REVIEW URRENT C OPINION
Prognostication after cardiac arrest Janneke Horn a, Tobias Cronberg b, and Fabio S. Taccone c
Purpose of review The prognosis of patients with postanoxic coma (PAC) after cardiac arrest is a challenging task for clinicians. The need for early and accurate prognostic predictors is crucial. Treatment with therapeutic hypothermia and sedation alters the reliability of neurological examination. Considering the extensive literature existing on this topic, we aimed to provide a practical approach on how to predict outcome in patients with PAC, particularly in those treated with therapeutic hypothermia. Recent findings Recovery of motor responses can take several days and can therefore not be used to assess the extent of brain injury in the early phase after cardiac arrest. Additional tools, including electroencephalography, somatosensory-evoked potentials, biomarkers and radiological imaging, may help to determine the prognosis. Nevertheless, treatment with therapeutic hypothermia, including prolonged sedation, has changed the predictive value of these tools. Summary For reliable prediction of outcome in patients with PAC, various prognostic methods should be combined with the standard neurological examination in a multimodal approach. Keywords cardiac arrest, electroencephalography, evoked potentials, neurological examination, prognosis
INTRODUCTION
neurological examination remains poorly reliable in the early phase after ROSC [6 ,7 ]. The aim of this review is to provide a practical approach to the patient with PAC treated with therapeutic hypothermia, and to outline when and how additional prognostic tools can be combined with neurological examination in a multimodal approach to improve the quality of the outcome assessment (Fig. 1). &&
Patients who are admitted after cardiac arrest are nowadays treated with therapeutic hypothermia. This treatment has been shown to improve neurological outcome, but the optimal target temperature is currently uncertain [1,2,3 ]. Despite therapeutic hypothermia, many patients remain comatose after the cessation of sedatives and analgesics, which are administered during therapeutic hypothermia treatment. Postanoxic coma (PAC) is due to the severe ischemia and subsequent reperfusion that occur during cardiac arrest and after the return of spontaneous circulation (ROSC). These two factors, which primarily define neurological outcome, lead to the ‘postcardiac arrest syndrome’ [4]. This is characterized by three components: brain injury, myocardial dysfunction and systemic ischemia– reperfusion response. Severe brain injury leading to PAC is the most common cause of death [5]. Prognostication of PAC is important to inform family members about the chances of recovery, and to identify those patients with irreversible brain damage to prevent futile treatment and prolonged suffering for patients and relatives. Unfortunately, the use of therapeutic hypothermia has substantially delayed the awakening of these patients, so that &&
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HOW WE DEFINE ‘GOOD’ OR ‘POOR’ OUTCOME? In the last 2 decades, several studies have been performed to study the reliability of diagnostic tools
a Department of Intensive Care, Academic Medical Center, Amsterdam, The Netherlands, bDepartment of Clinical Sciences, Section for Neurology, Lund University Hospital, Lund University, Lund, Sweden and c Department of Intensive Care, Hoˆpital Erasme, Universite´ Libre de Bruxelles (ULB), Brussels, Belgium
Correspondence to Janneke Horn, Neurologist-Intensivist, Intensive Care Unit C3-329, Academical Medical Center, PO Box 22660, 1100DD Amsterdam, The Netherlands. Tel: +31 20 5662509; e-mail: j.horn @amc.nl Curr Opin Crit Care 2014, 20:280–286 DOI:10.1097/MCC.0000000000000085 Volume 20 Number 3 June 2014
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Prognostication after cardiac arrest Horn et al.
Neurological examination
EEG
SSEPs
Imaging
Biomarkers
FIGURE 1. Additional tools available for prognostication in patients with PAC. EEG, electroencephalogram; PAC, postanoxic coma; SSEPs, somatosensory-evoked potentials.
used in patients with PAC to predict the outcome. To assess outcome, the Glasgow Outcome Scale (GOS) or the Cerebral Performance Category (CPC) scale are widely used [8,9]. They are both five-point scales (Table 1). The definition of a poor outcome was GOS 1–2 (CPC 4–5) in the majority of studies, but GOS 1–3 (CPC 3–5) in some studies
[10–12]. Different definitions of poor and good outcome and different periods of follow-up have to be taken into account when reading and interpreting the available studies. Ideally, follow-up should be at least 3–6 months, as neurological recovery in PAC patients has been described several weeks after arrest. However, most patients with good
Table 1. GOS and CPC outcome scales GOS
Clinical condition
CPC
5
Good cerebral performance: conscious, alert, able to work, might have mild neurologic or psychologic deficit.
1
4
Moderate cerebral disability: conscious, sufficient cerebral function for independent activities of daily life. Able to work in sheltered environment.
2
3
Severe cerebral disability: conscious, dependent on others for daily support because of impaired brain function. Ranges from ambulatory state to severe dementia or paralysis.
