The American Academy of Neurology has released a new set of evidence-based practice guidelines for the treatment of brain injury in patients who remain comatose after receiving cardiopulmonary resuscitation (CPR).1
The guidelines panel reported that outcomes to nontraumatic cardiac arrest are extremely bleak, with less than 6% to 9.6% short-term survival for patients who have out-of-hospital cardiac arrest (OHCA) and about 22.3% for those who experience in-hospital cardiac arrest.2,3 Of those who survive to discharge, brain injury becomes a major factor in disability and long-term survival because of complications including seizures, status epilepticus, myoclonus, and cerebral edema.4
For the new guidelines, the panel reviewed all relevant class I, II, and III studies published in the literature between 1966 and 2016. They undertook a meta-analysis to evaluate neurologic and mortality outcomes to common protocols used on patients who are comatose after CPR, including induced mild therapeutic hypothermia (TH) or targeted temperature management (TTM), proposed neuroprotective drug therapies, and other treatments or combinations of interventions.
The first therapy analyzed was induced mild TH, defined as achieving a core body temperature of 32°C to 34°C. The evidence from 2 class I studies showed that induced mild TH for 24 hours had a high likelihood of efficacy in improving neurologic outcomes compared with non-TH in comatose patients whose indication for CPR was an initial cardiac rhythm of ventricular tachycardia or ventricular fibrillation (VT/VF). Application of TTM above 36°C for 24 hours followed by 8 hours rewarming to 37°C and temperature maintenance below 37.5°C up to 72 hours was reported in 1 class I study as “likely as effective” as TH for improving neurologic outcome and survival in patients with VT/VF or pulseless electrical activity/asystole precipitating CPR.
The panel noted that as a result of differences in the trial designs of the 2 studies, the protocols might not be equivalent in efficacy, despite similar outcomes. Mortality was 84% in both groups, 82/98 patients in the TH group and 74/88 patients in the TTM group (hazard ratio, 1.08; 95% CI, 0.79-1.48). In laboratory studies, early initiation of cooling after CPR produced significant decreases in neurological damage.4-7 Additional studies indicated some benefits to prehospital cooling on outcomes, although the results were not consistently significant. The panel concluded that as an adjunct to in-hospital cooling, prehospital cooling was not likely to show significant efficacy and should not be offered.
Putative Drug Therapies
A number of putative neuroprotective therapies were evaluated, including xenon gas, nimodipine, lidoflazine, selenium, thiopental, magnesium, diazepam, and corticosteroids.8-15 There was insufficient class I evidence for or against the use of xenon gas in addition to TH, as well as selenium or nimodipine, or a single loading dose of magnesium sulfate. Thiopental, lidoflazine, and corticosteroids were deemed “likely to be ineffective in improving survival or neurologic outcome.” In addition, a single loading dose of diazepam was found to be unlikely to improve survival or the chance of awakening from coma. The panel determined that none of these therapeutic agents showed efficacy for comatose patients after CPR, and all incur the potential risks for serious adverse events.
Other Medical Therapies
One alternative therapy evaluated was oxygen, based on a single class I study of 28 OHCA patients with an initial VF rhythm with return of spontaneous circulation.[e2] The application of 30% to 100% oxygen followed by standard care in these patients resulted in no differences in survival or neurologic outcome, although the panel did not rule out the potential for benefit based on the single study.
High-volume hemofiltration (HF) was also assessed, based on a single class I study of 61 OHCA patients randomly assigned to isovolumetric high-volume HF, alone and in addition to TH or routine care.[e3] The study showed no differences in survival between the groups at a 95% CI, although at lower CIs (of uncertain clinical relevance), there was some improvement in odds of survival using pooled HF data.
The panel found that the evidence for both 100% oxygen and high-volume HF neither supported nor refuted their use in comatose patients after successful CPR.
The newly released guidelines provided an evaluation of neurologic outcomes and survival associated with the available therapies for comatose patients after CPR. Cooling therapies showed the most significant benefits, which varied depending on the initial cardiac rhythm, precluding the need for CPR:
- For OHCA patients with VT or VF, TH cooling to 32°C-34°C was the recommended course of action on the basis of several studies indicating a high likelihood of efficacy in improving functional neurologic outcome and survival (level A evidence).
