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 |