Temporal changes in perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin after subarachnoid hemorrhage

1998 ◽  
Vol 88 (3) ◽  
pp. 557-561 ◽  
Author(s):  
Ryszard M. Pluta ◽  
John K. B. Afshar ◽  
Robert J. Boock ◽  
Edward H. Oldfield
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Blood Clot ◽  
Saline Control ◽  
Control Group ◽  
Content Type ◽  
Delayed Cerebral Vasospasm ◽  
Arterial Blood ◽  
Fine Print

Hemoglobin released from hemolysed erythrocytes has been postulated to be responsible for delayed cerebral vasospasm after subarachnoid hemorrhage (SAH). However, the evidence is indirect and the mechanisms of action are unclear. Cerebrovascular tone is regulated by a dynamic balance of relaxing and contracting factors. Loss of the endothelium-derived relaxing factor—nitric oxide in the presence of oxyhemoglobin and overproduction of endothelin-1 stimulated by oxyhemoglobin have been postulated as causes of delayed cerebral vasospasm after SAH. Object. The authors aimed to investigate this hypothesis using in vivo microdialysis to examine time-dependent changes in the perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin in a primate model of SAH. Methods. Nine cynomolgus monkeys underwent right-sided frontotemporal craniectomy and placement of a semipermeable microdialysis catheter adjacent to the right middle cerebral artery (MCA). Saline (control group, three animals) or an arterial blood clot (SAH group, six animals) was then placed around the MCA and the catheter. Arteriographically confirmed vasospasm had developed in all animals with SAH but in none of the control animals on Day 7. The dialysate was collected daily for 12 days. Levels of oxyhemoglobin, deoxyhemoglobin, and methemoglobin were measured by means of spectrophotometry. Perivascular concentrations of oxyhemoglobin, deoxyhemoglobin, and methemoglobin peaked on Day 2 in the control monkeys and could not be detected on Days 5 to 12. Perivascular concentrations of oxyhemoglobin and deoxyhemoglobin peaked on Day 7 in the SAH group, at which time the concentrations in the dialysate were 100-fold higher than in any sample obtained from the control animals. Methemoglobin levels increased only slightly, peaking between Days 7 and 12, at which time the concentration in the dialysate was 10-fold higher than in samples from the control animals. Conclusions. This study provides in vivo evidence that the concentrations of oxyhemoglobin and deoxyhemoglobin increase in the cerebral subarachnoid perivascular space during the development of delayed cerebral vasospasm. The results support the hypothesis that oxyhemoglobin is involved in the pathogenesis of delayed cerebral vasospasm after SAH and implicate deoxyhemoglobin as a possible vasospastic agent.

Role of ferrous iron chelator 2,2′-dipyridyl in preventing delayed vasospasm in a primate model of subarachnoid hemorrhage

1998 ◽  
Vol 88 (2) ◽  
pp. 298-303 ◽  
Author(s):  
Laura L. Horky ◽  
Ryszard M. Pluta ◽  
Robert J. Boock ◽  
Edward H. Oldfield
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Blood Clot ◽  
Autologous Blood ◽  
Iron Chelator ◽  
Preventive Therapy ◽  
Control Group ◽  
Primate Model ◽  
Content Type ◽  
Fine Print

Object. Oxyhemoglobin (HbO2) causes vasospasm after subarachnoid hemorrhage (SAH). The most likely spasmogenic component of HbO2 is iron. Various iron chelators, such as deferoxamine, have prevented vasospasm in vivo with limited success. However, only chelators of iron in the ferric state have been studied in animal models of vasospasm after SAH. Because free radical formation requires the ferrous (Fe++) moiety and Fe++ is a potent binder of the vasodilator nitric oxide, the authors hypothesized that iron in the ferrous state causes vasospasm and that chelators of Fe++, such as 2,2′-dipyridyl, may prevent vasospasm. This study was undertaken to investigate the influence of 2,2′-dipyridyl on vasospasm after induction of SAH in a primate model. Methods. Twelve cynomolgus monkeys were randomly divided into two groups and then both groups underwent placement of an arterial autologous blood clot in the subarachnoid space around the right middle cerebral artery (MCA). The five animals in the control group received intravenously administered saline and the seven treated animals received intravenously administered chelator (2,2′-dipyridyl) for 14 days. Sequential arteriography for assessment of MCA diameter was performed before and on the 7th day after SAH. Conclusions. Prevention of cerebral vasospasm by means of treatment with continuous intravenous administration of 2,2′-dipyridyl is reported in a primate model of SAH. This result provides insight into the possible mechanism of delayed vasospasm after aneurysmal SAH and provides a potential preventive therapy for it.

