Article
Predictors of Outcome Post Cardiac Arrest
Journal of Intensive Care Medicine XX(X) 1-8 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0885066613511045 jic.sagepub.com
S. Bigham1, C. Bigham2, and D. Martin3
Abstract Early predictors of prognosis in comatose patients post cardiac arrest help inform decisions surrounding continuation or withdrawal of treatment and provide a framework on which to better inform relatives of the likely outcome. Markers defined prior to the widespread use of therapeutic hypothermia post arrest may no longer be reliable and an up-to-date analysis of the literature is presented. Keywords predictors, neurological, outcome, post cardiac arrest, hypothermia
Introduction
Clinical Predictors
Out-of-hospital cardiac arrest (OHCA) occurs in 60 000 people per year in the United Kingdom.1 The Department of Health in England figures state only 9.2% of the patients with OHCA survived to discharge in 2012.2 Of these, 25.7% of the patients who had a witnessed arrest, a heart rhythm compatible with defibrillation, and immediate commencement of resuscitation survived to discharge. The incidence of in-hospital cardiac arrest (IHCA) is approximately 1 to 5 per 1000 hospital admissions in the United Kingdom and survival is approximately 15% to 20%.3 A recent American study from 2000 to 2009 was more optimistic. A total of 84,625 patients with IHCA had survival rates improved from 13.7% in 2000 to 22.3% in 2009. Of the survivors, the incidence of clinically significant neurological disability was reduced from 32.9% to 28.1%.4 A good outcome in this setting can be defined as having minimal or no neurological injury, allowing for an independent or largely independent lifestyle in the long term. Outcome can be measured by scoring systems such as the Cerebral Performance Categories (CPC; Table 1) or the Glasgow Outcome Scores (GOS; Table 2) at 6 months post cardiac arrest. Early prognostic markers following cardiac arrest could help to make informed decisions on management and avoid unnecessary suffering for relatives of patients with a poor outlook. Alternatively, positive indicators could encourage clinicians to continue with supportive measures if a good neurological recovery was predicted. Reliable prognostic markers can also aid in clear and meaningful communication with relatives along with sensible resource use within the intensive care unit. Predictors of poor prognosis need to be accurate to avoid inappropriate withdrawal of care. This review looks at current clinical, biochemical, electrophysiological, and neuroradiological markers of poor prognosis and our current understanding of the impact that therapeutic hypothermia has on their predictive ability.
Clinical factors that improve survival to discharge rates for OHCA are a witnessed cardiac arrest by either a bystander or a member of the emergency services, giving immediate cardiopulmonary resuscitation (CPR), a shockable rhythm, or return of spontaneous circulation (ROSC) out of hospital.5 With IHCA, a short time until commencement of CPR and a shockable rhythm are associated with a better outcome. The quality of CPR prior to defibrillation directly affects clinical outcomes. Compressions 2 at 1 year), with and without TH (54 of 70 vs 126 of 153 patients, P ¼ .56). They do not support the use of TH in nonshockable rhythms. The National Institute for Clinical Excellence (NICE) recommend cooling a comatose cardiac arrest patient as soon as possible to 32 C to 34 C for 12 to 24 hours.16 There are risks associated with TH. In the 2002 studies, the Australian group found TH caused a low cardiac index, increased systemic vascular resistance, and more hyperglycemia; and the European group found a 22% increase in complications (particularly pneumonia, bleeding, and sepsis). The risk of bleeding was no greater with TH in a small study,17 involving 31 comatose patients post cardiac arrest and who had a thrombolysis and/or percutaneous coronary intervention and antiplatelet therapy. Other potential complications include shivering (which needs controlling), hepatic and renal impairment, electrolyte imbalance, lifethreatening arrhythmias, and pancreatitis, but these have not reached significance in the studies. In fact, mild hypothermia can stabilize cell membranes and increase chances of successful defibrillation.18 Therapeutic hypothermia is associated with delayed clinical recovery, and application of the AAN 2006 guidelines may therefore be pessimistic in this setting. The reason for the delay in recovery is probably multifactorial, involving slowing down of neuronal recovery and metabolism and reduced hepatic and renal clearance of sedative drugs. For example, in a retrospective study of 37 patients’ post cardiac arrest treated with TH, 2 of the 14 patients who had motor responses no better than extension to pain at 72 hours ended up obeying commands and interacting with their environment at day 6.19 Another prospectively designed study demonstrated that in 25 patients who had a good outcome, 1 had electroencephalogram (EEG) confirmed early myoclonic status epilepticus, 2 had at least 1 absent brain stem reflex, and 4 had absent motor responses or extension to pain at 72 hours.20 These observations suggest that clinical predictors at 72 hours, following a period of TH, should be interpreted with an increasing degree of caution.
