C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc          Page 1 of 14                WORKSHEET for Evidence-Based Review of...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc     Page 2 of 14                                                 Summary of...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc       Page 3 of 14                                   Evidence Neutral to Cl...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc     Page 4 of 14REVIEWER’S FINAL COMMENTS AND ASSESSMENT OF BENEFIT / RISK:...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc   Page 5 of 14         thiopental (30 mg per kilogram of body weight). The ...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc   Page 6 of 14         magnesium, diazepam, or both, when given immediately...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc   Page 7 of 14         OBJECTIVE: To evaluate the use of continuous amplitu...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc   Page 8 of 14Wijdicks, E. F., J. E. Parisi, et al. (1994). "Prognostic val...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc   Page 9 of 14         each occurred in at least 18 (28%) of the 63 patient...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc   Page 10 of 14         neuroprotection trials, recent and well-designed ra...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc   Page 11 of 14Hoesch, R. E., M. A. Koenig, et al. (2008). "Coma After Glob...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc   Page 12 of 14         Introduction: While pre-hospital factors related to...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc   Page 13 of 14So, H. Y., T. A. Buckley, et al. (1994). "Factors affecting ...
C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc   Page 14 of 14Wright, W. L. and R. G. Geocadin (2006). "Postresuscitative ...
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WORKSHEET for Evidence-Based Review of Science for Emergency ...

  1. 1. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 1 of 14 WORKSHEET for Evidence-Based Review of Science for Emergency Cardiac Care Comment [pm1]: Filename has beenWorksheet author(s) inserted into header Date Submitted for review: 06.08.2009Clinical question.In adult and pediatric patients with ROSC after cardiac arrest (P), does the use of seizure prophylaxis or effective seizure control (I) asopposed to standard care (no prophylaxis) (C) improve outcome (O) ?Is this question addressing an intervention/therapy, prognosis or diagnosis? Intervention/therapyState if this is a proposed new topic or revision of existing worksheet: This worksheet is newConflict of interest specific to this questionDo any of the authors listed above have conflict of interest disclosures relevant to this worksheet? None Comment [pm2]: Added as a result of popular request.Search strategy (including electronic databases searched). • Cochrane Library o N= 0 • Pubmed: "Heart Arrest"[Mesh] and cardiac arrest and seizures and survival N= 40, 8 abstracts, "Seizures"[Mesh] AND ("heart arrest"[MeSH Terms] OR ("heart"[All Fields] AND "arrest"[All Fields]) OR "heart arrest"[All Fields]) o N= 243 topics, 14 abstracts • EMBASE o Cardiac arrest and seizures o N= 310 topics, of these N=36 abstracts • Hand picked from PubMed from Related articles o N= 5• State inclusion and exclusion criteriaInclusion: only human, adult or pediatric cardiac arrest with ROSC, reporting on effect on survival, comparing seizure treatment to no treatment on survivorsExclusion: animal studies, comments or letters or editorials or only abstracts• Number of articles/sources meeting criteria for further review: 553 abstracts were reviewed for relevance, 25 articles were reviewed in depth, 8articles were used to formulate this worksheet
  2. 2. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 2 of 14 Summary of evidence Evidence Supporting Clinical QuestionTreatment of seizures is beneficial Good Fair Rossetti A, 2009 C Poor 1 2 3 4 5 Level of evidenceA = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpointB = Survival of event D = Intact neurological survival Italics = Animal studies Comment [pm3]: Reasonable suggestion!
  3. 3. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 3 of 14 Evidence Neutral to Clinical question Good Longstreth, 2002 C Brain Resuscitation Fair Clinical Trial I Study Rundgren M, 2006 C Group, 1986C Hui AC,2005C Poor Krumholz A, 1988 C Wijdicks EF, 1994 Sunde K, 2007C C 1 2 3 4 5 Level of evidenceA = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpointB = Survival of event D = Intact neurological survival Italics = Animal studies Evidence Opposing Clinical QuestionTreatment of seizures is not beneficial Good Fair Poor 1 2 3 4 5 Level of evidenceA = Return of spontaneous circulation C = Survival to hospital discharge E = Other endpointB = Survival of event D = Intact neurological survival Italics = Animal studies