3
2
Coma or vegetative state: any degree of coma without the presence of all brain death criteria. Unawareness, even if appears awake (vegetative state) without interaction with environment; may have spontaneous eye opening and sleep and awake cycles. Cerebral unresponsiveness.
4
1
Death or brain death: apnea, areflexia, EEG silence.
5
CPC, Cerebral Performance Category; GOS, Glasgow Outcome Scale.
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neurological outcome will improve within 1–2 weeks after brain injury. Although it is generally considered that almost all patients who survive after cardiac arrest have a good outcome (GOS 5 or CPC 1), it is also known that substantial cognitive disturbances can be detected in as much as 50% of this population [13,14]. An important task in the daily care of patients with PAC is the identification of patients who will certainly have a poor outcome; as such, diagnostic tools have mainly been investigated for this aim. To describe the reliability of these tests usually the false-positive rate (FPR) is used, which is defined as 1 minus specificity of the test involved [10,12]. This means that when a test has an FPR of 0.20, in 20% of the patients with a good outcome, the test results predicted a poor outcome. This explains that the FPR has to be as low as possible, with a small 95% confidence interval (CI).
DIAGNOSTIC TOOLS In this section, the available diagnostic tests and their advantages and disadvantages will be discussed.
Neurological examination Neurological recovery is altered by the sedative drugs and neuromuscular blockers administered during therapeutic hypothermia treatment in the first 24–48 h of admission [11]. Additionally, hypothermia prolongs the metabolism of sedative agents and induces drug accumulation, which also changes the timing of neurological recovery [15]. Early prediction of a poor prognosis based solely on neurological examination could lead to withdrawal of lifesustaining therapy in almost 20% of patients, who would otherwise have a complete neurological recovery [16]. Thus, when therapeutic hypothermia is used, only the loss of all brain-stem functions can be regarded as poor prognostic factors in the very early phase. These are usually signs of total brain infarction and herniation, which happens in only a small minority of patients after cardiac arrest [17]. As some confounders may exist in this setting, for a diagnosis of brain death additional tools should be used, including electroencephalography (EEG) and neuroimaging. After 48–72 h without sedative drugs, the presence of a motor response that localizes painful stimuli (Glasgow Coma Score – Motor Response, GCS-M, 5) is a sign of a favorable prognosis and no further diagnostic tests are necessary [18]. If the patient remains unresponsive to pain or with extension to painful stimuli (GCS-M 2) on day 3, a poor prognosis is likely in 80% of patients. Pupillary and corneal reflexes confer additional prognostic information, as a bilateral absence at 282
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72 h after arrest, although relatively uncommon, is related to a poor prognosis with low FPR [6 ,7 ,12]. The optimal timing to define prognosis based only on the neurological examination remains unknown. Although it has been suggested that the reliability 72 h after normothermia has been achieved (i.e., 4–5 days after cardiac arrest) is good, very limited data are available on the reliability and predictive value of clinical tests at this timepoint [6 ]. &&
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Seizures and myoclonus Clinical seizures are reported in about one-fourth of cardiac arrest victims, but various forms of motor manifestations are often misinterpreted as seizures [19,20 ,21]. Myoclonus is a common event following cardiac arrest that may or may not be an epileptic manifestation [22]. Occasional myoclonic jerks have little prognostic value in PAC. In a recent study, 9% of patients with posthypoxic myoclonus eventually had a good outcome [22]. On the opposite, generalized myoclonus (including face, trunk and limbs) and continuing for more than 30 min can be regarded as a status myoclonus. This is associated with a very high rate of poor neurological outcome, especially if this occurs in the first day after arrest [23]. Status myoclonus is often associated with burst suppression on EEG, further supporting extensive brain damage. Since the introduction of therapeutic hypothermia treatment, an early status myoclonus, which is usually easily suppressed by sedatives, has become more uncommon [24]. As survivors with good neurological recovery have been reported, a status myoclonus should no longer motivate a decision to withdraw intensive care [25]. &
Electroencephalography Nowadays, EEG is commonly used to detect seizures and postanoxic status epilepticus (PSE), which occur in 10–40% of patients and are associated with a poor outcome [19,20 ,26]. Nevertheless, good neurological outcome has been reported following aggressive antiepileptic therapy for seizures, especially in selected patients [preserved brainstem reflexes, present cortical response on somatosensory-evoked potentials (SSEPs) and reactive EEG] [27]. In addition to seizure detection, EEG has been used to identify specific patterns associated with poor outcome in PAC, but the classification of these patterns varies extensively between studies [28,29]. EEG patterns associated with a poor prognosis are PSE, alphacoma and burst suppression or generalized suppression. Other more or less pathologic EEG findings, including a generalized slow activity, generalized &