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3 A formal EEG can be useful to:
Biochemical Markers Serum biomarkers have been used to detect the magnitude of neuronal cell damage with some encouraging results. Both neuron-specific enolase (NSE), located in neurons, and serum S-100B, present in astrocytes, are released when there is neuronal damage. The 2006 AAN guidelines indicate that a serum NSE higher than 33 mg /L between day 1 and day 3 following a cardiac arrest is associated with a poor outcome (with a falsepositive rate of 0 in the largest study). A number of studies have explored the significance of serum NSE following TH with mixed results. Two studies of approximately 100 patients each21,22 demonstrated no false positives, while another has reported a false-positive rate of up to 29%.23 Other biochemical markers have been investigated (eg, neurofilament protein) but have not demonstrated the required specificity.8 S-100B has been shown to have a good specificity in 2 small studies, but larger studies are needed.23,24
Somatory Sensory-Evoked Potentials In this test, the median nerve is stimulated electrically and the primary cortical somatory sensory-evoked potential (SSEP) component is recorded over the parietal area contralateral to the stimulated median nerve. The components of SSEP are named after their polarity and peak latency: ‘‘N20’’ is a negative pulse that peaks at 20 msec after the median nerve stimulus. Somatory sensory-evoked potentials should ideally be performed off sedation, but the N20 response is only moderately affected, and clinically useful recordings can be reliably obtained even under anesthesia. Bilateral absence of the N20 component of median nerve stimulation at 72 hours is a marker of poor outcome that has a reported specificity of up to 100%.25 In some patients, N20 responses are intact at 24 hours but are lost irreversibly by 72 hours.26 However, the reliability and consistency of the N20 response following TH has recently been questioned. An individual who had an absent N20 response at 72 hours went on to make a good recovery.27 However, even in patients treated with hypothermia, the reliability of this test is considered excellent at 72 hours.21 Loss of N20 responses has a high specificity but low sensitivity for poor outcome. Preservation of the pathway does not predict a good outcome and in fact is maintained in patients with severe brain injury. One approach by Rossetti et al was to use at least 2 of the following 4 independent predictors of poor long-term neurological outcome: incomplete brain stem reflexes, myoclonus, unreactive EEG, and absent cortical SSEP had a positive predictive value (PPV) of 1 (PPV ¼ 1).21
Electroencephalogram Analysis Electroencephalogram is the recording of electrical activity generated from voltage changes across neuronal membranes and so can be considered a surrogate marker of neuronal activity. The electrical activity is measured from scalp electrodes.
1. 2. 3.
detect seizures, especially when not clinically apparent; observe generalized cortical suppression and pathological EEG traces, for example, burst suppression; and observe for reactivity to auditory, visual, or nociceptive stimuli.
Bedside EEG monitors such as the spectral edge frequency, spectral density array, or the bispectral index monitor may also have a role but are less well studied in this setting.
Seizures The prevalence of seizures on EEG post cardiac arrest is between 10%28 and 47%,29 and their presence is a marker of underlying cortical damage. The presence of epileptiform activity on EEG in patients treated with TH post cardiac arrest was 21%30 in 1 study, where the patients were sedated with midazolam and fentanyl. Control of seizure activity with anticonvulsant therapies is paramount before predicting a poor prognosis but not always achievable without the use of sedating antiepileptic agents. Prolonged epileptiform EEG activity both during and after TH is independently associated with poor outcome.31 The unfavorable outcome may be the result of the severity of the initial hypoxic– ischemic insult or the ongoing seizure activity itself. Because mild hypothermia and sedative drugs have anticonvulsant actions, it has been suggested that seizures during TH may reflect more severe and diffuse brain injury, while seizures that develop following rewarming may be less indicative of a poor prognosis.32 A small study investigating the timings of seizure development using continuous EEG indicated that most seizure activity was nonconvulsive status epilepticus and started prior to the rewarming phase.32 Treating any detected epileptic activity (including status epilepticus) can still result in a good outcome, and a trial of antiepileptic drugs (AEDs) is needed. In the studies of Rossetti et al,32,33 EEG evidence of status epilepticus was treated with intravenous antiepileptics (levetiracetam, valproate, phenytoin, benzodiazepines, or in selected cases with propofol targeting electrographic burst suppression for at least 24 hours).
Myoclonic Status Epilepticus Early myoclonic status epilepticus (MSE) has been associated with a grave prognosis. However, one of the difficulties with this prognostication lies in its diagnosis. Patients with MSE have prolonged, frequent, spontaneous myoclonic jerks that are thought to be subcortical in origin. It should be distinguished from generalized tonic clonic seizures with an EEG and treated with AEDs. Lance-Adams syndrome, a rare post anoxic condition characterized by later onset, usually intention myoclonus, awareness, and normal intellect, can also be mistaken for MSE. Several reports of patients who developed MSE post arrest went on to make a good recovery both with and without TH.25,34,35 Treatment with AEDs is also difficult; often phenytoin and valproate are ineffective, low-dose propofol can be
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used successfully.36 In a small study of 18 patients, not treated with TH post cardiac arrest, the mean number of AEDs used to control MSE was 2.3.37 The MSE can still be considered a poor prognostic sign but is not as reliable as once thought and is not true if the primary event is asphyxia.
Reactivity In a recent study of 111 patients treated with TH, an unreactive EEG following rewarming was found to be a strong predictor of a poor outcome with a false-positive rate of 7%,30 and other studies have demonstrated similar figures.38 Small studies looking at EEG reactivity during the hypothermic period have also demonstrated very low false-positive rates, and continuous EEG during hypothermia may become a standard of care in the future.17
Generalized Suppression There are certain EEG patterns that are indicative of a poor outcome and have a small (but not zero) false-positive rate. These should be interpreted within the clinical context and the presence of hypothermia and sedative drugs. Generalized suppression to 20 mV, burst-suppression pattern with generalized epileptiform activity, or generalized periodic complexes on a flat background are strongly but not invariably associated with poor outcome.39 Diffuse or predominantly frontal a coma (an unremitting 8-13 Hz EEG) unresponsive to stimulation or eye opening has been associated with a 90% probability of death or vegetative state.40 Formal EEG analysis provides prognostic information and treatment options and should be performed on all patients early in treatment. Detected seizures can be treated, while certain pathological patterns suggest a poor prognosis. The EEG reactivity looks promising as a prognostic tool, but larger studies are needed for its validation and optimal timing decided.
Continuous Bedside EEG There are many types of bedside EEG monitors. The amplitude integrated EEG (aEEG) is processed from biparietal electrodes and measures minimum and maximum amplitudes. These amplitudes are graphically represented against time. Two studies using early (during hypothermia) aEEG produced encouraging results.42,43 The first study detected 2 patients (from 34) with burst suppression and another with a coma (all subsequently confirmed with formal EEG). None of these regained consciousness. In the subsequent larger study, 14 of the 95 patients developed early burst suppression, and all failed to regain consciousness and subsequently died or had treatment withdrawn. The investigators also noted that a continuously active EEG activity, or a return of a continuous active pattern during hypothermia, had a PPV of 91% and 87%, respectively, for regaining consciousness.34 This is potentially one of the early markers of a positive outcome.
