Nahal Mavaddat, Barbara J. Sahakian, Peter J. A. Hutchinson and Peter J. Kirkpatrick
Object. This study was conducted to define neuropsychological changes following operation for subarachnoid hemorrhage (SAH) caused by rupture of an anterior communicating artery (ACoA) aneurysm and to assess the influence of the timing of surgery to clip the aneurysm.
Methods. Cognitive outcome was evaluated using the Cambridge Neuropsychological Test Automated Battery in patients with an ACoA aneurysm that had caused an SAH. Adult patients younger than 70 years of age who had achieved a favorable neurological outcome (Glasgow Outcome Scale scores of 4 or 5) were studied 6 to 24 months postsurgery. Patients were divided into early (Days 0–3) and late surgery groups (after Day 3) according to the timing of surgery after the ictus. Neuropsychological analysis was performed by reviewers who were blinded to the timing of surgery.
Forty-seven patients whose mean age was 51.5 years were tested. They were compared with age- and intelligence quotient (IQ)—matched controls by using premorbid IQ as estimated on the National Adult Reading Test. Patients showed deficiencies in several tasks of verbal fluency, pattern recognition, and spatial working memory; this profile of deficits was similar to that seen in patients who underwent temporal lobe excisions. However, there was no significant difference in cognitive performance between the early and late surgery groups.
Conclusions. After open surgery for ruptured ACoA aneurysms, patients who have achieved a favorable neurological outcome still exhibit significant cognitive deficits, primarily in tests sensitive to temporal lobe dysfunction. However, early surgery does not carry a higher risk of neuropsychological disability.
Ming-Yuan Tseng, Peter J. Hutchinson and Peter J. Kirkpatrick
In a previous randomized controlled trial, the authors demonstrated that acute erythropoietin (EPO) therapy reduced severe vasospasm and delayed ischemic deficits (DIDs) following aneurysmal subarachnoid hemorrhage. In this study, the authors aimed to investigate the potential interaction of neurovascular protection by EPO with age, sepsis, and concurrent statin therapy.
The clinical events of 80 adults older than 18 years and with < 72 hours of aneurysmal subarachnoid hemorrhage, who were randomized to receive 30,000 U of intravenous EPO-β or placebo every 48 hours for a total of 3 doses, were analyzed by stratification according to age (< or ≥ 60 years), sepsis, or concomitant statin therapy. End points in the trial included cerebral vasospasm and impaired autoregulation on transcranial Doppler ultrasonography, DIDs, and unfavorable outcome at discharge and at 6 months measured with the modified Rankin Scale and Glasgow Outcome Scale. Analyses were performed using the t-test and/or ANOVA for repeated measurements.
Younger patients (< 60 years old) or those without sepsis obtained benefits from EPO by a reduction in vasospasm, impaired autoregulation, and unfavorable outcome at discharge. Compared with nonseptic patients taking EPO, those with sepsis taking EPO had a lower absolute reticulocyte count (nonsepsis vs sepsis, 143.5 vs. 105.8 × 109/L on Day 6; p = 0.01), suggesting sepsis impaired both hematopoiesis and neurovascular protection by EPO. In the EPO group, none of the statin users suffered DIDs (p = 0.078), implying statins may potentiate neuroprotection by EPO.
Erythropoietin-related neurovascular protection appears to be attenuated by old age and sepsis and enhanced by statins, an important finding for designing Phase III trials.
Angelos G. Kolias, Peter J. Hutchinson, Dion G. Morton, Jane M. Blazeby and Peter McCulloch
Peter J. Hutchinson, Mark T. O'Connell, Pippa G. Al-Rawi, Lynn B. Maskell, Rupert Kett-White, Arun K. Gupta, Hugh K. Richards, David B. Hutchinson, Peter J. Kirkpatrick and John D. Pickard
Object. Clinical microdialysis enables monitoring of the cerebral extracellular chemistry of neurosurgical patients. Introduction of the technique into different hospitals' neurosurgical units has resulted in variations in the method of application. There are several variables to be considered, including length of the catheter membrane, type of perfusion fluid, flow rate of perfusion fluid, and on-line compared with delayed analysis of samples. The objects of this study were as follows: 1) to determine the effects of varying catheter characteristics on substance concentration; 2) to determine the relative recovery and true extracellular concentration by varying the flow rate and extrapolating to zero flow; and 3) to compare substance concentration obtained using a bedside enzyme analyzer with that of off-line high-performance liquid chromatography (HPLC).
Methods. A specially designed bolt was used to conduct two adjacent microdialysis catheters into the frontal cortex of patients with head injury or poor-grade subarachnoid hemorrhage who were receiving ventilation. One reference catheter (10-mm membrane, perfused with Ringer's solution at 0.3 µl/minute) was constant for all studies. The other catheter was varied in terms of membrane length (10 mm or 30 mm), perfusion fluid (Ringer's solution or normal saline), and flow rate (0.1–1.5 µl/minute). The effect of freezing the samples on substance concentration was established by on-line analysis and then repeated analysis after storage at −70°C for 3 months. Samples assayed with the bedside enzyme analyzer were reassessed using HPLC for the determination of glutamate concentrations.
