Ming-Yuan Tseng

Effects of Acute Treatment With Pravastatin on Cerebral Vasospasm, Autoregulation, and Delayed Ischemic Deficits After Aneurysmal Subarachnoid Hemorrhage: A Phase II Randomized Placebo-Controlled Trial

Background and Purpose— Statins may improve cerebral vasomotor reactivity through cholesterol-dependent and -independent mechanisms. A phase II randomized controlled trial was conducted to examine the hypothesis that acute pravastatin treatment could improve cerebrovascular autoregulation and reduce vasospasm-related complications after aneurysmal subarachnoid hemorrhage (SAH). Methods— A total of 80 aneurysmal SAH (aSAH) patients (18 to 84 years of age) within 72 hours from the ictus were randomized equally to receive either oral pravastatin (40 mg) or placebo daily for up to 14 days. Primary end points were the incidence, duration, and severity of cerebral vasospasm, and duration of impaired autoregulation estimated from transcranial Doppler ultrasonography. Secondary end points were the incidence of vasospasm-related delayed ischemic deficits (DIDs) and disability at discharge. Results— Prerandomization characteristics were balanced between the 2 groups. No treatment-related complication was observed. The incidences of vasospasm and severe vasospasm were reduced by 32% (P=0.006) and 42% (P=0.044), respectively, and the duration of severe vasospasm was shortened by 0.8 days (P=0.068) in the pravastatin group. These measurements were maximal on the ipsilateral side of ruptured aneurysms. The duration of impaired autoregulation was shortened bilaterally (P≤0.01), and the incidence of vasospasm-related DIDs and mortality were decreased by 83% (P<0.001) and 75% (P=0.037), respectively, in the pravastatin group. Conclusion— Acute treatment with pravastatin after aSAH is safe and ameliorates cerebral vasospasm, improves cerebral autoregulation, and reduces vasospasm-related DID. Unfavorable outcome at discharge was reduced primarily because of a reduction in overall mortality. This is the first demonstration of clinical benefits with immediate statin therapy for an acute cerebrovascular disorder.

Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial: Clinical article

OBJECT Delayed ischemic deficits (DIDs), a major source of disability following aneurysmal subarachnoid hemorrhage (aSAH), are usually associated with severe cerebral vasospasm and impaired autoregulation. Systemic erythropoietin (EPO) therapy has been demonstrated to have neuroprotective properties acting via EPO receptors on cerebrovascular endothelia and ischemic neurons. In this trial, the authors explored the potential neuroprotective effects of acute EPO therapy following aSAH. METHODS Within 72 hours of aSAH, 80 patients (age range 24-82 years) were randomized to receive intravenous EPO (30,000 U) or placebo every 48 hours for a total of 90,000 U. Primary end points were the incidence, duration, and severity of vasospasm and impaired autoregulation on transcranial Doppler ultrasonography. Secondary end points were incidence of DIDs and outcome at discharge and at 6 months. RESULTS Randomization characteristics were balanced except for age, with the EPO group being older (mean age 59.6 vs 53.3 years, p=0.034). No differences were demonstrated in the incidence of vasospasm and adverse events; however, patients receiving EPO had a decreased incidence of severe vasospasm from 27.5 to 7.5% (p=0.037), reduced DIDs with new cerebral infarcts from 40.0 to 7.5% (p=0.001), a shortened duration of impaired autoregulation (ipsilateral side, p<0.001), and more favorable outcome at discharge (favorable Glasgow Outcome Scale score, p=0.039). Among the 71 survivors, the EPO group had fewer deficits measured with National Institutes of Health Stroke Scale (median Score 2 vs 6, p=0.008). CONCLUSIONS This preliminary study showed that EPO seemed to reduce delayed cerebral ischemia following aSAH via decreasing severity of vasospasm and shortening impaired autoregulation.

Effects of Acute Pravastatin Treatment on Intensity of Rescue Therapy, Length of Inpatient Stay, and 6-Month Outcome in Patients After Aneurysmal Subarachnoid Hemorrhage

