occurred in 789 (68 %) patients. Independent factors associated with its onset were high blood lactate and creatinine levels at ICU admission. During the ICU stay, 269 (34.8 %) patients died from post-CA shock and 499 (65.2 %) from neurological injury. Age, raised blood lactate and creatinine values, and time from collapse to restoration of spontaneous circulation increased the risk of ICU mortality from both shock and brain injury, whereas a shockable rhythm was associated with reduced risk of death from these causes. Finally, bystander cardiopulmonary resuscitation (CPR) decreased the risk of death from neurological injury.
Brain injury accounts for the majority of deaths, but post-CA shock affects more than two-thirds of OHCA patients. Mortality from post-CA shock and brain injury share similar risk factors, which are related to the quality of the rescue process.
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.
37 studies (2375 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.
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.
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 survivors from cardiac arrest not treated using therapeutic hypothermia (TH). PubMed, Scopus and the Cochrane Database of Systematic reviews were searched for eligible studies. Sensitivity, specificity, false positive rates (FPR) for each predictor were calculated and results of predictors with similar time points and outcome definitions were pooled. Quality of evidence (QOE) was evaluated according to the GRADE guidelines.
50 studies (2828 patients) were included in final analysis. Presence of myoclonus at 24-48h, bilateral absence of short-latency somatosensory evoked potential (SSEP) N20 wave at 24-72h absence of electroencephalographic activity >20-21μV ≤72h and absence of pupillary reflex at 72h predicted CPC 4-5 with 0% FPR and narrow (<10%) 95% confidence intervals. Absence of SSEP N20 wave at 24h predicted CPC 3-5 with 0% [0-8] FPR. Serum thresholds for 0% FPR of biomarkers neuron specific enolase (NSE) and S-100B were highly inconsistent among studies. Most of the studies had a low or very low QOE and did not report blinding of the treating team from the results of the investigated predictor.
in comatose resuscitated patients not treated with TH presence of myoclonus, absence of pupillary reflex, bilateral absence of N20 SSEP wave and low EEG voltage each predicted poor outcome early and accurately, but with a relevant risk of bias.
Brain injury is the dominant cause of death for cardiac arrest patients who are admitted to an intensive care unit, and the majority of patients die after withdrawal of life sustaining therapy (WLST) based on a presumed poor neurologic outcome. Mild induced hypothermia was found to decrease the reliability of several methods for neurological prognostication. Algorithms for prediction of outcome, that were developed before the introduction of mild hypothermia after cardiac arrest, may have affected the results of studies with hypothermia-treated patients. In previous trials on neuroprotection after cardiac arrest, including the pivotal hypothermia trials, the methods for prognostication and the reasons for WLST were not reported and may have had an effect on outcome. In the Target Temperature Management trial, in which 950 cardiac arrest patients have been randomized to treatment at 33[degree sign]C or 36[degree sign]C, neuroprognostication and WLST-decisions are strictly protocolized and registered. Prognostication is delayed to at least 72 hours after the end of the intervention period, thus a minimum of 4.5 days after the cardiac arrest, and is based on multiple parameters to account for the possible effects of hypothermia.
Outcome from coma caused by cerebral hypoxia-ischemia (eg, cardiac arrest) was compared with serial neurological findings in 210 patients. Thirteen percent of patients regained independent function at some point during the first postarrest year. Computer application of new multivariate techniques to the prospectively observed findings generated easily utilized rules that classified patients by likely outcome. At the time of initial examination, 52 patients (one fourth of the total population) had absent pupillary light reflexes, and none of these patients ever regained independent daily function. By contrast, the initial presence of pupillary light reflexes, the development of spontaneous eye movements that were roving conjugate or better, and the findings of extensor, flexor, or withdrawal responses to pain identified a smaller group of 27 patients, 11 (41%) of whom regained independence in their daily lives. By 24 hours after onset, 93 poor-outcome patients were identified by motor responses that were absent, extensor, or flexor and by spontaneous eye movements that were neither orienting nor roving conjugate; only one regained independent function. This contrasts with recovery in 19 (63%) of 30 patients who at that time showed improvement in their eye-opening responses and obeyed commands or had motor responses that were withdrawal or localizing. Similarly simple rules distinguished between good- and poor-prognosis patients on postarrest days 3, 7, and 14.(JAMA 1985;253:1420-1426)
Therapeutic hypothermia (TH) is a recommended treatment for survivors of cardiac arrest. Prognostication is complicated since sedation and muscle relaxation are used and established indicators of a poor prognosis are lacking. This prospective, observational study describes the pattern of commonly used prognostic markers in a hypothermia-treated cohort of cardiac arrest patients with prolonged coma.