  4. 4. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 4 of 14REVIEWER’S FINAL COMMENTS AND ASSESSMENT OF BENEFIT / RISK: The question: In adult and pediatric patients with ROSC after cardiac arrest (P), does the use of seizure prophylaxis or effective seizure control (I) as opposed to standard care (no prophylaxis) (C) improve outcome (O) ? There was no studies looking at seizure treatment and the outcome of these treatments. One randomized study looked at the effects of thiopental when given randomly to all survivors of CA, the results showed that this prevention of seizures decreased the amount of seizures and that early seizures did not compromise the survival. Patient groups were really small. The use of thiopental for brain resuscitation was not supported (Brain Resuscitation Clinical Trial I Study Group, 1986, LOE 1, fair). One study (LOE 5, poor) shows that using a protocol including seizure medication when needed is beneficial for patients, but it does not report on results of treatments in general (Sunde K, 2007). Four studies (Hui AC 2005, Krumholz AC 1988 and Wijdicks EF 1994, all LOE 4, poor and Rundgren M 2006, 836, LOE 5, fair) stated that seizures were really hard to control even if many drugs were used aggressively, and the outcome was grim for the patients with seizures. One study (Longstreth WT 2002, 506, LOE 5 good) gave all ROSC patients randomized either magnesium, diazepam or both. This did not increase the proportion of awakenings. Only one study (Rossetti A 2009, 744) showed a benefit in treatment in five of six patients with PSE when monitored with EEG and treated as status epilepticus. Unfortunately, no studies directly address the given question in a controlled way, so any firm conclusions can not be drawn. It looks like seizures are hard to control, even with multiple drugs. No statement on effects on survival can be given.Conclusion DISCLAIMER: Potential possible wording for a Consensus on Science Statement. Final wording will differ due to other input and discussion. CONSENSUS ON SCIENCE: 1. There are no controlled clinical trials addressing this question directly. 2. Studies report (Sunde, 2007, 29, BRCT, 1986, 397) an incidence of 5-21 % for documented seizures post return of spontaneous circulation in post arrest patients. 3. There is one LOE 5 good study (Longstreth, 2002, 506) and one LOE 1 fair study (BRCT,1986, 397) that showed that there is no difference in neurologic outcome after use of single dose diazepam or magnesium or both; or thiopental given after return of spontaneous circulation. 4. There are no studies that advocate prompt and aggressive treatment after the first seizure in post arrest patients with return of spontaneous circulation. 5. Three LOE 4, poor studies (Krumholtz, 1988, 401, Wijdicks, 1994, 239, Hui, 2005, 10) and one LOE 5, fair study (Sunde K 2007, 29) that state that seizures may be refractory to multiple medications (i.e. benzodiazepines, phenytoin, phenobarbital and barbiturates). 6. There is one LOE 5, fair study (Rossetti A 2009, 744) showing a benefit and a good outcome when treating postanoxic status epilepticus aggressively in patients treated with mild hypothermia after ROSC.TREATMENT RECOMMENDATION: Acknowledgements: Citation List(1986). "Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest.Brain Resuscitation Clinical Trial I Study Group." N Engl J Med 314(7): 397-403. After restoration of spontaneous circulation and adequate oxygenation, 262 comatose survivors of cardiac arrest were randomly assigned to receive standard brain-oriented intensive care or the same standard therapy plus a single intravenous loading dose of
  5. 5. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 5 of 14 thiopental (30 mg per kilogram of body weight). The study was designed to have an 80 percent probability of detecting a 20 percent reduction in the incidence of permanent postischemic cerebral dysfunction. Base-line characteristics were similar in the two treatment groups. At the end of one year of follow-up, there was no statistically significant difference between treatment groups in the proportion of patients who died (77 percent of the thiopental vs. 80 percent of the standard-therapy group), survived with "good" cerebral recovery (20 percent of the thiopental vs. 15 percent of the standard-therapy group), or survived with permanent severe neurologic damage (2 percent of the thiopental vs. 5 percent of the standard-therapy group). The results of this study do not support the use of thiopental for brain resuscitation after cardiac arrest. Comments: A randomized trial from 12 hospitals in nine countries, 262 patients. The thiopental loading group received a single dose of up to 30 mg per kg intravenously. Incidence of seizures was 13 % vs 21 % and good recovery was 35 % vs 21 %. The occurrence of early seizures did not compromise survival. LOE 1, fair (was not targeted to look at seizures).Hui, A. C., C. Cheng, et al. (2005). "Prognosis following Postanoxic Myoclonus Status epilepticus."Eur Neurol 54(1): 10-3. Prediction of outcome after cardiac arrest has important ethical and socioeconomic implications. In general, delay in recovery of neurological function is associated with a worse prognosis. The presence of myoclonic seizures early after anoxia has been identified as a poor prognostic factor. We report a series of patients who developed postanoxic myoclonus status epilepticus (MSE), which was defined as continuous myoclonic seizure activity lasting 30 min or more. The results from 18 patients were retrieved, 11 men and 7 women, age ranging from 29 to 90 years. Myoclonus developed a mean of 11.7 h after cardiac arrest, persisting for a mean of 60.5 h. Sixteen (89%) died following MSE and the 2 survivors were highly dependent or remained in a persistent vegetative state, supporting the view that prognosis is poor in this condition. Comments: Reulst from 18 patients with seizures after CA. Multiple antiepileptic drugs were required, 2.3 drugs per patient. 