scholarly journals Increased levels of lipid peroxides as predictive of symptomatic vasospasm and poor outcome after aneurysmal subarachnoid hemorrhage

2002 ◽  
Vol 97 (6) ◽  
pp. 1302-1305 ◽  
Author(s):  
Takao Kamezaki ◽  
Kiyoyuki Yanaka ◽  
Sohji Nagase ◽  
Keishi Fujita ◽  
Noriyuki Kato ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Lipid Peroxides ◽  
Medical Complication ◽  
Content Type ◽  
Poor Outcome ◽  
Symptomatic Vasospasm ◽  
Delayed Cerebral Vasospasm ◽  
Fine Print

Object. Cerebral vasospasm remains a devastating medical complication of aneurysmal subarachnoid hemorrhage (SAH). Reactive oxygen species and subsequent lipid peroxidation are reported to participate in the causes of cerebral vasospasm. This clinical study was performed to investigate the relationships between levels of lipid peroxides in cerebrospinal fluid (CSF) and both delayed cerebral vasospasm and clinical outcome after SAH. Methods. Levels of phosphatidylcholine hydroperoxide (PCOOH) and cholesteryl ester hydroperoxide (CEOOH) in the CSF were measured in 20 patients with aneurysmal SAH. The patients' CSF was collected within 48 hours of hemorrhage onset and on Day 6 or 7 post-SAH. On Day 7, angiography was performed to verify the degree and extent of the vasospasm. The relationship between the patients' clinical profiles and the levels of lipid peroxides in the CSF were investigated. Both PCOOH and CEOOH were detectable in CSF, and their levels decreased within 7 days after onset of SAH. The levels of CEOOH within 48 hours after onset of hemorrhage were significantly higher in patients in whom symptomatic vasospasm later developed than in patients in whom symptomatic vasospasm did not develop (p = 0.002). Levels of PCOOH measured within 48 hours after onset of hemorrhage were significantly higher in patients with poor outcomes than in patients with good outcomes (p = 0.043). Conclusions. Increased levels of lipid peroxides measured in the CSF during the acute stage of SAH were predictive of both symptomatic vasospasm and poor outcome. Measurements of lipid peroxides in the CSF may be useful prognostically for patient outcomes as well as for predicting symptomatic vasospasm.

Subarachnoid hemorrhage—induced upregulation of the 5-HT1B receptor in cerebral arteries in rats

2003 ◽  
Vol 99 (1) ◽  
pp. 115-120 ◽  
Author(s):  
Jacob Hansen-Schwartz ◽  
Natalie Løvland Hoel ◽  
Cang-Bao Xu ◽  
Niels-Aage Svendgaard ◽  
Lars Edvinsson
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Real Time ◽  
Cerebral Vasospasm ◽  
Cerebral Arteries ◽  
Specific Treatment ◽  
Content Type ◽  
Sequence Of Events ◽  
Arterial Blood ◽  
Receptor Phenotype ◽  
Fine Print

Object. Cerebral vasospasm following subarachnoid hemorrhage (SAH) leads to reduced blood flow in the brain. Inspired by organ culture—induced changes in the receptor phenotype of cerebral arteries, the authors investigated possible changes in the 5-hydroxytryptamine (HT) receptor phenotype after experimental SAH. Methods. Experimental SAH was induced in rats by using an autologous prechiasmatic injection of arterial blood. Two days later, the middle cerebral artery (MCA), posterior communicating artery (PCoA), and basilar artery (BA) were harvested and examined functionally with the aid of a sensitive in vitro pharmacological method and molecularly by performing quantitative real-time reverse transcription—polymerase chain reaction (PCR). In the MCA and BA the 5-HT1B receptor was upregulated, as determined through both functional and molecular analysis. In response to selective 5-HT1 receptor agonists both the negative logarithm of the 50% effective concentration was increased (one log unit in the MCA and one half unit in the BA), as was the agonist's potency (increased by 50% in the MCA and doubled in the BA). In addition, the authors found an approximately fourfold increase in the number of copies of messenger RNA coding for the 5-HT1B receptor as determined by quantitative real-time PCR. In the PCoA no upregulation of the 5-HT1B receptor was observed. Conclusions. Changes in the receptor phenotype in favor of contractile receptors may well represent the end stage in a sequence of events leading from SAH to the actual development of cerebral vasospasm. Insight into the mechanism of upregulation may provide new targets for developing specific treatment against cerebral vasospasm.

