WORKSHEET for Evidence-Based Review of Science for Emergency Cardiac Care Worksheet author(s) Claudio Sandroni, Giuseppe La Torre

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1 Worksheet No. ALS-PA-041.doc Page 1 of 16 WORKSHEET for Evidence-Based Review of Science for Emergency Cardiac Care Worksheet author(s) Claudio Sandroni, Giuseppe La Torre Date Submitted for review: 27 December 2009 Clinical question. In adult and pediatric patients who are comatose after cardiac arrest (prehospital or in-hospital) (P), does the use of the bedside neurological exam (I) as opposed to standard care (C), allow accurate prediction of outcome (O) (eg. survival)? Prognosis, New Conflict of interest specific to this question Do any of the authors listed above have conflict of interest disclosures relevant to this worksheet? No Search strategy (including electronic databases searched). Databases MEDLINE via Pubmed was searched with the following query based on MESH terms: Heart arrest OR Death (sudden cardiac) OR Cardiopulmonary resuscitation AND Hypoxia-Ischemia, Brain OR Coma AND Glasgow Coma Scale OR Prognosis OR Physical examination Cochrane database of systematic reviews was searched for the terms Coma AND Prognosis in all fields. Other sources Forward search was performed using ISI Web of Science The reference list of the relevant articles and systematic reviews was scanned for additional studies. State inclusion and exclusion criteria Inclusion criteria P type Adult and paediatric patients comatose after cardiac arrest. I type Every clinical sign that can be collected during a bedside neurological examination. These include signs as: o Glasgow Coma Scale (GCS) and motor response to pain o Pupillary light reflex (present/absent) o Brainstem reflexes, as corneal, vestibulo-ocular, oculocephalic, gag or carinal reflex (present/absent) o Eye movements (present/absent) o Myoclonus or myoclonus status (present/absent) O type Neurological outcome described using the Cerebral Performance Categories (CPC; see Table 1) or in such a manner that an equivalent CPC score could be determined. Sensitivity and specificity directly reported or data for their calculation included.

2 Worksheet No. ALS-PA-041.doc Page 2 of 16 Table 1 Cerebral Performance Categories (CPC) Glasgow-Pittsburgh Cerebral Performance Categories 1. Good Cerebral Performance Conscious: Alert, able to work and lead a normal life. May have minor psychological or neurological deficits (mild dysphasia, nonincapacitating hemiparesis, or minor cranial nerve abnormalities). 2. Moderate Cerebral Disability Conscious. Sufficient cerebral function for part-time work in sheltered environment or independent activities of daily life (dressing, travelling by public transportation, and preparing food). May have hemiplegia, seizures, ataxia, dysarthria, dysphasia, or permanent memory or mental changes. 3. Severe Cerebral Disability Conscious. Dependent on others for daily support because of impaired brain function (in an institution or at home with exceptional family effort). At least limited cognition. Includes a wide range of cerebral abnormalities from ambulatory with severe memory disturbance or dementia precluding independent existence to paralytic and able to communicate only with eyes, as in the locked-in syndrome. 4. Coma, Vegetative State Not conscious. Unaware of surroundings, no cognition. No verbal or psychological interactions with environment. 5. Death Certified brain dead or dead by traditional criteria. Exclusion criteria P type Newborn Papers including non-comatose patients or patients with coma from other causes than cardiac arrest, except when the population of interest could be analysed separately. I type Clinical signs whose collection requires the use of instrumental recording, e.g. seizures. Papers where clinical signs were used only in combination with other investigations to produce combined scores/clinical decision rules so that the specific predictive value of the neurological clinical sign could not be evaluated separately. Paper type Review papers Congress abstracts, textbooks and other non-peer reviewed material. Data extraction For each study included in the final analysis, the following data were reported: Number of patients included and number of comatose patients Length of follow-up Age range, when included Number of patients with abnormal test result Number of patients with poor outcome Timing of neurological assessment Statistical methods For each study included in the final analysis, the following parameters has been calculated: a. Sensitivity, Specificity, Positive Predictive Value (PPV), False Positive Rate and Positive Likelihood Ratio (LR+) of each clinical predictive sign. In cases when there was a 0 false positive rate, the LR+ were infinite, so we added 0.1 to each cell of the 2 x 2 calculations, and LR+ was expressed as Corrected LR+. b. For Sensitivity and Specificity, range and 95 confidence intervals (95 CIs). c. A summary measure of accuracy, where applicable, using a pooled analysis.

