sodium-nitrite and Subarachnoid-Hemorrhage

Topics: Animals; Blood-Brain Barrier; Brain Diseases; Cerebral Arteries; Hemoglobins; Humans; Nitric Oxide; Nitric Oxide Donors; Sodium Nitrite; Subarachnoid Hemorrhage; Vasodilator Agents; Vasospasm, Intracranial

Subarachnoid haemorrhage (SAH) is associated with long-term disability, serious reduction in quality of life and significant mortality. Early brain injury (EBI) refers to the pathological changes in cerebral metabolism and blood flow that happen in the first few days after ictus and may lead on to delayed cerebral ischaemia (DCI). A disruption of the nitric oxide (NO) pathway is hypothesised as a key mechanism underlying EBI. A decrease in the alpha-delta power ratio (ADR) of the electroencephalogram has been related to cerebral ischaemia. In an experimental medicine study, we tested the hypothesis that intravenous sodium nitrite, an NO donor, would lead to increases in ADR. We studied 33 patients with acute aneurysmal SAH in the EBI phase. Participants were randomised to either sodium nitrite or saline infusion for 1 h. EEG measurements were taken before the start of and during the infusion. Twenty-eight patients did not develop DCI and five patients developed DCI. In the patients who did not develop DCI, we found an increase in ADR during sodium nitrite versus saline infusion. In the five patients who developed DCI, we did not observe a consistent pattern of ADR changes. We suggest that ADR power changes in response to nitrite infusion reflect a NO-mediated reduction in cerebral ischaemia and increase in perfusion, adding further evidence to the role of the NO pathway in EBI after SAH. Our findings provide the basis for future clinical trials employing NO donors after SAH.

Topics: Biomarkers; Brain Injuries; Brain Ischemia; Cerebral Infarction; Electroencephalography; Humans; Quality of Life; Sodium Nitrite; Subarachnoid Hemorrhage

Intravenous sodium nitrite has been shown to prevent and reverse cerebral vasospasm in a primate model of subarachnoid hemorrhage (SAH). The present Phase IIA dose-escalation study of sodium nitrite was conducted to determine the compound's safety in humans with aneurysmal SAH and to establish its pharmacokinetics during a 14-day infusion. Methods In 18 patients (3 cohorts of 6 patients each) with SAH from a ruptured cerebral aneurysm, nitrite (3 patients) or saline (3 patients) was infused. Sodium nitrite and saline were delivered intravenously for 14 days, and a dose-escalation scheme was used for the nitrite, with a maximum dose of 64 nmol/kg/min. Sodium nitrite blood levels were frequently sampled and measured using mass spectroscopy, and blood methemoglobin levels were continuously monitored using a pulse oximeter.. In the 14-day infusions in critically ill patients with SAH, there was no toxicity or systemic hypotension, and blood methemoglobin levels remained at 3.3% or less in all patients. Nitrite levels increased rapidly during intravenous infusion and reached steady-state levels by 12 hours after the start of infusion on Day 1. The nitrite plasma half-life was less than 1 hour across all dose levels evaluated after stopping nitrite infusions on Day 14.. Previous preclinical investigations of sodium nitrite for the prevention and reversal of vasospasm in a primate model of SAH were effective using doses similar to the highest dose examined in the current study (64 nmol/kg/min). Results of the current study suggest that safe and potentially therapeutic levels of nitrite can be achieved and sustained in critically ill patients after SAH from a ruptured cerebral aneurysm.

Topics: Adult; Aged; Aneurysm, Ruptured; Critical Illness; Drug Administration Schedule; Female; Humans; Indicators and Reagents; Infusions, Intravenous; Intracranial Aneurysm; Male; Middle Aged; Sodium Nitrite; Subarachnoid Hemorrhage

Aneurysmal subarachnoid haemorrhage (SAH) is a devastating subset of stroke. One of the major determinates of morbidity is the development of delayed cerebral ischemia (DCI). Disruption of the nitric oxide (NO) pathway and consequently the control of cerebral blood flow (CBF), known as cerebral autoregulation, is believed to play a role in its pathophysiology. Through the pharmacological manipulation of in vivo NO levels using an exogenous NO donor we sought to explore this relationship. Phase synchronisation index (PSI), an expression of the interdependence between CBF and arterial blood pressure (ABP) and thus cerebral autoregulation, was calculated before and during sodium nitrite administration in 10 high-grade SAH patients acutely post-rupture. In patients that did not develop DCI, there was a significant increase in PSI around 0.1 Hz during the administration of sodium nitrite (33%; p-value 0.006). In patients that developed DCI, PSI did not change significantly. Synchronisation between ABP and CBF at 0.1 Hz has been proposed as a mechanism by which organ perfusion is maintained, during periods of physiological stress. These findings suggest that functional NO depletion plays a role in impaired cerebral autoregulation following SAH, but the development of DCI may have a distinct pathophysiological aetiology.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arterial Pressure; Cerebrovascular Circulation; Female; Humans; Male; Middle Aged; Nitric Oxide; Sodium Nitrite; Subarachnoid Hemorrhage; Young Adult