Background and Purpose— We have previously demonstrated that acute pravastatin therapy after aneurysmal subarachnoid hemorrhage ameliorates vasospasm-related delayed ischemic deficits. This study assesses the effects of pravastatin on the frequency and intensity for rescue therapy, length of inpatient stay, and long-term outcome at 6 months. Methods— Eighty aneurysmal subarachnoid hemorrhage patients (age 18 to 84 years, onset 1.8±1.3 days) were randomized to receive daily oral pravastatin (40 mg) or placebo for up to 14 days. Clinical events were recorded during the trial. Six-month outcome was assessed using the Short Form 36 and the modified Rankin Scale. Results— Although no significant difference in the outcome at discharge was found between the trial groups, multivariate analysis showed pravastatin therapy reduced unfavorable outcome by 73% (P=0.041). The benefit persisted at 6 months (P=0.063) and was notable in the physical (P<0.001) and psychosocial (P<0.001) aspects measured using Short Form 36. Furthermore, the acute pravastatin therapy reduced the requirement for triple-H therapy (hypertensive, hypervolemic, hemodilution; P=0.045) and mortality related to vasospasm (P=0.02) and sepsis (P=0.001); no significant difference was found in the length of inpatient stay between the trial groups. Conclusions— This trial demonstrates that acute statin treatment reduces traditional rescue therapy for vasospasm after aneurysmal subarachnoid hemorrhage. Improvement in early outcome has proved robust at 6 months, particularly in relation to physical and psychosocial (Short Form 36) outcome.

Effect of Hypertonic Saline on Cerebral Blood Flow in Poor-Grade Patients With Subarachnoid Hemorrhage

Background and Purpose— The goal of this study was to examine the effects of hypertonic saline on cerebral blood flow (CBF) in poor-grade patients with subarachnoid hemorrhage. Methods— We administered 23.5% hypertonic saline (2 mL/kg IV) 1 time to 10 patients, 2 times to 7 patients, and 3 times to 1 patient. All patients had transcranial Doppler (TCD), intracranial pressure (ICP) monitoring, and analysis of serum sodium and osmolality; 6 had xenon CT (XeCT). Data were used to characterize the changes in CBF, cerebral vascular resistance (CVR), ICP, cerebral perfusion pressure (CPP), and potential rheological mechanisms of action. Results— In the first treatment episode, CPP increased 26.8% (P =0.0003, at 28.3 minutes) from a rise in mean arterial blood pressure (ABP) of 10.5% (P =0.02, at 22.2 minutes) and a fall in ICP (−74.7%, P =0.002, at 60.0 minutes). Flow velocity (FV) of the middle cerebral artery increased 70.8% (P =0.00005, at 20.0 minutes), resulting in a corresponding fall in estimated CVR (−26.6%, P =0.01, at 16.3 minutes). The half-lives of effects on ABP, CPP, ICP, FV, and estimated CVR were 20.0, 53.6, 139.1, 42.7, and 27.1 minutes, respectively. In the second treatment episode, all these parameters had the same response except estimated CVR, which did not reach statistical significance. XeCT confirmed the increase in CBF (22.9%, P =0.02) without regional differences. A fall in CBF after hypertonic saline was identified in only a single region of interest in a patient in whom baseline flow was low but not infarcted. Serum sodium rose by 11.4 and 8.8 mmol/L, and osmolality rose by 26.7 and 16.3 mosm/L in the first and second treatment episodes, respectively. Hemoglobin decreased by 0.7 and 0.6 g/L and hematocrit decreased by 1.9% and 2.4% in the first and second treatment episodes, respectively. Conclusions— We found that 23.5% hypertonic saline increases CBF in poor-grade patients with subarachnoid hemorrhage. These effects are associated with improved indexes of blood rheology. Potential therapeutic benefits are discussed.

Hypertonic Saline In Patients With Poor-Grade Subarachnoid Hemorrhage Improves Cerebral Blood Flow, Brain Tissue Oxygen, and pH

Background and Purpose— Delayed cerebral ischemia and infarction due to reduced CBF remains the leading cause of poor outcome after aneurysmal subarachnoid hemorrhage. Hypertonic saline (HS) is associated with an increase in CBF. This study explores whether CBF enhancement with HS in patients with poor-grade subarachnoid hemorrhage is associated with improved cerebral tissue oxygenation. Methods— Continuous monitoring of arterial blood pressure, intracranial pressure, cerebral perfusion pressure, brain tissue oxygen, carbon dioxide, pH, and middle cerebral artery flow velocity was performed in 44 patients. Patients were given an infusion (2 mL/kg) of 23.5% HS. In 16 patients, xenon CT scanning was also performed. CBF in a region surrounding the tissue oxygen sensor was calculated. Data are mean±SD. Results— Thirty minutes postinfusion, a significant increase in arterial blood pressure, cerebral perfusion pressure, flow velocity, brain tissue pH, and brain tissue oxygen was seen together with a decrease in intracranial pressure (P<0.05). Intracranial pressure remained reduced for >300 minutes and flow velocity elevated for >240 minutes. A significant increase in brain tissue oxygen persisted for 240 minutes. Average baseline regional CBF was 33.9±13.5 mL/100 g/min, rising by 20.3%±37.4% (P<0.05) after HS. Patients with favorable outcome responded better to HS in terms of increased CBF, brain tissue oxygen, and pH and reduced intracranial pressure compared with those with an unfavorable outcome. A sustained increase in brain tissue oxygen (beyond 210 minutes) was associated with favorable outcome (P<0.023). Conclusion— HS augments CBF in patients with poor-grade subarachnoid hemorrhage and significantly improves cerebral oxygenation for 4 hours postinfusion. Favorable outcome is associated with an improvement in brain tissue oxygen beyond 210 minutes.

