See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/6820731 Biomarkers and Neuroimaging of Brain Injury after Cardiac Arrest Article in Seminars in Neurology · October 2006 DOI: 10.1055/s-2006-948322 · Source: PubMed CITATIONS READS 17 387 3 authors, including: Prem Kandiah Michel Torbey Emory University The Ohio State University 15 PUBLICATIONS 78 CITATIONS 93 PUBLICATIONS 2,694 CITATIONS SEE PROFILE Some of the authors of this publication are also working on these related projects: The intracerebral spot sign View project Hyperchloremia and acute kidney injury in subarachnoid hemorrhage patients View project All content following this page was uploaded by Michel Torbey on 01 June 2014. The user has requested enhancement of the downloaded file. SEE PROFILE Biomarkers and Neuroimaging of Brain Injury after Cardiac Arrest Prem Kandiah, M.D.,1 Santiago Ortega, M.D.,1 and Michel T. Torbey, M.D., M.P.H., F.A.H.A.1,2 ABSTRACT Unfortunately, it remains a difficult task to predict with certainty which patients will have a poor neurological outcome following cardiac arrest. Finding a quantitative prognostic model of outcome has become the objective of many intensivists to assist grieving families in making early difficult decisions regarding withdrawal of life support. An ideal prognostic test should be readily available, easily reproducible, and associated with a high degree of specificity for poor outcome. The goal is not to define which patients may recover, but rather which patients have no likelihood of meaningful neurological recovery at all to justify early withdrawal of support. The literature and the role of biochemical markers in the blood and in the cerebrospinal fluid will be evaluated as prognosticators following cardiac arrest. Radiological indicators of anoxic cerebral damage are reviewed. Each serum or radiological marker has its pros and cons. To accurately prognosticate following cardiac arrest, a multimodal scale or algorithm that incorporates serum markers, radiological markers, and the neurological exam is clearly needed. As these techniques are being evaluated more closely and as imaging modalities increase in sensitivity and portability, physicians will continue to assist families by providing some guidance as to which patients have no chance of meaningful recovery. KEYWORDS: Neuron-specific enolase, S-100, cardiac arrest, radiological markers, serum markers, prognostication P rior to the advent of modern cardiopulmonary resuscitation (CPR), most patients who suffered a cardiac arrest died.1 Now, larger numbers of patients are successfully resuscitated, but more than half die during hospitalization, many from secondary brain injury.2,3 Many of those who do survive do not regain independent function.4 Since the 1970s, several investigators have attempted to better predict coma outcome using several predictors, such as pupillary and oculocephalic reflexes and variations in pain response. Several scoring systems, including the Longstreth Awakening score and Glasgow Coma Scale, have been developed.4–8 Unfortunately, despite much study, it has remained difficult to predict with certainty which patients will have a poor neurological outcome. Finding a quantitative prognostic model of outcome has become the objective of many intensivists to assist grieving families in making early difficult decisions regarding withdrawal of life support. An ideal prognostic test should be readily available, easily reproducible, and associated with a high degree of specificity for poor outcome. The goal is not to define which patients may recover, but rather which patients have no likelihood of meaningful neurological recovery 1 Department of Neurology and 2Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin. Address for correspondence and reprint requests: Michel T. Torbey, M.D., M.P.H., F.A.H.A., Director, Neurointensive Care Unit, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226. Hypoxic-Ischemic Encephalopathy; Guest Editor, Romergryko G. Geocadin, M.D. Semin Neurol 2006;26:413–421. Copyright # 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-2006-948322. ISSN 0271-8235. 413 This document was prepared for the exclusive use of Jeffrey Burns. Unauthorized distribution is strictly prohibited. 