Table 2.

Summary of neuroprotective strategies for global cerebral ischemia associated with cardiac arrest

Therapy	Proposed mechanism	Study subject	Blind	Placebo control	Rando-mized	Delivery route	Effect (positive, negative, neutral)	Outcomes evaluated
Category of Mechanisms I: Modulating neuronal cell death
MK-80115	NMDA antagonist	Dogs	Yes	Yes	Yes	Intravenous	Negative	Survival16, neurological function15,16; neurohistopathology15,16
GPI 300016
Lamotrigine21	Inhibition of glutamate release	Rats	Not mentioned	Yes	Yes	Intravenous	Positive	Neurohistopathology
Xenon26, 30--32	NMDA antagonist	Pigs26, 30–32	Yes26, 30–32	Yes26, 30–32	Yes26, 30–32	Inhale26, 30–32	Early intervention (10 minutes post-ROSC) Neutral26	Neurologic function26, 30–32; neurohistopathology26,30,31
		Human (2 ongoing clinical trials: NCT00879892, NCT01262729)					Late intervention (1 h post-ROSC) Positive30–32
Argon33,34	Anti-apoptosis	Rats	Yes	Yes	Yes	Inhale	Positive	Neurologic function; neurohistopathology;
Ischemic post-conditioning 42,43	Anti-apoptosis	Pigs	Yes	Yes	Yes	Intravenous	Positive	Survival43; neurological function42,43; neurohistopathology43; Left ventricular ejection function42,43
Caspase 3 inhibitor zDEVD-FMK45	Anti-apoptosis	Rats	Yes	Yes	Yes	Intracerebro-ventricular	Neutral	Neurologic function; neurohistopathology
Sodium bicarbonate48,50–52	Buffering of metabolic acidosis	Dogs48	Yes48,52	Yes48	Yes48,52	Intravenous	Positive for long cardiac arrest (15 minutes) and neurtral for short cardiac arrest (5 minutes)48,52	Return of spontaneous circulation48, 50–52; survival48,50–52; neurological function48,50–52
		Humans (retrospective50,51; perspective52; ongoing clinical trial: NCT01377337)	No50,51	No50–52	No50,51
							Positive at low dose (1 mEq/kg) and negative at high dose (>1 mEq/kg)50	Mean arterial pressure and coronary perfusion pressure48
							Positive at high usage (dose not specified)51	Neurohistopathology48
Carbicarb49	Buffering of metabolic acidosis	Rats	Yes	Yes	Yes	Intravenous	Positive at low dose (3 ml/kg); Negative at high dose (6 ml/kg)	Mean arterial pressure; survival; neurological function; neurohistopathology
Fluoxetine55	Anti-inflammatory	Mice	Yes	Yes	Yes	Intravenous	Neutral at low dose (10 mg/kg); Positive at high dose (5 mg/kg)	Neurologic function; neurohistopathology
Matrix metalloproteinase-9 inhibitor56	Anti-inflammatory	Rats	Not mentioned	Yes	Yes	Intraperiton-eal	Positive	Brain water content; neurohistopathology
Category of Mechanisms II: Influencing oxygen free-radicals
Hyperoixa (100%) ventilation57--62	Increased oxidative stress	Dogs57–60	Not men-tioned57, 59–62	No	Yes	Inhale	Negative57–61	Neurological function57–61; neurohistopathology58–61; plasma biomarkers of neuronal damage62
		Pigs61	Yes58				Neutral when co-treated with hypothermia and Negative when not co-treated with hypothermia 62
		Human62
Methylene blue65–67	Attenuation of oxidative and inflammatory injury	Pigs	Not mentioned	Yes	Yes	Intravenous	positive	Survival65; inflammatory markers65; neurohistopathology 66; genomics67
Inhaled nitric oxide68,69	Inhibition of reactive oxygen species	Mice	Not mentioned	Yes	yes	Genotype68	positive	Survival68,69; neurological function68,69; neurohistopathology68,69; LVEF68,69; brain edema69; diffusion weighted imaing69
						Inhale69
Nitrite70,71	Reversible inhibition of mitochondrial complex I with reduced free radical production70	Rats70	Yes	Yes	Yes	Intravenous	Positive	Survival; neurological function; neurohistopathology
	Improved mitochondrial function and S-nitrosylation for pro-survival71
		Mice71
N-acetylcysteine75	Free-radical scavenger	dogs	Yes	Yes	Yes	Intravenous	Neutral	Neurologic function
Category of Mechanisms III: Improving cerebral hemodynamics
Intrathoracic pressure during CPR76–79	Improved organ perfusion	Pigs76,77	Not men-tioned76,77	Yes	Yes	Intrathoracic pressure regulator76	Positive76–79	Survival76–79; neurological function76–79; brain and heart blood flow76
		Humans78,79	No78			Active compression-decompression device + impedance threshold device77–79	Neutral for neurologic recovery78
			Yes79
Sodium nitroprusside + active compression/decompression + impedance threshold device80–82	Improved organ perfusion	Pigs	Yes	Yes	Yes	Intravenous	Positive	Survival and neurological function80; return of spontaneous circulation and carotid blood flow81,82; cerebral perfusion pressure and coronary perfusion pressure81
Hypertonic saline hydroxyethyl starch83	Improve perfusion, decrease intracranial pressure, decrease brain edema	Rats	Yes	Yes	Yes	Intravenous	Positive for cerebral blood flow during early reperfuion; neutral at late time point (7-day post-resuscitation)	Survival; cerebral blood flow; neurological function; neurohistopathology

Superscript numbers indicate the citation number of studies reviewed.