16/18 died so no outcome figures could be stated for different treatments. LOE 4, poor.Krumholz, A., B. J. Stern, et al. (1988). "Outcome from coma after cardiopulmonary resuscitation:relation to seizures and myoclonus." Neurology 38(3): 401-5. We studied the effect of seizures and myoclonus following cardiopulmonary resuscitation (CPR) on the outcome of all comatose adult survivors of CPR over an 8-year period. Either seizures or myoclonus occurred in 50 of 114 patients (44%): seizures in 41 patients (36%) and myoclonus in 40 (35%). Status epilepticus or status myoclonus occurred in 36 patients (32%), and 19 (17%) had myoclonic status epilepticus (MSE). Seizures and myoclonus per se were not significantly related to outcome, but status epilepticus, status myoclonus, and, particularly, MSE were predictive of poor outcome as judged by survival and recovery of consciousness. Comments: Seizures were treated aggressively with benzodiazepines, phenytoin and barbiturates. The seizures were often difficult to stop. Outcome did nod seem to improve even if seizures were controlled. LOE 4, poor.Longstreth, W. T., Jr., C. E. Fahrenbruch, et al. (2002). "Randomized clinical trial of magnesium,diazepam, or both after out-of-hospital cardiac arrest." Neurology 59(4): 506-14. OBJECTIVE: To evaluate the feasibility, safety, and efficacy of interventions aimed at improving neurologic outcome after cardiac arrest. METHODS: The authors conducted a double-blind, placebo-controlled, randomized clinical trial with factorial design to see if
  6. 6. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 6 of 14 magnesium, diazepam, or both, when given immediately following resuscitation from out-of- hospital cardiac arrest, would increase the proportion of patients awakening, defined as following commands or having comprehensible speech. If the patient regained a systolic blood pressure of at least 90 mm Hg and had not awakened, paramedics injected IV two syringes stored in a sealed kit. The first always contained either 2 g magnesium sulfate (M) or placebo (P); the second contained either 10 mg diazepam (D) or P. Awakening at any time by 3 months was determined by record review, and independence at 3 months was determined by telephone calls. Over 30 months, 300 patients were randomized in balanced blocks of 4, 75 each to MD, MP, PD, or PP. The study was conducted under waiver of consent. RESULTS: Despite the design, the four treatment groups differed on baseline variables collected before randomization. Percent awake by 3 months for each group were: MD, 29.3%; MP, 46.7%; PD, 30.7%; PP, 37.3%. Percent independent at 3 months were: MD, 17.3%; MP, 34.7%; PD, 17.3%; PP, 25.3%. Significant interactions were lacking. After adjusting for baseline imbalances, none of these differences was significant, and no adverse effects were identified. CONCLUSIONS: Neither magnesium nor diazepam significantly improved neurologic outcome from cardiac arrest. Comments: A randomized study were all patients with OHCA were randomized to get bentsodiatzepin, Mg or placebo. Aim to look at survival, not seizure treatment. LOE 5, good.Rossetti AO, Oddo M, Liaudet L, Kaplan PW. Predictors of awakening from postanoxic statusepilepticus after therapeutic hypothermia. Neurology. 2009 Feb 24;72(8):744-9. BACKGROUND: Postanoxic status epilepticus (PSE) is considered a predictor of fatal outcome and therefore not intensively treated; however, some patients have had favorable outcomes. The aim of this study was to identify favorable predictors for awakening beyond vegetative state in PSE. METHODS: We studied six subjects treated with hypothermia improving beyond vegetative state after cerebral anoxia, despite PSE. They were among a cohort of patients treated for anoxic encephalopathy with therapeutic hypothermia in our institution between October 1999 and May 2006 (retrospectively, 3/107 patients) and June 2006 and May 2008 (prospectively, 3/74 patients). PSE was defined by clinical and EEG criteria. Outcome was assessed according to the Glasgow-Pittsburgh Cerebral Performance Categories (CPC). RESULTS: All improving patients had preserved brainstem reflexes, cortical somatosensory evoked potentials, and reactive EEG background during PSE. Half of them had myoclonic PSE, while three had nonconvulsive PSE. In the prospective arm, 3/28 patients with PSE showed this clinical-electrophysiologic profile; all awoke. Treatments consisted of benzodiazepines, various antiepileptic drugs, and propofol. One subject died of pneumonia in a minimally conscious state, one patient returned to baseline (CPC1), three had moderate impairment (CPC2), and one remained dependent (CPC3). Patients with nonconvulsive PSE showed a better prognosis than subjects with myoclonic PSE (p = 0.042). CONCLUSION: Patients with postanoxic status epilepticus and preserved brainstem reactions, somatosensory evoked potentials, and EEG reactivity may have a favorable outcome if their condition is treated as status epilepticus. Comments: The study was not aimed for seizure treatment. Six patients were studied. All were treated with hypothermia. All of them had PSE in the EEG, three also clinically. All patients received benzodiazepines, five got levetiracetam and valproate, three propofol and two phenytoin. One died, four out of five had a favourable outcome. Hypothermia might have increased the possibility for survival for these patients. LOE 5, fair.Rundgren, M., I. Rosen, et al. (2006). "Amplitude-integrated EEG (aEEG) predicts outcome aftercardiac arrest and induced hypothermia." Intensive Care Med 32(6): 836-42.