414 SEMINARS IN NEUROLOGY/VOLUME 26, NUMBER 4 2006 Table 1 Ranges of Cutoff Values Reported for Neuron-Specific Enolase (NSE) and S-100 NSE S-100 Time (h) Serum (ng/mL) CSF (ng/mL) Serum (ng/mL) 24–48 8.8–25 24 0.2–0.7 48–72 16.4–100 50 0.2 CSF (ng/mL) 6 at all to justify early withdrawal of support. In this review, we will present an assessment of serum and radiological markers for neurological recovery following cardiac arrest. SEROLOGICAL MARKERS The most convenient markers are those that can be readily obtained at the bedside. Studies have measured markers of brain injury in serum and cerebrospinal fluid (CSF). There have been contradictory reports about the development of elevated intracranial pressure (ICP) following cardiac arrest,9,10 but none of these studies reported herniation as a direct result of lumbar puncture. Nonetheless, elevated ICP remains at least a theoretical concern, and the search continues for prognostic peripheral markers in the bloodstream. Table 1 provides a list of published biomarkers values. Neuron-Specific Enolase Neuron-specific enolase is a glycolytic enzyme found mainly in neurons and neuroectodermal cells. High serum levels have been reported with malignant tumors such as neuroblastomas and small cell carcinoma of the lung.11 Studies have shown that neuron-specific enolase is a marker for severity of neuronal injury and clinical outcomes in stroke,12 head injury,13 encephalitis,14 brain metastasis,15 and status epilepticus.16 The prognostic role of neuron-specific enolase as a biochemical marker of neuronal injury in cardiac arrest was first investigated in the 1980s.17 Several authors have since measured neuron-specific enolase in serum17–25 or CSF17,26 to help prognosticate more accurately neurological outcome following cardiac arrest. Only two studies compared the performance of neuronspecific enolase in CSF and plasma.17,26 Roine et al17 measured neuron-specific enolase 24 hours following cardiac arrest. Different cutoff levels of neuron-specific enolase were used in CSF (> 24 ng/mL) compared with serum (> 17 ng/mL). The specificity of neuron-specific enolase was comparable between CSF and serum, but sensitivity was lower in serum (40%) than CSF (74%). All patients in the study with a CSF neuron-specific enolase level > 24 ng/mL 24 hours after cardiac arrest remained unconscious and died.17 These results contradicted the findings of Martens et al26 who reported a higher specificity for neuron-specific enolase when measured in serum compared with CSF. Thus, it seems that at this stage there is no clear-cut evidence that either serum or CSF are any better. Measuring CSF neuron-specific enolase is not very practical and may add a theoretical risk of brain herniation from cerebral edema that may be present following cardiac arrest. Hence, it appears to be more practical and safer to measure serum neuron-specific enolase levels. In an attempt to determine the optimum time to measure neuron-specific enolase, different studies have used different time parameters. Some used 24 hours,17,25,26 others 24 to 48 hour24,25,27 or 72 hours18–20,27 as their time frames. Fogel et al20 and Schoerkhuber et al23 measured serial serum neuronspecific enolase for the subsequent 7 days following cardiac arrest. Both studies reported improved prediction when neuron-specific enolase levels were measured within 48 to 72 hours following cardiac arrest. Neuronspecific enolase value at 72 hours after return of spontaneous circulation was the best predictor of neurological outcome.28 Table 2 summarizes the performance of neuron-specific enolase at different time frames. S-100 S-100, a member of the Ca2þ-modulated proteins family, has both intracellular and extracellular regulatory activities.29 It is expressed in varying abundance in astrocytes, Schwann cells, adipocytes, melanocytes, chondrocytes, skin Langerhans cells, lymphocyte subpopulations, skeletal muscle cells, and many neuronal Table 2 Predictive Indices of Biomarkers in Serum and CSF 24 h NSE Time 48 h S-100 Serum NSE Serum S-100 Serum CSF CSF Serum Specificity (%) 89–100 100 80–96 100 83 70–100 60 Sensitivity (%) 51–59 74 55–100 59–100 89 79–100 93 PPV (%) 86–100 100 71–95 100 96 75–100 93 NPV (%) 65–70 89 63–100 10–100 63 89–100 63 This document was prepared for the exclusive use of Jeffrey Burns. Unauthorized distribution is strictly prohibited. CSF BIOMARKERS AND NEUROIMAGING OF BRAIN