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alpha-theta frequencies or epileptiform discharges, are yet of unclear significance. To improve the accuracy of EEG to predict both poor and good outcome, different studies have tested the ‘reactivity’ of the EEG background pattern. Reactivity is defined as any reproducible change in amplitude or frequency upon patient stimulation [10,30]. EEG reactivity was found to have a better predictive value for neurological outcome than malignant and benign EEG patterns and evoked potentials, and predicted awakening in patients with an EEG pattern of alpha-coma after cardiac arrest [31]. As this research has not been done in large multicenter studies, potential sources of bias including sedation and technique of testing exist. The true value of reactivity testing in PAC needs to be established in new studies: a multicenter setting. Although intermittent EEG recordings is most commonly used, continuous monitoring (cEEG) has many advantages, especially during the period of therapeutic hypothermia treatment when the patient is inaccessible to clinical testing. For use during cEEG monitoring, a simplified classification with four major EEG patterns was proposed: flat pattern, continuous pattern, suppression-burst pattern and electrographic status epilepticus [28,32 ]. This approach provided valuable prognostic information, could be interpreted easily and may facilitate data comparison among studies. However, these single-center findings need to be validated in a larger patient cohort. Also, further studies are necessary to show the added benefit of cEEG monitoring in cardiac arrest patients when compared with intermittent recordings, either for seizure detection or to assess prognosis [33]. &
Somatosensory-evoked potentials The SSEP is a small electrical signal that can be recorded noninvasively from the skull after administering a set of electrical stimuli to one of the peripheral nerves. In cardiac arrest patients, the median nerve is most commonly stimulated bilaterally at the wrist. For prognosis of a poor outcome after cardiac arrest, only the short cortical latencies (N20, expected to appear 20 ms after median nerve stimulation) are used [34]. In order to have ‘absent SSEPs’, predictive of a poor outcome, cortical responses have to be absent bilaterally in a technically well performed test [35]. In patients with PAC, SSEPs have been shown to reliably predict poor outcome, with a FPR of 0.007 (95% CI 0.001–0.047) [6 ]. Cortical N20 responses are not influenced by moderate sedation or metabolic disturbances [36]. False positives were identified when SSEP was performed too early (within 24 h) after cardiac arrest [37]. Only a small proportion of patients with a poor outcome after resuscitation have absent SSEPs, &&
resulting in a low sensitivity. Preservation of the N20 response does not imply a favorable outcome, almost half the patients with a present N20 will have a poor outcome. A limitation of SSEP is that it has moderate interpretation reproducibility with kappa values of 0.52 (95% CI 0.20–0.65), with the main source of disagreement related to noise levels [38]. Other evoked potentials have been investigated in patients with PAC but only in small studies, leaving too much uncertainty at the moment to advocate their use in daily clinical care. Potentially, cognitiveevoked potentials, such as the P300 and ‘mismatch negativity’, may be useful to predict a good outcome [39,40].
Biomarkers Biomarkers are quantifiable biological substances, usually peptides, measured in the cerebrospinal fluid or in peripheral blood. The most extensively studied biomarkers of brain injury in cardiac arrest patients are neuron-specific enolase (NSE) and S-100b [7 ,41 ]. Serum NSE levels above 33 mg/l, 72 h after cardiac arrest, were suggested as a good indicator of poor prognosis [35,42]. However, this cutoff value could not be confirmed in other studies. Especially in patients treated with therapeutic hypothermia, the FPR of 33 mg/l ranged from 7 to 29% and much higher NSE cutoffs (>50–80 mg/l) would be necessary to reliably predict a poor outcome [12,30,43,44]. Elevated levels of S-100b were found in patients with PAC, but different cutoff levels, ranging from 0.2 to 1.5 mg/l, were proposed to use for outcome prediction [45,46]. It should be emphasized that both biomarkers have important pitfalls. NSE levels may increase by hemolysis or by an NSE-producing tumor, whereas S-100b can be released from adipocytes and chondrocytes and levels may thus increase as a result of chest compressions [47]. There is a lack of standardized assays, which may explain the differences in reported cutoff levels [48,49]. Finally, if cardiac arrest occurs concomitantly with other brain diseases (e.g. traumatic brain injury), this may also contribute to elevated biomarker levels. New biomarkers, such as glial fibrillary acid protein and procalcitonin, have been investigated [50,51]. Further research is needed before these diagnostic tools can be added to the standard tests for prognostication in PAC. &&
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Imaging The currently available data are insufficient to support the use of computed tomography (CT) imaging as a prognostic tool in patients with PAC [52]. However, in patients with preceding neurological symptoms, nonshockable rhythms or in young patients without cardiovascular risk factors,
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a CT scan on admission is helpful to rule out the cerebral causes of coma or cardiac arrest [53,54]. For prognostication in PAC, MRI seems to be a more promising tool. Especially, apparent diffusion coefficient techniques can reveal the details of hypoxic–ischemic brain injury and may provide useful additional information to predict outcome in patients with PAC [55–57]. The optimal timing to perform MRI would be 2–5 days after cardiac arrest. However, until today, studies of neuroimaging for PAC are retrospective, small, included heterogeneous populations and suffer from interobserver variability [58]. Therefore, robust advice on use of neuroimaging cannot be given.