Enhancement of cerebral blood flow using systemic hypertonic saline therapy improves outcome in patients with poor-grade spontaneous subarachnoid hemorrhage.

OBJECT Systemic administration of 23.5% hypertonic saline enhances cerebral blood flow (CBF) in patients with poor-grade spontaneous subarachnoid hemorrhage (SAH). Whether the increment of change in CBF correlates with changes in autoregulation of CBF or outcome at discharge remains unknown. METHODS Thirty-five patients with poor-grade spontaneous SAH received 2 ml/kg 23.5% hypertonic saline intravenously, and they underwent bedside transcranial Doppler (TCD) ultrasonography and intracranial pressure (ICP) monitoring. Seventeen of them underwent Xe-enhanced computed tomography (CT) scanning for measuring CBF. Outcome was assessed using the modified Rankin Scale (mRS) at discharge from the hospital. The data were analyzed using repeated-measurement analysis of variance and Dunnett correction. A comparison was made between patients with favorable and unfavorable outcomes using multivariate logistic regression. RESULTS The authors observed a maximum increase in blood pressure by 10.3% (p < 0.05) and cerebral perfusion pressure (CPP) by 21.2% (p < 0.01) at 30 minutes, followed by a maximum decrease in ICP by 93.1% (p < 0.01) at 60 minutes. Changes in ICP and CPP persisted for longer than 180 and 90 minutes, respectively. The results of TCD ultrasonography showed that the baseline autoregulation was impaired on the ipsilateral side of ruptured aneurysm, and increments in flow velocities were higher and lasted longer on the contralateral side (48.75% compared with 31.96% [p = 0.045] and 180 minutes compared with 90 minutes [p < 0.05], respectively). The autoregulation was briefly impaired on the contralateral side during the infusion. A dose-dependent effect of CBF increments on favorable outcome was seen on Xe-CT scans (mRS Score 1-3, odds ratio 1.27 per 1 ml/100 g tissue x min, p = 0.045). CONCLUSIONS Bolus systemic hypertonic saline therapy may be used for reversal of cerebral ischemia to normal perfusion in patients with poor-grade SAH.

Effects of fluid therapy following aneurysmal subarachnoid haemorrhage: a prospective clinical study.

Blood transfusions and intravenous fluids are commonly employed as rescue therapy for delayed cerebral ischaemia following aneurysmal subarachnoid haemorrhage (aSAH). We sought to determine effects of various fluid supplements on clinical outcome in patients following aSAH. Clinical events and laboratory data of 160 aSAH patients were prospectively collected as part of 2 randomised controlled trials. Outcomes at discharge and at 6 months were measured with Glasgow Outcome Scale (GOS). Favourable outcome was defined as good recovery or moderate disability on GOS. All of the 160 patients received intravenous fluid supplements with crystalloids; 122 (76.3%) also received synthetic colloids (4% succinylated gelatine or 6% pentastarch). A higher daily dose of synthetic colloids for initial resuscitation seemed to be associated with more requirements for blood transfusions (p = 0.003) and occurrence of vasospasm in poor-grade patients (p = 0.081), but blood transfusions themselves were not associated with occurrence of vasospasm. Compared with patients not receiving synthetic colloids, those receiving synthetic colloids had increased haemodilution, elevated inflammatory profiles, and decreased duration and strength of intact cerebral autoregulation. Multivariate analyses identified that blood transfusions (odds ratio, OR 3.38, p = 0.035) were associated with unfavourable outcome at discharge. Colloid fluids (OR 2.53/L/day, p = 0.025) promoted unfavourable outcome at 6 months (OR 4.45, p = 0.035), while crystalloids decreased unfavourable outcome (OR 0.27/L/day, p = 0.005). Associations between synthetic colloids and crystalloids with GOS at 6 months were dose-related. Intravenous fluid therapy using synthetic colloids or blood transfusions may be associated with increased unfavourable outcome following aSAH.