  7. 7. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 7 of 14 OBJECTIVE: To evaluate the use of continuous amplitude-integrated EEG (aEEG) as a prognostic tool for survival and neurological outcome in cardiac arrest patients treated with hypothermia. DESIGN: Prospective, observational study. SETTING: Multidisciplinary intensive care unit in a university hospital. INTERVENTION: Comatose survivors of cardiac arrest were treated with induced hypothermia for 24 h. An aEEG recording was initiated upon arrival at the ICU and continued until the patient regained consciousness or, if the patient remained in coma, no longer than 120 h. The aEEG recording was not available to the ICU physician, and the aEEG tracings were interpreted by a neurophysiologist with no knowledge of the patients clinical status. Only clinically visible seizures were treated. MEASUREMENTS AND RESULTS: Thirty-four consecutive hypothermia-treated cardiac arrest survivors were included. At normothermia (mean 37 h after cardiac arrest), the aEEG pattern was discriminative for outcome. All 20 patients with a continuous aEEG at this time regained consciousness, whereas 14 patients with pathological aEEG patterns (flat, suppression-burst or status epilepticus) did not regain consciousness and died in hospital. Patients were evaluated neurologically upon discharge from the ICU and after 6 months, using the Cerebral Performance Category (CPC) scale. Eighteen patients were alive with a good cerebral outcome (CPC 1--2) at 6-month follow-up. CONCLUSION: A continuous aEEG pattern at the time of normothermia was discriminative for regaining consciousness. aEEG is an easily applied method in the ICU setting. Comments: Did not address seizures primarily. All seven patients with clinical seizures received propofol, and four also fentanyl infusion. Four where treated with midazolam, two in combination with fosfenytoin. Only transient effects on seizures could be seen. All died. LOE 5, good.Sunde, K., M. Pytte, et al. (2007). "Implementation of a standardised treatment protocol for postresuscitation care after out-of-hospital cardiac arrest." Resuscitation 73(1): 29-39. Background: Mortality among patients admitted to hospital after out-of-hospital cardiac arrest (OHCA) is high. Based on recent scientific evidence with a main goal of improving survival, we introduced and implemented a standardised post resuscitation protocol focusing on vital organ function including therapeutic hypothermia, percutaneous coronary intervention (PCI), control of haemodynamics, blood glucose, ventilation and seizures. Methods: All patients with OHCA of cardiac aetiology admitted to the ICU from September 2003 to May 2005 (intervention period) were included in a prospective, observational study and compared to controls from February 1996 to February 1998. Results: In the control period 15/58 (26%) survived to hospital discharge with a favourable neurological outcome versus 34 of 61 (56%) in the intervention period (OR 3.61, CI 1.66-7.84, p = 0.001). All survivors with a favourable neurological outcome in both groups were still alive 1 year after discharge. Two patients from the control period were revascularised with thrombolytics versus 30 (49%) receiving PCI treatment in the intervention period (47 patients (77%) underwent cardiac angiography). Therapeutic hypothermia was not used in the control period, but 40 of 52 (77%) comatose patients received this treatment in the intervention period. Conclusions: Discharge rate from hospital, neurological outcome and 1-year survival improved after standardisation of post resuscitation care. Based on a multivariate logistic analysis, hospital treatment in the intervention period was the most important independent predictor of survival. Comments: A study looking at the benefit of a protocol. The protocol also states that seizurs have to be treated with increased sedation or specific anticonvulsive medication. Patients treated with this protocol had an increased survival compared to historical controls not treated wit a protocol. 5% of patients in the control group had status epilepticus and 8% in the intervention group. Outcome spefically of these patients were not addressed. LOE 5, poor.
  8. 8. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 8 of 14Wijdicks, E. F., J. E. Parisi, et al. (1994). "Prognostic value of myoclonus status in comatosesurvivors of cardiac arrest." Ann Neurol 35(2): 239-43. Generalized myoclonus status is common in comatose patients after cardiac resuscitation, but its prognostic value is uncertain. We studied the clinical, radiologic, and pathologic findings in 107 consecutive patients who remained comatose after cardiac resuscitation. Myoclonus status was present in 40 patients (37%). Features more prevalent in patients with myoclonus status were burst suppression on electroencephalograms, cerebral edema or cerebral infarcts on computed tomography scans, and acute ischemic neuronal change in all cortical laminae. All patients with myoclonus status died. Of 67 patients without myoclonus, 20 awakened. We conclude that myoclonus status in postanoxic coma should be considered an agonal phenomenon that indicates devastating neocortical damage. Its presence in comatose patients after cardiac arrest must strongly influence the decision to withdraw life support. Comments: 107 cardiac arrest patients, 67 had myoclonus and only 20 of them woke up. Half of the patients were treated with phenytoin, phenobarbital and benzodiazepines without any effect. LOE 4, poor.Not included in the final recommendation:Agarwal, P. and S. J. Frucht (2003). "Myoclonus." Curr Opin Neurol 16(4): 515-21. PURPOSE OF REVIEW: Myoclonus, one of the most common involuntary movement disorders, poses particular challenges for the treating physician. The evaluation of a patient with myoclonus depends completely on the clinical history and examination, supported when necessary by electrophysiology, neuroimaging and selected genetic and laboratory testing. The sudden, shock-like jerks which