approach can increase the number of patients correctly identified as having a poor outcome (see Fig. 2). The multimodal approach used will vary among centers depending on the availability of electrophysiological techniques, expertise and laboratory facilities [10,59]. After initial neurological examination, continuous or repeated standard EEG monitoring should be started to identify early seizures or ‘malignant’ EEG patterns. A reactive EEG or continuous background activity indicates a high probability of good outcome and these patients usually wake up quickly after discontinuation of sedation. In contrast, malignant EEG patterns are associated with a poor outcome. Aggressive therapy should be considered for PSE, especially if it occurs in the re-warming phase and in the absence of other signs of extensive brain injury. Importantly, no EEG finding alone should be used to predict poor outcome. The ‘malignant’ EEG patterns need
Multimodal prognostic algorithm In patients with PAC, considerable efforts should be made to combine the different variables to accurately predict outcome. A multimodal diagnostic
Day 0–2 (during TH)
Continuous reactive EEG
Awakening FPR 0–10%
EEG Malignant patterns Unreactive EEG Uncontrolled PSE
Day 3
FPR 0–5%
Awakening
GCS-M ≥ 5
Neurological examination
FPR 0–10% FPR 0–7%
Persistent coma
FPR 0% Persistent coma
GCS-M ≤ 2
FPR 21%
Absent PR or CR
SSEP
Biomarkers
After day 3
FPR 0–2%
Bilateral N20 absence
Persistent coma FPR 0–1%
Persistent coma NSE > 33 µg/ml
FPR 7–23%
GWR on CT-scan
Imaging
FPR NA
Persistent coma
Diffuse lesions on MRI
FPR NA
FIGURE 2. Overview of the available tools for prediction of outcome in patients with PAC with their FPR. References used for this figure: EEG data [7 ,10,29]; neurological examination [6 ,7 ,18]; SSEP [6 ]; biomarkers [7 ]; MRI and CT [58]. CR, corneal reflex; CT, computer tomography; EEG, electroencephalogram; FPR, false-positive rate; GCS-M, Glasgow Coma Scale Motor Score; GWR, gray matter attenuation to white matter attenuation ratio; MRI, magnetic resonance imaging; NA, not available; NSE, neuron-specific enolase; PAC, postanoxic coma; PR, papillary reaction; PSE, postanoxic status epilepticus; SSEP, somatosensory-evoked potential; TH, therapeutic hypothermia. &&
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Prognostication after cardiac arrest Horn et al.
to be correlated with neurological examination at 24–48 h after discontinuation of sedation. If patients have generalized persistent status myoclonus during the first day, outcome is likely to be poor if this clinical finding is combined with a bilateral absence of N20 during normothermia [60]. Neurological outcome is poor in patients with absent pupillary and corneal reflexes and GCS-M 2 or less on day 3 after cardiac arrest, but the prognostic certainty increases if these signs are associated with bilaterally absent N20 or an unreactive EEG or malignant patterns. In all other comatose patients, bilateral absence of N20 potentials 24–48 h after the discontinuation of sedation indicates irreversible brain damage. If these findings (absent brainstem reflexes, malignant EEG pattern and bilateral absence of N20 potentials) are absent, prognostication becomes more difficult. A prolonged observation period (1–2 weeks) should be considered to allow for delayed neurological recovery.
CONCLUSION Accurate prognostication in PAC requires a multimodal approach. Neurological examination remains the ‘gold standard’ but is influenced by the sedative drugs used during therapeutic hypothermia. The addition of EEG improves prognostic accuracy. The presence of an early reactive EEG pattern is suggestive of good prognosis, whereas ‘malignant’ EEG patterns are associated with a poor outcome. SSEP is less sensitive to sedation. Bilateral absence of N20 responses is predictive of poor prognosis. In patients who remain in coma despite benign EEG patterns and present SSEP responses, serum biomarkers and MRI may give useful additional information on the severity of brain injury. (1) In patients with PAC treated with therapeutic hypothermia, the neurological examination after 72 h is not a reliable tool to predict outcome. (2) Neurological examination should be combined with other tools in a multimodal approach. (3) Neurophysiological tests like EEG and SSEP are reliable and helpful tools. Acknowledgements None. Conflicts of interest J.H. received grants from the Dutch Heart foundation and Dutch Brain Foundation for work on prognostication after cardiac arrest. Studies were investigator driven. There are no other conflicts of interest. F.S.T. and T.C. do not report any conflicts of interest.