INJURY/KANDIAH ET AL populations.30 It modulates differentiation and proliferation of neurons and glia. S-100 effects are protective if kept within cells at physiological levels. Animal models, however, reveal that once secreted, large (micromolar) concentrations can have a detrimental effect resulting in apoptosis and neurodegeneration, and small (nanomolar) concentrations can be neuroprotective in nature.31 The first study, published by Rosen in 1998,22 demonstrated a significant correlation between S-100 serum levels, anoxia time, and degree of coma at day 1 and day 2. Comatose cardiac arrest patients with serum S-100 levels persistently > 0.2 mg/L over 48 hours died within 14 days of cardiac arrest.22 Martens21 obtained similar results with a post hoc cutoff value of 0.7 mg/L at 24 and 48 hours following cardiac arrest. The cutoff value of 0.7 mg/L has also been supported by HachimiIdrissi and colleagues32 with a good specificity, even using S-100 admission levels. Table 2 summarizes the performance of S-100 as a prognosticator of brain injury. Long-term outcomes related to S-100 and neuron-specific enolase levels in cardiac arrest have also been evaluated. Rosen et al27 found that high levels of serum S-100 but not neuron-specific enolase predicted poor outcome according to the Glasgow Outcome Scale measured 1 year following cardiac arrest. Comparison Between Neuron-Specific Enolase and S-100 Very few studies actually compared neuron-specific enolase and S-100 head to head. Martens et al26 compared serum S-100 and serum neuron-specific enolase at 24 hours, CSF S-100, and CSF neuron-specific enolase at 48 hours as predictors of coma following cardiac arrest. The positive predictive value (PPV) and negative predictive value (NPV) for serum S-100 was 95 and 63%; for neuron-specific enolase it was 86% and 65%, respectively. Cutoff levels was 0.7 mg/L for serum S-100 and 20 mg/L for neuron-specific enolase. This study found a good correlation between serum and CSF S-100 and neuron-specific enolase. Moreover, serum S-100 at 24 hours was noted to be as good as or superior to CSF S-100 in predicting outcome. Bottiger et al28 studied the predictive value of sequential levels of S-100 and found that predictive value was greatest at 24 hours. Results also revealed that the odds ratio of having brain damage was 15 (95% confidence interval, 2.02 to 111.2) if S-100 level was elevated within 2 hours after cardiac arrest. ROLE OF NEURON-SPECIFIC ENOLASE AND S-100 IN THERAPEUTIC HYPOTHERMIA In two independent randomized clinical trials, hypothermia for 12 or 24 hours resulted in improved neuro- logical outcome in comatose survivors of out-ofhospital cardiac arrest.33,34 In 2003, Tiainen et al25 conducted a study assessing the role of neuron-specific enolase and S-100 in patients after out-of-hospital cardiac arrest requiring resuscitation under the conditions of hypothermia (33 18C). Blood samples for neuron-specific enolase and S-100 were collected at 24, 36, and 48 hours after return of spontaneous circulation. Neuron-specific enolase and S-100 levels were lower in the hypothermia group compared with the normothermia group. A decrease in neuron-specific enolase value between 24 and 48 hours was observed in 30 of 34 patients (88%) in the hypothermia group and 16 of 32 patients (50%) in the normothermia group. The decrease in neuron-specific enolase value was associated with good outcome at 6 months. It was also associated with regaining consciousness and survival for at least 6 months after return of spontaneous circulation. A decrease in S-100 values was observed between 24 and 48 hours in 17 of 34 patients (50%) in the hypothermia group and in 15 of 33 patients (45%) in the normothermia group. Decreased S-100 values, however, had no relation to outcome. Tiainen et al25 concluded that hypothermia resulted in rapidly decreasing levels of serum neuron-specific enolase, reflecting amelioration of secondary ischemic neuronal injury. This is the first study to incorporate a therapeutic intervention with serum markers. This is certainly very important as it could open the door to test more neuroprotective agents. OTHER POTENTIAL BIOMARKERS Glucose Several investigators reported a significant association between elevated blood glucose following cardiac arrest and poor neurological recovery.6,35–38 In 