define myoclonus may be highly disabling, and when they persist, often require treatment. RECENT FINDINGS: In a paper published in this journal, we reviewed the published trials of antimyoclonic agents, and formulated a treatment algorithm based on the available evidence. In the current paper, we present our approach for evaluating patients with myoclonus, and suggest practical guidelines for treating patients based on the pre-2000 literature and on studies published in the last 2 years. The newer medications which are being used in management of myoclonus are levetiracetam and gamma-hydroxybutyric acid. Levetiracetam is especially useful for posthypoxic myoclonus and gamma- hydroxybutyric acid for alcohol-sensitive myoclonus. A combination of medications is often needed to obtain adequate control of symptoms. Botulinum toxin is also being introduced for focal myoclonus with encouraging results. SUMMARY: There are no approved medications for myoclonus, and most therapies are borrowed from the antiepileptic and psychiatric armamentarium. Nonetheless, there is a logic to the choice and dosing of antimyoclonic drugs, and we hope that by applying a few simple principles, neurologists will approach the care of these patients with confidence. Comments : Describes chronic situations.Bjork, R. J., B. D. Snyder, et al. (1982). "Medical complications of cardiopulmonary arrest." ArchIntern Med 142(3): 500-3. The clinical courses of 63 survivors of cardiopulmonary arrest were reviewed to determine the incidence and temporal occurrence of noncardiac complications and their relationships to mortality. Complications were grouped as occurring within 48 hours or less, within 48 to 96 hours, or more than 96 hours after cardiopulmonary arrest. Pneumonia, electrolyte level disturbances, and gastrointestinal tract hemorrhage each occurred in more than 28 (45%) of the 63 patients. Resuscitation-related injuries, seizures, and liver function test abnormalities
  9. 9. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 9 of 14 each occurred in at least 18 (28%) of the 63 patients. Pneumonia and liver function test abnormalities were each significantly correlated with increased mortality. Septicemia, acute renal failure, and adult respiratory distress syndrome each occurred in three (5%) to four (7%) of the 63 patients and were always associated with mortality. Comments: Does not study the treatment of seizures.Busch, M., E. Soreide, et al. (2006). "Rapid implementation of therapeutic hypothermia in comatoseout-of-hospital cardiac arrest survivors." Acta Anaesthesiologica Scandinavica 50(10): 1277-1283. Background: The implementation of therapeutic hypothermia (TH) into daily clinical practice appears to be slow. We present our experiences with rapid implementation of a simple protocol for TH in comatose out-of-hospital cardiac arrest (OHCA) survivors. Methods: From June 2002, we started cooling pre-hospitally with sport ice packs in the groin and over the neck. In the intensive care unit (ICU), we used ice-water soaked towels over the torso. All patients were endotracheally intubated, on mechanical ventilation and sedated and paralysed. The target temperature was 33 (plus or minus) 1(degrees)C to be maintained for 12-24 h. We used simple inclusion criteria: (i) no response to verbal command during the ambulance transport independent of initial rhythm and cause of CA; (ii) age 18-80 years; and (iii) absence of cardiogenic shock (SBP < 90 mmHg despite vasopressors). We compared the first 27 comatose survivors with a presumed cardiac origin of their OHCA with 34 historic controls treated just before implementation. Results: TH was initiated in all 27 eligible patients. The target temperature was reached in 24 patients (89% success rate). ICU- and hospital- length of stay did not differ significantly before and after implementation of TH. Hypokalemia (P = 0.001) and insulin resistance (P = 0.025) were more common and seizures (P = 0.01) less frequently reported with the use of TH. The implementation of TH was associated with a higher hospital survival rate (16/27; 59% vs. 11/34; 32%, respectively; P (less-than or equal to) 0.05). Our results indicate a population-based need of approximately seven cooling patients per 100,000 person-years served. Conclusion: Our simple, external cooling protocol can be implemented overnight in any system already treating post-resuscitation patients. It was well accepted, feasible and safe, but not optimal in terms of cooling rate. Neither safety concerns nor costs should be a barrier for implementation of TH. Comments: Does not study the treatment of seizures.Geocadin, R. G., M. A. Koenig, et al. (2008). "Management of Brain Injury After Resuscitation FromCardiac Arrest." Neurologic Clinics 26(2): 487-506. The devastating neurologic injury in survivors of cardiac arrest has been recognized since the development of modern resuscitation techniques. After numerous failed clinical trials, two trials showed that induced mild hypothermia can ameliorate brain injury and improve survival and functional neurologic outcome in comatose survivors of out-of-hospital cardiac arrest. This article provides a comprehensive review of the advances in the care of brain injury after cardiac arrest, with updates on the process of prognostication, the use of therapeutic hypothermia and adjunctive intensive care unit care for cardiac arrest survivors. Comments: A review only stating that seizures should be treated with standard medication.Geocadin, R. G., M. A. Koenig, et al. (2006). "Intensive care for brain injury after cardiac arrest:therapeutic hypothermia and related neuroprotective strategies." Crit Care Clin 22(4): 619-36;abstract viii. Neurologic injury is the predominant cause of poor functional outcome in patients who are resuscitated from cardiac arrest. The management of these patients in the ICU can be challenging because of the paucity of effective therapies and lack of readily available diagnostic and prognostic tools. After several decades of failed pharmacologic