Similar prognostic studies have been performed using the bispectral index monitor (BIS). This is a frontal EEG monitor with a complicated waveform analysis designed to detect depth of anesthesia. During TH (and administration of pharmacological neuromuscular blockade to reduce electromyogram interference), a BIS of less than 22, measured as the sustained plateau value 5 to 10 minutes after the first neuromuscular blockade dose, predicted a poor neurological outcome (CPC 3-5) with a likelihood ratio of 14.2.44 Unfortunately, in this study, involving 83 patients, there was less than 100% specificity but higher BIS scores were associated with improved outcomes. Both forms of processed EEG generate relevant information that can be incorporated into an overall picture; however, the reliability of this information is questionable. A formal EEG is required before treatment or prognostication. Proof of a continuously active EEG with a bedside monitor appears to have a positive correlation with good outcome, while any abnormalities detected might instigate an earlier formal EEG. Bedside EEG monitors are gradually becoming an accepted standard of care in post arrest patients.
Computed Tomography Scan A brain computed tomography (CT) scan is often performed early following a cardiac arrest to rule out intracranial pathology such as intracerebral hemorrhages. Although initial imaging is frequently unremarkable, by day 2 to 3 post cardiac arrest some patients demonstrate diffuse swelling with effacement of the basal cisterns, ventricles, and sulci and attenuation of the gray–white matter interface. The extent and timings of these changes are still unclear. Current evidence suggests that loss of gray–white differentiation may happen first and can occur within hours, and sulcal effacement develops a little later.45 Both of these signs early on are associated with a poor outcome at 6 months. Further analysis of Hounsfield units (a measurement of radiodensity) of CTs taken within 48 hours has led to the development of the Brain Arrest Neurological Outcome Score (BrANOS) developed before TH, a combination of the duration of arrest, best GCS, and the Hounsfield unit ratio between caudate (gray) and posterior limb of the internal capsule (white).46 A more recent study47 compared density changes (with Hounsfield units) in the putamen and the posterior limb of the internal capsule on CT and GCS at 72 hours. They found the combination of tests had 72% sensitivity and 100% specificity at predicting poor outcome. Unfortunately, only 33 (21%) of the 155 patients recruited were treated with hypothermia, and the inclusion of this subset of patients reduced the accuracy. Other CT scoring systems used in the first 24 hours have been developed, which show good specificity. Scheel et al48 examined CT scans from 91 post cardiac arrest patients, all treated with TH. They were particularly interested in the gray–white matter ratio (GWR). A GWR 48 hours later to ensure no changes
Detecting seizures Detecting myoclonic status epilepticus Assessing for burst suppression Assessing for EEG reactivity Assessing for continuous EEG activity Evidence of burst suppression Assessing degree of cerebral oedema Detecting brain stem reflexes Detecting motor response to pain Assessing for bilaterally absent N20 response FPR 0% (0-3) for poor outcome Assessing degree of brain damage visually or with a scoring system
Early processed bedside EEG CT at 48-72 hours Clinical examination at 72 hours SSEPs at 48-72 hours Serum NSE >33 ug/L at 24-72 hours MRI at 24-120 hours
Abbreviations: CT, computed tomography; EEG, electroencephalogram; FPR, false-positive rate; MRI, magnetic resonance imaging; NSE, neuron-specific enolase; SSEPs, somatory sensory-evoked potentials.
Table 4. Markers Associated With a Worse Outcome But With Lower Specificity, Especially in the Context of Therapeutic Hypothermia. Clinical Features NSE EEG
No motor response or an extensor response to painful stimuli at 72 hours following cardiac arrest Serum NSE higher than 33 mg/L between days 1 and 3 Low-voltage EEG including during the hypothermia a coma
Abbreviations: EEG, electroencephalogram; NSE, neuron-specific enolase.
in 62 patients to improve the sensitivity for predicting a poor outcome to 53%. This is a developing area of prognostication.
Magnetic Resonance Imaging Magnetic resonance imaging (MRI) modalities analyzing the movement/diffusion of water molecules (diffusion-weighted imaging [DWI]) provide information about the extent of any damage to neurons, the microcirculation, and larger vessels in the context of a hypoxic–ischemic arrest. Studies using quantitative DWI (using apparent diffusion coefficient [ADC] values) MRI have revealed that the brain injury takes time to develop, and imaging within the first 24 hours may not reflect the true extent of the hypoxic–ischemic injury. The timedependent changes are presumably due to ongoing apoptosis following the original injury or ongoing secondary neurological damage.49 Relatively small studies suggest that MRI findings could be prognostic between day 2 and 5. Those with moderate to severe abnormalities (eg, brain swelling, cortical necrosis, high signal within the basal ganglia) have a poor outcome while those with minimal or no changes having a good outcome. In a small study of 20 patients post cardiac arrest and treated with TH, diffusion and perfusion MRI brain scans at 5 days showed the greatest acute ischemic changes in the parietal lobe in those not surviving.49 There are attempts to quantify the extent of the damage in patients treated with and without TH, for example, using the median ADC value or the percentage volume of the brain below a certain ADC value.51,52 Wijman et al51 studied MRIs in 51 patients of which 61% were treated with TH. Those patients with 10% of brain volume less than 650 106 mm2/sec on the ADC map did not regain
consciousness. Although MRI seems to be a promising modality for predicting both good and poor outcome between days 2 and 5, this has to be balanced against the availability of the MRI and the many inherent difficulties and risks posed by obtaining the images in a critically ill patient.
