Clinical Trials in Cardiac Arrest and Subarachnoid Hemorrhage: Lessons from the Past and Ideas for the Future

Table 2

Randomized controlled trials assessing neurologic outcomes after cardiac arrest—completed trials.

Trial name	Study design	Treatment group	Control group	Outcome measure	Results	Reference
Calcium channel blockers
Effects of nimodipine on cerebral blood flow and cerebrospinal fluid pressure after cardiac arrest: correlation with neurologic outcome	Randomized, double-blind study	Nimodipine IV 0.25 mcg/kg/min; (N = 25)	Placebo; (N = 26)	Primary outcome: CBF measured by Xenon CT; Secondary outcomes: ICP, neurological disability	Higher CBF in nimodipine group in first 4 hours after arrest (P < 0.05) but no difference at 24 hours. No difference in neurological outcomes	Forsman et al.,; Anesth Analg 1989 [64]
Neuropsychological sequelae of cardiac arrest	Randomized, double-blind, placebo-controlled, study of out-of-hospital ventricular fibrillation	Nimodipine 10 mcg/kg IV then 0.5 mcg/kg/min × 24 hours; (N = 35)	Placebo; (N = 33)	Primary outcome: 3- and 12-month neuropsychological and cognitive batteries	No difference in neuropsychological or cognitive outcome between groups	Roine et al.,; JAMA 1992 [65]
A randomized clinical study of a calcium-entry blocker (lidoflazine) in the treatment of comatose survivors of cardiac arrest	Randomized, double-blind, placebo-controlled, multicenter study	Lidoflazine 1 mg/kg loading dose then 0.25 mg/kg at 8 and 16 hours after resuscitation; (N = 259)	Placebo; (N = 257)	Primary outcome: Pittsburgh Cerebral Performance Scale at 6 months; Secondary outcomes: mortality, complications	No difference in 6-month neurological outcome or mortality between groups	Brain Resuscitation Clinical Trial II Study Group, NEJM 1991 [66]
Nimodipine after resuscitation from out-of-hospital ventricular fibrillation: a placebo-controlled, double-blind, randomized trial	Randomized, double-blind, placebo-controlled, study of out-of-hospital ventricular fibrillation	Nimodipine 10 mcg/kg IV then 0.5 mcg/kg/min × 24 hours; (N = 75)	Placebo; (N = 80)	Primary outcome: survival, 1-year GOS; Secondary outcomes: death related to anoxic encephalopathy, GCS at 24 hours and 1 week, 3- and 12-month mini-mental state exam, activities of daily living, Barthel index, neurological exam, seizure, SPECT, myocardial infarction, arrhythmias	No difference in the survival rate, GOS at 3 or 12 months. No difference in minimental state exam, activities of daily living, or seizures	Roine et al.,; JAMA 1990 [67]
Neuroprotective
Coenzyme Q 10 combined with mild hypothermia after cardiac arrest: a preliminary study	Randomized, placebo-controlled, double-blind, single-center study of out-of-hospital cardiac arrest	Hypothermia 35-36°C × 24 hours + Coenzyme Q 10 250 mg PO × 1 then 150 mg PO TID; (N = 25)	Hypothermia 35-36°C × 24 hours + Placebo; (N = 24)	Primary outcome: survival to ICU discharge; Secondary outcomes: 3-month survival, 3-month GOS, S100 levels	3-month survival was 68% in the treatment group and 29% in the control group (P = 0.0413). There was no significant difference in survival until discharge or GOS outcome	Damian et al., Circulation 2004 [68]
Thrombolytics
A pilot randomized trial of thrombolysis in cardiac arrest (the TICA trial)	Randomized, double-blind, placebo controlled, single-center, feasibility trial for out-of-hospital cardiac arrest	Tenecteplase 50 mg IV × 1; (N = 19)	Placebo; (N = 16)	Primary outcome: ROSC; Secondary outcomes: survival to ED, ICU and hospital discharge	ROSC in 42% of tenecteplase and 6% of placebo group. No difference in survival to hospital discharge	Fatovich et al., Resuscitation 2004 [69]