3 Worksheet No. ALS-PA-041.doc Page 3 of 16 A fixed effect model was applied. The Q test was used in order to find heterogeneity among studies. If heterogeneity was found, a random effect model was applied for calculating 95 confidence intervals. Sections b and c of the analysis have been carried out by the Co-Author Dr. Giuseppe La Torre. The statistical analysis was performed using R, a freeware package, available from the web at Number of articles/sources meeting criteria for further review: 1 Heart arrest OR Death (sudden cardiac) OR Cardiopulmonary resuscitation - 38,517 hits 2 Hypoxia-Ischemia, Brain" OR "Coma" - 30,785 hits 3 Glasgow Coma Scale OR Prognosis OR Physical examination - 426,352 hits #1 AND #2 AND #3-319 hits Last search run on December 27, Cochrane database of systematic reviews 1 hit Twelve additional papers were identified using forward search. The search yielded a total of 332 studies. Of these, 41 were full-text articles describing prediction of outcome after cardiac arrest using clinical examination. Twenty-two of these 41 studies were excluded for the following reasons: inclusion of non-cardiac arrest patients (10 studies); inclusion of non-comatose patients (4 studies); use of neurological examination as a part of more complex scores including other predictive variables (3 studies); poor definition of the neurological signs used and/or their timing (2 studies); neurological evaluation performed before or during resuscitation (1 study); use of neurophysiological predictors only (1 study); inclusion of the Glasgow Coma Scale as a predictive covariate in a multivariate analysis without providing data on its specific predictive value (1 study). The remaining 19 studies fulfilled the inclusion criteria and were selected for further analysis. Of those, ten were LOE P1 ((Bassetti, 1996, 610-5, Edgren, 1987, 820-5, Fischer, 2006, , Krumholz, 1988, 401-5, Pfeifer, 2005, 49-55, Prohl, 2007, , Rosen, 2001, , Schefold, 2009, , Young, 2005, , Zandbergen, 2006, 62-8)), two were LOE P2 (Edgren, 1994, , Mullie, 1988, ), three were LOE P3 (Al Thenayan, 2008, , Bertini, 1989, , Wijdicks, 1994, ) three were LOE P4 (Celesia, 1988, , Thomke, 2005, 14). The quality of evidence (QOE) was good in two studies (Fischer, 2006, , Zandbergen, 2006, 62-8), fair in nine studies (Al Thenayan, 2008, , Bassetti, 1996, 610-5, Edgren, 1994, , Edgren, 1987, 820-5, Krumholz, 1988, 401-5, Prohl, 2007, , Rosen, 2001, , Wijdicks, 1994, , Young, 2005, ), poor in six studies (Bertini, 1989, , Celesia, 1988, , Mullie, 1988, , Pfeifer, 2005, 49-55, Schefold, 2009, , Thomke, 2005, 14) while two studies (Earnest MP, 1979, 56-60, Kano, 1992, ) had insufficient QOE and were excluded from final analysis. The remaining 17 studies included a total of 1548 comatose patients. All of them were adults (age range years). Heterogeneity/confounding factors Time of the first neurological assessment The first neurological assessment was performed on admission in 3 studies, within 24 hours in 5 studies, within 48 hours in 3 studies and within 72 hours in two studies. In one study (Rosen, 2001, ) neurological examination was performed within a mean of 3.6 days after cardiac arrest, in one study (Schefold, 2009, ) it was performed after suspension of sedation for therapeutic hypothermia, in another study (Al Thenayan, 2008, ) it was performed on days 3-6, while in one study (Celesia, 1988, ) the timing of assessment was not reported. Definition of poor outcome In all studies except one (Bertini, 1989, ) the outcome was expressed as neurological outcome. In eleven studies poor neurological outcome was defined as a Cerebral Performance Category (CPC) 4 or 5 (persistent vegetative state or death) while in four studies poor outcome was defined as a CPC of 3-5 (severe cerebral disability, persistent vegetative state or death). In one study (Al Thenayan, 2008, ), poor neurological outcome was defined as absence of awareness on hospital discharge. Suspension of sedation/paralysis Suspension of sedation/paralysis before neurological assessment was described in 5/17 studies.

4 Worksheet No. ALS-PA-041.doc Page 4 of 16 Therapeutic hypothermia Only two papers (Al Thenayan, 2008, , Schefold, 2009, ) described the use of therapeutic hypothermia in the included patient population. This represents a gap in knowledge, as the predictive value of neurological clinical signs could be different than expected when therapeutic hypothermia is used. Spectrum bias To investigate the presence of spectrum bias, the survival rates reported in the included papers were compared with those of recent observational studies on in-hospital cardiac arrest. Results are reported on Table 1. The mean and median survival rates for the included patients were 39.0 and 40,4, respectively (range: ). Timing of assessment for survival varied from 7 days to 12 months, the commonest being 1 month (4 studies; see Table 1). Survival was assessed at hospital discharge in 2 studies (Bertini, 1989, , Krumholz, 1988, 401-5), while in other 3 studies (Al Thenayan, 2008, , Celesia, 1988, , Thomke, 2005, 14) patient survival was not reported. Six over 17 studies included only patients after out-of-hospital cardiac arrest (OHCA). In three studies (Edgren, 1994, , Schefold, 2009, , Zandbergen, 2006, 62-8) a mixed population of both OHCA patients and in-hospital cardiac arrest (IHCA) patients were included, but OHCA patients prevailed (75 and 85 respectively). In eight studies the location of cardiac arrest was not reported. The survival rates reported above were much higher than those usually reported for OHCA. For example, in two recent papers (Herlitz, 2007, , Nichol, 2008, ) the reported survival rates for OHCA in Sweden and in North America were 5.5 and 4.4 respectively. This is because the studies examined here included patients who survived 24 hours after cardiac arrest thus excluding from the initial population both the most unstable patients who died immediately after an initially successful resuscitation, and, of course, those who did not have ROSC, who are instead usually included in the general outcome statistics of a cardiac arrest population. In comparison with other studies on patients admitted to hospital after cardiac arrest (Bernard, 2002, , Sunde, 2007, 29-39), the survival to discharge in the included studies does not appear very different (see Table 1). We think that, although preselected, those patients who are comatose after cardiac arrest represent the typical population in which the use of neurological outcome predictors is indicated. A minor spectrum bias may have occurred because the IHCA population is underrepresented in the studies conducted so far. The incidence of preexistent neurological damage is probably higher among in-hospital patients who suffer cardiac arrest and this can represent a possible limitation for patient inclusion. Further studies are needed to evaluate this specific population.