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Prognostication after cardiac arrest Janneke Horn a, Tobias Cronberg b, and Fabio S. Taccone c
Purpose of review The prognosis of patients with postanoxic coma (PAC) after cardiac arrest is a challenging task for clinicians. The need for early and accurate prognostic predictors is crucial. Treatment with therapeutic hypothermia and sedation alters the reliability of neurological examination. Considering the extensive literature existing on this topic, we aimed to provide a practical approach on how to predict outcome in patients with PAC, particularly in those treated with therapeutic hypothermia. Recent findings Recovery of motor responses can take several days and can therefore not be used to assess the extent of brain injury in the early phase after cardiac arrest. Additional tools, including electroencephalography, somatosensory-evoked potentials, biomarkers and radiological imaging, may help to determine the prognosis. Nevertheless, treatment with therapeutic hypothermia, including prolonged sedation, has changed the predictive value of these tools. Summary For reliable prediction of outcome in patients with PAC, various prognostic methods should be combined with the standard neurological examination in a multimodal approach. Keywords cardiac arrest, electroencephalography, evoked potentials, neurological examination, prognosis
INTRODUCTION
neurological examination remains poorly reliable in the early phase after ROSC [6 ,7 ]. The aim of this review is to provide a practical approach to the patient with PAC treated with therapeutic hypothermia, and to outline when and how additional prognostic tools can be combined with neurological examination in a multimodal approach to improve the quality of the outcome assessment (Fig. 1). &&
Patients who are admitted after cardiac arrest are nowadays treated with therapeutic hypothermia. This treatment has been shown to improve neurological outcome, but the optimal target temperature is currently uncertain [1,2,3 ]. Despite therapeutic hypothermia, many patients remain comatose after the cessation of sedatives and analgesics, which are administered during therapeutic hypothermia treatment. Postanoxic coma (PAC) is due to the severe ischemia and subsequent reperfusion that occur during cardiac arrest and after the return of spontaneous circulation (ROSC). These two factors, which primarily define neurological outcome, lead to the ‘postcardiac arrest syndrome’ [4]. This is characterized by three components: brain injury, myocardial dysfunction and systemic ischemia– reperfusion response. Severe brain injury leading to PAC is the most common cause of death [5]. Prognostication of PAC is important to inform family members about the chances of recovery, and to identify those patients with irreversible brain damage to prevent futile treatment and prolonged suffering for patients and relatives. Unfortunately, the use of therapeutic hypothermia has substantially delayed the awakening of these patients, so that &&
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HOW WE DEFINE ‘GOOD’ OR ‘POOR’ OUTCOME? In the last 2 decades, several studies have been performed to study the reliability of diagnostic tools
a Department of Intensive Care, Academic Medical Center, Amsterdam, The Netherlands, bDepartment of Clinical Sciences, Section for Neurology, Lund University Hospital, Lund University, Lund, Sweden and c Department of Intensive Care, Hoˆpital Erasme, Universite´ Libre de Bruxelles (ULB), Brussels, Belgium
Correspondence to Janneke Horn, Neurologist-Intensivist, Intensive Care Unit C3-329, Academical Medical Center, PO Box 22660, 1100DD Amsterdam, The Netherlands. Tel: +31 20 5662509; e-mail: j.horn @amc.nl Curr Opin Crit Care 2014, 20:280–286 DOI:10.1097/MCC.0000000000000085 Volume 20 Number 3 June 2014
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Prognostication after cardiac arrest Horn et al.
Neurological examination
EEG
SSEPs
Imaging
Biomarkers
FIGURE 1. Additional tools available for prognostication in patients with PAC. EEG, electroencephalogram; PAC, postanoxic coma; SSEPs, somatosensory-evoked potentials.
used in patients with PAC to predict the outcome. To assess outcome, the Glasgow Outcome Scale (GOS) or the Cerebral Performance Category (CPC) scale are widely used [8,9]. They are both five-point scales (Table 1). The definition of a poor outcome was GOS 1–2 (CPC 4–5) in the majority of studies, but GOS 1–3 (CPC 3–5) in some studies
[10–12]. Different definitions of poor and good outcome and different periods of follow-up have to be taken into account when reading and interpreting the available studies. Ideally, follow-up should be at least 3–6 months, as neurological recovery in PAC patients has been described several weeks after arrest. However, most patients with good
Table 1. GOS and CPC outcome scales GOS
Clinical condition
CPC
5
Good cerebral performance: conscious, alert, able to work, might have mild neurologic or psychologic deficit.
1
4
Moderate cerebral disability: conscious, sufficient cerebral function for independent activities of daily life. Able to work in sheltered environment.
2
3
Severe cerebral disability: conscious, dependent on others for daily support because of impaired brain function. Ranges from ambulatory state to severe dementia or paralysis.