1997, Mullner and colleagues39 evaluated the role of postischemic blood glucose levels in patients with witnessed ventricular fibrillatory arrest. They found that, in cardiac arrest survivors, high blood glucose levels over the first 24 hours after return of spontaneous circulation were independently associated with unfavorable functional neurological recovery (146 39 mg/dL compared with 184 88 mg/dL). Despite that, there does not appear to be support for using glucose as a primary variable in predicting outcome following cardiac arrest. However, the admission glucose and median glucose over the first 24 hours can be used as an adjunctive measurement supporting the gestalt of the individual patient’s prognosis. Lactate Measurements of serum lactate levels on admission have not been particularly accurate at predicting prognosis in This document was prepared for the exclusive use of Jeffrey Burns. Unauthorized distribution is strictly prohibited. 415 416 SEMINARS IN NEUROLOGY/VOLUME 26, NUMBER 4 2006 postanoxic patients, requiring excessively high levels to achieve 100% specificity for poor neurological outcome.39,40 Serial lactate measurements fared slightly better, with levels higher than 2 mmol/L after 48 hours correlating well with mortality or severe neurological disability. Much like the use of glucose, both serum and CSF levels of lactate can be used as supporting data, but neither should be used as the primary method of prognostication in an individual patient. Brain-Type Isoenzyme of Creatine Kinase The brain-type isoenzyme of creatine kinase (CK-BB) is primarily located in neurons and astrocytes, and as such comprises 95% of the total creatine kinase activity of the brain.41 Levels of CK-BB have been noted to be elevated following global cerebral ischemic injury.42 There have been several difficulties noted in the use of serum CKBB as a prognostic indicator. Many patients suffering cardiac arrest will also develop myocardial infarctions with resultant release of myocardial CK-MB isoenzyme into the serum. Many of the available assays have some cross-reactivity between the MB and BB isoenzymes, making a serum test less accurate. In addition, the CKBB fraction peaks rapidly in the serum and is rapidly inactivated with individual variation as to the speed of inactivation.43 RADIOLOGICAL MARKERS Despite studies supporting the potential use of serological or electrophysiological markers in prognostication following cardiac arrest, families and physicians continue to require additional evidence prior to withdrawal of life support. Hence, short of an autopsy, neuroimaging provides a noninvasive reliable method to assess for a structural brain injury. Gray matter, in particular the hippocampus, caudate-putamen, thalamus, large cell layers of the neocortex, and Purkinje cells of the cerebellar cortex, are selectively vulnerable to hypoxic injury. White matter injury is believed to occur weeks to months after global hypoxic injury. The imaging findings of diffuse anoxia include diffuse cerebral edema, loss of gray-white matter distinction, and selective neuronal necrosis affecting the deep gray nuclei and of the cortical layers III, IV, and V.44–47 Computerized tomography (CT) and conventional magnetic resonance imaging (MRI) could play a role in prognostication following diffuse cerebral anoxia. Computerized Tomography CT scan is one of the most frequently used ancillary tests in comatose patients. A normal CT scan of the brain shows a clear difference between white matter with its high lipid content and gray matter with its high water content.48 After cardiac arrest, the inadequate production of adenosine triphosphate that accompanies global ischemia results in an overall increase in water content (cytotoxic edema).49,50 Furthermore, a delayed hyperemia after resuscitation can lead to increased ICP and occasionally to brain swelling.51 Initially, the cerebral blood vessels collapse so as to decrease intracranial volume and prevent further increase in ICP. If systemic hypotension is corrected, this results in a distention of the deep medullary veins.52–54 As a result, white matter becomes distended with blood and appears denser on unenhanced CT scans. Therefore, a loss of distinction between gray matter and white matter after cardiac arrest could result from the combination of a decreased