Discussion The American Association of Neurologists 2006 guidelines for prognostication are still considered reliable in patients managed without TH following a cardiac arrest. Some combination of clinical predictors at 72 hours, SSEP at 48 to 72 hours, EEGs, an NSE at days 1 to 3, and neuroimaging to provide a clear prognostic overview is recommended. Table 3 includes current suggestions for assessing prognosis following a cardiac arrest in these circumstances. Since therapeutic hypothermia has become a standard of care, reduced test accuracy has been demonstrated (Table 4), while other tests retain their sensitivity and specificity better (Table 5). The current International Liaison Committee on Resuscitation guidelines53 on prognostication post-TH are detailed in Table 6. Absent brain stem reflexes and the presence of myoclonic status epilepticus at 72 hours post arrest are not 100% specific in the absence of sedation, while a poor motor response is even less specific. Absent SSEPs at 72 hours retain a high specificity. The EEGs are still useful for diagnosing seizures and providing specific prognostic information when burst suppression and nonreactivity are detected. Diffusion-weighted MRI performed between days 2 and 5 demonstrating significant damage is associated with a poor outcome, although the
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Table 5. Highly Probable of a Poor Outcome Even in the Context of Therapeutic Hypothermia. EEG SSEPs MRI
Burst suppression with generalized epileptiform activity even during hypothermia; nonreactivity of EEG once normothermic Bilateral absent N20 response at 72 hours following cardiac arrest Significant MRI changes compatible with severe hypoxic ischaemic damage at day 2 to 5
Abbreviations: EEG, electroencephalogram; MRI, magnetic resonance imaging; SSEPs, somatory sensory-evoked potentials.
Table 6. International Liason Committee on Resuscitation (ILCOR) Guidelines53 for Prognostication of Favorable Neurological Outcome Post cardiac Arrest and Treatment With TH.a Pre-cardiac arrest factors Intracardiac arrest factors Postcardiac arrest factors Clinical features EEG SSEPs54 NSE and S10055
There are no studies reliably predicting the neurological outcome of patients treated with TH post cardiac arrest There are no studies reliably predicting the neurological outcome of patients treated with TH post cardiac arrest The absence of neurological function immediately post-ROSC does not reliably predict outcome There are no studies reliably predicting the outcome of patients treated with TH post cardiac arrest EEG alone is insufficient to determine futility. Poor functional outcome is most reliably predicted with generalized suppression to 25 vs 8.8 mg/L; S100ß 0.23 vs 0.12 mg/L)
Abbreviations: CI, confidence interval; EEG, electroencephalogram; FPR, false-positive rate; NSE, neuron-specific enolase; ROSC, return of spontaneous circulation; SSEPs, somatory sensory-evoked potentials; TH, therapeutic hypothermia. a The relative impact of hypothermia on prognostic accuracy appears to vary among individual strategies and is inadequately studied. Prognostication should be delayed but the optimal time has yet to be determined.
studies in this area are small. The damage can be assessed visually or using one of the developing scoring systems. To reliably place a patient who has been treated with therapeutic hypothermia in a poor outcome category, more time off sedation may be required. Clinical prognostic tests could be performed relative to achieving normothermia rather than from the time of the arrest, and prognostic tests could be repeated later in the clinical course. There should also be a greater reliance of SSEP, as loss of N20 has a high specificity39 although low sensitivity for poor outcome.56 Markers of a good prognosis include a good motor response (withdrawal, localizing or obeying) within 24 hours of stopping sedation, continuous nonpathological EEG activity during hypothermia, and minimal changes in MRI at 2 to 5 days. However, due to the lack of trials, these are not as well validated as the poor prognostic markers.
Conclusion Following a cardiac arrest, accurate prognostic markers would help with family communication and decisions concerning continuation of care. Therapeutic hypothermia, while resulting in improved neurological recovery, has reduced the sensitivity and specificity of clinical testing at 72 hours and of the biochemical and electrophysiological tests. It may also delay any associated anatomical changes that can be seen on neuroradiological imaging. In difficult clinical situations, integration
of the clinical tests, other prognostic tests, and perhaps repeating some of these tests after a longer period off sedation may be required. In general, reliance on a single prognostic test should probably be avoided for irreversible treatment decisions. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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39. Zandbergen EG, Hijdra A, Koelman JHTM, et al. For the PROPAC study group. Prediction of poor outcome within the first three days of postanoxic coma. Neurology. 2006;66(1):62-68. 40. Kaplan PW. Electrophysiological prognostication and brain injury from cardiac arrest. Semin Neurol. 2006;26(4):403-412. 41. Rundgren M, Rosen I, Friberg H. Amplitude-integrated (aEEG) predicts outcome after cardiac arrest and induced hypothermia. Intensive Care Med 2006;32(6):836-842. 42. Kawai M, Thapalia U, Verma A. Outcome from therapeutic hypothermia and EEG. J Clin Neurophysiol. 2011;28(5):483-488. 43. Rundgren M, Westhall E, Cronberg T, et al. Continuous amplitude-integrated electroencephalogram predicts outcome in hypothermia-treated cardiac arrest patients. Crit Care Med. 2010;38(9):1838-1844. 44. Seder DB, Fraser GL, Robbins T, Libby L, Riker RR. The bispectral index and suppression ratio are very early predictors of neurological outcome during therapeutic hypothermia after cardiac arrest. Intensive Care Med. 2010;36(2):281-288. 45. Inamasu J, Miyatake S, Suzuki M, et al. Early CT signs in out-ofhospital cardiac arrest survivors: temporal profile and prognostic significance. Resuscitation. 2010;81(5):531-538. 46. Torbey MT, Geocadin R, Bhardwaj A. Brain arrest neurological outcome scale (BrANOS): predicting mortality and severe disability following cardiac arrest. Resuscitation. 2004;63(1): 55-63. 47. Wu O, Batista L, Lima F, Vangel M, Furie K, Greer D. Predicting clinical outcome in comatose cardiac arrest patients using early noncontrast computed tomography. Stroke. 2011;42(4):985-992. 48. Scheel M, Storm C, Gentsch A, et al. The prognostic value of gray-white-matter ratio in cardiac arrest patients treated with hypothermia. Scand J Trauma Resusc Emerg Med. 2013; 21(1):23.