5 Worksheet No. ALS-PA-041.doc Page 5 of 16 Summary of evidence All 17 studies supported clinical question. The evidence is summarised below. Evidence Supporting Clinical Question Good Fair Poor Fischer 2006 D Zandbergen 2006 D Bassetti 1996 D Edgren 1987 D Krumholz 1988 D Prohl 2007 D Rosen 2001 D Young 2005 D Pfeifer 2005 D Schefold 2009 D Edgren 1994 D Al Thenayan 2008 E Wijdicks 1994 D Mullie 1988 D Bertini 1989 C Celesia 1989 D Thomke 2005 D Level of evidence (P) A = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpoint B = Survival of event D = Intact neurological survival Italics = Animal studies

6 Worksheet No. ALS-PA-041.doc Page 6 of 16 Evidence Neutral to Clinical question Good Fair Poor Level of evidence (P) A = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpoint B = Survival of event D = Intact neurological survival Italics = Animal studies Evidence Opposing Clinical Question Good Fair Poor Level of evidence (P) A = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpoint B = Survival of event D = Intact neurological survival Italics = Animal studies

7 Worksheet No. ALS-PA-041.doc Page 7 of 16 Table 1 Patient survival rates. Tables Origin First Author, Year n. of patients survival rate Time of the assessment N/A Bassetti mo 75 OHCA Edgren mo N/A Edgren d OHCA Fischer mo N/A Krumholz Hospital discharge OHCA Mullie d N/A Pfeifer d OHCA Prohl mo OHCA Rosen mo OHCA Wijdicks months N/A Young months 85 OHCA Zandbergen mo N/A Al Thenayan N/A N/A OHCA Bertini Hospital discharge N/A Celesia N/A N/A Thomke N/A N/A 88 OHCA Schefold ICU discharge TOTAL 1548 Mean 39.0 Median 40.4 Trials on patients comatose after cardiac arrest (control groups) OHCA Bernard hospital discharge OHCA Sunde hospital discharge Table 2 Prognostic value of ocular reflexes. Prognostic variable First author, year Sensitivity Specificity PPV LR+ Corrected LR+ Pupillary reflex (pupillary light response) Absence of pupillary reflex on admission Absence of pupillary reflex on admission Bertini Absence of pupillary reflex at 24h Absence of pupillary reflex on day 1 Young Absence of pupillary light reflex 24 h post arrest Edgren Absence of pupillary reflex at 48-72h Absence of pupillary light reflex at 48 h Edgren Absence of pupillary light reflex at 72 h Edgren Absence of pupillary reflex at other times

8 Worksheet No. ALS-PA-041.doc Page 8 of 16 Absent pupillary reflex on days 1-5 Rosen Absent pupillary reflex at unspecified time Fischer Absent pupillary reflex on days 3-6 Al Thenayan Corneal reflex Absent corneal reflex at 24 h Edgren Absent corneal reflex at day 1 Young Absent corneal reflex after 48 h Edgren Absent corneal reflex at day 1-5 Rosen Absent corneal reflex on days 3-6 Al Thenayan Vestibulo-ocular reflex Absent vestibulo-ocular reflex after 24 h Edgren Absent vestibulo-ocular reflex at day 1 Young Absent vestibulo-ocular reflex after 48 h Edgren Combination of ocular reflexes >1 ocular reflexes (2) absent at 6-12 h Bassetti No pupillary and corneal reflexes at 24 h Zandbergen No pupillary and corneal reflexes at 48 h Zandbergen No pupillary and corneal reflexes at 72 h Zandbergen Other ocular reflexes No normal eye movements on days 1-5 Rosen Abbreviations PPV: Positive Predictive Value; LR+: Positive Likelihood Ratio.

9 Worksheet No. ALS-PA-041.doc Page 9 of 16 Table 3 Prognostic value of Glasgow Coma Score and other predictive variables. Prognostic variable First author, year Sensitivity Specificity PPV LR+ Corrected LR+ Glasgow Coma Score GCS 4 on admission Fischer GCS 4 up to day 2 Mullie GCS <5 at 48 hours Bassetti GCS <5 on day 3 Edgren GCS <6 on day 3 in nonsedated patients Pfeifer GCS <8 up to day 6 Mullie GCS = 4 on day 4 after MTH Schefold ,4 Single GCS components No response to pain on admission Bertini Absent withdrawal to pain at 24 h Edgren No motor response to pain at 24 h Zandbergen Motor response decorticate or worse at 48h Bassetti No motor response at 48 h Zandbergen No motor response on day 3 Edgren Extension to pain on day 3 Edgren No motor response at 72 h Zandbergen Extension or worse on days 3-6 Al Thenayan No eye opening to pain on day 3 Edgren Other CES on day 2 (cutoff 11) Prohl CES on day 4 (cutoff 15) Prohl Spontaneous breathing on admission Bertini Abbreviations PPV: Positive Predictive Value; LR+: Positive Likelihood Ratio; GCS: Glasgow Coma Score; CES: Clinical Examination Score. MTH: Mild Therapeutic Hypothermia.