Among 111 consecutive patients, 19 died, 58 recovered, and 34 were in coma 3 days after normothermia (4.5 days after cardiac arrest), defined as prolonged coma. All patients were monitored with continuous amplitude-integrated EEG and repeated samples of neuron-specific enolase (NSE) were collected. In patients with prolonged coma, somatosensory evoked potentials (SSEP) and brain MRI were performed. A postmortem brain investigation was undertaken in patients who died.
Six of the 17 patients (35%) with NSE levels <33 μg/L at 48 hours regained the capacity to obey verbal commands. By contrast, all 17 patients with NSE levels >33 failed to recover consciousness. In the >33 NSE group, all 10 studied with MRI had extensive brain injury on diffusion-weighted images, 12/16 lacked cortical responses on SSEP, and all 6 who underwent autopsy had extensive severe histologic damage. NSE levels also correlated with EEG pattern, but less uniformly, since 11/17 with NSE <33 had an electrographic status epilepticus (ESE), only one of whom recovered. A continuous EEG pattern correlated to NSE <33 and awakening.
NSE correlates well with other markers of ischemic brain injury. In patients with no other signs of brain injury, postanoxic ESE may explain a poor outcome.
The following guidelines are an interpretation of the evidence presented in the 2010 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations 1 ). They apply primarily to newly born infants undergoing transition from intrauterine to extrauterine life, but the recommendations are also applicable to neonates who have completed perinatal transition and require resuscitation during the first few weeks to months following birth. Practitioners who resuscitate infants at birth or at any time during the initial hospital admission should consider following these guidelines. For the purposes of these guidelines, the terms newborn and neonate are intended to apply to any infant during the initial hospitalization. The term newly born is intended to apply specifically to an infant at the time of birth. Approximately 10% of newborns require some assistance to begin breathing at birth. Less than 1% require extensive resuscitative measures. 2,3 Although the vast majority of newly born infants do not require intervention to make the transition from intrauterine to extrauterine life, because of the large total number of births, a sizable number will require some degree of resuscitation. Those newly born infants who do not require resuscitation can generally be identified by a rapid assessment of the following 3 characteristics: ● Term gestation? ● Crying or breathing? ● Good muscle tone? If the answer to all 3 of these questions is “yes,” the baby does not need resuscitation and should not be separated from the mother. The baby should be dried, placed skin-to-skin with the mother, and covered with dry linen to maintain temperature. Observation of breathing, activity, and color should be ongoing. If the answer to any of these assessment questions is “no,” the infant should receive one or more of the following 4 categories of action in sequence:
Cardiac arrest outside the hospital is common and has a poor outcome. Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome, but there have been no conclusive studies in humans. In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest.
The study subjects were 77 patients who were randomly assigned to treatment with hypothermia (with the core body temperature reduced to 33 degrees C within 2 hours after the return of spontaneous circulation and maintained at that temperature for 12 hours) or normothermia. The primary outcome measure was survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility.
The demographic characteristics of the patients were similar in the hypothermia and normothermia groups. Twenty-one of the 43 patients treated with hypothermia (49 percent) survived and had a good outcome--that is, they were discharged home or to a rehabilitation facility--as compared with 9 of the 34 treated with normothermia (26 percent, P=0.046). After adjustment for base-line differences in age and time from collapse to the return of spontaneous circulation, the odds ratio for a good outcome with hypothermia as compared with normothermia was 5.25 (95 percent confidence interval, 1.47 to 18.76; P=0.011). Hypothermia was associated with a lower cardiac index, higher systemic vascular resistance, and hyperglycemia. There was no difference in the frequency of adverse events.
Our preliminary observations suggest that treatment with moderate hypothermia appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest.
Background
Cardiac arrest with widespread cerebral ischemia frequently leads to severe neurologic impairment. We studied whether mild systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation.