49. Mlynash M, Campbell DM, Leproust EM, et al. Temporal and spatial profile of brain diffusion weighted MRI after cardiac arrest. Stroke. 2010;41(8):1665-1672. 50. Jarnum H, Knutsson L, Rundgren M, et al. Diffusion and perfusion MRI of the brain in comatose patients treated with mild hypothermia after cardiac arrest: a prospective observational study. Resuscitation. 2009;80(4):425-430. 51. Wijman CA, Mlynash M, Caulfield AF, et al. Prognostic value of brain diffusion-weighted imaging after cardiac arrest. Ann Neurol. 2009;65(4):394-402. 52. Wu O, Sorensen AG, Benner, Singhal AB, Furie KL, Greer DM. Comatose patients with cardiac arrest: predicting clinical outcome with diffusion-weighted MR imaging. Radiology. 2009;252(1): 173-181. 53. Jerry P. Nolan, Robert W. Neumar, Christophe Adrie, et al. Post-cardiac arrest syndrome: Epidemiology, pathophysiology, treatment, and prognostication. A scientific statement from the international liaison committee on Resuscitation; the American heart association emergency cardiovascular care committee; the council on cardiovascular surgery and anesthesia; the council on cardiopulmonary, perioperative, and critical care; the council on clinical cardiology; the council on stroke. Resuscitation. 2008;79(3):350-379. 54. Zandbergen EG, Koelman JH, de Haan RJ, Hijdra A. SSEPs and prognosis in postanoxic coma: only short or also long latency responses? Neurology. 2006;67(4):583-586. 55. Tiainen M, Kovala TT, Takkunen OS, Roine RO. Somatosensory and brainstem auditory evoked potentials in cardiac arrest patients treated with hypothermia. Crit Care Med. 2005;33(8):1736-1740. 56. Tiainen M, Roine RO, Pettila V, Takkunen O. Serum neuronspecific enolase and S-100B protein in cardiac arrest patients treated with hypothermia. Stroke. 2003;34(12):2881-2886.
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Predictors of Outcome Post Cardiac Arrest
Journal of Intensive Care Medicine XX(X) 1-8 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0885066613511045 jic.sagepub.com
S. Bigham1, C. Bigham2, and D. Martin3
Abstract Early predictors of prognosis in comatose patients post cardiac arrest help inform decisions surrounding continuation or withdrawal of treatment and provide a framework on which to better inform relatives of the likely outcome. Markers defined prior to the widespread use of therapeutic hypothermia post arrest may no longer be reliable and an up-to-date analysis of the literature is presented. Keywords predictors, neurological, outcome, post cardiac arrest, hypothermia
Introduction
Clinical Predictors
Out-of-hospital cardiac arrest (OHCA) occurs in 60 000 people per year in the United Kingdom.1 The Department of Health in England figures state only 9.2% of the patients with OHCA survived to discharge in 2012.2 Of these, 25.7% of the patients who had a witnessed arrest, a heart rhythm compatible with defibrillation, and immediate commencement of resuscitation survived to discharge. The incidence of in-hospital cardiac arrest (IHCA) is approximately 1 to 5 per 1000 hospital admissions in the United Kingdom and survival is approximately 15% to 20%.3 A recent American study from 2000 to 2009 was more optimistic. A total of 84,625 patients with IHCA had survival rates improved from 13.7% in 2000 to 22.3% in 2009. Of the survivors, the incidence of clinically significant neurological disability was reduced from 32.9% to 28.1%.4 A good outcome in this setting can be defined as having minimal or no neurological injury, allowing for an independent or largely independent lifestyle in the long term. Outcome can be measured by scoring systems such as the Cerebral Performance Categories (CPC; Table 1) or the Glasgow Outcome Scores (GOS; Table 2) at 6 months post cardiac arrest. Early prognostic markers following cardiac arrest could help to make informed decisions on management and avoid unnecessary suffering for relatives of patients with a poor outlook. Alternatively, positive indicators could encourage clinicians to continue with supportive measures if a good neurological recovery was predicted. Reliable prognostic markers can also aid in clear and meaningful communication with relatives along with sensible resource use within the intensive care unit. Predictors of poor prognosis need to be accurate to avoid inappropriate withdrawal of care. This review looks at current clinical, biochemical, electrophysiological, and neuroradiological markers of poor prognosis and our current understanding of the impact that therapeutic hypothermia has on their predictive ability.
Clinical factors that improve survival to discharge rates for OHCA are a witnessed cardiac arrest by either a bystander or a member of the emergency services, giving immediate cardiopulmonary resuscitation (CPR), a shockable rhythm, or return of spontaneous circulation (ROSC) out of hospital.5 With IHCA, a short time until commencement of CPR and a shockable rhythm are associated with a better outcome. The quality of CPR prior to defibrillation directly affects clinical outcomes. Compressions 2 at 1 year), with and without TH (54 of 70 vs 126 of 153 patients, P ¼ .56). They do not support the use of TH in nonshockable rhythms. The National Institute for Clinical Excellence (NICE) recommend cooling a comatose cardiac arrest patient as soon as possible to 32 C to 34 C for 12 to 24 hours.16 There are risks associated with TH. In the 2002 studies, the Australian group found TH caused a low cardiac index, increased systemic vascular resistance, and more hyperglycemia; and the European group found a 22% increase in complications (particularly pneumonia, bleeding, and sepsis). The risk of bleeding was no greater with TH in a small study,17 involving 31 comatose patients post cardiac arrest and who had a thrombolysis and/or percutaneous coronary intervention and antiplatelet therapy. Other potential complications include shivering (which needs controlling), hepatic and renal impairment, electrolyte imbalance, lifethreatening arrhythmias, and pancreatitis, but these have not reached significance in the studies. In fact, mild hypothermia can stabilize cell membranes and increase chances of successful defibrillation.18 Therapeutic hypothermia is associated with delayed clinical recovery, and application of the AAN 2006 guidelines may therefore be pessimistic in this setting. The reason for the delay in recovery is probably multifactorial, involving slowing down of neuronal recovery and metabolism and reduced hepatic and renal clearance of sedative drugs. For example, in a retrospective study of 37 patients’ post cardiac arrest treated with TH, 2 of the 14 patients who had motor responses no better than extension to pain at 72 hours ended up obeying commands and interacting with their environment at day 6.19 Another prospectively designed study demonstrated that in 25 patients who had a good outcome, 1 had electroencephalogram (EEG) confirmed early myoclonic status epilepticus, 2 had at least 1 absent brain stem reflex, and 4 had absent motor responses or extension to pain at 72 hours.20 These observations suggest that clinical predictors at 72 hours, following a period of TH, should be interpreted with an increasing degree of caution.