- For OHCA patients with VT, VF, or pulseless electrical activity/asystole before CPR, TTM was found to be as effective as TH and was deemed an acceptable alternative therapy by the American Academy of Neurology guidelines panel (level B evidence).
Prehospital cooling was not found to be beneficial in OHCA, and was recommended not to be used.
Overall, there were no outstanding benefits to known pharmacotherapies or adjuncts, including oxygen or high-volume HF.
The panel recommended that future research target benefits of TH and TTM across all cardiac rhythm types, while evaluating more specific use of these therapies, such as temperature settings and therapeutic windows.
- Romergryko G. Geocadin, Eelco Wijdicks, Melissa J. Armstrong, et al. Practice guideline summary: Reducing brain injury following cardiopulmonary resuscitation: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology [published online May 10, 2017]. Neurology. doi: 10.1212/WNL.0000000000003966
- Bigham BL, Koprowicz K, Rea T, et al; ROC Investigators. Cardiac arrest survival did not increase in the Resuscitation Outcomes Consortium after implementation of the 2005 AHA CPR and ECC guidelines. Resuscitation. 2011;82:979-983.
- McNally B, Robb R, Mehta M, et al; Centers for Disease Control and Prevention. Out-of-hospital cardiac arrest surveillance: Cardiac Arrest Registry to Enhance Survival (CARES), United States, October 1, 2005–December31, 2010. MMWR Surveill Summ. 2011;60:1-19.
- Jia X, Koenig MA, Shin HC, et al. Improving neurological outcomes post-cardiac arrest in a rat model: immediate hypothermia and quantitative EEG monitoring. Resuscitation. 2008;76:431-442.
- Kuboyama K, Safar P, Radovsky A, Tisherman SA, Stezoski SW, Alexander H. Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study. Crit Care Med. 1993;21:1348-1358.
- Sterz F, Safar P, Tisherman S, Radovsky A, Kuboyama K, Oku K. Mild hypothermic cardiopulmonary resuscitation improves outcome after prolonged cardiac arrest in dogs. Crit Care Med. 1991;19:379-389.
- Abella BS, Zhao D, Alvarado J, Hamann K, Vanden Hoek TL, Becker LB. Intra-arrest cooling improves outcomes in a murine cardiac arrest model. Circulation. 2004;109:2786-2791.
- Girotra S, Nallamothu BK, Spertus JA, Li Y, Krumholz HM, Chan PS; American Heart Association Get With the Guidelines—Resuscitation Investigators. Trends in survival after in-hospital cardiac arrest. N Engl J Med. 2012;367:1912-1920.
- Laitio R, Hynninen M, Arola O, et al. Effect of inhaled xenon on cerebral white matter damage in comatose survivors of out-of-hospital cardiac arrest: a randomized clinical trial. JAMA. 2016;315:1120-1128.
- Roine RO, Kaste M, Kinnunen A, Nikki P, Sarna S, Kajaste S. Nimodipine after resuscitation from out-of hospital ventricular fibrillation: a placebo-controlled, double-blind, randomized trial. JAMA. 1990;264:3171-3177.
- Brain Resuscitation Clinical Trial II Study Group. A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest. N Engl J Med. 1991;324:1225-1231.
- Reisinger J, Höllinger K, Lang W, et al. Does early administration of selenium improve neurological outcome after cardiac arrest? Am J Emerg Med. 2009;27:176-181.
- Brain Resuscitation Clinical Trial I Study Group. Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest. N Engl J Med. 1986;314:397-403.
- Longstreth WT Jr, Fahrenbruch CE, Olsufka M, Walsh TR, Copass MK, Cobb LA. Randomized clinical trial of magnesium, diazepam, or both after out-of hospital cardiac arrest. Neurology. 2002;59:506-514.
- Jastremski M, Sutton-Tyrrell K, Vaagenes P, Abramson N, Heiselman D, Safar P. Glucocorticoid treatment does not improve neurological recovery following cardiac arrest: Brain Resuscitation Clinical Trial I Study Group. JAMA. 1989;262:3427-3430.
- e2 – reference not released to the public
- e3 – reference not released to the public