Methods
In this multicenter trial with blinded assessment of the outcome, patients who had been resuscitated after cardiac arrest due to ventricular fibrillation were randomly assigned to undergo therapeutic hypothermia (target temperature, 32°C to 34°C, measured in the bladder) over a period of 24 hours or to receive standard treatment with normothermia. The primary end point was a favorable neurologic outcome within six months after cardiac arrest; secondary end points were mortality within six months and the rate of complications within seven days.
Results
Seventy-five of the 136 patients in the hypothermia group for whom data were available (55 percent) had a favorable neurologic outcome (cerebral-performance category, 1 [good recovery] or 2 [moderate disability]), as compared with 54 of 137 (39 percent) in the normothermia group (risk ratio, 1.40; 95 percent confidence interval, 1.08 to 1.81). Mortality at six months was 41 percent in the hypothermia group (56 of 137 patients died), as compared with 55 percent in the normothermia group (76 of 138 patients; risk ratio, 0.74; 95 percent confidence interval, 0.58 to 0.95). The complication rate did not differ significantly between the two groups.
Conclusions
In patients who have been successfully resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality.
Brain injury affects neurologic function and quality of life in survivors after cardiac arrest.
To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest.
In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939.
Targeted temperature management at 33°C vs 36°C.
Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2.
In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33°C group (interquartile range [IQR], 0-28) vs 17 in the 36°C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33°C and 36°C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33°C group median, 28; IQR, 26-30; vs 36°C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33°C group median, 79.5; IQR, 78.0-85.9; vs 36°C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33°C group vs 61.8% in the 36°C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm.
Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33°C or 36°C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales.
ClinicalTrials.gov NCT01020916.
In Reply.—
We were aware of the possibility that a self-fulfilling prophecy might have influenced our data. Although we did not communicate findings to physicians in our hospitals, Hart and colleagues correctly point out that "conventional" wisdom could have led to premature withdrawal of care in some patients. We think, however, that this did not exert a major influence on our results.1To estimate the magnitude of this potential problem, we have reanalyzed the data for patients with preserved or absent pupillary light reflexes on the initial examination. One would expect patients with absent pupillary light reflexes to die more rapidly than those with preserved reflexes for at least two reasons: (1) a poorer clinical condition and (2) the possibility of premature withdrawal of care. Fifty-two of 53 patients with absent pupillary reflexes died within the first month, and 112 of 157 patients with preserved reflexes also died within
Targeted temperature management improves survival and neurologic outcomes for adult out-of-hospital cardiac arrest survivors but may alter the accuracy of tests for predicting neurologic outcome after cardiac arrest.
We systematically searched Medline, Embase, CINAHL, and CENTRAL from database inception to September 2012.
Citations were screened for studies that examined diagnostic tests to predict poor neurologic outcome or death following targeted temperature management in adult cardiac arrest survivors.
Data on study outcomes and quality were abstracted in duplicate. We constructed contingency tables for each diagnostic test and calculated sensitivity, specificity, and positive and negative likelihood ratios.
Of 2,737 citations, 20 studies (n = 1,845) met inclusion criteria. Meta-analysis showed that three tests accurately predicted poor neurologic outcome with low false-positive rates: bilateral absence of pupillary reflexes more than 24 hours after a return of spontaneous circulation (false-positive rate, 0.02; 95% CI, 0.01-0.06; summary positive likelihood ratio, 10.45; 95% CI, 3.37-32.43), bilateral absence of corneal reflexes more than 24 hours (false-positive rate, 0.04; 95% CI, 0.01-0.09; positive likelihood ratio, 6.8; 95% CI, 2.52-18.38), and bilateral absence of somatosensory-evoked potentials between days 1 and 7 (false-positive rate, 0.03; 95% CI, 0.01-0.07; positive likelihood ratio, 12.79; 95% CI, 5.35-30.62). False-positive rates were higher for a Glasgow Coma Scale motor score showing extensor posturing or worse (false-positive rate, 0.09; 95% CI, 0.06-0.13; positive likelihood ratio, 7.11; 95% CI, 5.01-10.08), unfavorable electroencephalogram patterns (false-positive rate, 0.07; 95% CI, 0.04-0.12; positive likelihood ratio, 8.85; 95% CI, 4.87-16.08), myoclonic status epilepticus (false-positive rate, 0.05; 95% CI, 0.02-0.11; positive likelihood ratio, 5.58; 95% CI, 2.56-12.16), and elevated neuron-specific enolase (false-positive rate, 0.12; 95% CI, 0.06-0.23; positive likelihood ratio, 4.14; 95% CI, 1.82-9.42). The specificity of available tests improved when these were performed beyond 72 hours. Data on neuroimaging, biomarkers, or combination testing were limited and inconclusive.