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3 A formal EEG can be useful to:
Biochemical Markers Serum biomarkers have been used to detect the magnitude of neuronal cell damage with some encouraging results. Both neuron-specific enolase (NSE), located in neurons, and serum S-100B, present in astrocytes, are released when there is neuronal damage. The 2006 AAN guidelines indicate that a serum NSE higher than 33 mg /L between day 1 and day 3 following a cardiac arrest is associated with a poor outcome (with a falsepositive rate of 0 in the largest study). A number of studies have explored the significance of serum NSE following TH with mixed results. Two studies of approximately 100 patients each21,22 demonstrated no false positives, while another has reported a false-positive rate of up to 29%.23 Other biochemical markers have been investigated (eg, neurofilament protein) but have not demonstrated the required specificity.8 S-100B has been shown to have a good specificity in 2 small studies, but larger studies are needed.23,24
Somatory Sensory-Evoked Potentials In this test, the median nerve is stimulated electrically and the primary cortical somatory sensory-evoked potential (SSEP) component is recorded over the parietal area contralateral to the stimulated median nerve. The components of SSEP are named after their polarity and peak latency: ‘‘N20’’ is a negative pulse that peaks at 20 msec after the median nerve stimulus. Somatory sensory-evoked potentials should ideally be performed off sedation, but the N20 response is only moderately affected, and clinically useful recordings can be reliably obtained even under anesthesia. Bilateral absence of the N20 component of median nerve stimulation at 72 hours is a marker of poor outcome that has a reported specificity of up to 100%.25 In some patients, N20 responses are intact at 24 hours but are lost irreversibly by 72 hours.26 However, the reliability and consistency of the N20 response following TH has recently been questioned. An individual who had an absent N20 response at 72 hours went on to make a good recovery.27 However, even in patients treated with hypothermia, the reliability of this test is considered excellent at 72 hours.21 Loss of N20 responses has a high specificity but low sensitivity for poor outcome. Preservation of the pathway does not predict a good outcome and in fact is maintained in patients with severe brain injury. One approach by Rossetti et al was to use at least 2 of the following 4 independent predictors of poor long-term neurological outcome: incomplete brain stem reflexes, myoclonus, unreactive EEG, and absent cortical SSEP had a positive predictive value (PPV) of 1 (PPV ¼ 1).21
Electroencephalogram Analysis Electroencephalogram is the recording of electrical activity generated from voltage changes across neuronal membranes and so can be considered a surrogate marker of neuronal activity. The electrical activity is measured from scalp electrodes.
1. 2. 3.
detect seizures, especially when not clinically apparent; observe generalized cortical suppression and pathological EEG traces, for example, burst suppression; and observe for reactivity to auditory, visual, or nociceptive stimuli.
Bedside EEG monitors such as the spectral edge frequency, spectral density array, or the bispectral index monitor may also have a role but are less well studied in this setting.
Seizures The prevalence of seizures on EEG post cardiac arrest is between 10%28 and 47%,29 and their presence is a marker of underlying cortical damage. The presence of epileptiform activity on EEG in patients treated with TH post cardiac arrest was 21%30 in 1 study, where the patients were sedated with midazolam and fentanyl. Control of seizure activity with anticonvulsant therapies is paramount before predicting a poor prognosis but not always achievable without the use of sedating antiepileptic agents. Prolonged epileptiform EEG activity both during and after TH is independently associated with poor outcome.31 The unfavorable outcome may be the result of the severity of the initial hypoxic– ischemic insult or the ongoing seizure activity itself. Because mild hypothermia and sedative drugs have anticonvulsant actions, it has been suggested that seizures during TH may reflect more severe and diffuse brain injury, while seizures that develop following rewarming may be less indicative of a poor prognosis.32 A small study investigating the timings of seizure development using continuous EEG indicated that most seizure activity was nonconvulsive status epilepticus and started prior to the rewarming phase.32 Treating any detected epileptic activity (including status epilepticus) can still result in a good outcome, and a trial of antiepileptic drugs (AEDs) is needed. In the studies of Rossetti et al,32,33 EEG evidence of status epilepticus was treated with intravenous antiepileptics (levetiracetam, valproate, phenytoin, benzodiazepines, or in selected cases with propofol targeting electrographic burst suppression for at least 24 hours).
Myoclonic Status Epilepticus Early myoclonic status epilepticus (MSE) has been associated with a grave prognosis. However, one of the difficulties with this prognostication lies in its diagnosis. Patients with MSE have prolonged, frequent, spontaneous myoclonic jerks that are thought to be subcortical in origin. It should be distinguished from generalized tonic clonic seizures with an EEG and treated with AEDs. Lance-Adams syndrome, a rare post anoxic condition characterized by later onset, usually intention myoclonus, awareness, and normal intellect, can also be mistaken for MSE. Several reports of patients who developed MSE post arrest went on to make a good recovery both with and without TH.25,34,35 Treatment with AEDs is also difficult; often phenytoin and valproate are ineffective, low-dose propofol can be
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used successfully.36 In a small study of 18 patients, not treated with TH post cardiac arrest, the mean number of AEDs used to control MSE was 2.3.37 The MSE can still be considered a poor prognostic sign but is not as reliable as once thought and is not true if the primary event is asphyxia.