Biological effects of acute pravastatin treatment in patients after aneurysmal subarachnoid hemorrhage : a double-blind, placebo-controlled trial

OBJECT The authors previously demonstrated that acute pravastatin therapy in patients after aneurysmal subarachnoid hemorrhage (SAH) ameliorates vasospasm-related delayed ischemic neurological deficits. The object of this study was to continue to examine potential mechanisms of these beneficial effects. METHODS Eighty patients with aneurysmal SAH (age range 18-84 years; time to onset 1.8 +/- 1.3 days) were enrolled in a double-blind study and randomized to receive 40 mg of oral pravastatin or placebo daily for as long as 14 days. Daily transcranial Doppler ultrasonography and blood tests every 3 days (including full blood cell counts, coagulation profiles, fasting glucose and lipid profiles, and serum biochemistry) were performed during the trial period. RESULTS No significant differences were found in baseline laboratory data between the trial groups. Subsequent measurements during the 14-day trial showed reduced low-density lipoprotein (LDL) cholesterol levels and total/high-density lipoprotein cholesterol ratios between Days 3 and 15 (p < 0.05), and increased D-dimer levels (p < 0.05) on Day 6, in the pravastatin group. Patients who received pravastatin but developed vasospasm had significantly lower baseline LDL cholesterol levels or a less extensive reduction in LDL cholesterol levels (p < 0.05), and greater increases in plasma fibrinogen (p = 0.009) and serum C-reactive protein on Day 3 (p = 0.007), compared with those patients without vasospasm. The reduction in LDL cholesterol levels on Day 3 in the placebo group correlated with the duration of normal cerebral autoregulation on the ipsilateral side of the ruptured aneurysm (p = 0.002). CONCLUSIONS In addition to functioning through a cholesterol-independent pathway, cerebrovascular protection from acute statin therapy following aneurysmal SAH may also function through cholesterol-dependent mechanisms.

Cerebral blood flow augmentation in patients with severe subarachnoid haemorrhage

Following aneurysmal subarachnoid haemorrhage (SAH), cerebral blood flow (CBF) may be reduced, resulting in poor outcome due to cerebral ischaemia and subsequent stroke. Hypertonic saline (HS) is known to be effective in reducing intracranial pressure (ICP). We have previously shown a 20-50% increase in CBF in ischaemic regions after intravenous infusion of HS. This study aims to determine the effect of HS on CBF augmentation, substrate delivery and metabolism. Continuous monitoring of arterial blood pressure (ABP), ICP, cerebral perfusion pressure (CPP), brain tissue oxygen (PbO2), middle cerebral artery flow velocity (FV), and microdialysis was performed in 14 poor grade SAH patients. Patients were given an infusion of 23.5% HS, and quantified xenon computerised tomography scanning (XeCT) was carried out before and after the infusion in 9 patients. The results showed a significant increase in ABP, CPP, FV and PbO2, and a significant decrease in ICP (p < 0.05). Nine patients showed a decrease in lactate-pyruvate ratio at 60 minutes following HS infusion. These results show that HS safely and effectively augments CBF in patients with poor grade SAH and significantly improves cerebral oxygenation. An improvement in cerebral metabolic status in terms of lactate-pyruvate ratio is also associated with HS infusion.

The VASOGRADE: A Simple Grading Scale for Prediction of Delayed Cerebral Ischemia After Subarachnoid Hemorrhage

Background and Purpose— Patients are classically at risk of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. We validated a grading scale—the VASOGRADE—for prediction of DCI. Methods— We used data of 3 phase II randomized clinical trials and a single hospital series to assess the relationship between the VASOGRADE and DCI. The VASOGRADE derived from previously published risk charts and consists of 3 categories: VASOGRADE-Green (modified Fisher scale 1 or 2 and World Federation of Neurosurgical Societies scale [WFNS] 1 or 2); VASOGRADE-Yellow (modified Fisher 3 or 4 and WFNS 1–3); and VASOGRADE-Red (WFNS 4 or 5, irrespective of modified Fisher grade). The relation between the VASOGRADE and DCI was assessed by logistic regression models. The predictive accuracy of the VASOGRADE was assessed by receiver operating characteristics curve and calibration plots. Results— In a cohort of 746 patients, the VASOGRADE significantly predicted DCI (P<0.001). The VASOGRADE-Yellow had a tendency for increased risk for DCI (odds ratio [OR], 1.31; 95% CI, 0.77–2.23) when compared with VASOGRADE-Green; those with VASOGRADE-Red had a 3-fold higher risk of DCI (OR, 3.19; 95% CI, 2.07–4.50). Studies were not a significant confounding factor between the VASOGRADE and DCI. The VASOGRADE had an adequate discrimination for prediction of DCI (area under the receiver operating characteristics curve=0.63) and good calibration. Conclusions— The VASOGRADE results validated previously published risk charts in a large and diverse sample of subarachnoid hemorrhage patients, which allows DCI risk stratification on presentation after subarachnoid hemorrhage. It could help to select patients at high risk of DCI, as well as standardize treatment protocols and research studies.