Thrombolysis during resuscitation for out-of-hospital cardiac arrest	Randomized, double-blind, controlled, multicenter study of out-of-hospital cardiac arrest	Tenecteplase 0.5 mg/kg IV; (N = 525)	Placebo; (N = 525)	Primary outcome: survival at 30 days; Secondary outcomes: survival to admission, ROSC, 24-hour survival, survival to discharge, cerebral performance score at discharge	No difference in 30-day survival, hospital admission, ROSC, 24-hour survival, discharge, or neurologic outcome. More intracranial hemorrhages in treatment group	Böttiger et al., NEJM 2008 [70]
Steroids and pressors
Vasopressin, epinephrine, and corticosteroids for In-hospital cardiac arrest	Randomized, double-blind, placebo-controlled, single-center study	Vasopressin 20 IU IV + epinephrine 1 mg IV + methylprednisolone 40 mg IV followed by hydrocortisone; (N = 48)	Epinephrine + placebo; (N = 52)	Primary outcome: ROSC, survival to discharge; Secondary outcomes: blood pressure after CPR, organ failure-free days, discharge Glasgow-Pittsburg cerebral performance scale	More ROSC in treatment group (81% versus 52%, P = 0.003) and more survival to discharge (19% versus 4%, P = 0.02)	Mentzelopoulos et al.,; Arch Intern Med 2009 [71]
Pressors
A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital	Randomized, double-blind, prospective, multi-center study	Epinephrine 0.2 mg/kg IV; (N = 648)	Epinephrine 0.02 mg/kg IV; (N = 632)	Primary outcome: return of spontaneous circulation (ROSC), admission to the hospital; Secondary outcome: cerebral performance scale at admission, and discharge	No difference in ROSC rates, admission, survival, or discharge neurological status	Brown et al., NEJM 1992 [72]
Standard doses versus repeated high doses of epinephrine in cardiac arrest outside the hospital	Randomized, double-blind, prospective, single-center study	Repeated epinephrine 5 mg IV; (N = 271)	Repeated epinephrine 1 mg IV; (N = 265)	Primary outcome: ROSC; Secondary outcomes: admission to the hospital, discharge, cerebral performance category at discharge and 6 months	No difference in ROSC, admission, discharge, or 6-month neurological outcomes	Choux et al., Resuscitation 1995 [73]
A randomized, double-blind comparison of methoxamine and epinephrine in human cardiopulmonary arrest	Randomized, double-blind, single-center study	Methoxamine 40 mg bolus IV then 40 mg 4 minutes later; (N = 77)	Epinephrine 2 mg bolus then 2 mg IV q 4 min; (N = 68)	Primary outcome: Mortality and Glasgow-Pittsburgh coma score; Secondary outcomes: ROSC, successful resuscitation	No difference in ROSC or neurologic outcome, initial resuscitation, or survival to discharge	Patrick et al.,; Am J Respir Crit Care Med 1995 [74]
Randomised comparison of epinephrine and vasopressin in patients with out-of-hospital ventricular fibrillation	Randomized, double-blind, single-center, controlled study of out-of-hospital ventricular fibrillation patients who failed defibrillation	Vasopressin 40 IU IV; (N = 20)	Epinephrine 1 mg IV; (N = 20)	Primary outcome: survival to admission; Secondary outcome: 24-hour survival, survival to discharge, GCS at discharge	No significant difference in survival to admission but more vasopressin patients survived 24 hours (60% versus 20%, P = 0.02). No difference in survival to discharge or GCS at discharge	Lindner et al.,; Lancet 1997 [75]
High-dose versus standard-dose epinephrine treatment of cardiac arrest after failure of standard therapy	Randomized, controlled, single-blind, multicenter study of patients who had failed on standard dose of epinephrine 0.5–1.0 mg IV	Epinephrine 0.1 mg/kg IV up to 4 doses; (N = 78)	Epinephrine 0.01 mg/kg IV up to 4 doses; (N = 62)	Primary outcome: improvement in cardiac rhythm or ROSC; Secondary outcomes: GCS at 6, 24, and 72 hours	No differences in ROSC, survival, or neurologic function between groups	Sherman et al., Pharmacotherarpy 1997 [76]