gray matter intensity due to cytotoxic edema and an increased white matter intensity due to distention of the medullary draining veins. It has been a general impression that a decreased distinction between gray matter and white matter on CT predicts poor outcome after cerebral insults. However, qualitative assessment is not very reliable.55 Hence, measuring the Hounsfield unit (HU) density may allow a reliable quantifiable comparison between gray matter and white matter. Torbey and colleagues56 compared the HU density of gray matter of the caudate nucleus and the HU of the white matter of the posterior limb of the internal capsule. On noncontrast CT scans performed within 48 hours of cardiac arrest, the gray matter/white matter ratios were significantly lower than those of control patients. Using a receiver operating characteristic curve analysis, a gray matter/white matter ratio of < 1.18 was 100% predictive of death, whereas the survival rate was 46% among patients with a gray matter/white matter ratio of 1.18. Additional studies confirmed that CT scan could be used as a reliable tool to evaluate long term brain injury after cardiac arrest. Nunes et al57 have demonstrated that CT imaging revealed atrophy in quantitative and qualitative analysis in patients between 1 and 3 years after cardiac arrest and this correlated with impairment in cognitive testing. Table 3 summarizes the findings in published studies that used CT as a prognosticator for cardiac arrest. Magnetic Resonance Imaging MRI during global cerebral hypoxia is possibly a valuable tool for early prognosis of clinical outcome. Although there is no doubt of the accuracy of MRI in identifying early ischemic changes, the use of this technique is still limited by several factors, such as the lack of availability and expertise needed to interpret the images in several centers and the long duration of the test, which may expose critically ill patients with the potential for recurrent cardiac arrhythmias to undue risk. In the hyperacute period (< 24 hours following cardiac arrest), Arbelaez and colleagues58 evaluated This document was prepared for the exclusive use of Jeffrey Burns. Unauthorized distribution is strictly prohibited. BIOMARKERS AND NEUROIMAGING OF BRAIN INJURY/KANDIAH ET AL Table 3 Studies Using CT Scan for Prognosis in Cardiac Arrest Patients Study Year n Time to CT Findings Prognosis Kjos et al74 1983 10 24 h–5 d Diffuse mass effect 90% died within 31 d LD in GM LD in BG LD in watershed areas Fujioka et al75 1994 8 24 h No abnormal findings 2–6 d Diffuse cerebral edema 62% died within 53 d 1 wk–2 mo LD in caud, lenticular 48 h Diffuse cerebral atrophy LD in caud and put 100% died ID in posterior limb of IC HU ratio < 1.18 nuclei and thalamus Torbey et al56 2000 25 LD, low density; ID, increased density; GM, gray matter; BG, basal ganglia; caud, caudate; put, putamen; IC, internal capsule; HU, Hounsfield unit. diffusion-weighted imaging (DWI) findings in 10 patients with global cerebral anoxia. Using both low-b value (B ¼ 30 s/mm2) and high-b value (B ¼ 1100 s/mm2) diffusion imaging, investigators were able to find abnormal signal in the cerebellum, basal ganglia, and cortex in under 24 hours. All of the patients demonstrating DWI changes had a poor neurological outcome (death or vegetative state). Interestingly, conventional T1- and T2-weighted imaging were normal. In the acute-subacute period (24 hours to 20 days), abnormalities on MRI could now be seen on T1- and T2-weighted images.58–61 During this period there is a reperfusion of the ischemic regions, but this may not be sufficient to restore normal cellular homeostasis and cytotoxic edema may result. In addition, the phenomenon of ‘‘late neuronal death,’’62 which predominantly affects the neocortex, hippocampus, and basal ganglia, also may contribute to the abnormalities present on conventional T2-weighted and DWI. Els et al61 evaluated both DWI and apparent diffusion coefficient (ADC) changes following global hypoxia and found that an increase of signal intensity on DWI is associated with an ADC decrease to 60 to 70% of control in large areas of the parietal, temporal, and occipital cortex correlates with irreversible tissue injury. However, in contrast with DWI, this decrease was not observed in the cerebellum and thalamus. Several studies have also