Brain Death:

Greer DM, Shemie SD, Lewis A, et al. Determination of Brain Death/Death by neurologic criteria: The World Brain Death Project. JAMA. 2020; 324:1078-1097. A comprehensive review conducted by a multi-disciplinary panel with recommendations on the clinical criteria, testing, and documentation required to determine brain death. Specific circumstances including ECMO and therapeutic hypothermia are discussed as well as ongoing somatic support.

Coma/Anoxic Brain Injury:

Sandroni C, D’Arrigo S, Nolan JP. Prognostication after cardiac arrest. Crit Care. 2018; 22:150.  This review provides an excellent overview of the predictive value and limitations of the various predictors of neurologic outcome including physical exam, EEG, evoked potentials, biomarkers, and imaging. A multimodality strategy for deriving prognosis is outlined.
PMID: 29871657
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Wijdicks EF, Hijdra A, Young GB, et al. Practice parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2006; 67:203-10. Excellent, practical review from the AAN.
PMID: 16864809
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Coplin WM, Pierson DJ, Cooley KD, et al. Implications of extubation delay in brain-injured patients meeting standard weaning criteria. Am J Respir Crit Care Med 2000;161:1530-6. Prospective cohort study found patients with "delayed" extubation had increased incidence of nosocomial pneumonia, longer ICU and hospital stays, and greater hospital charges.
PMID: 10806150
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Therapeutic hypothermia following cardiac arrest:

The following simultaneously-published smaller studies found reducing core body temperature to 32°C to 34°C for 12 or 24 hours improved neurologic outcomes in comatose survivors of out-of-hospital cardiac arrest with an initial shockable rhythm:
Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346:557-63.
PMID: 11856794
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The Hypothermia After Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549-56.
PMID: 11856793
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The following two large trials are noteworthy for finding no improvement in outcomes with therapeutic hypothermia compared to normothermia.
Nielsen N, Wettersley J, Cronberg T, et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med. 2013;369: 2197-206.
PMID: 24237006
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Dankiewicz J, Cronberg T, Lilja G, et al. Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med. 2021; 384:2283-2294. TTM2 Trial found no difference in 6-month survival or functional outcomes among 1,850 patients randomized to targeted hypothermia at 33°C for 28 hours followed by controlled rewarming or targeted normothermia with early treatment of fever (body temperature > 37.8°C).  Temperature was managed for a total of 72 hours in both groups.
PMID: 34133859

Lascarrou JB, Merdji H, Le Grouge A, et al. Targeted temperature management for cardiac arrest with nonshockable rhythm. N Engl J Med. 2019; 381:2327-2337. RCT of 581 patients with out-of-hospital or in-hospital cardiac arrest with nonshockable rhythm admitted to the ICU with coma were randomized to target temperature of 33°C for 24 hours or 37°C with total targeted temperature time of 48 hours. At 90 days, favorable neurological outcome occurred in 10.2% in the hypothermia group vs 5.7% in normothermia group with no difference in mortality. Of note, the fragility index value was 1.
PMID: 31577396
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Jabre P, Bougouin W, Dumas F, et al. Early identification of patients with out-of-hospital cardiac arrest with no chance of survival and consideration for organ donation. Ann Intern Med. 2016; 165: 770-8. This retrospective analysis of a French registry from 2011 to 2014 found no survivors to hospital discharge among 772 patients who met all of the following 3 criteria: 1) OHCA not witnessed by medics, 2) non-shockable initial cardiac rhythm, and 3) no ROSC prior to receipt of a 3rd 1-mg dose of epinephrine. Validation in an additional 2,000 patients who met these criteria from other registries and trials found 1 survivor, in a persistent vegetative state.
PMID: 27618681

Acute hemorrhagic stroke:

Hemphill JC 3rd, Greenberg SM, Anderson CS, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015; 46:2032-60. These guidelines provide a useful overview on initial imaging, prognostication, surgical intervention, and medical management including reversal of anticoagulation and blood pressure management.
PMID: 26022637
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Qureshi A, Palesch Y, Barsan W, et al. Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. N Engl J Med. 2016;375:1033-43. The ATACH-2 randomized open label trial of aggressive (110-139 mmHg) versus standard (140-179 mmHg) BP management of patients with spontaneous supratentorial cerebral hemorrhage within 4.5 hours of onset. The mean SBP at 2 hours was 128 mm Hg in the aggressive group and 141 mmHg in the standard group. There were no differences in death or disability at 3 months, and the rate of renal adverse events within 7 days of randomization were higher in the aggressive control group.
PMID: 27276234
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Acute Ischemic Stroke:

Thrombolytic Therapy:

The following 2 landmark studies established the use of thrombolytics within 3 hours and between 3 and 4.5 hours following onset of acute ischemic stroke.