10 Worksheet No. ALS-PA-041.doc Page 10 of 16 Table 4 Predictive value of myoclonus. First author, year Prognostic variable Sensitivity Specificity PPV False Positive Rate Corrected LR+ Myoclonus Krumholz 1988 Presence of myoclonus at 36 h Zandbergen 2006 Myoclonus status at 24 h Zandbergen 2006 Myoclonus status at 48 h Zandbergen 2006 Myoclonus status at 72 h Wijdicks 1994 Presence of myoclonus on admission Celesia 1989 Presence of myoclonus N/A N/A Thomke 2005 Presence of myoclonus 24 h N/A N/A Al Thenayan 2008 Presence of myoclonus N/A N/A Abbreviations PPV: Positive Predictive Value. LR+: Positive Likelihood Ratio. Table 5 Predictors with 100 specificity. First author, year Prognostic variable Sens. Spec. 95 CI Zandbergen 2006 No pupillary and corneal reflexes at 72 h n.c. 100 n.c. Edgren 1987 Absent vestibulo-ocular reflex after 24 h [0.7584; ] Young 2005 Absent vestibulo-ocular reflex at day [0.7768; ] Edgren 1987 Absent vestibulo-ocular reflex after 48 h [0.7584; ] Bassetti 1996 GCS <5 at 48 hours [0.7873; ] Edgren 1994 GCS <5 on day [0.7968; ] Prohl 2007 CES on day 4 (cutoff 15) [0.9306; ] Abbreviations Sens.: Sensitivity; Spec: Specificity; 95 CI: 95 confidence intervals; n.c.: not computable. Note for 95 CI specificity has been expressed as an index rather than as a percentage (i.e. 100 = 1).

11 Worksheet No. ALS-PA-041.doc Page 11 of 16 REVIEWER S FINAL COMMENTS AND ASSESSMENT OF BENEFIT / RISK: General comments Several neurological clinical signs allowed prediction of poor outcome with 100 specificity but sensitivity was low. The use of supplemental clinical investigations as electrophysiological or biochemical markers should be considered with the aim of increasing sensitivity of outcome prediction after cardiac arrest. In adults, the earliest single predictor of a poor outcome was the vestibulo-ocular reflex, which showed 100 specificity after 24 hours. No studies on children could be included in the present review. Prediction of outcome Clinical neurological signs predicted poor outcome with a high specificity (median 95; range ) but their sensitivity was generally low (median 43; range 6-98). Detailed results are listed on Tables 2, 3, and 4. For several signs, prediction of poor outcome had 100 specificity. See Table 5. Myoclonus The presence of myoclonus was almost invariably associated with poor outcome. Two LOE P2 studies (Krumholz, 1988, 401-5, Zandbergen, 2006, 62-8), one P3 study (Wijdicks, 1994, ) and one LOE P4 study (Thomke, 2005, 14) including a total of 678 comatose patients showed that myoclonus occurring at 36 hours from cardiac arrest is associated with poor outcome in 100 of cases (see Table 4). However, one LOE P4 study (Celesia, 1988, ) reported that 1 of 13 comatose patients with myoclonus after cardiac arrest had good neurological recovery. Six other cases of good recovery after post-arrest myoclonus status have been described as case reports (Arnoldus and Lammers, 1995, 697-8, Datta, 2009, 39-41, English, 2009, , Morris, 1998, ). These contrasting results could be explained by the presence of two distinct form of myoclonus - one acute form of spontaneous generalized myoclonus appearing within one day after cardiac arrest and one chronic form appearing days or weeks after cardiac arrest and restricted to extremities during spontaneous movements. Only the acute form would be associated with invariably poor prognosis. Predictors with 100 specificity The clinical signs listed below predicted an invariably poor outcome (100 specificity, 0 false positive rate, 100 positive predictive value) in normothermic adult patients: Absent vestibulo-ocular reflex at 24 hours and 48 hours (Edgren, 1987, 820-5, Young, 2005, ) Absent corneal and pupillary light reflex at 72 hours (Zandbergen, 2006, 62-8) A GCS <5 at 48 hours and on day 3 (Bassetti, 1996, 610-5, Edgren, 1994, ) A CES (Clinical Examination Score) <15 on day 4 (Prohl, 2007, ) The number of patients with positive test result was generally small (e.g. 3 patients for vestibulo-ocular reflex at 48h). The list above excludes those clinical signs which showed a 100 specificity in some studies, but a specificity <100 in other studies. It is not clear how GCS was computed in the studies from Bassetti (Bassetti, 1996, 610-5) and Edgren (Edgren, 1994, ). A GCS <5 in a patient who is presumably intubated may result from the presence either of an eye opening or of an extension response to pain. In this last case, the findings from papers (Bassetti, 1996, 610-5, Edgren, 1994, ) would contrast with those of papers (Al Thenayan, 2008, , Zandbergen, 2006, 62-8) which showed that a motor response consisting of extension or worse to pain was not 100 specific as a predictor of poor neurological outcome. Outcome prediction after mild therapeutic hypothermia One study including patients treated with mild therapeutic hypothermia (MTH) (Al Thenayan, 2008, ) confirmed the findings of previous studies in normothermic patients, i.e. the 100 positive predictive value of pupillary and corneal reflexes (already described in a paper from Edgren, 1987, 820-5) and the <100 positive predictive value (presence of false positives) for motor response to pain (already described in a paper from Zandbergen 2006, 62-8). That study had several limitations: small sample size (37 patients), retrospective data collection, and late clinical assessment (days 3-6, therefore presumably hours after the administration of MTH). Another study (Schefold, 2009, ) investigated on the predictive value of Glasgow Coma Scale (GCS) in patients treated with MTH. The GCS was determined three times a day during the first four days after suspension of sedation. In this study, a GCS = 4 on day 4 predicted poor outcome (CPC >2) with 95 specificity. This contrasts with the findings of Bassetti and Edgren (Bassetti, 1996, 610-5, Edgren, 1994, ) who demonstrated that a GCS <5 at 48 hours and on day 3 predicted poor outcome with 100 specificity. Whether this is due to a possible effect of MTH or to an interference of sedation (in the study from Schefold, in 21/72 patients [29] sedation was not suspended) is difficult to say. Acknowledgements: The Authors are indebted with Dr. Cristina Marano and Dr. Alice Mannocci for their precious collaboration. Citation List 1. Al Thenayan, E., et al., Predictors of poor neurologic outcome after induced mild hypothermia following cardiac arrest. Neurology, : p LOE 3 QOE Fair