3
2
Coma or vegetative state: any degree of coma without the presence of all brain death criteria. Unawareness, even if appears awake (vegetative state) without interaction with environment; may have spontaneous eye opening and sleep and awake cycles. Cerebral unresponsiveness.
4
1
Death or brain death: apnea, areflexia, EEG silence.
5
CPC, Cerebral Performance Category; GOS, Glasgow Outcome Scale.
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neurological outcome will improve within 1–2 weeks after brain injury. Although it is generally considered that almost all patients who survive after cardiac arrest have a good outcome (GOS 5 or CPC 1), it is also known that substantial cognitive disturbances can be detected in as much as 50% of this population [13,14]. An important task in the daily care of patients with PAC is the identification of patients who will certainly have a poor outcome; as such, diagnostic tools have mainly been investigated for this aim. To describe the reliability of these tests usually the false-positive rate (FPR) is used, which is defined as 1 minus specificity of the test involved [10,12]. This means that when a test has an FPR of 0.20, in 20% of the patients with a good outcome, the test results predicted a poor outcome. This explains that the FPR has to be as low as possible, with a small 95% confidence interval (CI).
DIAGNOSTIC TOOLS In this section, the available diagnostic tests and their advantages and disadvantages will be discussed.
Neurological examination Neurological recovery is altered by the sedative drugs and neuromuscular blockers administered during therapeutic hypothermia treatment in the first 24–48 h of admission [11]. Additionally, hypothermia prolongs the metabolism of sedative agents and induces drug accumulation, which also changes the timing of neurological recovery [15]. Early prediction of a poor prognosis based solely on neurological examination could lead to withdrawal of lifesustaining therapy in almost 20% of patients, who would otherwise have a complete neurological recovery [16]. Thus, when therapeutic hypothermia is used, only the loss of all brain-stem functions can be regarded as poor prognostic factors in the very early phase. These are usually signs of total brain infarction and herniation, which happens in only a small minority of patients after cardiac arrest [17]. As some confounders may exist in this setting, for a diagnosis of brain death additional tools should be used, including electroencephalography (EEG) and neuroimaging. After 48–72 h without sedative drugs, the presence of a motor response that localizes painful stimuli (Glasgow Coma Score – Motor Response, GCS-M, 5) is a sign of a favorable prognosis and no further diagnostic tests are necessary [18]. If the patient remains unresponsive to pain or with extension to painful stimuli (GCS-M 2) on day 3, a poor prognosis is likely in 80% of patients. Pupillary and corneal reflexes confer additional prognostic information, as a bilateral absence at 282
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72 h after arrest, although relatively uncommon, is related to a poor prognosis with low FPR [6 ,7 ,12]. The optimal timing to define prognosis based only on the neurological examination remains unknown. Although it has been suggested that the reliability 72 h after normothermia has been achieved (i.e., 4–5 days after cardiac arrest) is good, very limited data are available on the reliability and predictive value of clinical tests at this timepoint [6 ]. &&
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Seizures and myoclonus Clinical seizures are reported in about one-fourth of cardiac arrest victims, but various forms of motor manifestations are often misinterpreted as seizures [19,20 ,21]. Myoclonus is a common event following cardiac arrest that may or may not be an epileptic manifestation [22]. Occasional myoclonic jerks have little prognostic value in PAC. In a recent study, 9% of patients with posthypoxic myoclonus eventually had a good outcome [22]. On the opposite, generalized myoclonus (including face, trunk and limbs) and continuing for more than 30 min can be regarded as a status myoclonus. This is associated with a very high rate of poor neurological outcome, especially if this occurs in the first day after arrest [23]. Status myoclonus is often associated with burst suppression on EEG, further supporting extensive brain damage. Since the introduction of therapeutic hypothermia treatment, an early status myoclonus, which is usually easily suppressed by sedatives, has become more uncommon [24]. As survivors with good neurological recovery have been reported, a status myoclonus should no longer motivate a decision to withdraw intensive care [25]. &
Electroencephalography Nowadays, EEG is commonly used to detect seizures and postanoxic status epilepticus (PSE), which occur in 10–40% of patients and are associated with a poor outcome [19,20 ,26]. Nevertheless, good neurological outcome has been reported following aggressive antiepileptic therapy for seizures, especially in selected patients [preserved brainstem reflexes, present cortical response on somatosensory-evoked potentials (SSEPs) and reactive EEG] [27]. In addition to seizure detection, EEG has been used to identify specific patterns associated with poor outcome in PAC, but the classification of these patterns varies extensively between studies [28,29]. EEG patterns associated with a poor prognosis are PSE, alphacoma and burst suppression or generalized suppression. Other more or less pathologic EEG findings, including a generalized slow activity, generalized &
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Prognostication after cardiac arrest Horn et al.