A comparison of repeated high doses and repeated standard doses of epinephrine for cardiac arrest outside the hospital	Randomized, controlled, prospective multicenter study	Epinephrine 5 mg IV up to 15 doses at 3-minute intervals; (N = 1677)	Epinephrine 1 mg IV up to 15 doses at 3-minute intervals; (𝑀 = 1650)	Primary outcome: ROSC, admission to the hospital, number of admissions after a single dose of epinephrine, hospital discharge; Secondary outcomes: survival, neurological outcome by GCS and cerebral performance scale	Significantly more ROSC in high dose group (40% versus 36% of control group, P = 0.02) and more survival to admission (26.5% versus 23.6% of controls, P = 0.05). No difference in survival to discharge or neurological status	Gueugniaud et al., NEJM 1998 [77]
Vasopressin versus epinephrine for in hospital cardiac arrest: a randomized controlled trial	Randomized, controlled, triple-blind, multicenter study of in-hospital cardiac arrest for asystole, PEA, or refractory ventricular fibrillation	Vasopressin 40 IU IV (first pressor); (N = 104)	Epinephrine 1 mg IV (first pressor); (N = 96)	Primary outcome: survival for 1 hour; Secondary outcomes: survival to hospital discharge, modified mini-mental state exam at discharge, cerebral performance score at discharge, ROSC, adverse events	No difference in survival at 1 hour or survival to hospital discharge. No difference in mini-mental state exam scores or cerebral performance scores	Stiell et al.,; Lancet 2001 [78]
A comparison of vasopressin and epinephrine for out-of-hospital cardiopulmonary resuscitation	Randomized, controlled, multicenter study of out-of-hospital cardiac arrest with ventricular fibrillation failing defibrillation, PEA, or asystole	Vasopressin 40 IU IV × 2 doses maximum; (N = 589)	Epinephrine 1 mg IV × 2 doses maximum; (N = 597)	Primary outcome: survival to hospital admission; Secondary outcomes: survival to hospital discharge, cerebral performance score in survivors	No difference in survival to admission among patients with ventricular fibrillation or PEA. Higher rates of hospital admission for asystole in vasopressin group (29% versus 20%, P = 0.02) and hospital discharge (4.7% versus 1.5% with epinephrine, P = 0.04). Patients who received rescue epinephrine after vasopressin had better survival to admission and discharge than the epinephrine alone group. No difference in cerebral performance	Wenzel et al.,; NEJM 2004 [79]
Vasopressin and epinephrine versus epinephrine alone in cardiopulmonary resuscitation	Randomized, controlled, multicenter trial	Epinephrine 1 mg IV + Vasopressin 40 IU IV; (N = 1442)	Epinephrine 1 mg IV + Placebo; (N = 1452)	Primary outcome: Survival to hospital admission; Secondary outcomes: ROSC, survival to hospital discharge, good neurological recovery by cerebral performance scale, and GCS, 1-year survival	No differences in survival to admission, ROSC, survival to discharge, 1-year survival, or good neurologic recovery	Gueugniaud et al., NEJM 2008 [80]
Magnesium
Randomised trial of magnesium in in-hospital cardiac arrest (MAGIC trial)	Randomized, placebo-controlled, single-center study of cardiac arrest in the ICU or general ward	Magnesium 2 g IV bolus then 8 g over 24 hours; (N = 76)	Placebo; (N = 80)	Primary outcome: ROSC; Secondary outcomes: 24-hour survival, survival to hospital discharge, GCS, and discharge Karnofsky	No difference in ROSC, 24-hour survival, survival to discharge, or GCS	Thel et al.,; Lancet 1997 [81]