Neuropeptide Y in the primate model of subarachnoid hemorrhage

1992 ◽  
Vol 77 (3) ◽  
pp. 417-423 ◽  
Author(s):  
Ryszard M. Pluta ◽  
Anna Deka-Starosta ◽  
Alois Zauner ◽  
Jay K. Morgan ◽  
Karin M. Muraszko ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Neuropeptide Y ◽  
Cerebral Vasospasm ◽  
Primate Model ◽  
Content Type ◽  
Peripheral Plasma ◽  
Delayed Cerebral Vasospasm ◽  
Arterial Plasma ◽  
Fine Print

✓ The cause of cerebral vasospasm after subarachnoid hemorrhage (SAH) remains unknown. Recently, an association between the potent vasoconstricting peptide, neuropeptide Y, and delayed cerebral vasospasm after SAH has been postulated. This was based on the findings of increased neuropeptide Y levels in the cerebrospinal fluid (CSF) and plasma after SAH in animals and humans. For this study, the primate model of SAH was used to assess the possible role of neuropeptide Y in delayed vasospasm after SAH. Fifteen cynomolgus monkeys underwent placement of a clot of either whole blood or red blood cells in the subarachnoid space around the middle cerebral artery (MCA). Sequential arteriography for assessment of MCA diameter and sampling of blood and CSF for neuropeptide Y were performed: before SAH (Day 0); 7 days after SAH, when signs of delayed cerebral vasospasm peak in this model and in humans; 12 days after SAH; and 28 days after SAH. Subarachnoid hemorrhage did not evoke changes in CSF or plasma levels of neuropeptide Y. Nine monkeys had arteriographic evidence of vasospasm on Day 7, but no change in neuropeptide Y levels occurred in plasma or CSF. In addition, neuropeptide Y levels did not change, even after resolution of vasospasm on Day 12 or Day 28. Neuropeptide Y levels were substantially higher in CSF than in arterial plasma (p < 0.003 at each interval). No correlation was found between neuropeptide Y levels in CSF and in plasma. These results do not confirm a relationship between neuropeptide Y levels in the CSF or peripheral plasma and delayed cerebral vasospasm in SAH.

Relative importance of hypertension compared with hypervolemia for increasing cerebral oxygenation in patients with cerebral vasospasm after subarachnoid hemorrhage

2005 ◽  
Vol 103 (6) ◽  
pp. 974-981 ◽  
Author(s):  
Andreas Raabe ◽  
Jügen Beck ◽  
Mike Keller ◽  
Hartmuth Vatter ◽  
Michael Zimmermann ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Tissue ◽  
Cerebral Vasospasm ◽  
Moderate Hypertension ◽  
Cerebral Oxygenation ◽  
Brain Oxygenation ◽  
Content Type ◽  
Arterial Blood ◽  
Hypertension Therapy ◽  
Fine Print