demonstrated that ADC declines as a function of time following global cerebral ischemia.63,64 In the late subacute period (14 to 20 days), DWI shows a diffusely bright white matter, a finding that was not that obvious on conventional MRI. Several mechanisms may explain these findings, including increased pH secondary to lactic acid, release of protons that contribute to glial cell damage,60,65 and glutamate effect on glial cells receptors.66 In the chronic period (21 to 22 days), DWI images may be normal. Laminar necrosis can now seen on conventional MRI. During this period cellular death and axonal destruction occur, which may lead to an increase in extracellular space and greater freedom for Brownian motion.67 Although earlier studies focused primarily on gray matter injury following cerebral ischemia, DWI opened the door for evaluating white matter injury as well. The results of these studies were contradictory to the common belief that white matter injury usually occurs later in the course following cardiac arrest. Chalela et al59 presented a case series in which MRI with T2-weighted imaging and DWI was obtained on seven comatose patients between 1 and 6 days following severe anoxic injury. Only two of the seven patients had primary cardiac arrest; the rest had a multitude of causes including cocaine overdose, carbon monoxide intoxication, hypoxemic respiratory failure, and septic shock. Restricted DWI lesions were prominent throughout the white matter in the periventricular region, corpus callosum, and internal capsule. These findings were corroborated with decreased ADC mapping. Similarly, Arbelaez and colleagues58 evaluated DWI findings in 10 patients with global cerebral anoxia. Investigators were able to find white matter changes in the subacute period of 14 to 20 days following injury. These studies demonstrated that myelinopathy can occur quite early following anoxic injury and holds potential for evaluation as a prognostic indicator. The fact that this leukencephalopathy occurred earlier than would be expected for a Wallerian degeneration suggests that it may be a result of the primary insult caused by diffuse cerebral anoxia, impaired cerebral perfusion, or both.58 As a result, an early axonal and oligodendrocity injury is produced independently of neuronal injury.68 Some studies have hypothesized that DWI could be used to determine the cause of the global hypoxic damage as different types of anoxic brain injury can lead to different imaging features. DWI hyperintensity throughout the cerebral cortex suggests devastating, diffuse hypoxic ischemia typically seen after cardiac This document was prepared for the exclusive use of Jeffrey Burns. Unauthorized distribution is strictly prohibited. 417 418 SEMINARS IN NEUROLOGY/VOLUME 26, NUMBER 4 2006 Table 4 Review of MRI Studies Time Study n Imaging Hyperacute (< 24 h) Acute-Subacute (24 h–13 d) Late Subacute (14–20 d) Chronic (> 21 d) Arbelaez et al58 10 T1 Normal Abnormal Normal Abnormal T2 Abnormal Abnormal Normal Abnormal DWI Abnormal Abnormal Abnormal Normal Chalela et al59 7 T1 Abnormal T2 Abnormal DWI Abnormal Abnormal Abnormal Wijdicks et al60 10 ADC Flair DWI Normal Els et al61 12 DWI Abnormal ADC Abnormal arrest, whereas a pattern of DWI hyperintensity restricted to the thalamus and selected cortical regions suggests primary hypoxic injury.46,69 Nevertheless, in all these studies the main areas affected in early anoxia were gray matter areas. Therefore, it can be concluded that MRI and DWI/ADC imaging may be a useful tool to assess prognosis in comatose patients after cardiac arrest. Table 4 summarizes the findings of four studies using MRI as a marker of brain injury. Hence, further randomized controlled trials, with higher sample of patients, are needed to evaluate the significance of different radiological patterns and their relationship to clinical prognosis and survival. Positron Emission Tomography Scan Very few authors have investigated the prognostic role of positron emission tomography during the early period after cardiopulmonary resuscitation. Edgren et al40 reported a noticeable decrease in blood flow and oxygen metabolism in comatose patients 1 day after CPR. Interestingly, an increase in the oxygen extraction ratio was also found. Furthermore, comatose patients showed a progressive decline in oxygen metabolism