Simple bedside tests and somatosensory-evoked potentials predict poor neurologic outcome for survivors of cardiac arrest treated with targeted temperature management, and specificity improves when performed beyond 72 hours. Clinicians should use caution with these predictors as they carry the inherent risk of becoming self-fulfilling.
Persisting disability after brain damage usually comprises both mental and physical handicap. The mental component is often the more important in contributing to overall social disability. Lack of an objective scale leads to vague and over-optimistic estimates of outcome, which obscure the ultimate results of early management. A five-point scale is described—death, persistent vegetative state, severe disability, moderate disability, and good recovery. Duration as well as intensity of disability should be included in an index of ill-health; this applies particularly after head injury, because many disabled survivors are young.
When a patient resuscitated from cardiac arrest remains unconscious the clinician would like to have a reliable early method for predicting the outcome. The objective of our study was to predict cerebral outcome after cardiac arrest by clinical neurological examination. The data were drawn from an international multicentre controlled clinical trial of thiopentone. Twelve hospitals in nine countries took part. 262 comatose cardiac arrest survivors were followed up for one year. These patients were given advanced life support (American Heart Association guidelines) followed by intensive care to a standardised protocol. Glasgow and Glasgow-Pittsburgh coma scores and their constituent signs were recorded at fixed times. Outcome was taken to be the best cerebral performance at any time during follow-up, and for that purpose we used cerebral performance categories (CPC 1-5) of the Glasgow outcome categories. A poor outcome (CPC 3-5) could be predicted immediately after reperfusion (at entry into the study) with an accuracy ranging from 52% to 84% for various signs and scores. On the third day it was possible to identify severely disabled or permanently comatose survivors without false predictions using both coma scores and several of their constituent variables. The best predictor was absence of motor response to pain. This modelling exercise now needs to be repeated on a new series of patients but the results do suggest that, after 3 days, stringent ethical criteria can be met and used in decision-making about termination of care in comatose cardiac arrest survivors.
To assess the sensitivity and false positive rate (FPR) of neurological examination and somatosensory evoked potentials (SSEPs) to predict poor outcome in adult patients treated with therapeutic hypothermia after cardiopulmonary resuscitation (CPR).
MEDLINE and EMBASE were searched for cohort studies describing the association of clinical neurological examination or SSEPs after return of spontaneous circulation with neurological outcome. Poor outcome was defined as severe disability, vegetative state and death. Sensitivity and FPR were determined.
A total of 1,153 patients from ten studies were included. The FPR of a bilaterally absent cortical N20 response of the SSEP could be calculated from nine studies including 492 patients. The SSEP had an FPR of 0.007 (confidence interval, CI, 0.001-0.047) to predict poor outcome. The Glasgow coma score (GCS) motor response was assessed in 811 patients from nine studies. A GCS motor score of 1-2 at 72 h had a high FPR of 0.21 (CI 0.08-0.43). Corneal reflex and pupillary reactivity at 72 h after the arrest were available in 429 and 566 patients, respectively. Bilaterally absent corneal reflexes had an FPR of 0.02 (CI 0.002-0.13). Bilaterally absent pupillary reflexes had an FPR of 0.004 (CI 0.001-0.03).
At 72 h after the arrest the motor response to painful stimuli and the corneal reflexes are not a reliable tool for the early prediction of poor outcome in patients treated with hypothermia. The reliability of the pupillary response to light and the SSEP is comparable to that in patients not treated with hypothermia.
Objectives:
To examine the natural clinical course of patients admitted to inpatient neurorehabilitation in a coma, vegetative state (VS), or minimally conscious state (MCS) after anoxic-ischaemic encephalopathy (AIE).