Object. Hypervolemia and hypertension therapy is routinely used for prophylaxis and treatment of symptomatic cerebral vasospasm at many institutions. Nevertheless, there is an ongoing debate about the preferred modality (hypervolemia, hypertension, or both), the degree of therapy (moderate or aggressive), and the risk or benefit of hypervolemia, moderate hypertension, and aggressive hypertension in patients following subarachnoid hemorrhage. Methods. Monitoring data and patient charts for 45 patients were retrospectively searched to identify periods of hypervolemia, moderate hypertension, or aggressive hypertension. Measurements of central venous pressure, fluid input, urine output, arterial blood pressure, intracranial pressure, and oxygen partial pressure (PO2) in the brain tissue were extracted from periods ranging from 1 hour to 24 hours. For these periods, the change in brain tissue PO2 and the incidence of complications were analyzed. During the 55 periods of moderate hypertension, an increase in brain tissue PO2 was found in 50 cases (90%), with complications occurring in three patients (8%). During the 25 periods of hypervolemia, an increase in brain oxygenation was found during three intervals (12%), with complications occurring in nine patients (53%). During the 10 periods of aggressive hypervolemic hypertension, an increase in brain oxygenation was found during six of the intervals (60%), with complications in five patients (50%). Conclusions. When hypervolemia treatment is applied as in this study, it may be associated with increased risks. Note, however, that further studies are needed to determine the role of this therapeutic modality in the care of patients with cerebral vasospasm. In poor-grade patients, moderate hypertension (cerebral perfusion pressure 80–120 mm Hg) in a normovolemic, hemodiluted patient is an effective method of improving cerebral oxygenation and is associated with a lower complication rate compared with hypervolemia or aggressive hypertension therapy.

Chymopapain-induced reduction of proinflammatory phospholipase A2 activity and amelioration of neuropathic behavioral changes in an in vivo model of acute sciatica

1997 ◽  
Vol 86 (6) ◽  
pp. 998-1006 ◽  
Author(s):  
Paul D. Sawin ◽  
Vincent C. Traynelis ◽  
Gretchen Rich ◽  
Bruce A. Smith ◽  
Timothy J. Maves ◽  
...  
Keyword(s):  
Thermal Hyperalgesia ◽  
Behavioral Changes ◽  
Mechanical Hyperalgesia ◽  
In Vivo Model ◽  
Saline Control ◽  
Control Group ◽  
Content Type ◽  
Sciatic Nerves ◽  
Fine Print

✓ The mechanism of action underlying chymopapain (Chymodiactin) chemonucleolysis remains obscure. Radiographic studies suggest that chymopapain does not alter disc fragment size acutely; nonetheless, patients often report symptom resolution within a few days, even hours, of treatment. The authors postulate that, in addition to its chemonucleolytic action, chymopapain may possess antiinflammatory properties. To test this hypothesis, the authors assessed the ability of chymopapain to modulate the activity of the proinflammatory enzyme phospholipase A2 (PLA2) and to ameliorate behavioral changes associated with inflammatory neuropathy in an in vivo model of sciatica. Thirty-nine male Fischer rats were randomly assigned to one of three treatment groups: 1) saline, 2) betamethasone, or 3) chymopapain. All of the rats underwent unilateral sciatic nerve ligation with loose chromic gut suture to induce inflammatory mononeuropathy. The animals were tested for thermal and mechanical hyperalgesia on Days 0 (preoperation), 7 (pretreatment), and 14 (prior to death). Three animals were killed on Day 0 to determine the baseline PLA2 activity within unmanipulated rat sciatic nerves. On Day 7, three animals from each group were killed to assess PLA2 activity prior to treatment. The remainder were given a single infusion of saline, betamethasone (0.3 mg/kg), or chymopapain (100 pKat U) around the inflamed nerve. On Day 14, the remaining animals were killed and their sciatic nerves were removed. The tissue was homogenized and the PLA2 activity was determined using [14C]arachidonate—labeled Escherichia coli phospholipid membrane as a substrate. Lipids were extracted and separated by thin-layer chromatography. All animals developed behavioral changes consistent with inflammatory mononeuropathy 24 to 72 hours postoperatively; these included gait disturbance, flexion deformity, and hyperalgesia of the involved hindlimb. The degree of mechanical and thermal hyperalgesia was comparable between groups at Day 7. By Day 14, the thermal hyperalgesia had resolved; the mechanical hyperalgesia was less evident in the betamethasone- and chymopapain-treated groups than in the saline-treated controls (p = 0.003; saline- vs. chymopapain-treated groups p = 0.004; saline- vs. betamethasone-treated groups p = 0.008). The mean PLA2 activity at baseline (Day 0) was 11.6 ± 4.9 nmol phospholipid hydrolyzed per minute per milligram of protein. The PLA2 activity at Day 7 was 74.4 ± 18.2 (ligated side) and 21.2 ± 11.7 (nonligated side). At Day 14, PLA2 activity was reduced in the chymopapain- (47.8 ± 12.3) and betamethasone- (39.7 ± 9.5) treated groups compared with the saline control group (62.3 ± 11.2), (saline- vs. chymopapain-treated groups p < 0.05; saline- vs. betamethasone-treated groups p < 0.01). The PLA2 activity in nonligated specimens was 18.6 ± 10.1. These data indicate that chymopapain exhibits antiinflammatory properties in vivo, reducing PLA2 activity and ameliorating mechanical hyperalgesia in this model of inflammatory sciatic neuropathy.

