Table 1 Selected Studies of SAH in Rats Examining Mortality and Neurological Endpoints
From: Neurological and neurobehavioral assessment of experimental subarachnoid hemorrhage
Author | Model | Mortality | Behavior Tests | Controls | Experimental findings | Disconnect between vasospasm and outcomes |
|---|---|---|---|---|---|---|
Davella1990A | Single 300 μl injection into cisterna magnia within 10-15 seconds, ICP not monitored | 34/200 (17%) | No specific scales, observed rats for neurological dysfunction, drinking and feeding and body weight | SAH (n = 200), saline-injected (n = 100) controls or untreated controls (n = 60) | No acute or delayed neurological dysfunction, >90% of surviving rats resumed normal activity within 3 days, 2.6% reduction in body weight 36 hours after SAH but eating/feeding returned to normal within 3 days. CSF levels of eicosanoids (PGE2, PGF2a, TXB2) were significantly higher after SAH compared to noninjected and mock-CSF injected rats. The increase in eicosanoids was accompanied by a decrease in the mean vascular diameter (78~82% of control) 2 days after cisternal injection | They correlated |
Germano1994 | Single 400 μl injection into cisterna magna within 15-20 seconds, no ICP monitoring | None reported | Duration of suppression of simple nonpostural (pinna reflex, corneal reflexes, startle response) and complex postural somatomotor function (righting response, spontaneous locomotion, escape response) after SAH. Beam balance, beam walking tests and body weight for 5 days after SAH | SAH (n = 10), saline-injected (n = 10) and sham-operated (n = 10) controls | No acute neurological deficits or difference between SAH or saline-injected controls, significant deficits seen with SAH rats on beam balance 1 day after, beam walking test 1-4 days and body weight 1-5 days after SAH | Not assessed |
Germano1998C | Single 400 μl injection into cisterna magna within 30 seconds, no ICP monitoring | None reported | beam balance, beam walking, body weight | SAH or sham-operated controls | SAH associated with impaired beam balance and walking and decreased body weight compared to sham, AVS improved neurological function, preserved the blood-brain barrier and decreased vasospasm | They correlated |
Imperatore2000 | Single 400 μl injection into cisterna magna within 30 seconds, no ICP monitoring | None reported | Beam balance, beam walking | SAH or sham-operated controls | SAH associated with impaired beam balance and walking and decreased body weight compared to sham, AVS preserved the blood-brain barrier at 48 hours and improved behavior, no assessment of vasospasm | Not assessed |
Carpenter2001 | 2 injections of 250-300 μl into cisterna magna, no ICP monitoring | 3/80 (3%) | General observations | SAH or saline injected controls | All animals drowsy the day after injection but then recovered, SAH associated with changes in purinergic receptors in the basilar artery | Not assessed |
Germano2002 | Single 400 μl injection into cisterna magna within 30 seconds, no ICP monitoring | None reported | Beam balance, beam walking, body weight | SAH or sham-operated controls | SAH associated with impaired beam balance and walking and decreased body weight compared to sham, calpain inhibitor decreased deficits and improved blood-brain barrier integrity at 48 hours | Not assessed |
Prunell2002 | Single injection 200 - 300 μl into chiasmatic cistern, ICP monitoring | 25% with 200, 50% with 250 and 100% with 300 μl | None | SAH or saline-injected controls | ICP, amount of SAH were measured | Not assessed |
Gules2002 | Single or double injections into cisterna magna or endovascular perforation | 0% single hemorrhage, 9% double hemorrhage, 57% endovascular perforation | None | None | Mortality highest with endovascular perforation model | Not assessed |
Prunell2003 | Chiasmatic injection 200 μl, cisterna magna injection or endovascular perforation, with ICP monitoring | 44% endovascular, 25% chiasmatic, 0% cisterna magna injection | None | None | Mortality highest with endovascular perforation model | Not assessed |