Conclusions. Two adjacent microdialysis catheters that were identical in membrane length, perfusion fluid, and flow rate showed equivalent results. Variations in perfusion fluid and freezing and thawing of samples did not result in differences in substance concentration. Catheter length had a significant impact on substance recovery. Variations in flow rate enabled the relative recovery to be calculated using a modification of the extrapolation-to-zero-flow method. The recovery was approximately 70% at 0.3 µl/minute and 30% at 1 µl/minute (10-mm membrane) for all analytes. Glutamate results obtained with the enzyme analyzer showed good correlation with those from HPLC.
Marek Czosnyka, Marcella Balestreri, Luzius Steiner, Piotr Smielewski, Peter J. Hutchinson, Basil Matta and John D. Pickard
Object. The object of this study was to investigate whether a failure of cerebrovascular autoregulation contributes to the relationship between age and outcome in patients following head injury.
Methods. Data obtained from continuous bedside monitoring of intracranial pressure (ICP), arterial blood pressure (ABP), and cerebral perfusion pressure (CPP = ABP — ICP) in 358 patients with head injuries and intermittent monitoring of transcranial Doppler blood flow velocity (FV) in the middle cerebral artery in 237 patients were analyzed retrospectively. Indices used to describe cerebral autoregulation and pressure reactivity were calculated as correlation coefficients between slow waves of systolic FV and CPP (autoregulation index [ARI]) and between ABP and ICP (pressure reactivity index [PRI]).
Older patients had worse outcomes after brain trauma than younger patients (p = 0.00001), despite the fact that the older patients had higher initial Glasgow Coma Scale scores (p = 0.006). When age was considered as an independent variable, it appeared that ICP decreased with age (p = 0.005), resulting in an increasing mean CPP (p = 0.0005). Blood FV was not dependent on age (p = 0.58). Indices of autoregulation and pressure reactivity demonstrated a deterioration in cerebrovascular control with advancing age (PRI: p = 0.003; ARI: p = 0.007).
Conclusions. An age-related decline in cerebrovascular autoregulation was associated with a relative deterioration in outcome in elderly patients following head trauma.
Ming-Yuan Tseng, Pippa G. Al-Rawi, Marek Czosnyka, Peter J. Hutchinson, Hugh Richards, John D. Pickard and Peter J. Kirkpatrick
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.
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.
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).
Bolus systemic hypertonic saline therapy may be used for reversal of cerebral ischemia to normal perfusion in patients with poor-grade SAH.
Rupert Kett-White, Peter J. Hutchinson, Pippa G. Al-Rawi, Marek Czosnyka, Arun K. Gupta, John D. Pickard and Peter J. Kirkpatrick
Object. The aim of this study was to investigate potential episodes of cerebral ischemia during surgery for large and complicated aneurysms, by examining the effects of arterial temporary clipping and the impact of confounding variables such as blood pressure and cerebrospinal fluid (CSF) drainage.
Methods. Brain tissue PO2, PCO2, and pH, as well as temperature and extracellular glucose, lactate, pyruvate, and glutamate were monitored in 46 patients by using multiparameter sensors and microdialysis. Baseline data showed that brain tissue PO2 decreased significantly, below a mean arterial pressure (MAP) threshold of 70 mm Hg. Further evidence of its relationship with cerebral perfusion pressure was shown by an increase in mean brain tissue PO2 after drainage of CSF from the basal cisterns (Wilcoxon test, p < 0.01). Temporary clipping was required in 31 patients, with a mean total duration of 14 minutes (range 3–52 minutes), causing brain tissue PO2 to decrease and brain tissue PCO2 to increase (Wilcoxon test, p < 0.01). In patients in whom no subsequent infarction developed in the monitored region, brain tissue PO2 fell to 11 mm Hg (95% confidence interval 8–14 mm Hg). A brain tissue PO2 level below 8 mm Hg for 30 minutes was associated with infarction in any region (p < 0.05 according to the Fisher exact test); other parameters were not predictive of infarction. Intermittent occlusions of less than 30 minutes in total had little effect on extracellular chemistry. Large glutamate increases were only seen in two patients, in both of whom brain tissue PO2 during occlusion was continuously lower than 8 mm Hg for longer than 38 minutes.
Conclusions. The brain tissue PO2 decreases with hypotension, and, when it is below 8 mm Hg for longer than 30 minutes during temporary clipping, it is associated with increasing extracellular glutamate levels and cerebral infarction.
Ming-Yuan Tseng, Peter J. Hutchinson, Hugh K. Richards, Marek Czosnyka, John D. Pickard, Wendy N. Erber, Stephen Brown and Peter J. Kirkpatrick
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.
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.
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).
This preliminary study showed that EPO seemed to reduce delayed cerebral ischemia following aSAH via decreasing severity of vasospasm and shortening impaired autoregulation.
Ming-Yuan Tseng, Peter J. Hutchinson, Carole L. Turner, Marek Czosnyka, Hugh Richards, John D. Pickard and Peter J. Kirkpatrick
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.
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.
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).
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.