Aneurysmal subarachnoid hemorrhage often leads to death and poor clinical outcome. Injury occurring during the first 72 hours is termed "early brain injury," with disruption of the nitric oxide pathway playing an important pathophysiologic role in its development. Quantitative electroencephalographic variables, such as α/δ frequency ratio, are surrogate markers of cerebral ischemia. This study assessed the quantitative electroencephalographic response to a cerebral nitric oxide donor (intravenous sodium nitrite) to explore whether this correlates with the eventual development of delayed cerebral ischemia.. Unblinded pilot study testing response to drug intervention.. Neuroscience ICU, John Radcliffe Hospital, Oxford, United Kingdom.. Fourteen World Federation of Neurosurgeons grades 3, 4, and 5 patients (mean age, 52.8 yr [range, 41-69 yr]; 11 women).. IV sodium nitrite (10 μg/kg/min) for 1 hour.. Continuous electroencephalographic recording for 2 hours. The alpha/delta frequency ratio was measured before and during IV sodium nitrite infusion. Seven of 14 patients developed delayed cerebral ischemia. There was a +30% to +118% (range) increase in the alpha/delta frequency ratio in patients who did not develop delayed cerebral ischemia (p < 0.0001) but an overall decrease in the alpha/delta frequency ratio in those patients who did develop delayed cerebral ischemia (range, +11% to -31%) (p = 0.006, multivariate analysis accounting for major confounds).. Administration of sodium nitrite after severe subarachnoid hemorrhage differentially influences quantitative electroencephalographic variables depending on the patient's susceptibility to development of delayed cerebral ischemia. With further validation in a larger sample size, this response may be developed as a tool for risk stratification after aneurysmal subarachnoid hemorrhage.

Topics: Adult; Aged; Aneurysm, Ruptured; Brain Ischemia; Electroencephalography; Female; Humans; Infusions, Intravenous; Intensive Care Units; Intracranial Aneurysm; Male; Middle Aged; Nitric Oxide Donors; Pilot Projects; Sodium Nitrite; Subarachnoid Hemorrhage

Topics: Animals; Sodium Nitrite; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Subarachnoid hemorrhage (SAH)-induced vasospasm is a significant underlying cause of aneurysm rupture-related morbidity and death. While long-term intravenous infusion of sodium nitrite (NaNO(2)) can prevent cerebral vasospasm after SAH, it is not known if the intravenous administration of this compound can reverse established SAH-induced vasospasm. To determine if the intravenous infusion of NaNO(2) can reverse established vasospasm, the authors infused primates with the compound after SAH-induced vasospasm was established.. Subarachnoid hemorrhage-induced vasospasm was created in 14 cynomolgus macaques via subarachnoid implantation of a 5-ml blood clot. On Day 7 after clot implantation, animals were randomized to either control (saline infusion, 5 monkeys) or treatment groups (intravenous NaNO(2) infusion at 300 μg/kg/hr for 3 hours [7 monkeys] or 8 hours [2 monkeys]). Arteriographic vessel diameter was blindly analyzed to determine the degree of vasospasm before, during, and after treatment. Nitric oxide metabolites (nitrite, nitrate, and S-nitrosothiols) were measured in whole blood and CSF.. Moderate-to-severe vasospasm was present in all animals before treatment (control, 36.2% ± 8.8% [mean ± SD]; treatment, 45.5% ± 12.5%; p = 0.9). While saline infusion did not reduce vasospasm, NaNO(2) infusion significantly reduced the degree of vasospasm (26.9% ± 7.6%; p = 0.008). Reversal of the vasospasm lasted more than 2 hours after cessation of the infusion and could be maintained with a prolonged infusion. Nitrite (peak value, 3.7 ± 2.1 μmol/L), nitrate (18.2 ± 5.3 μmol/L), and S-nitrosothiols (33.4 ± 11.4 nmol/L) increased significantly in whole blood, and nitrite increased significantly in CSF.. These findings indicate that the intravenous infusion of NaNO(2) can reverse SAH-induced vasospasm in primates. Further, these findings indicate that a similar treatment paradigm could be useful in reversing cerebral vasospasm after aneurysmal SAH.