alpha-theta frequencies or epileptiform discharges, are yet of unclear significance. To improve the accuracy of EEG to predict both poor and good outcome, different studies have tested the ‘reactivity’ of the EEG background pattern. Reactivity is defined as any reproducible change in amplitude or frequency upon patient stimulation [10,30]. EEG reactivity was found to have a better predictive value for neurological outcome than malignant and benign EEG patterns and evoked potentials, and predicted awakening in patients with an EEG pattern of alpha-coma after cardiac arrest [31]. As this research has not been done in large multicenter studies, potential sources of bias including sedation and technique of testing exist. The true value of reactivity testing in PAC needs to be established in new studies: a multicenter setting. Although intermittent EEG recordings is most commonly used, continuous monitoring (cEEG) has many advantages, especially during the period of therapeutic hypothermia treatment when the patient is inaccessible to clinical testing. For use during cEEG monitoring, a simplified classification with four major EEG patterns was proposed: flat pattern, continuous pattern, suppression-burst pattern and electrographic status epilepticus [28,32 ]. This approach provided valuable prognostic information, could be interpreted easily and may facilitate data comparison among studies. However, these single-center findings need to be validated in a larger patient cohort. Also, further studies are necessary to show the added benefit of cEEG monitoring in cardiac arrest patients when compared with intermittent recordings, either for seizure detection or to assess prognosis [33]. &
Somatosensory-evoked potentials The SSEP is a small electrical signal that can be recorded noninvasively from the skull after administering a set of electrical stimuli to one of the peripheral nerves. In cardiac arrest patients, the median nerve is most commonly stimulated bilaterally at the wrist. For prognosis of a poor outcome after cardiac arrest, only the short cortical latencies (N20, expected to appear 20 ms after median nerve stimulation) are used [34]. In order to have ‘absent SSEPs’, predictive of a poor outcome, cortical responses have to be absent bilaterally in a technically well performed test [35]. In patients with PAC, SSEPs have been shown to reliably predict poor outcome, with a FPR of 0.007 (95% CI 0.001–0.047) [6 ]. Cortical N20 responses are not influenced by moderate sedation or metabolic disturbances [36]. False positives were identified when SSEP was performed too early (within 24 h) after cardiac arrest [37]. Only a small proportion of patients with a poor outcome after resuscitation have absent SSEPs, &&
resulting in a low sensitivity. Preservation of the N20 response does not imply a favorable outcome, almost half the patients with a present N20 will have a poor outcome. A limitation of SSEP is that it has moderate interpretation reproducibility with kappa values of 0.52 (95% CI 0.20–0.65), with the main source of disagreement related to noise levels [38]. Other evoked potentials have been investigated in patients with PAC but only in small studies, leaving too much uncertainty at the moment to advocate their use in daily clinical care. Potentially, cognitiveevoked potentials, such as the P300 and ‘mismatch negativity’, may be useful to predict a good outcome [39,40].
Biomarkers Biomarkers are quantifiable biological substances, usually peptides, measured in the cerebrospinal fluid or in peripheral blood. The most extensively studied biomarkers of brain injury in cardiac arrest patients are neuron-specific enolase (NSE) and S-100b [7 ,41 ]. Serum NSE levels above 33 mg/l, 72 h after cardiac arrest, were suggested as a good indicator of poor prognosis [35,42]. However, this cutoff value could not be confirmed in other studies. Especially in patients treated with therapeutic hypothermia, the FPR of 33 mg/l ranged from 7 to 29% and much higher NSE cutoffs (>50–80 mg/l) would be necessary to reliably predict a poor outcome [12,30,43,44]. Elevated levels of S-100b were found in patients with PAC, but different cutoff levels, ranging from 0.2 to 1.5 mg/l, were proposed to use for outcome prediction [45,46]. It should be emphasized that both biomarkers have important pitfalls. NSE levels may increase by hemolysis or by an NSE-producing tumor, whereas S-100b can be released from adipocytes and chondrocytes and levels may thus increase as a result of chest compressions [47]. There is a lack of standardized assays, which may explain the differences in reported cutoff levels [48,49]. Finally, if cardiac arrest occurs concomitantly with other brain diseases (e.g. traumatic brain injury), this may also contribute to elevated biomarker levels. New biomarkers, such as glial fibrillary acid protein and procalcitonin, have been investigated [50,51]. Further research is needed before these diagnostic tools can be added to the standard tests for prognostication in PAC. &&
&&
Imaging The currently available data are insufficient to support the use of computed tomography (CT) imaging as a prognostic tool in patients with PAC [52]. However, in patients with preceding neurological symptoms, nonshockable rhythms or in young patients without cardiovascular risk factors,
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a CT scan on admission is helpful to rule out the cerebral causes of coma or cardiac arrest [53,54]. For prognostication in PAC, MRI seems to be a more promising tool. Especially, apparent diffusion coefficient techniques can reveal the details of hypoxic–ischemic brain injury and may provide useful additional information to predict outcome in patients with PAC [55–57]. The optimal timing to perform MRI would be 2–5 days after cardiac arrest. However, until today, studies of neuroimaging for PAC are retrospective, small, included heterogeneous populations and suffer from interobserver variability [58]. Therefore, robust advice on use of neuroimaging cannot be given.