12 Worksheet No. ALS-PA-041.doc Page 12 of 16 This small retrospective study included 37 adults who were comatose (GCS < 9) after resuscitation from cardiac arrest and treated with TMH. The location of cardiac arrest (in-hospital vs. out-of-hospital) was not specified. The presence of pupillary reflex, corneal reflex and motor response from day 3 to day 6 and the presence of myoclonus status epilepticus were evaluated. Awareness was defined as the ability to obey simple commands. The authors state that Glasgow Outcome Scale (GOS) was collected on survivors at 3 months but data were not reported. The protocol for TMH is not reported. Duration of TMH was 24 hours and continuous infusions of midazolam, fentanyl, and cisatracurium were used and discontinued once the patient reached a core temperature of 36 C. The dose of cisatracurium was titrated according to a train of four response and muscle response to stimulation was verified in all patients immediately following discontinuation of hypothermia. Results showed that none of six patients without pupillary reactivity, six without corneal reflexes on day 3, or 8 with myoclonus status epilepticus recovered awareness. Two of 14 patients with motor responses no better than extension at day 3 recovered motor responses after 6 days postarrest (one at 5 and one at 6 days post-rewarming) and regained awareness. The number of patients with poor/good outcome in the overall population is not reported. The neurological outcome of patients who regained consciousness is not reported. The outcome of those with negative test is not reported, making calculation of sensitivity and specificity impossible. The authors conclude that loss of motor responses better than extension on day 3 was not prognostically reliable after therapeutic induced mild hypothermia for comatose cardiac arrest survivors. Persistance of effects of sedatives or muscle relaxants cannot be excluded completely. Blood levels of sedative drugs, EEG and EMG would have been helpful. 2. Arnoldus, E.P. and G.J. Lammers, Postanoxic coma: good recovery despite myoclonus status. Ann Neurol, : p LOE/QOE not applicable (Case report) This paper reports on a 41-year-old woman with an unremarkable medical history who had a cardiac arrest due to laryngeal edema. The estimated time of hypoxia was 15 minutes. A generalised myoclonus status appeared 4 hours after the arrest and was treated with high doses of midazolam, which was suspended on day 3. The patient regained consciousness on day 5. Myoclonus status changed to action myoclonus which still persisted two weeks after the event. The patient regained normal cognitive functions. No EEG data are available. 3. Bassetti, C., et al., Early prognosis in coma after cardiac arrest: a prospective clinical, electrophysiological, and biochemical study of 60 patients. J Neurol Neurosurg Psychiatry, : p LOE1, QOE fair. Sixty patients in coma for more than six hours after cardiac arrest were prospectively examined by means of repeated clinical examinations including GCS, EEG and somatosensory evoked potentials (SEPs). In 16 patients, the early concentrations of serum neuron specific enolase and ionised calcium were also measured. Poor outcome was observed in 48 (80) patients at 1 year. Clinical examination was more accurate in predicting outcome than SEP and EEG, while serum neuron specific enolase and ionised calcium were of no additional prognostic help. A combination of 2 or more ocular reflexes at 6-12 and a GCS < 5 at 48 h predicted poor outcome with 100 specificity. 4. Bernard, S.A., et al., Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med, : p No information on industry funding. 5. Bertini, G., et al., Prognostic significance of early clinical manifestations in postanoxic coma: a retrospective study of 58 patients resuscitated after prehospital cardiac arrest. Crit Care Med, : p LOE 3 QOE Poor The paper included non-comatose patients but the outcome of comatose patients can be evaluated separately, Thirty-four comatose patients after cardiac arrest underwent clnical examination on admission. The clinical signs included presence of spontaneous breathing, pupillary light reflex and response to pain. The outcome was evaluated on hospital discharge as survivors vs. nonsurvivors. Sensitivity and specificity for the three clinical signs were 61 and 94, 50 and 69, and 28 and 88 respectively. Small, poor-quality, retrospective study. 6. Celesia, G.G., M.M. Grigg, and E. Ross, Generalized status myoclonus in acute anoxic and toxic-metabolic encephalopathies. Arch Neurol, : p LOE 4 QOE Poor