Zausinger2004 | Endovascular perforation | 65% in control saline, 60% with 7.5% NaCl and 35% with 7.5% NaCl and dextran | 100 point neurological score composed of general behavior and respiration (40), cranial nerves (20), sensitivity to tactile stimuli (10), motor (10), coordination (20) {Katz1995} | None | Significantly better neurological scores within first days of SAH and less neuronal death at 7 days after 7.5% NaCl plus dextran treatment, trend towards better weight and lower mortality | Not assessed |
Park2004 | Endovascular perforation | 11/26 (42%) of SAH rats died at 24 hours, statistically insignificant decrease from 43% with sham DMSO to 25% of z-VAD-FMK group | Modified 25-point scale testing neurological function {Garcia1995} | SAH or sham-operated controls | SAH reduced significantly the neurological score at 6 and 24 hours, pancaspase inhibitor z-VAD-FMK decreased TUNEL and caspase 3 in endothelial cells, decreased caspase 3 activation, reduced blood-brain barrier permeability, decreased vasospasm and brain edema and improved neurological outcome | They correlated |
Ostrowski2005 | Endovascular perforation | 20/42 (48%) | Modified 25-point scale testing neurological function {Garcia1995} | SAH or sham-operated controls | SAH reduced neurological function significantly 24 hours after SAH, hyperbaric oxygen marked reduced mortality and also decreased ICP, improved CBF, slightly improved brain edema and neuronal death, decreased TUNEL staining in hippocampus | Not assessed |
Prunell2005 | Endovascular perforation or prechiasmatic SAH | 46% endovascular, 24% prechiasmatic | None | SAH or sham-operated controls | SAH associated with TUNEL positive cells, no vasospasm, reduced CBF did occur | No vasospasm yet TUNEL positive neurons and decreased CBF |
Cahill2006 | Endovascular perforation | 35/140 (33%) | Modified 25-point scale testing neurological function {Garcia1995} | SAH or sham-operated controls | Increased mortality and poorer neurological scores after SAH than sham surgery, pifithrin α associated with better neurological scores, less brain edema and blood-brain barrier breakdown, less vasospasm, less basilar artery apoptosis | They correlated |
Bermueller2006 | Endovascular perforation | 60% SAH, 40% saline, 73% saline + dextran, 73% mannitol | 91 point neurological score composed of general behavior and respiration (40), cranial nerves (16), sensitivity to tactile stimuli (10), motor (10), coordination (15) {Katz1995}, 6 grade neuroscore {Bederson1986} and prehensile traction test {Zausinger2000} | None | Better behavior with NaCl 7.5% + dextran 70 6%, less brain damage, lower ICP than after treatment with NaCl or mannitol | Not assessed |
Cahill2007 | Endovascular perforation | 35% of 195 | Modified 25-point scale testing neurological function {Garcia1995} | SAH or sham-operated controls | Pifithrin α decreased mortality, improved behavior and decreased blood-brain barrier disruption, brain edema, p53, cytochrome C, TUNEL staining and neuron injury | No vasospasm measurements but neuronal damage in areas not thought to be supplied by arteries that develop vasospasm in this model |
Germano2007 | Single 400 μl injection into cisterna magna within 30 seconds, no ICP monitoring | None reported | Beam balance, beam walking, body weight | SAH or sham-operated controls | SAH associated with significant deficits in beam balance scores on days 1 and 2 and in beam balance times days 1-3. SAH also increased latency to cross beam days 1-4. Body weight decreased days 1-5. Felbamate improved behavior scores, body weight and decreased blood-brain barrier disruption | Not assessed |
Scholler2007 | Endovascular perforation | 32% at 72 hours | 175 point neurological score composed of general behavior and respiration (40), cranial nerves (20), sensitivity to tactile stimuli (50), motor (50), coordination (15) {Katz1995} | SAH or sham-operated controls | Significant deficits 6 and 24 hours after SAH, less by 72 hours in surviving animals compared to sham-operated. SAH associated with blood-brain barrier disruption as evidenced by albumin leakage into brain, fewer microvessels and disrupted collagen 4 all on the side of the SAH | Not assessed |