Methods:
This is a retrospective cohort study of 113 consecutive patients admitted to a German inpatient neurorehabilitation centre with severe disorders of consciousness (DOC) following AIE due to cardiac arrest over a 6-year period. Functional independence was measured with the Glasgow Outcome Scale (GOS) and recovery of consciousness with the Coma Remission Scale (CRS). Separate binary logistic regression models were used to identify independent predictors for functional and behavioural outcomes.
Results:
Seven patients (6.2%) achieved a good functional outcome (GOS 4-5). Five of these showed significant functional improvement within the first 8 weeks. 22 patients (19.5%) recovered consciousness; the last patient began to make significant improvement between weeks 10 and 12. Logistic regression showed that both increasing age and lower admission CRS predicted unfavourable functional outcome and persistent DOC. A longer stay in the ICU also predicted persistent DOC at the end of neurorehabilitation. However, neither malignant somatosensory evoked potential (SEP) test results nor hypothermia treatment on the ICU were outcome predictors in either outcome category.
Conclusion:
Even among severely affected AIE patients arriving at a neurological rehabilitation centre in a DOC, there remains potential for functional and behavioural improvement. However, significant improvements may not begin for up to 3 months post-injury. This study suggests that recovery of consciousness and even a good neurological outcome are possible despite malignant SEP test results.
Cardiopulmonary resuscitation is started in 5000 victims of out-of-hospital cardiac arrest in Sweden each year and the survival rate is approximately 10%. The subsequent development of a global ischemic brain injury is the major determinant of the neurological prognosis for those patients who reach the hospital alive. Induced hypothermia is a recommended treatment after cardiac arrest and has been implemented in most Swedish hospitals. Recent studies indicate that induced hypothermia may affect neurological prognostication and previous international recommendations are therefore no longer valid when hypothermia is applied. An expert group from the Swedish Resuscitation Council has reviewed the literature and made recommendations taking into account the effects of induced hypothermia and concomitant sedation. A delayed neurological evaluation at 72hours after rewarming is recommended for hypothermia treated patients. This evaluation should be based on several independent methods and the possibility of lingering pharmacological effects should be considered.
Experimental animal studies and previous randomized trials suggest an improvement in mortality and neurologic function with induced hypothermia after cardiac arrest. International guidelines advocate the use of a target temperature management of 32°C to 34°C for 12 to 24 hours after resuscitation from out-of-hospital cardiac arrest. A systematic review indicates that the evidence for recommending this intervention is inconclusive, and the GRADE level of evidence is low. Previous trials were small, with high risk of bias, evaluated select populations, and did not treat hyperthermia in the control groups. The optimal target temperature management strategy is not known.
The TTM trial is an investigator-initiated, international, randomized, parallel-group, and assessor-blinded clinical trial designed to enroll at least 850 adult, unconscious patients resuscitated after out-of-hospital cardiac arrest of a presumed cardiac cause. The patients will be randomized to a target temperature management of either 33°C or 36°C after return of spontaneous circulation. In both groups, the intervention will last 36 hours. The primary outcome is all-cause mortality at maximal follow-up. The main secondary outcomes are the composite outcome of all-cause mortality and poor neurologic function (cerebral performance categories 3 and 4) at hospital discharge and at 180 days, cognitive status and quality of life at 180 days, assessment of safety and harm.
The TTM trial will investigate potential benefit and harm of 2 target temperature strategies, both avoiding hyperthermia in a large proportion of the out-of-hospital cardiac arrest population.
This study was designed to establish the reliability of neurologic examination, neuron-specific enolase (NSE), and median nerve somatosensory-evoked potentials (SEPs) to predict poor outcome in patients treated with mild hypothermia after cardiopulmonary resuscitation (CPR).
This multicenter prospective cohort study included adult comatose patients admitted to the intensive care unit (ICU) after CPR and treated with hypothermia (32-34°C). False-positive rates (FPRs 1 - specificity) with their 95% confidence intervals (CIs) were calculated for pupillary light responses, corneal reflexes, and motor scores 72 hours after CPR; NSE levels at admission, 12 hours after reaching target temperature, and 36 hours and 48 hours after collapse; and SEPs during hypothermia and after rewarming. The primary outcome was poor outcome, defined as death, vegetative state, or severe disability (Glasgow Outcome Scale 1-3) after 6 months.