13 Worksheet No. ALS-PA-041.doc Page 13 of 16 The study included nineteen cases of generalised status myoclonus, which was arbitrarily defined as a fixed and enduring state lasting at least 30 minutes characterised by continuous generalised jerks at a frequency of 1-5 secs. Of 19 cases. 13 were subsequent to cardiac arrest, while 6 were associated with acute toxic metabolic encephalopathy. The outcome of patients resuscitated from cardiac arrest could be evaluated separately. Among them, eight patients died, four survived in persistent vegetative state, one had complete recovery. Another recovery was observed in the non-cardiac arrest group The EEG was recorded in 14/19 patients, but it was not available for the two patients who survived. 7. Datta, S., et al., Post-hypoxic myoclonic status: the prognosis is not always hopeless. Crit Care Resusc, : p QOE/LOE not applicable (case report) A 67-year-old woman abruptly developed acute pulmonary oedema, severe bradycardia and then cardiac arrest while in hospital 6 days after an elective hernia repair. She was resuscitated, intubated and transferred to the intensive care unit. Within 24 hours, she began to display repetitive, generalised myoclonic jerks that failed to respond to therapy with conventional anticonvulsants; an electroencephalogram confirmed myoclonic status. After administration of levetiracetam was begun on Day 3, myoclonic jerks reduced, and there was gradual clinical improvement. By Day 6 after the arrest, the patient was alert and oriented (Glasgow Coma Score, 15/15). Although she died on Day 11 after massive haemoptysis and cardiac arrest, this patient demonstrates the possibility of reasonable neurological recovery despite early onset of myoclonic status. 8. Earnest MP, B.J., Yarnell PR, Olivia PB., Quality of survival after out-of-hospital cardiac arrest: predictive value of early neurologic evaluation.. Neurology, : p LOE 2 QOE Insufficient. The study included 117 patients admitted following out-of-hospital cardiac arrest. Seventeen patients were not comatose when admitted. The remaining 100 patients were "not alert, i.e. their eyes were closed and they did not talk or make any purposeful movements". Neurologic evaluation was performed on admission. The outcome was evaluated at discharge (no follow-up). In-hospital mortality among the 100 initially comatose patients was 60. Neurological outcome cannot be evaluated exactly because there is a mismatch between the proportion of patients with poor outcome as reported in text versus those reported on Table 3. Moreover some data are missing. 9. Edgren, E., et al., Assessment of neurological prognosis in comatose survivors of cardiac arrest. BRCT I Study Group. Lancet, : p LOE 2 QOE Fair The study was a follow-up on the untreated control group of multicentre controlled clinical trial of thiopentone. A total of 131 cardiac arrest survivors were evaluated using Glasgow and Glasgow-Pittsburgh coma scores and their components on admittance and at subsequent intervals (8h, 16h, 24h, days 2 to 7). Outcome was taken to be the best cerebral performance category at any time during follow-up. On day 3, a GCS < 5 and a motor reponse to pain extension or worse predicted poor outcome with 100 specificity (109 patients). The study was supported by the Laerdal Fundation for Acute Medicine. 10. Edgren, E., et al., Prediction of outcome after cardiac arrest. Crit Care Med, : p LOE 1 QOE Fair The predictive value of pupillary light reflex, response to painful stimulus, corneal and vestibulo-ocular reflex were evaluated on 32 comatose cardiac arrest survivors. Samples collected 24 and 48 h after the ischemic insult. Other variables studied were the EEG and adenylate kinase, lactate and glutathione in the cerebrospinal fluid (CSF). Outcome was termed good if the patients resumed an independent life within a 6-month follow-up period. The absence of pupillary light reflex at 24h and the absence of withdrawal response to pain or corneal reflex or vestibulo-ocular reflex at 48h predicted poor outcome with 100 specificity. 11. English, W.A., N.J. Giffin, and J.P. Nolan, Myoclonus after cardiac arrest: pitfalls in diagnosis and prognosis. Anaesthesia, : p LOE/QOE not applicable (case report) Accurate prediction of neurological outcome in survivors of cardiac arrest may be difficult. We report the case of a 44-year-old survivor of a hypoxic cardiac arrest who repeatedly developed relentless myoclonic jerks on attempted discontinuation of his propofol infusion. These were initially thought to represent myoclonic status epilepticus before the correct diagnosis of Lance-Adams syndrome was made. Lance-Adams syndrome is a rare disorder seen in survivors of profound hypoxic episodes. It is characterised by intention myoclonus but preserved intellect. Accurate distinction between myoclonic status