Reactivity In a recent study of 111 patients treated with TH, an unreactive EEG following rewarming was found to be a strong predictor of a poor outcome with a false-positive rate of 7%,30 and other studies have demonstrated similar figures.38 Small studies looking at EEG reactivity during the hypothermic period have also demonstrated very low false-positive rates, and continuous EEG during hypothermia may become a standard of care in the future.17
Generalized Suppression There are certain EEG patterns that are indicative of a poor outcome and have a small (but not zero) false-positive rate. These should be interpreted within the clinical context and the presence of hypothermia and sedative drugs. Generalized suppression to 20 mV, burst-suppression pattern with generalized epileptiform activity, or generalized periodic complexes on a flat background are strongly but not invariably associated with poor outcome.39 Diffuse or predominantly frontal a coma (an unremitting 8-13 Hz EEG) unresponsive to stimulation or eye opening has been associated with a 90% probability of death or vegetative state.40 Formal EEG analysis provides prognostic information and treatment options and should be performed on all patients early in treatment. Detected seizures can be treated, while certain pathological patterns suggest a poor prognosis. The EEG reactivity looks promising as a prognostic tool, but larger studies are needed for its validation and optimal timing decided.
Continuous Bedside EEG There are many types of bedside EEG monitors. The amplitude integrated EEG (aEEG) is processed from biparietal electrodes and measures minimum and maximum amplitudes. These amplitudes are graphically represented against time. Two studies using early (during hypothermia) aEEG produced encouraging results.42,43 The first study detected 2 patients (from 34) with burst suppression and another with a coma (all subsequently confirmed with formal EEG). None of these regained consciousness. In the subsequent larger study, 14 of the 95 patients developed early burst suppression, and all failed to regain consciousness and subsequently died or had treatment withdrawn. The investigators also noted that a continuously active EEG activity, or a return of a continuous active pattern during hypothermia, had a PPV of 91% and 87%, respectively, for regaining consciousness.34 This is potentially one of the early markers of a positive outcome.
Similar prognostic studies have been performed using the bispectral index monitor (BIS). This is a frontal EEG monitor with a complicated waveform analysis designed to detect depth of anesthesia. During TH (and administration of pharmacological neuromuscular blockade to reduce electromyogram interference), a BIS of less than 22, measured as the sustained plateau value 5 to 10 minutes after the first neuromuscular blockade dose, predicted a poor neurological outcome (CPC 3-5) with a likelihood ratio of 14.2.44 Unfortunately, in this study, involving 83 patients, there was less than 100% specificity but higher BIS scores were associated with improved outcomes. Both forms of processed EEG generate relevant information that can be incorporated into an overall picture; however, the reliability of this information is questionable. A formal EEG is required before treatment or prognostication. Proof of a continuously active EEG with a bedside monitor appears to have a positive correlation with good outcome, while any abnormalities detected might instigate an earlier formal EEG. Bedside EEG monitors are gradually becoming an accepted standard of care in post arrest patients.
Computed Tomography Scan A brain computed tomography (CT) scan is often performed early following a cardiac arrest to rule out intracranial pathology such as intracerebral hemorrhages. Although initial imaging is frequently unremarkable, by day 2 to 3 post cardiac arrest some patients demonstrate diffuse swelling with effacement of the basal cisterns, ventricles, and sulci and attenuation of the gray–white matter interface. The extent and timings of these changes are still unclear. Current evidence suggests that loss of gray–white differentiation may happen first and can occur within hours, and sulcal effacement develops a little later.45 Both of these signs early on are associated with a poor outcome at 6 months. Further analysis of Hounsfield units (a measurement of radiodensity) of CTs taken within 48 hours has led to the development of the Brain Arrest Neurological Outcome Score (BrANOS) developed before TH, a combination of the duration of arrest, best GCS, and the Hounsfield unit ratio between caudate (gray) and posterior limb of the internal capsule (white).46 A more recent study47 compared density changes (with Hounsfield units) in the putamen and the posterior limb of the internal capsule on CT and GCS at 72 hours. They found the combination of tests had 72% sensitivity and 100% specificity at predicting poor outcome. Unfortunately, only 33 (21%) of the 155 patients recruited were treated with hypothermia, and the inclusion of this subset of patients reduced the accuracy. Other CT scoring systems used in the first 24 hours have been developed, which show good specificity. Scheel et al48 examined CT scans from 91 post cardiac arrest patients, all treated with TH. They were particularly interested in the gray–white matter ratio (GWR). A GWR 48 hours later to ensure no changes
Detecting seizures Detecting myoclonic status epilepticus Assessing for burst suppression Assessing for EEG reactivity Assessing for continuous EEG activity Evidence of burst suppression Assessing degree of cerebral oedema Detecting brain stem reflexes Detecting motor response to pain Assessing for bilaterally absent N20 response FPR 0% (0-3) for poor outcome Assessing degree of brain damage visually or with a scoring system
Early processed bedside EEG CT at 48-72 hours Clinical examination at 72 hours SSEPs at 48-72 hours Serum NSE >33 ug/L at 24-72 hours MRI at 24-120 hours
Abbreviations: CT, computed tomography; EEG, electroencephalogram; FPR, false-positive rate; MRI, magnetic resonance imaging; NSE, neuron-specific enolase; SSEPs, somatory sensory-evoked potentials.
Table 4. Markers Associated With a Worse Outcome But With Lower Specificity, Especially in the Context of Therapeutic Hypothermia. Clinical Features NSE EEG
No motor response or an extensor response to painful stimuli at 72 hours following cardiac arrest Serum NSE higher than 33 mg/L between days 1 and 3 Low-voltage EEG including during the hypothermia a coma
Abbreviations: EEG, electroencephalogram; NSE, neuron-specific enolase.
in 62 patients to improve the sensitivity for predicting a poor outcome to 53%. This is a developing area of prognostication.