approach can increase the number of patients correctly identified as having a poor outcome (see Fig. 2). The multimodal approach used will vary among centers depending on the availability of electrophysiological techniques, expertise and laboratory facilities [10,59]. After initial neurological examination, continuous or repeated standard EEG monitoring should be started to identify early seizures or ‘malignant’ EEG patterns. A reactive EEG or continuous background activity indicates a high probability of good outcome and these patients usually wake up quickly after discontinuation of sedation. In contrast, malignant EEG patterns are associated with a poor outcome. Aggressive therapy should be considered for PSE, especially if it occurs in the re-warming phase and in the absence of other signs of extensive brain injury. Importantly, no EEG finding alone should be used to predict poor outcome. The ‘malignant’ EEG patterns need
Multimodal prognostic algorithm In patients with PAC, considerable efforts should be made to combine the different variables to accurately predict outcome. A multimodal diagnostic
Day 0–2 (during TH)
Continuous reactive EEG
Awakening FPR 0–10%
EEG Malignant patterns Unreactive EEG Uncontrolled PSE
Day 3
FPR 0–5%
Awakening
GCS-M ≥ 5
Neurological examination
FPR 0–10% FPR 0–7%
Persistent coma
FPR 0% Persistent coma
GCS-M ≤ 2
FPR 21%
Absent PR or CR
SSEP
Biomarkers
After day 3
FPR 0–2%
Bilateral N20 absence
Persistent coma FPR 0–1%
Persistent coma NSE > 33 µg/ml
FPR 7–23%
GWR on CT-scan
Imaging
FPR NA
Persistent coma
Diffuse lesions on MRI
FPR NA
FIGURE 2. Overview of the available tools for prediction of outcome in patients with PAC with their FPR. References used for this figure: EEG data [7 ,10,29]; neurological examination [6 ,7 ,18]; SSEP [6 ]; biomarkers [7 ]; MRI and CT [58]. CR, corneal reflex; CT, computer tomography; EEG, electroencephalogram; FPR, false-positive rate; GCS-M, Glasgow Coma Scale Motor Score; GWR, gray matter attenuation to white matter attenuation ratio; MRI, magnetic resonance imaging; NA, not available; NSE, neuron-specific enolase; PAC, postanoxic coma; PR, papillary reaction; PSE, postanoxic status epilepticus; SSEP, somatosensory-evoked potential; TH, therapeutic hypothermia. &&
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Prognostication after cardiac arrest Horn et al.
to be correlated with neurological examination at 24–48 h after discontinuation of sedation. If patients have generalized persistent status myoclonus during the first day, outcome is likely to be poor if this clinical finding is combined with a bilateral absence of N20 during normothermia [60]. Neurological outcome is poor in patients with absent pupillary and corneal reflexes and GCS-M 2 or less on day 3 after cardiac arrest, but the prognostic certainty increases if these signs are associated with bilaterally absent N20 or an unreactive EEG or malignant patterns. In all other comatose patients, bilateral absence of N20 potentials 24–48 h after the discontinuation of sedation indicates irreversible brain damage. If these findings (absent brainstem reflexes, malignant EEG pattern and bilateral absence of N20 potentials) are absent, prognostication becomes more difficult. A prolonged observation period (1–2 weeks) should be considered to allow for delayed neurological recovery.
CONCLUSION Accurate prognostication in PAC requires a multimodal approach. Neurological examination remains the ‘gold standard’ but is influenced by the sedative drugs used during therapeutic hypothermia. The addition of EEG improves prognostic accuracy. The presence of an early reactive EEG pattern is suggestive of good prognosis, whereas ‘malignant’ EEG patterns are associated with a poor outcome. SSEP is less sensitive to sedation. Bilateral absence of N20 responses is predictive of poor prognosis. In patients who remain in coma despite benign EEG patterns and present SSEP responses, serum biomarkers and MRI may give useful additional information on the severity of brain injury. (1) In patients with PAC treated with therapeutic hypothermia, the neurological examination after 72 h is not a reliable tool to predict outcome. (2) Neurological examination should be combined with other tools in a multimodal approach. (3) Neurophysiological tests like EEG and SSEP are reliable and helpful tools. Acknowledgements None. Conflicts of interest J.H. received grants from the Dutch Heart foundation and Dutch Brain Foundation for work on prognostication after cardiac arrest. Studies were investigator driven. There are no other conflicts of interest. F.S.T. and T.C. do not report any conflicts of interest.
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Volume 20 Number 3 June 2014
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