14 Worksheet No. ALS-PA-041.doc Page 14 of 16 epilepticus and Lance-Adams syndrome is vital as they have very different prognoses. The different pathophysiology and distinguishing clinical features of these two conditions are highlighted. 12. Fischer, C., et al., Improved prediction of awakening or nonawakening from severe anoxic coma using tree-based classification analysis. Crit Care Med, : p LOE 1 QOE Good The study is mainly focused on outcome prediction using evoked potentials, but GCS and pupillary light reflex were also recorded and their data are reported separately. GCS was recorded on admission, while the timing for the pupillary light response was not specified. Clinical neurological signs are included in a decision tree together with evoked potentials. The final neurological outcome was evaluated at 12 months. A GCS <4 predicted a poor outcome with 74 sensitivity and 60 specificity, while for pupillary light response the values were 69 and 95 respectively. No industry funding data are included. 13. Herlitz, J., et al., Characteristics of cardiac arrest and resuscitation by age group: an analysis from the Swedish Cardiac Arrest Registry. Am J Emerg Med, : p Kano, T., et al., Evaluation of the central nervous function in resuscitated comatose patients by multilevel evoked potentials. Resuscitation, : p QOE 4 LOE Insufficient Multilevel evoked potentials were examined in 17 patients who became comatose after cardiac arrest and resuscitation. Pupillary light response and corneal reflex were also collected, but their timing was not specified. There are some data missing. 15. Krumholz, A., B.J. Stern, and H.D. Weiss, Outcome from coma after cardiopulmonary resuscitation: relation to seizures and myoclonus. Neurology, : p LOE 1 QOE Fair The study included 114 comatose CPR survivors. Clinical evaluation was performed within 36 from the arrest and repeated regularly during hospital stay. Survivors were evaluated at discharge and at 6 months. EEG was recorded as considering necessary by the treatment physicians. Status myoclonus was defined as myoclonus that persisted for at least 40 minutes. The outcome was evaluated at 6 months. Nine patients developed isolated myoclonus, 19 patients developed status myoclonus was associated with seizures (myoclonus status epilepticus, MSE) while in 7 patients status myoclonus occurred alone. Myoclonus alone did not correlate with poor survival. None of the 19 patients with MSE was conscious at any time, and only 3 survived at discharge. None of 7 patients with status myoclonus survived at discharge neither was conscious at any time. The study shows that MSE and status myoclonus was associated with poor outcome in 100 of cases. No comment about industry funding. 16. Morris, H., R. Howard, and P. Brown, Early myoclonic status and outcome after cardiorespiratory arrest. J Neurol Neurosurg Psychiatry, : p LOE, QOE: not applicable (case report) The paper reports on 3 cases of early myoclonus status after respiratory arrest who had a favourable neurological outcome. The three cases have some points in common: 1) young age (19, 23 and 54 years); 2) asthma as a precipitating cause of cardiac arrest; 3) an initial phase of generalised myoclonus treated with benzodiazepines and other sedative drugs followed by action myoclonus (Lance/Adams syndrome) on recovery of consciousness. None of the patients had EEG recorded. Follow up lasted from 5 to 48 months. 17. Mullie, A., et al., Predictive value of Glasgow coma score for awakening after out-of-hospital cardiac arrest. Cerebral Resuscitation Study Group of the Belgian Society for Intensive Care. Lancet, : p QOE 2 LOE Poor In this study a predictive rule based on the best GCS of 216 patients resuscitated from cardiac arrest was constructed, and its predictive power was tested on further 133 patients (test group). Neurological outcome was defined as CPCR success (equivalent to CPC = 1-3) and CPCR failure (persistent vegetative state or death). Neurological vs. non-neurological causes of death were explicitly not distinguished. The length of follow-up was 14 days. In the 133 patients of the test group, a GCS 4 up to day 2 predicted poor outcome with 62 sensitivity and 98 specificity. 18. Nichol, G., et al., Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA, : p