Of 391 patients included, 53% had a poor outcome. Absent pupillary light responses (FPR 1; 95% CI, 0-7) or absent corneal reflexes (FPR 4; 95% CI, 1-13) 72 hours after CPR, and absent SEPs during hypothermia (FPR 3; 95% CI, 1-7) and after rewarming (FPR 0; 95% CI, 0-18) were reliable predictors. Motor scores 72 hours after CPR (FPR 10; 95% CI, 6-16) and NSE levels were not.
In patients with persisting coma after CPR and therapeutic hypothermia, use of motor score or NSE, as recommended in current guidelines, could possibly lead to inappropriate withdrawal of treatment. Poor outcomes can reliably be predicted by testing brainstem reflexes 72 hours after CPR and performing SEP.
Outcome studies in patients with anoxic-ischemic encephalopathy focus on the early and reliable prediction of an outcome no better than a vegetative state or severe disability. We determined the effect of mild therapeutic hypothermia on the validity of the currently used clinical practice parameters.
We conducted a retrospective cohort study of adult comatose patients after cardiac arrest treated with hypothermia. All data were collected from medical charts and laboratory files and analyzed from the day of admission to the intensive care unit until day 7, discharge from the intensive care unit or death using the Utstein definitions for the registration of the data.
We analyzed the data of 103 patients. The combination of an M1 or M2 on the Glasgow Coma Scale or absent pupillary reactions or absent corneal reflexes on day 3 was present in 80.6% of patients with an unfavourable and 11.1% of patients with a favourable outcome. The combination of M1 or M2 and absent pupillary reactions to light and absent corneal reflexes on day 3 was present in 14.9% of patients with an unfavourable and none of the patients with a favourable outcome. None of the patients with a favourable outcome had a bilaterally absent somatosensory evoked potential of the median nerve. The value of electroencephalogram patterns in predicting outcome was low, except for reactivity to noxious stimuli.
No single clinical or electrophysiological parameter has sufficient accuracy to determine prognosis and decision making in patients after cardiac arrest, treated with hypothermia.
The goal of immediate post-cardiac arrest care is to optimize systemic perfusion, restore metabolic homeostasis, and support organ system function to increase the likelihood of intact neurological survival. The post-cardiac arrest period is often marked by hemodynamic instability as well as metabolic abnormalities. Support and treatment of acute myocardial dysfunction and acute myocardial ischemia can increase the probability of survival. Interventions to reduce secondary brain injury, such as therapeutic hypothermia, can improve survival and neurological recovery. Every organ system is at risk during this period, and patients are at risk of developing multiorgan dysfunction. The comprehensive treatment of diverse problems after cardiac arrest involves multidisciplinary aspects of critical care, cardiology, and neurology. For this reason, it is important to admit patients to appropriate critical-care units with a prospective plan of care to anticipate, monitor, and treat each of these diverse problems. It is also important to appreciate the relative strengths and weaknesses of different tools for estimating the prognosis of patients after cardiac arrest.
Therapeutic hypothermia is commonly used in comatose survivors' post-cardiopulmonary resuscitation (CPR). It is unknown whether outcome predictors perform accurately after hypothermia treatment.
Post-CPR comatose survivors were prospectively enrolled. Six outcome predictors [pupillary and corneal reflexes, motor response to pain, and somatosensory-evoked potentials (SSEP) >72 h; status myoclonus, and serum neuron-specific enolase (NSE) levels <72 h] were systematically recorded. Poor outcome was defined as death or vegetative state at 3 months. Patients were considered "sedated" if they received any sedative drugs ≤ 12 h prior the 72 h neurological assessment.
Of 85 prospectively enrolled patients, 53 (62%) underwent hypothermia. Furthermore, 53 of the 85 patients (62%) had a poor outcome. Baseline characteristics did not differ between the hypothermia and normothermia groups. Sedative drugs at 72 h were used in 62 (73%) patients overall, and more frequently in hypothermia than in normothermia patients: 83 versus 60% (P = 0.02). Status myoclonus <72 h, absent cortical responses by SSEPs >72 h, and absent pupillary reflexes >72 h predicted poor outcome with a 100% specificity both in hypothermia and n