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Ming-Yuan Tseng, Marek Czosnyka, Hugh Richards, John D. Pickard, and Peter J. Kirkpatrick

Object

The authors previously have demonstrated that acute treatment with pravastatin after aneurysmal subarachnoid hemorrhage (SAH) can ameliorate vasospasm-related delayed ischemic neurological deficits (DINDs). In the current study, they test the hypothesis that these effects are associated with improvement in indices describing autoregulation of cerebral blood flow.

Methods

In this double-blind study, 80 patients between the ages of 18 and 84 years who had aneurysmal SAH were randomized equally to receive either 40 mg of oral pravastatin or placebo once daily for up to 14 days (medication was started 1.8 ± 1.3 days after ictus). Autoregulation was measured using a daily transient hyperemic response test (THRT) on transcranial Doppler ultrasonography (800 measurements in 80 patients), and data were compared between the pravastatin and placebo groups and between patients with or without vasospasm, DINDs, or unfavorable outcome. Measurement of autoregulation also was performed using the pressure-reactivity index, a moving correlation coefficient between mean arterial and intracranial pressures (Days 0–5, 132 measurements in 32 patients).

There was no difference in baseline autoregulation indices between the trial groups. The members of the pravastatin group not only had a shorter duration of impaired autoregulation but also had stronger transient hyperemic response ratios (THRRs) bilaterally. A negative correlation existed between the mean flow velocity in the middle cerebral artery and THRRs. Onset of DINDs occurred when bilateral autoregulation failed. On Days 3, 4, and 5, the pressure-reactivity index correlated significantly with ipsilateral impaired autoregulation.

Conclusions

The neuroprotective effects of acute treatment with pravastatin following aneurysmal SAH are associated with enhancement of autoregulation. A routine and daily assessment of cerebral autoregulation by using the THRT may help identify patients at high risk of DINDs.

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Ming-Yuan Tseng, Pippa G. Al-Rawi, Marek Czosnyka, Peter J. Hutchinson, Hugh Richards, John D. Pickard, and Peter J. Kirkpatrick

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 × 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.

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Ming-Yuan Tseng, Peter J. Hutchinson, Carole L. Turner, Marek Czosnyka, Hugh Richards, John D. Pickard, and Peter J. Kirkpatrick

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.

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Ming-Yuan Tseng, Peter J. Hutchinson, Hugh K. Richards, Marek Czosnyka, John D. Pickard, Wendy N. Erber, Stephen Brown, and Peter J. Kirkpatrick

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.

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Mauro Bergui and Gianni Boris Bradac