  10. 10. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 10 of 14 neuroprotection trials, recent and well-designed randomized trials showed that therapeutic hypothermia is an effective neuroprotective measure in comatose survivors of cardiac arrest. Therapeutic hypothermia has been recommended by the International Liaison Committee on Resuscitation and has been incorporated in the American Heart Association CPR Guidelines. The American Academy of Neurology recently enhanced the delivery of care in survivors of cardiac arrest by providing evidence-based practice parameters on the prediction of poor outcome in comatose survivors of cardiac arrest, based on clinical evaluation and diagnostic tests. This article discusses these advances and their potential impact on the care provided in the ICU. Comments: A review only stating that seizures should be treated with standard medication.Gunn, A. J. and M. Thoresen (2006). "Hypothermic neuroprotection." NeuroRx : the journal of theAmerican Society for Experimental NeuroTherapeutics. 3(2): 154-169. The possibility that hypothermia during or after resuscitation from asphyxia at birth, or cardiac arrest in adults, might reduce evolving damage has tantalized clinicians for a very long time. It is now known that severe hypoxia-ischemia may not necessarily cause immediate cell death, but can precipitate a complex biochemical cascade leading to the delayed neuronal loss. Clinically and experimentally, the key phases of injury include a latent phase after reperfusion, with initial recovery of cerebral energy metabolism but EEG suppression, followed by a secondary phase characterized by accumulation of cytotoxins, seizures, cytotoxic edema, and failure of cerebral oxidative metabolism starting 6 to 15 h post insult. Although many of the secondary processes can be injurious, they appear to be primarily epiphenomena of the execution phase of cell death. Studies designed around this conceptual framework have shown that moderate cerebral hypothermia initiated as early as possible before the onset of secondary deterioration, and continued for a sufficient duration in relation to the severity of the cerebral injury, has been associated with potent, long-lasting neuroprotection in both adult and perinatal species. Two large controlled trials, one of head cooling with mild hypothermia, and one of moderate whole body cooling have demonstrated that post resuscitation cooling is generally safe in intensive care, and reduces death or disability at 18 months of age after neonatal encephalopathy. These studies, however, show that only a subset of babies seemed to benefit. The challenge for the future is to find ways of improving the effectiveness of treatment. Comments: Does not study the treatment of seizures.Herlitz, J., M. Castren, et al. (2006). "Post resuscitation care. What are the therapeutic alternativesand what do we know?" Resuscitation 69(1): 15-22. A large proportion of deaths in the Western World are caused by ischaemic heart disease. Among these patients a majority die outside hospital due to sudden cardiac death. The prognosis among these patients is in general, poor. However, a significant proportion are admitted to a hospital ward alive. The proportion of patients who survive the hospital phase of an out of hospital cardiac arrest varies considerably. Several treatment strategies are applicable during the post resuscitation care phase, but the level of evidence is weak for most of them. Four treatments are recommended for selected patients based on relatively good clinical evidence: therapeutic hypothermia, beta-blockers, coronary artery bypass grafting, and an implantable cardioverter defibrillator. The patients cerebral function might influence implementation of the latter two alternatives. There is some evidence for revascularisation treatment in patients with suspected myocardial infarction. On pathophysiological grounds, an early coronary angiogram is a reasonable alternative. Further randomised clinical trials of other post resuscitation therapies are essential. Comments: Review. Does not study the treatment of seizures.
  11. 11. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 11 of 14Hoesch, R. E., M. A. Koenig, et al. (2008). "Coma After Global Ischemic Brain Injury:Pathophysiology and Emerging Therapies." Critical Care Clinics 24(1): 25-44. Cardiac arrest is a major cause of death and morbidity in the United States, and neurological injury contributes significantly to this. Neurological complications associated with global cerebral ischemia include disorders of responsiveness, such as coma and the vegetative state, seizures, motor deficits, and brain death. Coma, complete unresponsiveness, is the most pervasive of these. Therapies that improve neurological outcomes in general after cardiac arrest and therapies that stimulate arousal from coma could have enormous clinical impact. The authors review the physiology of arousal and describe the biochemical and pathophysiological derangements that develop after global cerebral ischemia. We then describe the potential therapeutic mechanisms of hypothermia and deep brain stimulation, which provide hope for better neurological outcomes after global cerebral ischemia. Comments: Review. Does not address the treatment of seizures.Khot, S. and D. L. Tirschwell (2006). "Long-term neurological complications after hypoxic-ischemicencephalopathy." Seminars in Neurology 26(4): 422-431. Hypoxic-ischemic encephalopathy accompanying cardiac arrest is a common cause of long- term neurological dysfunction. With the improvement in prehospital emergency systems, larger numbers of people are resuscitated from cardiac arrests, although with the increased prospect of neurological sequelae. Neurological impairment after cardiac arrest is dependent on the degree of brain damage suffered during the arrest. Although the duration and severity of brain ischemia is often difficult to determine, clinicians are often faced with difficult issues related to predicting outcome related