The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581-7.
PMID: 7477192
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Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 2 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008; 359:1317-29.
PMID: 18815396
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Thomalla G, Simonsen CZ, Boutitie F, et al. MRI-guided thrombolysis for stroke with unknown time of onset. N Engl J Med. 2018; 379:611-622. The WAKE-UP trial was a RCT of 503 patients with ischemic stroke with unknown time of onset but MRI indicative of onset within the previous 4.5 hours. Excluded patients in whom thrombectomy was planned. Favorable neurologic outcome (modified Rankin scale of 0 or 1) at 90 days was seen in 53.3% in alteplase group vs 41.8% in placebo group. Rate of symptomatic intracranial hemorrhage was 2% vs 0.4% in alteplase vs placebo.
PMID: 29766770
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Ma H, Campbell BCV, Parsons MW, et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N Engl J Med. 2019; 380:1795-1803. The EXTEND trial was a RCT of 225 patients with ischemic stroke and salvageable brain tissue on automated perfusion scanning. The use of alteplase (vs placebo) between 4.5 hours and 9 hours after stroke onset or at the time patient awoke from stroke symptoms resulted in higher percentage of patients with modified Rankin scale of 0 or 1 at 90 days (35.4% vs 29.5%). Symptomatic cerebral hemorrhage occurred in 6.2% in alteplase group vs 0.9% in placebo. This study was stopped early due to publication of WAKE-UP trial.
PMID: 31067369
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Thrombectomy:

Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018; 378:11-21. The DAWN trial looked at 206 patients with occlusion of the intracranial internal carotid artery or proximal middle cerebral artery last known to be well 6 to 24 hours earlier who also had a mismatch between the severity of the clinical deficit and the infarct volume. Patients were randomly assigned to thrombectomy plus standard care or to standard care alone. The coprimary endpoints were the mean score for disability on the utility-weighted modified Rankin scale and the rate of functional independence at 90 days. Functional independence at 90 days was 49% in the thrombectomy group compared to 13% in the control group.
PMID: 29129157
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Albers GW, Marks MP, Kemp S et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018; 378:708-718. The DEFUSE 3 multicenter RCT included 182 patients last known to be well 6 to 16 hours earlier who also had remaining ischemic brain tissue that was not yet infarcted. Patients randomized to thrombectomy + standard medical therapy were more likely to be functionally independent at 90 days (45% vs 17%, p < .001) and had lower 90-day mortality (14% vs 26%, p = 0.5) compared to standard medical therapy alone.
PMID: 29364767
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Saver JL, Goyal M, Bonafe A, et al. Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke. N Engl J Med. 2015; 372: 2285-95. 196 patients evaluated within 6 hours of symptom onset were randomized to t-PA alone or t-PA combined with endovascular thrombectomy with the use of a stent retriever. Imaging confirmed proximal anterior occlusions without a large infarct. Thrombectomy increased the proportion of patients with functional independence (60% vs 35%, p <.001) based on modified Rankin score without difference in mortality.
PMID: 25882376
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Subarachnoid Hemorrhage:

Pickard JD, Murray GD, Illingworth R, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989; 298:636-42. Although published in1989, this sentinel study is still cited as the basis for calcium channel blocker use in SAH. The study found ischemic stroke developed in 22% of patients receiving nimodipine compared to 33% in the placebo group.
PMID: 2496789
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Bacterial Meningitis:

DeGans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002; 347:1549-56. High quality RCT including 301 patients found early administration of 10 mg dexamethasone q 6 hrs for 4 days reduced the risk of poor outcome (score of 5 vs. score of 1-4 on Glasgow Outcome Scale) [relative risk 0.59] and was associated with a relative risk of death of 0.48. Subgroup analysis showed that the outcome improvement was restricted to patients with pneumococcal meningitis.
PMID: 12432041
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