Yatsushige2007 | Endovascular perforation | 0% sham, 35% SAH at 24 hours, 23% with treatment with SP600125 | 16 point score that graded mobility, reflexes, behavior and beam walking tests {Feldman1996} | SAH or sham-operated controls | SAH associated with significant behavior abnormalities, SP600125 decreased neuronal injury by decreasing caspase-3 activation and deoxyribonucleic acid damage, decreased aquaporin 1 upregulation and brain water, reduced MMP 9 activation and collagen 4 degradation, prevented blood-brain barrier disruption and a trend towards reduced mortality and better neurological function | Not assessed |
Thal2008 | Endovascular perforation | 13/20 SAH (65%), 12/20 hypertonic saline group (60%), 7/20 hypertonic saline + dextran (35%) | Beam balance, prehensile traction, rotarod, 6 point score {Bederson1995} which is actually {Bederson1986A}, 100 point neuroscore general behavior and respiration (40), cranial nerves (20), sensitivity to tactile stimuli (10), motor (10), coordination (20) {Katz1995} | None | No significant differences among groups except on 100 point neuroscore on which hypertonic saline + dextran group had significantly less neurological deficit on day 1 as compared to other groups | Not assessed |
Takata2008 | Cisterna magna injection 0.5 ml over 10 minutes, 0.3 ml 2 days later, shams had saline injection, ICP not monitored | None reported | Longterm sensorimotor and cognitive function, cerebrovascular diameter and microangiography, 8-hydroxy-2-deoxyguanosine immunohistocchemistry, regional CBF | SAH or saline-injected controls | Deficits in rotarod, vertical screen and balance beam, Morris water maze detected deficits in visual spatial memory, decreased CBF for days, minimal proximal large artery vasospasm (at 3 days), significant neuronal loss in CA1 hippocampus associated with microvascular filling defects | Vasospasm was minimal but many other deficits were noted, authors suggested changes were not due to increased ICP because they injected slowly and the blood pressure increased so cerebral perfusion pressure was thought to be adequate |
Silasi2008 | Endovascular perforation | 33% | Tapered beam, limb use asymmetry, horizontal ladder tasks, Morris water maze | SAH or sham-operated controls | SAH not associated with deficits in tapered beam, limb use asymmetry, horizontal ladder tasks, SAH did cause deficits in Morris water maze when they had to learn new location of the platform (longer mean latency and distance swum to find platform) | Not assessed |
Sugawara2008 | Endovascular perforation | 0% sham, 16% SAH, 4% simvastatin | SAH grading (0-3 in 6 cisterns), neurological assessment (0-3 points on spontaneous movement, spont movement of all limbs, movement of forelimbs while being held by tail, climbing in cage, reaction to touch on both sides of trunk, response to vibrissae touch) {Garcia1995} | SAH or sham-operated controls | SAH associated with neurological deficits, simvastatin prevents vasospasm and improved neurological grade | Correlation between SAH grade, vasospasm and neurological score |
Sugawara2008A | Endovascular perforation | 0% for sham-operated, varied with SAH from 4-35%, lowest with high-dose simvastatin but none of SAH groups significantly different | SAH grading (0-3 in 6 cisterns), neurological assessment (0-3 points on spontaneous movement, spont movement of all limbs, movement of forelimbs while being held by tail, climbing in cage, reaction to touch on both sides of trunk, response to vibrissae touch) {Garcia1995} | SAH or sham-operated controls | SAH or SAH with low-dose simvastatin associated with neurological deficits, these were prevented by high dose simvastatin, the phosphatidylinositol 3-kinase inhibitor wortmannin antagonized effects of simvastatin | Correlation between vasospasm and neurological score |
Gao2008A | Endovascular perforation | 44% (7/16) with SAH and placebo treatment died, 38% (6/16) with SAH + tetramethylpyrazine died, none of the sham-operated controls died, not significantly decreased by tetramethylpyrazine | Modified 25-point scale testing neurological function {Garcia1995} | SAH or sham-operated controls | SAH associated with behavior deficicts, tetramethylpyrazine improved behavior at 24 hours compared to SAH, as well as brain water content, Evans blue leakage, vasospasm and decreased apoptosis markers | They correlated |