Cerebral arterial responses to induced hypertension following subarachnoid hemorrhage in the monkey

1978 ◽  
Vol 49 (1) ◽  
pp. 75-83 ◽  
Author(s):  
Donald P. Boisvert ◽  
Thomas R. Overton ◽  
Bryce Weir ◽  
Michael G. Grace
Keyword(s):  
Blood Pressure ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Arteries ◽  
Control Group ◽  
Content Type ◽  
Csf Pressure ◽  
Arterial Blood ◽  
Subarachnoid Injection ◽  
Arterial Responses ◽  
Fine Print

✓ Regional cerebral blood flow (rCBF), angiographic cerebral arterial caliber, and cerebrospinal fluid (CSF) pressure were measured in rhesus monkeys to determine the effect of experimentally induced subarachnoid hemorrhage (SAH) on cerebral arterial responses to graded increases in blood pressure. These measurements were also performed in a control group of monkeys subjected to a mock SAH by injection of artificial CSF into the cerebral space. Before subarachnoid injection of blood or artificial CSF, graded increases in mean arterial blood pressure (MABP) to a level 40% to 50% above baseline values had no effect on rCBF. The major cerebral arteries constricted and CSF pressure remained unchanged. Similar responses were observed after injection of artificial CSF. When MABP was increased in animals that had been subjected to subarachnoid injection of blood, rCBF increased and was associated with dilatation of the major cerebral arteries and moderate increases in CSF pressure. These results demonstrate that cerebral arterial responses to increases in blood pressure may be abnormal in the presence of subarachnoid blood. The manner in which abnormal cerebral arterial reactivity, changes in blood pressure, and vasospasm combine to determine the level of cerebral perfusion following SAH is postulated.

Prevention of delayed vasospasm by an endothelin ETA receptor antagonist, BQ-123: change of ETA receptor mRNA expression in a canine subarachnoid hemorrhage model

1994 ◽  
Vol 81 (5) ◽  
pp. 759-764 ◽  
Author(s):  
Shouichi Itoh ◽  
Tomio Sasaki ◽  
Akio Asai ◽  
Yoshiyuki Kuchino
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Receptor Antagonist ◽  
Cerebral Vasospasm ◽  
Group Versus ◽  
Intrathecal Administration ◽  
Control Group ◽  
Content Type ◽  
Messenger Ribonucleic Acid ◽  
Delayed Cerebral Vasospasm ◽  
Eta Receptor

✓ The authors investigated the roles of endothelin (ET)-1 and the ETA receptor in the pathogenesis of delayed cerebral vasospasm following subarachnoid hemorrhage (SAH). A study was made of the preventive effect of a novel ETA receptor antagonist, BQ-123, on vasospasm and the expression of the ETA receptor messenger ribonucleic acid (mRNA) using a canine two-hemorrhage SAH model. Continuous intrathecal administration of BQ-123 (5 × 10−6 mol/day) prevented narrowing of the basilar artery on Day 7 after SAH in 97.6% of cases in the study group versus 70.7% of cases in the control group (p < 0.05). While expression of the mRNA-coding ETA receptor was not detected in the control animals, it markedly increased on Day 3 after SAH and was also detected on Day 7. The results suggest that endothelin-1 and the ETA receptor participate in the pathogenesis of delayed cerebral vasospasm following SAH.