Magnesium in cardiac arrest (the MAGIC trial)	Randomized, double-blind, placebo-controlled, single-center study of out-of-hospital cardiac arrest	MgSO4 5 g IV × 1; (N = 31)	Placebo; (N = 36)	Primary outcome: ECG rhythm 2 minutes after drug, ROSC; Secondary outcomes: survival to ED, ICU, and hospital discharge	No differences in ROSC or survival	Fatovich et al., Resuscitation 1997 [82]
Magnesium sulfate in the treatment of refractory ventricular fibrillation in the prehospital setting	Randomized, double-blind, placebo-controlled, multicenter study of prehospital ventricular fibrillation refractory to 3 shocks	MgSO4 2 g IV × 1; (N = 58)	Placebo; (N = 58)	Primary outcome: ROSC; Secondary outcomes: admission to hospital, hospital discharge	No difference in ROSC, survival to admission or discharge	Allegra et al.,; Resuscitation 2001 [83]
A randomized trial to investigate the efficacy of magnesium sulphate for refractory ventricular fibrillation	Randomized, double-blind, placebo-controlled trial of ventricular fibrillation refractory to 3 shocks	MgSO4 2–4 g IV × 1; (N = 52)	Placebo; (N = 53)	Primary outcome: ROSC; Secondary outcome: hospital discharge	No differences in ROSC or survival to discharge	Hassan et al.,; Emerg Med J 2002 [84]
Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest	Randomized, double-blind, placebo-controlled factorial design study	Tier 1: magnesium 2 g IV + placebo; (N = 75); Tier 2: diazepam 10 mg IV + placebo; (N = 75); Tier 3: magnesium 2 g IV + Diazepam 10 g IV; (N = 75)	Placebo only; (N = 75)	Primary outcome: awakening at 3 months (comprehensible speech and command following); Secondary outcome: days to awakening, days to death, independent at 3 months	No difference in neurological outcome between the 3 groups	Longstreth et al., Neurology 2002 [85]
Insulin
Intravenous glucose after out-of-hospital cardiopulmonary arrest: a community-based randomized trial	Randomized, single-center controlled study	5% dextrose (D5W) infusion; (N = 374)	0.45 saline infusion; (N = 374)	Primary outcome: command following or comprehensible speech; Secondary outcomes: survival to hospital admission and discharge	No difference in neurological outcomes, or survival to admission or discharge	Longstreth et al., Neurology 1993 [86]
Strict versus moderate glucose control after resuscitation from ventricular fibrillation	Randomized, controlled, multicenter study of out-of-hospital ventricular fibrillation cardiac arrest	Strict glucose control (4–6 mmol/L) with insulin infusion × 48 hours; (N = 39)	Moderate glucose control (6–8 mmol/L) with insulin infusion × 48 hours; (N = 51)	Primary outcome: 30-day all-cause mortality after ROSC; Secondary outcomes: neuron-specific enolase levels at 24 and 48 hours	No difference in 30-day mortality	Oksanen et al., Intensive Care Med 2007 [87]
Hypothermia
Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia	Randomized, controlled, single-blind, prospective study	Hypothermia 33°C × 12 h; (N = 43)	Normothermia 37°C; (N = 34)	Primary outcome: discharge disposition; Secondary outcomes: adverse events, hemodynamic parameters	Good discharge disposition in 49% of treatment group compared to 26% of normothermia group (P = 0.046). No difference in adverse events	Bernard et al., NEJM 2002 [88]
Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest	Randomized, controlled, single-blind, multicenter, prospective study	Hypothermia 32–34°C × 24 h; (N = 137)	Normothermia 37°C; (N = 138)	Primary outcome: 6 month neurologic outcome using Pittsburgh cerebral performance scale; Secondary outcome: 6-month mortality, complications at 7 days	Hypothermia group had more favorable neurological outcome at 6 months (55% versus 39% of normothermia group, P = 0.009). Less death in hypothermia group (41% versus 55% in normothermia group, P = 0.02). No difference in complication rates	The hypothermia after cardiac arrest study group, NEJM 2002 [89]
Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline	Randomized, controlled, safety and feasibility study of out-of-hospital cardiac arrest	2 L 4°C normal saline infusion; (N = 63)	Standard care; (N = 62)	Primary outcome: esophageal temperature, adverse events; Secondary outcomes: awakening, hospital discharge	Significant differences in temperature between groups (P < 0.001). No difference in awakening or hospital discharge	Kim et al.,; Circulation 2007 [90]
Prehospital therapeutic hypothermia for comatose survivors of cardiac arrest: a randomized controlled trial	Randomized controlled trail of out-of-hospital cardiac arrest	4°C Ringers solution 30 mL/kg to target temperature 33°C; (N = 19)	Conventional fluid therapy; (N = 18)	Primary outcome: nasopharyngeal temperature; Secondary outcomes: hospital mortality and cerebral performance scale	Lower core temperature in the treatment group (P < 0.001). No difference in safety, mortality, or neurologic outcome	KÄmÄrÄinen et al., Acta Anaesthesiol Scand 2009 [91]
Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: pre-rosc intranasal cooling effectiveness)	Randomized, controlled, prospective, single-blind, multicenter study for out-of-hospital arrest	Intra-arrest intranasal cooling with RhinoChill device + cooling at hospital arrival to 34°C; (N = 93)	Standard care with cooling at hospital arrival to 34°C; (N = 101)	Primary Outcome: adverse events, length of stay, mechanical ventilation days, ROSC, survival to discharge, discharge Pittsburgh cerebral performance scale.	Time to target temperature was shorter in the intranasal cooling group (P = 0.03). No difference in ROSC, survival of admitted patients, or neurologic outcome at discharge	Castrén et al., Circulation 2010 [92]
Chest compressions
A comparison of active compression-decompression cardiopulmonary resuscitation with standard cardiopulmonary resuscitation for cardiac arrests occurring in the hospital	Randomized, controlled, single center study	CPR using suction device (Ambu CardioPump); (N = 29)	Standard CPR; (N = 33)	Primary outcome: ROSC; Secondary outcomes: 24-hour survival, hospital discharge, GCS at 24 hours	ROSC occurred in 62% of treatment group versus 30% of control group (P < 0.03) and 45% of treatment group survived 24 hours compared to 9% of control group (P < 0.004). GCS at 24 hours was better in the treatment group (P < 0.02)	Cohen et al.,; NEJM 1993 [93]
The Ontario Trial of Active Compression-Decompression Cardiopulmonary Resuscitation for In-Hospital and; Prehospital Cardiac Arrest	Randomized, single-blind, multicenter controlled trial of prehospital and in-hospital cardiac arrest	Active compression-decompression CPR using a suction device; (N = 906)	Standard CPR; (N = 878)	Primary outcome: survival for 1 hour; Secondary outcome: survival to hospital discharge, modified mini-mental state exam, cerebral performance scale	No differences in survival at 1 hour, survival until hospital discharge or mini-mental state exam for either prehospital or in-hospital arrest	Stiell et al.,; JAMA 1996 [94]
Cardiopulmonary resuscitation by chest compression alone or with mouth-to-mouth ventilation	Randomized controlled study of out-of-hospital cardiac arrest	Bystander chest compression plus mouth to mouth resuscitation; (N = 279)	Bystander chest compressions alone; (N = 241)	Primary outcome: survival to hospital discharge; Secondary outcomes: admission to the hospital, neurological status	Similar outcome with bystander chest compressions alone versus chest compressions with mouth to mouth	Hallstrom et al.,; NEJM 2000 [95]