to awakening and long-term neurological deficits after the arrest. Neurological impairments range from mild cognitive deficits to severe motor and cognitive deficits that preclude independence in many activities of daily living. Several neurological syndromes have been described in patients who awaken from hypoxic-ischemic coma with lasting motor and cognitive deficits. This review will address many of the common syndromes after hypoxic-ischemic encephalopathy, including persistent vegetative states, seizures, myoclonus, movement disorders, cognitive dysfunction, and other neurological abnormalities. Comments: Review. Intravenous loading with phenytoin was not as effective in patients with anoxic status than in other patients (40% vs 80%). Does not address outcome of treatments, only states that outcome is not as good if the patient has seizures.Kleinman, M. E. and V. Srinivasan (2008). "Postresuscitation Care." Pediatric Clinics of NorthAmerica 55(4): 943-967. Cardiac arrest in infants and children is a rare but critical event that typically follows a period of respiratory or circulatory compromise and has a low survival rate. The only intervention demonstrated to increase survival rate is the provision of bystander CPR. This article examines the pathophysiology of the postarrest reperfusion state; postresuscitation care of the respiratory and cardiovascular systems; postresuscitation neurologic management; therapeutic hypothermia; blood glucose control; immunologic disturbances and infections; coagulation abnormalities; and gastrointestinal and hepatic dysfunction, among other topics. Comments: Review. Seizures place the brain in risk for secondary injury. Aggressive treatment is indicated to prevent progression to status epilepticus.Langhelle, A., S. S. Tyvold, et al. (2003). "In-hospital factors associated with improved outcome afterout-of-hospital cardiac arrest. A comparison between four regions in Norway." Resuscitation 56(3):247-263.
  12. 12. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 12 of 14 Introduction: While pre-hospital factors related to outcome after out-of-hospital cardiac arrest (OHCA) are well known, little is known about possible in-hospitals factors related to outcome. Hypothesis: Some in-hospital factors are associated with outcome in terms of survival. Material and methods: An historical cohort observational study of all patients admitted to hospital with a spontaneous circulation after OHCA due to a cardiac cause in four different regions in Norway 1995-1999: Oslo, Akershus, Ostfold and Stavanger. Results: In Oslo, Akershus, Ostfold and Stavanger 98, 84, 91 and 186 patients were included, respectively. Hospital mortality was higher in Oslo (66%) and Akershus (64%) than in Ostfold (56%) and Stavanger (44%), P=0.002. By multivariate analysis the following pre-arrest and pre-hospital factors were associated with in-hospital survival: age (less-than or equal to)71 years, better pre-arrest overall performance, a call-receipt-start CPR interval (less-than or equal to)1 min, and no use of adrenaline (epinephrine). The in-hospital factors associated with survival were: no seizures, base excess >-3.5 mmol l-1, body temperature (less-than or equal to)37.8(degrees)C, and serum glucose (less-than or equal to)10.6 mmol l-1 1-24 h after admittance with OR (95% CI) 2.72 (1.09-8.82, P=0.033), 1.12 (1.02-1.23, P=0.016), 2.67 (1.17-6.20, P=0.019) and 2.50 (1.11-5.65, P=0.028), respectively. Pre-arrest overall function, whether adrenaline was used, body temperature, the occurrence of hypotensive episodes, and the degree of metabolic acidosis differed between the four regions in parallel with the in- hospital survival rates. Conclusion: Both pre-arrest, pre- and in-hospital factors were associated with in-hospital survival after OCHA. It seems important also to report in-hospital factors in outcome studies of OCHA. The design of the study precludes a conclusion on causability. Comments: Does not address seizure treatment. No seizures was a factor associated with survival.Little, C. M., N. A. Paradis, et al. (2006). "Prehospital interventions to improve neurological outcomefollowing cardiac arrest." Semin Neurol 26(4): 380-6. As many cases of cardiac arrest occur outside of the health care setting, prehospital treatment may dramatically affect patient outcomes. The three major interventions that have been studied are chest compressions and ventilation, electrical defibrillation, and medications. Recent studies show that increasing the rate of cardiopulmonary resuscitation (CPR), decreasing the rate of ventilation, and initiation of CPR prior to defibrillation may result in improved survival. Biphasic defibrillators can restore perfusing rhythms while minimizing myocardial injury. Public access to automatic defibrillators has been shown to increase the survival of cardiac arrest patients. Medications such as amiodarone, vasopressin, and thrombolytics also may have a role in the prehospital treatment of cardiac arrest. Recent advances in these areas will be reviewed with a discussion of the effect of each intervention on the restoration of circulation and neurological outcomes. Comments: Does not address seizures.Schulman, S. P., T. K. Hartmann, et al. (2006). "Intensive care after resuscitation from cardiac arrest:A focus on heart and brain injury." Neurologic Clinics 24(1): 41-49. Less than 3% of all patients who have out-of-hospital cardiac arrests have return of spontaneous circulation (ROSC), survive the hospitalization, and have a reasonable functional recovery. The fact that many patients who have ROSC ultimately die or fail to have favorable neurologic recovery suggests that processes that occur after hospitalization, especially in the ICU, have an impact on survival and neurologic recovery. This article addresses the acute care, with emphasis on the cardiac and neurologic aspects, that patients who have postcardiac arrest are provided in the cardiac ICU. Comments: Seizures can delay the recovery and should be treated aggressively.