Suramin-induced reversal of chronic cerebral vasospasm in experimental subarachnoid hemorrhage

2002 ◽  
Vol 97 (1) ◽  
pp. 129-135 ◽  
Author(s):  
Hitoshi Kimura ◽  
Toshinari Meguro ◽  
Ahmed Badr ◽  
John H. Zhang
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Tyrosine Kinase ◽  
Cerebral Vasospasm ◽  
Disulfonic Acid ◽  
Control Group ◽  
Content Type ◽  
Basilar Arteries ◽  
Blood Injection ◽  
The Mean ◽  
Fine Print

Object. The naphthylsulfonate derivative suramin is an inhibitor of growth factor receptors (receptor tyrosine kinases) and G protein—coupled P2Y receptors. Both types of these receptors are suspected of being involved in cerebral vasospasm after subarachnoid hemorrhage (SAH). In the current study, the authors examined the therapeutic effects of suramin and a selective P2X-receptor antagonist, pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), in the reversal of vasospasm in an established canine double-hemorrhage model. Methods. Twenty-four dogs underwent double blood injection into the cisterna magna, with injections given on Days 0 and 2. The dogs were divided randomly into three groups (six animals in each group) to be treated from Days 2 through 6 with the vehicle dimethyl sulfoxide, suramin, or PPADS. An additional group of six dogs received double blood injection without any treatment and served as an SAH control group. The animals were killed on Day 7. Angiography was performed on Day 0 before blood injection and again on Day 7 before the animals were killed. After the death of the animals, the basilar arteries (BAs) were collected for morphological studies and determination of tyrosine kinase expression, and the bloody cerebrospinal fluid (CSF) produced by the hemorrhages was collected for measurement of oxyhemoglobin and adenosine triphosphate (ATP). In the SAH control group, the mean diameter of the BAs on Day 7 was 46.23 ± 6.32% of the value on Day 0 (which served as a reference of 100%). In the DMSO-treated group, the mean residual diameter of the BA was 47.77 ± 0.8% on Day 7 compared with the value on Day 0. Suramin, but not PPADS, increased the residual diameter to 74.02 ± 4.24% on Day 7. On Day 7 the level of ATP in the CSF was decreased and the level of oxyhemoglobin was increased, compared with values measured on Day 0. Suramin, but not PPADS, reduced tyrosine phosphorylation in the spastic BAs. Conclusions. By reducing tyrosine kinase activity, suramin may be useful in the treatment of cerebral vasospasm.

Effect of AT877 on cerebral vasospasm after aneurysmal subarachnoid hemorrhage

1992 ◽  
Vol 76 (4) ◽  
pp. 571-577 ◽  
Author(s):  
Masato Shibuya ◽  
Yoshio Suzuki ◽  
Kenichiro Sugita ◽  
Isamu Saito ◽  
Tomio Sasaki ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Cerebral Vasospasm ◽  
Double Blind Trial ◽  
Double Blind ◽  
Content Type ◽  
Blind Trial ◽  
Symptomatic Vasospasm ◽  
Delayed Cerebral Vasospasm ◽  
Number Of Patients ◽  
Fine Print

✓ With the cooperation of 60 neurosurgical centers in Japan, a prospective randomized placebo-controlled double-blind trial of a new calcium antagonist AT877 (hexahydro-1-(5-isoquinolinesulfonyl)-1H-1,4-diazepine hydrochloride, or fasudil hydrochloride) was undertaken to determine the drug's effect on delayed cerebral vasospasm in patients with a ruptured cerebral aneurysm. A total of 276 patients, who underwent surgery within 3 days after subarachnoid hemorrhage (SAH) of Hunt and Hess Grades I to IV, were entered into the study. Nine patients were excluded because of protocol violation. The remaining 267 patients received either 30 mg AT877 or a placebo (saline) by intravenous injection over 30 minutes, three times a day for 14 days following surgery. Demographic and clinical data were well matched between the two groups. It was found that AT877 reduced angiographically demonstrable vasospasm by 38% (from 61% in the placebo group to 38% in the AT877 group, p = 0.0023), low-density regions on computerized tomography associated with vasospasm by 58% (from 38% to 16%, p = 0.0013), and symptomatic vasospasm by 30% (from 50% to 35%, p = 0.0247). Furthermore, AT877 reduced the number of patients with a poor clinical outcome associated with vasospasm (moderate disability or worse on the Glasgow Outcome Scale at 1 month after SAH) by 54% (from 26% to 12%, p = 0.0152). There were no serious adverse events reported in the AT877 group. This is the first report of a placebo-controlled double-blind trial that has demonstrated a significant reduction in angiographically revealed vasospasm by intravenous drug therapy.

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