Constant flow insufflations of oxygen as the sole mode of ventilation during out-of-hospital cardiac arrest	Randomized, controlled study of out-of-hospital cardiac arrest	Constant flow insufflations of oxygen; (N = 487)	Standard endotracheal intubation and mechanical ventilation; (N = 457)	Primary outcome: survival to ICU discharge; Secondary outcomes: ROSC, survival to hospital admission, spO2 > 70%	No difference in ROSC, hospital admission or ICU discharge. Higher O2 sats in continuous flow insufflation group	Bertrand et al., Intensive Care Med 2006 [96]
Compression-only CPR or standard CPR in out-of-hospital cardiac arrest	Randomized, controlled, multicenter study of out-of-hospital cardiac arrest	Compression only CPR; (N = 620)	Standard CPR; (N = 656)	Primary outcome: 30 day survival; Secondary outcomes: 1 day survival, ROSC, survival to hospital discharge	Similar 30-day survival, 1-day survival and survival to hospital discharge	Svensson et al.,; NEJM 2010 [97]
CPR with chest compression alone or with rescue breathing	Randomized, controlled, multicenter study of out-of-hospital cardiac arrest	Chest compressions alone; (N = 981)	Chest Compressions + Rescue breathing (2 breaths to 15 chest compressions); (N = 960)	Primary outcome: survival to hospital discharge; Secondary outcomes: discharge cerebral performance Score,; ROSC	No difference in survival to hospital discharge or in neurologic outcome. Trend toward improved survival at discharge in those with cardiac cause of arrest and shockable rhythm (P = 0.09)	Rea et al.,; NEJM 2010 [98]
A trial of an impedance threshold device in out-of-hospital cardiac arrest	Randomized, controlled, double-blinded, multicenter study of out-of-hospital cardiac arrest	Impedance threshold device (ITD) which increasing negative intrathoracic pressure and improves cardiac output; (N = 4373)	Sham ITD; (N = 4345)	Primary outcome: survival to hospital discharge with mRS 0–3; Secondary outcomes: survival to ED admission, hospital admission and hospital discharge, adverse events	No difference in survival with good mRS	Aufderheide et al., NEJM 2011 [99]
Adenosine antagonist
Aminophylline in bradyasystolic cardiac arrest: a randomized placebo-controlled trial	Randomized, placebo-controlled, double-blind, multicenter study of asystole and PEA arrest unresponsive to epinephrine and atropine	Aminophylline 250 mg; (N = 486)	Placebo; (N = 485)	Primary outcome: ROSC; Secondary outcomes: duration of ROSC, survival to admission, survival to discharge, length of stay, 24-hour tachyarrhythmias, 24-hour seizures, 1-year neurologic outcome by GCS, Glasgow-Pittsburgh cerebral and overall performance scales, modified mini-mental state exam, functional status questionnaire	No difference in ROSC. More tachyarrhythmias in the treatment group. Survival to hospital admission and survival to discharge were not different	Abu-Laban et al., Lancet 2006 [100]
Fluid management
Capillary leakage in postcardiac arrest survivors during therapeutic hypothermia: a prospective, randomized study	Randomized, controlled study	7.2% hypertonic saline with 6% poly starch solution × 24 hours; (N = 10)	Standard Fluid (Ringer’s acetate) × 24 hours; (N = 9)	Primary outcome: amount of fluid administered in 24 hours; Secondary outcome: MRI vasogenic edema	The treatment group required significantly less fluid than the control group. There was no difference in MRI brain edema	Heradstveit et al., Scand J Trauma Resusc Emerg Med 2010 [101]
Barbiturate
Randomized clinical study of thiopental loading in comatose survivors of cardiac arrest	Randomized, controlled, multicenter study	Thiopental 30 mg/kg IV load; (N = 131)	Standard therapy (N = 131)	Primary outcome: Pittsburgh cerebral Performance scale at 6 and 12 months; Secondary outcomes: best neurological performance ever obtained during followup, time to recovery	No difference in neurological outcome or mortality between groups	Brain Resuscitation Clinical Trial I Study Group.; NEJM 1986 [102]