15 Worksheet No. ALS-PA-041.doc Page 15 of 16 Medtronic Physio-Control Inc loaned equipment to several EMS agencies participating in the Alabama ROC site. These devices were used routinely in the course of the EMS duties and were not exclusively for ROC, but they were also used with ROC patients. Role of the Sponsor: The funding organizations had no role in the collection, management, analysis, and interpretation of the data or the preparation of the manuscript. 19. Pfeifer, R., et al., Outcome after cardiac arrest: predictive values and limitations of the neuroproteins neuron-specific enolase and protein S-100 and the Glasgow Coma Scale. Resuscitation, : p LOE 1 QOE Poor The study included 97 patients resuscitated after non-traumatic cardiac arrest. The predictive value of GCS at 72h and NSE was evaluated. The outcome was evaluated using Glasgow Outcome Scale at 28 days. In non-sedated patients, GCS at 72 predicted poor neurological outcome (equivalent to CPC 4-5) with 73.5 sensitivity and 90.5 specificity. However, raw data are not reported. In the whole group the respective values are 68 and Prohl, J., et al., Prediction of short-term and long-term outcomes after cardiac arrest: a prospective multivariate approach combining biochemical, clinical, electrophysiological, and neuropsychological investigations. Crit Care Med, : p LOE 1 QOE Fair The study included 80 patients resuscitated after cardiac arrest. The predictive value of S-100B and NSE was evaluated. Clinical evaluation was performed on day 2 and 4 using Clinical Examination Score (CES), which includes corneal response, pupillary reaction, size of pupils, bulbar divergence, oculocephalic reflexes, tracheal/gag reflexes, respiratory patterns, motor response to painful stimulation, skeletal muscle tone, pyramidal tract signs, tendon reflexes and myoclonus. The maximum achievable score of CES was 32. Outcome was evaluated at 6 months using CPC (1-3 vs. 4.5). A CES > 15 on day 4 predicted poor outcome with 100 specificity and 43 sensitivity. The AUC of CES was larger than that of S-100B and slightly smaller than that of NSE. 21. Rosen, H., et al., Serum levels of the brain-derived proteins S-100 and NSE predict long-term outcome after cardiac arrest. Resuscitation, : p LOE 1 QOE Fair The predictive value of S-100 and NSE was evaluated on 66 patients after cardiac arrest. Biochemical markers were determined during the first 3 days of post arrest, while neurological examinations were performed during the first 5 days (mean 3.6 days) post-arrest. The main outcome variable was the Glasgow Outcome Scale (GOS). Follow-up was 12 months. Sensitivity and specificity of eye movements, pupillary light reflex and corneal reflex were 98 and 76, 31 and 95, and 73 and 86 respectively. 22. Schefold, J.C., et al., The Glasgow Coma Score is a predictor of good outcome in cardiac arrest patients treated with therapeutic hypothermia. Resuscitation, : p LOE 1 QOE Poor 23. Sunde, K., et al., Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest. Resuscitation, : p Thomke, F., et al., Observations on comatose survivors of cardiopulmonary resuscitation with generalized myoclonus. BMC Neurol, : p. 14. LOE 4 QOE Poor The paper is a case series which included 50 comatose survivors of CPR with generalized myoclonus seen over an 8 years period. Generalized myoclonus occurred within 24 hours after CPR in all cases, and it was associated with burst-suppression EEG (n = 42), continuous generalized epileptiform discharges (n = 5), alpha-coma-eeg (n = 52), and low amplitude EEG (n = 1). Forty-five patients died within 2 weeks, 5 patients survived and remained in a permanent vegetative state. 25. Wijdicks, E.F., J.E. Parisi, and F.W. Sharbrough, Prognostic value of myoclonus status in comatose survivors of cardiac arrest. Ann Neurol, : p LOE 3 QOE Fair The study included 107 comatose patients resuscitated after cardiac arrest, 40 of them had generalised myoclonus status. EEG was recorded on the first postresuscitation day. Burst suppression was significantly more common on patients with myoclonus

16 Worksheet No. ALS-PA-041.doc Page 16 of 16 status. All patients with myoclonus status died, three of them became brain dead. Of 67 patients without myoclonus, 20 awakened. Duration of follow-up was 6 months. 26. Young, G.B., G. Doig, and A. Ragazzoni, Anoxic-ischemic encephalopathy: clinical and electrophysiological associations with outcome.. Neurocrit Care, LOE 1 QOE Fair The study includes 75 comatose patients resuscitated from cardiac arrest excluding those who were brain dead or continuously sedated. The predictive value of clinical examination, EEG and SEP was assessed. Clinical examination was performed on day 1. The outcome was evaluated using GOS at 3 months. Absence of pupillary reflex, corneal reflex and vestibulo-ocular reflex predicted poor outcome with 29 and 90, 54 and 89, and 42 and 100 sensitivity and specificity, respectively. Vestibulo-ocular reflex was elicited in only 44/75 patients. SEP was recoded in 47/75 patients. EEG categorization produced such small numbers to make analysis difficult. No information available on industry funding. 27. Zandbergen, E.G., et al., Prediction of poor outcome within the first 3 days of postanoxic coma. Neurology, : p LOE 1 QOE Good Multicenter cohort study conducted in 32 intensive care units including adult patients still unconscious 24 hours after CPR. Clinical, neurophysiologic, and biochemical variables were recorded 24, 48, and 72 hours after CPR and related to death or persisting unconsciousness after 1 month. Tested predictors were NSE, SEP and clinical evaluation (myoclonus status, corneal and pupillary light reflex, motor response). All patients with myoclonus status had a poor outcome. At 72 hours, pupillary and corneal reflexes had a 0 false positive rate while motor response had a 5 false positive rate. Bilateral absence of N20 SEP and NSE at 24h and S-100 at 72h had a 0 false positive rate with higher prevalence of abnormal test results and narrower CI in comparison with clinical tests. The performance of all clinical tests was inferior to SSEP and NSE testing, with lower sensitivity and wider 95 CI of false positive rates. No comment about industry funding.