Magnetic Resonance Imaging Magnetic resonance imaging (MRI) modalities analyzing the movement/diffusion of water molecules (diffusion-weighted imaging [DWI]) provide information about the extent of any damage to neurons, the microcirculation, and larger vessels in the context of a hypoxic–ischemic arrest. Studies using quantitative DWI (using apparent diffusion coefficient [ADC] values) MRI have revealed that the brain injury takes time to develop, and imaging within the first 24 hours may not reflect the true extent of the hypoxic–ischemic injury. The timedependent changes are presumably due to ongoing apoptosis following the original injury or ongoing secondary neurological damage.49 Relatively small studies suggest that MRI findings could be prognostic between day 2 and 5. Those with moderate to severe abnormalities (eg, brain swelling, cortical necrosis, high signal within the basal ganglia) have a poor outcome while those with minimal or no changes having a good outcome. In a small study of 20 patients post cardiac arrest and treated with TH, diffusion and perfusion MRI brain scans at 5 days showed the greatest acute ischemic changes in the parietal lobe in those not surviving.49 There are attempts to quantify the extent of the damage in patients treated with and without TH, for example, using the median ADC value or the percentage volume of the brain below a certain ADC value.51,52 Wijman et al51 studied MRIs in 51 patients of which 61% were treated with TH. Those patients with 10% of brain volume less than 650 106 mm2/sec on the ADC map did not regain
consciousness. Although MRI seems to be a promising modality for predicting both good and poor outcome between days 2 and 5, this has to be balanced against the availability of the MRI and the many inherent difficulties and risks posed by obtaining the images in a critically ill patient.
Discussion The American Association of Neurologists 2006 guidelines for prognostication are still considered reliable in patients managed without TH following a cardiac arrest. Some combination of clinical predictors at 72 hours, SSEP at 48 to 72 hours, EEGs, an NSE at days 1 to 3, and neuroimaging to provide a clear prognostic overview is recommended. Table 3 includes current suggestions for assessing prognosis following a cardiac arrest in these circumstances. Since therapeutic hypothermia has become a standard of care, reduced test accuracy has been demonstrated (Table 4), while other tests retain their sensitivity and specificity better (Table 5). The current International Liaison Committee on Resuscitation guidelines53 on prognostication post-TH are detailed in Table 6. Absent brain stem reflexes and the presence of myoclonic status epilepticus at 72 hours post arrest are not 100% specific in the absence of sedation, while a poor motor response is even less specific. Absent SSEPs at 72 hours retain a high specificity. The EEGs are still useful for diagnosing seizures and providing specific prognostic information when burst suppression and nonreactivity are detected. Diffusion-weighted MRI performed between days 2 and 5 demonstrating significant damage is associated with a poor outcome, although the
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Table 5. Highly Probable of a Poor Outcome Even in the Context of Therapeutic Hypothermia. EEG SSEPs MRI
Burst suppression with generalized epileptiform activity even during hypothermia; nonreactivity of EEG once normothermic Bilateral absent N20 response at 72 hours following cardiac arrest Significant MRI changes compatible with severe hypoxic ischaemic damage at day 2 to 5
Abbreviations: EEG, electroencephalogram; MRI, magnetic resonance imaging; SSEPs, somatory sensory-evoked potentials.
Table 6. International Liason Committee on Resuscitation (ILCOR) Guidelines53 for Prognostication of Favorable Neurological Outcome Post cardiac Arrest and Treatment With TH.a Pre-cardiac arrest factors Intracardiac arrest factors Postcardiac arrest factors Clinical features EEG SSEPs54 NSE and S10055
There are no studies reliably predicting the neurological outcome of patients treated with TH post cardiac arrest There are no studies reliably predicting the neurological outcome of patients treated with TH post cardiac arrest The absence of neurological function immediately post-ROSC does not reliably predict outcome There are no studies reliably predicting the outcome of patients treated with TH post cardiac arrest EEG alone is insufficient to determine futility. Poor functional outcome is most reliably predicted with generalized suppression to 25 vs 8.8 mg/L; S100ß 0.23 vs 0.12 mg/L)
Abbreviations: CI, confidence interval; EEG, electroencephalogram; FPR, false-positive rate; NSE, neuron-specific enolase; ROSC, return of spontaneous circulation; SSEPs, somatory sensory-evoked potentials; TH, therapeutic hypothermia. a The relative impact of hypothermia on prognostic accuracy appears to vary among individual strategies and is inadequately studied. Prognostication should be delayed but the optimal time has yet to be determined.
studies in this area are small. The damage can be assessed visually or using one of the developing scoring systems. To reliably place a patient who has been treated with therapeutic hypothermia in a poor outcome category, more time off sedation may be required. Clinical prognostic tests could be performed relative to achieving normothermia rather than from the time of the arrest, and prognostic tests could be repeated later in the clinical course. There should also be a greater reliance of SSEP, as loss of N20 has a high specificity39 although low sensitivity for poor outcome.56 Markers of a good prognosis include a good motor response (withdrawal, localizing or obeying) within 24 hours of stopping sedation, continuous nonpathological EEG activity during hypothermia, and minimal changes in MRI at 2 to 5 days. However, due to the lack of trials, these are not as well validated as the poor prognostic markers.
Conclusion Following a cardiac arrest, accurate prognostic markers would help with family communication and decisions concerning continuation of care. Therapeutic hypothermia, while resulting in improved neurological recovery, has reduced the sensitivity and specificity of clinical testing at 72 hours and of the biochemical and electrophysiological tests. It may also delay any associated anatomical changes that can be seen on neuroradiological imaging. In difficult clinical situations, integration
of the clinical tests, other prognostic tests, and perhaps repeating some of these tests after a longer period off sedation may be required. In general, reliance on a single prognostic test should probably be avoided for irreversible treatment decisions. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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