that was more remarkable in the putamen and occipital cortex in comparison with patients who woke up.40 A MULTIMODAL APPROACH TO PROGNOSTICATION To avoid false pessimistic prognostication, the cutoff values in most studies for both S-100 and neuronspecific enolase are designed to produce (100%) specificity for poor outcome. Unfortunately, by using this method, the sensitivity of these biomarkers is signifi- cantly lowered. Some studies have tried to bridge this problem by using a multimodal approach to collectively improve prognostication after cardiac arrest. Zingler and colleagues70 prospectively investigated the predictive power of serum concentrations of neuron-specific enolase and S-100 as well as somatosensory-evoked potentials (SEPs) after cardiac arrest. By combining both S-100 and neuron-specific enolase (at 100% specificity), the sensitivities could be markedly increased on day 1 (from 52.9 to 58.8%), day 3 (from 75.9 to 87.5%), and day 7 (from 57.1 to 71.4%). The best predictor of negative outcome was neuron-specific enolase alone at cutoff point 43 mg/L on day 2. This value resulted in a sensitivity of 91% and a specificity of 100%. SEPs showing bilateral loss of cortical responses identified patients who did not regain consciousness with a specificity of 100%.70 Meynaar et al24 found an improved predictability of poor neurological outcome when they combined neuron-specific enolase, Glascow Coma Scale, and SEP. The sensitivity increased from 64 to 76% with a specificity of 100%.24 These findings were in contradiction to the finding of Bassetti et al.71 Bassetti’s group found that both neuron-specific enolase and ionized calcium did not provide any additional prognostic assistance to repeated clinical exam (including Glascow Coma Scale), electroencephalogram, and median nerve SEP. It is important to keep in mind that neuronspecific enolase levels and ionized calcium levels were only measured in 16 patients out of 60. Similarly, Pfeifer and colleagues72 demonstrated that the combination of three variables—(1) Glasgow Coma Scale < 6; (2) serum neuron-specific enolase 65 ng/mL; and (3) serum S-100 1.5 mg/L—at 72 hours after return of spontaneous circulation improved the pre- diction of outcome in postarrest coma. Unconsciousness for > 48 hour and Glascow Coma This document was prepared for the exclusive use of Jeffrey Burns. Unauthorized distribution is strictly prohibited. BIOMARKERS AND NEUROIMAGING OF BRAIN INJURY/KANDIAH ET AL Table 5 BrANOS Scale Table 6 Summary of Poor Prognostic Indicators Points Admission GCS < 8 0–5 1 Serial neuron-specific enolase levels on days 0–3 > 35 ng/mL 6–15 2 Serial S-100 levels on days 0–3 > 0.2 ng/mL > 15 3 Head CT at 24–48 h GM/WM ratio < 1.18 0–12 MRI at 72 hours 1 Restricted diffusion in the cerebral and cerebellar cortices, caudate nuclei, putamen, globus pallidi, and/or thalami 0 GCS, Glasgow Coma Scale; GM, gray matter; WM, white matter. Duration of arrest (min) BrANOS score 10 Best reverse GCS (15-GCS) in 24 h Hounsfield unit ratio < 1.18 1.18 Total 1–16 GCS, Glasgow Coma Scale. Scale < 6 predicted a 61-fold and a 11-fold risk of poor neurological outcome, respectively, 72 hours post–cardiac arrest. Serum neuron-specific enolase levels 65 ng/mL and S-100 levels 1.5 mg/L increased the risk of death and persistent vegetative state by 17- and 13-fold, respectively. Combining the Glascow Coma Scale with elevated serum concentrations of both neuroproteins above the cutoff levels resulted in an improved prediction of poor neurological outcome with a specificity of 100%.72 The Brain Arrest Neurologic Outcome Scale (BrANOS) was developed as a way of encompassing both clinical and radiological markers of brain injury into a predictive model in the setting of global anoxic injury following cardiac arrest.73 The scoring system is outlined in Table 5. In 32 patients with witnessed cardiac arrest, survivors had a significantly lower BrANOS score (8 2 points) compared with nonsurvivors (13 1 points). The scale predicted death within 2 weeks with 100% PPV and 100% specificity for a score 14. Using a perhaps more realistic measurement of outcome, the scale also predicted the combined outcome of death and severe disability (Glasgow Outcome Score ¼ 3) with 100% PPV and specificity for a score 10. 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