Topics: Animals; Cerebral Angiography; Disease Models, Animal; Infusions, Intravenous; Macaca fascicularis; Middle Cerebral Artery; Nitrates; Nitric Oxide; Nitrites; S-Nitrosothiols; Sodium Nitrite; Subarachnoid Hemorrhage; Treatment Outcome; Vasospasm, Intracranial

Delayed cerebral vasospasm causes permanent neurological deficits or death in at least 15% of patients following otherwise successful treatment for ruptured intracranial aneurysm. Decreased bioavailability of nitric oxide has been associated with the development of cerebral vasospasm.. To determine whether infusions of nitrite will prevent delayed cerebral vasospasm.. A total of 14 anesthetized cynomolgus monkeys had an autologous blood clot placed around the right middle cerebral artery. Cerebral arteriography was performed before clot placement and on days 7 and 14 to assess vasospasm. The study was conducted from August 2003 to February 2004.. A 90-mg sodium nitrite intravenous solution infused over 24 hours plus a 45-mg sodium nitrite bolus daily (n = 3); a 180-mg sodium nitrite intravenous solution infused over 24 hours (n = 3); or a control saline solution infusion (n = 8). Each was infused continuously for 14 days.. Nitrite, S-nitrosothiol, and methemoglobin levels in blood and cerebrospinal fluid and degree of arteriographic vasospasm.. In control monkeys, mean (SD) cerebrospinal fluid nitrite levels decreased from 3.1 (1.5) micromol/L to 0.4 (0.1) micromol/L at day 7 and to 0.4 (0.4) micromol/L at day 14 (P = .03). All 8 control monkeys developed significant vasospasm of the right middle cerebral artery, which was complicated by stroke and death in 1 animal. Sodium nitrite infusions increased the nitrite and methemoglobin levels (<2.1% of total hemoglobin) in the blood and cerebrospinal fluid without evoking systemic hypotension. Nitrite infusion prevented development of vasospasm (no animals developed significant vasospasm; mean [SD] reduction in right middle cerebral artery area on day 7 after subarachnoid hemorrhage of 8% [9%] in nitrite-treated monkeys vs 47% [5%] in saline-treated controls; P<.001). There was a negative correlation between the concentration of nitrite in cerebrospinal fluid and the degree of cerebral vasospasm (P<.001). Pharmacological effects of nitrite infusion were also associated with the formation of S-nitrosothiol in cerebrospinal fluid. There was no clinical or pathological evidence of nitrite toxicity.. Subacute sodium nitrite infusions prevented delayed cerebral vasospasm in a primate model of subarachnoid hemorrhage.

Topics: Animals; Cerebral Angiography; Disease Models, Animal; Infarction, Middle Cerebral Artery; Infusions, Intravenous; Macaca fascicularis; Methemoglobin; Nitrites; S-Nitrosothiols; Sodium Nitrite; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Topics: Animals; Disease Models, Animal; Haplorhini; Randomized Controlled Trials as Topic; Research Design; Sodium Nitrite; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Fresh blood and supernatants of blood-CSF mixtures incubated for 1 to 15 days were applied to the basilar artery of adult cats, and the degree of constriction was measured with a surgical microscope. The constriction due to fresh blood was weak and transient. It seems possible to assume that serotonin isolated from platelets participates greatly in the transient vasoconstriction induced by fresh blood. Supernatants of blood-CSF mixtures incubated for three days had weak activity in comparison with the powerful and long-lasting activity of those incubated for seven days. Furthermore, mixtures incubated for 15 days had little or no activity. This change in the vasoconstrictive activity was similar to, and coincides chronologically with clinical late spasm following subarachnoid haemorrhage 34. We investigated the vasospasmogenic substance in the seventh day mixture. Heat coagulation, ultrafiltration, sephadex G-100 gel-chromatography, disc-electrophoresis, and Spectrophotography show that extracellular oxyHb has a strong spasmogenic activity. In the 15th day mixture, oxyHb is spontaneously converted to metHb. Experimentally, oxyHb has a strong vasoconstrictive activity, and metHb has no vasoconstrictive activity. We have had success in oxidizing oxyHb into metHb with sodium nitrite, thus preventing experimental vasospasm.

Topics: Animals; Basilar Artery; Cats; Ischemic Attack, Transient; Methemoglobin; Oxyhemoglobins; Sodium Nitrite; Subarachnoid Hemorrhage; Vasoconstrictor Agents