  13. 13. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 13 of 14So, H. Y., T. A. Buckley, et al. (1994). "Factors affecting outcome following cardiopulmonaryresuscitation." Anaesth Intensive Care 22(6): 647-58. Many patients who receive cardiopulmonary resuscitation (CPR) for cardiac arrest do not survive to leave hospital. Factors associated with adverse outcomes include unwitnessed cardiac arrest in general wards, particularly at night, prolonged resuscitation, asystole, associated disorders (e.g. sepsis, malignancy, renal failure, and left ventricular dysfunction), absent pupillary responses, hypoxaemia, low PetCO2 during resuscitation, and severe acid base imbalance. Outside hospitals, cardiac arrests result in more favourable outcomes if they occur at work, and bystander CPR and early defibrillation are initiated. On admission to ICU, likely predictors of death or severe neurological disability include prolonged coma, impaired brainstem reflexes, and persistent convulsions. Experience with cerebrospinal fluid enzymes and electrophysiological measurements is limited. Multivariate scoring systems are not sufficiently reliable. The importance of hyperglycaemia, the required level of CPR training, and the appropriateness of responding to some cases, remain debatable. Comments: Review.Stevens, R. D. and P. A. Nyquist (2008). "Types of Brain Dysfunction in Critical Illness." NeurologicClinics 26(2): 469-486. Cerebral dysfunction and injury in the ICU presents as focal neurologic deficits, seizures, coma, and delirium. These syndromes may result from a primary brain insult, such as stroke or trauma, but commonly are a complication of a systemic insult, such as cardiac arrest, hypoxemia, sepsis, metabolic derangements, and pharmacologic exposures. Many survivors of critical illness have cognitive impairment, which is believed to underlie the poor long-term functional status and quality of life observed in many critical illness survivors. Although progress has been made in characterizing the epidemiology of cerebral dysfunction in the ICU, more research is needed to elucidate underlying mechanisms that might represent targets for therapeutic intervention. Comments: Does not address seizures after cardiac arrest.Weigl, M., G. Tenze, et al. (2005). "A systematic review of currently available pharmacologicalneuroprotective agents as a sole intervention before anticipated or induced cardiac arrest."Resuscitation 65(1): 21-39. We conducted a Medline search for controlled studies evaluating currently available drugs for pharmacological neuroprotection. They had to be administered prior to transient global cerebral ischaemia without further non-pharmacological measures. We deliberately excluded focal ischaemia since its pathophysiology is substantially different from global ischaemia. A total of 45 articles conducted exclusively in laboratory animals met these criteria. The following classes of agents were evaluated: anaesthetics, GABAergic drugs, calcium- antagonists, anticonvulsives, sodium-channel blockers, potassium-channel activators, NMDA- receptor antagonists, hormones, vasodilators, dopamine- and alpha2-agonists, magnesium, xanthine oxidase- and cyclooxygenase inhibitors, a nootropic, a protease inhibitor, and immunosuppressants. Some of them were applied chronically and others administered via clinically impracticable routes. The available literature favours isoflurane, phenytoin, lamotrigine, magnesium, and potentially, nimodipine, and flunarizine. If factors like costs, toxicity, side effects, route and mode of application are considered, isoflurane and MgSO4 that have also been safely applied to patients with compromised left ventricular pump function are advantageous but their true role in human neuroprotection remains unclear. Comments: Does not address seizure treatment.
  14. 14. C2010 Worksheet:ALS-PA-050B.R2 07-Aug-2009.doc Page 14 of 14Wright, W. L. and R. G. Geocadin (2006). "Postresuscitative Intensive Care: Neuroprotectivestrategies after cardiac arrest." Seminars in Neurology 26(4): 396-402. Cardiac arrest is a common disease in the United States, and many patients will die as a result of the neurological damage suffered during the anoxic period, or will live in a neurologically debilitated state. When cardiopulmonary-cerebral resuscitation results in the return of spontaneous circulation, intensive care is required to optimize neurological recovery. Such "brain-oriented" therapies include routine care, such as positioning and maintenance of volume status; optimization of cerebral perfusion, with the use of vasopressors if needed; management of increased intracranial pressure with agents such as hypertonic saline; assuring adequate oxygenation and avoiding hypercapnia; aggressive fever control; intensive glucose control, with the use of an insulin drip if needed; and management of seizures if they occur. To date, no neuroprotectant medications have been shown to improve neurological outcome. Induced moderate therapeutic hypothermia is utilized as a neuroprotective maneuver. Future treatment options and advanced monitoring techniques are also discussed. Further study to optimize neuroprotective strategies when treating patients who survive cardiac arrest is needed. Comments: Review. Not systematically looking at seizure treatment. Seizures should be treated. Seizures are predictors for bad outcome.

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