Calcium
Calcium chloride: reassessment of use in asystole	Randomized, double-blind, placebo-controlled study in prehospital asystolic cardiac arrest refractory to epinephrine, bicarbonate, and atropine	Calcium chloride; (N = 18)	Placebo; (N = 14)	Primary outcome: ROSC; Secondary outcome: hospital discharge	No difference in ROSC	Stueven et al.,; Ann Emerg Med 1984 [103]
The effectiveness of calcium chloride in refractory electromechanical dissociation	Randomized, blinded, placebo-controlled study of prehospital PEA arrest refractory to epinephrine and bicarbonate	Calcium chloride; (N = 48)	Placebo; (N = 42)	Primary outcome: ROSC; Secondary outcomes: survival to hospital discharge	No difference in ROSC but subgroup of patients with widened QRS did have more ROSC in calcium group (P = 0.028)	Stueven et al.,; Ann Emerg Med; 1985 [104]
Lack of effectiveness of; calcium chloride in refractory asystole	Randomized, blinded, placebo controlled; study of prehospital asystolic cardiac arrest refractory to epinephrine, bicarbonate, and atropine	Calcium chloride; (N = 39)	Placebo; (N = 34)	Primary outcome: ROSC; Secondary outcomes: survival to hospital discharge	No difference in ROSC or hospital discharge	Stueven et al.,; Ann Emerg Med 1985 [105]
Sodium bicarbonate
Buffer therapy during out-of-hospital cardiopulmonary resuscitation	Randomized, double-blind, placebo-controlled study of out-of-hospital asystole or ventricular fibrillation refractory to first defibrillation attempt	Sodium bicarbonate 250 mL IV × 1; (N = 245)	Placebo; (N = 257)	Primary outcome: survival to ICU admission, survival to hospital discharge	No difference in survival to ICU admission or hospital discharge	Dybvik et al.,; Resuscitation 1995 [106]
Sodium bicarbonate improves outcome in prolonged prehospital cardiac arrest	Randomized, double-blind, placebo-controlled trial of prehospital cardiac arrest	Sodium bicarbonate (1 meq/kg) IV × 1; (N = 175)	Placebo; (N = 155)	Primary outcome: survival to ED; Secondary outcomes: ROSC	No difference in survival to ED admission or ROSC. Better survival with bicarbonate in the prolonged (>15 minute) arrest group (P = 0.007)	Vukmir and Katz,Am J Emerg Med; 2006 [107]
Hemofiltration
High-volume hemofiltration after out-of-hospital cardiac arrest: a randomized study	Randomized, controlled trial of out-of-hospital ventricular fibrillation or asystole cardiac arrest	Tier 1: hemofiltration (200 mL/kg/h) over 8 hours; (N = 20); Tier 2: hemofiltration plus hypothermia to 32°C × 24 hours; (N = 22)	Standard care; (N = 19)	Primary outcome: survival at 6 months; Secondary outcome: intractable shock, Pittsburgh cerebral performance scale	Significantly better survival compared to control in hemofiltration group (P = 0.026) and hemofiltration plus hypothermia group (P = 0.018). No difference in 6-month neurologic outcome	Laurent et al.,; J Am Coll Cardiol 2005 [108]
Rhythm analysis
Early versus later rhythm analysis in patients with out-of-hospital cardiac arrest	Cluster randomized, controlled, multicenter study of out-of-hospital cardiac arrest	Early rhythm analysis: 30–60 seconds of EMS CPR followed by ECG analysis; (N = 5290)	Later rhythm analysis: 180 seconds of EMS CPR followed by ECG analysis; (N = 4643)	Primary outcome: survival to hospital discharge with mRS 0–3; Secondary outcomes: survival to discharge, survival to hospital admission, ROSC	No difference in outcome between a brief and longer period of CPR before ECG analysis of rhythm	Stiell et al.,; NEJM 2011 [109]