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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.

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Ming-Yuan Tseng, Peter J. Hutchinson, and Peter J. Kirkpatrick

Object

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.

Methods

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.

Results

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.

Conclusions

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.

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Paul S. Slosberg

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Carole L. Turner, Susan Tebbs, Piotr Smielewski, and Peter J. Kirkpatrick

Object. Applanation tonometry is a noninvasive method of assessing both peripheral and central arterial blood pressure (BP) profiles. In this study the authors examine whether there are differences in these profiles in patients with intracranial aneurysms when compared with age-matched controls.

Methods. Carotid artery (CA) and derived aortic BP waveforms were obtained using a pulse wave analysis system. The ratio of the pressure wave amplitude above the systolic shoulder to the total systolic BP (augmentation index [AI]) was recorded.

One hundred seventy-three patients with intracranial aneurysms (23 unruptured lesions) and 173 healthy control volunteers were examined. For the patients with aneurysms the right and left CA AIs (mean ± standard deviation) were 125.6 ± 23.1% and 128.3 ± 22.1%, respectively. Corresponding values for the control group were 118.4 ± 22.6% and 119.4 ± 21.8%. The calculated AI for the ascending aorta was 29.8 ± 10.5% and 25.6 ± 12.2% for patients with aneurysms and control volunteers, respectively. Significant asymmetry in CA AI was seen in patients with aneurysms, the left being greater (p = 0.002). No significant differences were seen in mean BP (108 ± 14 mm Hg in patients with aneurysms compared with 106 ± 16 mm Hg in controls; p = 0.2). Multivariate analysis excluded the influence of BP and other potential confounding vascular risk factors for increased AI.

Conclusions. Significant differences in AI, both in magnitude and symmetry, were identified in patients with intracranial aneurysms when compared with matched controls.

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Peter J. Kirkpatrick, Joseph Lam, Pippa Al-Rawi, Piotr Smielewski, and Marek Czosnyka

Object. Signal changes in adult extracranial tissues may have a profound effect on cerebral near-infrared spectroscopy (NIRS) measurements. During carotid surgery NIRS signals provide the opportunity to determine the relative contributions from the intra- and extracranial vascular territories, allowing for a more accurate quantification. In this study the authors applied multimodal monitoring methods to patients undergoing carotid endarterectomy and explored the hypothesis that NIRS can define thresholds for cerebral ischemia, provided extracranial NIRS signal changes are identified and removed. Relative criteria for intraoperative severe cerebral ischemia (SCI) were applied to 103 patients undergoing carotid endarterectomy.

Methods. One hundred three patients underwent carotid endarterectomy. An intraoperative fall in transcranial Doppler—detected middle cerebral artery flow velocity (%ΔFV) of greater than 60% accompanied by a sustained fall in cortical electrical activity were adopted as criteria for SCI. Ipsilateral frontal NIRS recorded the total difference in concentrations of oxyhemoglobin and deoxyhemoglobin (Total ΔHbdiff). Interrupted time series analysis following clamping of the external carotid artery (ECA) and the internal carotid artery (ICA) allowed the different vascular components of Total ΔHbdiff (ECA ΔHbdiff and ICA ΔHbdiff) to be identified.

Data obtained in 76 patients were deemed suitable. A good correlation between %ΔFV and ICA ΔHbdiff (r = 0.73, p < 0.0001) was evident. Sixteen patients (21%) fulfilled the criteria for SCI. All patients who demonstrated an ICA ΔHbdiff of greater than 6.8 µmol/L showed SCI, and in two patients within this group nondisabling watershed infarction developed, as seen on postoperative computerized tomography scans. No patient with an ICA ΔHbdiff less than 5 µmol/L exhibited SCI or suffered a stroke. Within the resolution of the criteria used an ICA ΔHbdiff threshold of 6.8 µmol/L provided 100% specificity for SCI, whereas an ICA ΔHbdiff less than 5 µmol/L was 100% sensitive for excluding SCI. When Total ΔHbdiff was used without removing the ECA component, no thresholds for SCI were apparent.

Conclusions. Carotid endarterectomy provides a stable environment for exploring NIRS-quantified thresholds for SCI in the adult head.

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Carole L. Turner, Ian B. Wilkinson, and Peter J. Kirkpatrick

Object

Patients with intracranial aneurysms tend toward raised blood pressure and abnormal pulse pressure profiles. The authors have investigated the influence of three antihypertension agents on blood pressure and pulse pressure waveforms in patients with known intracranial aneurysms, with a view to assessing the potential benefits of longterm antihypertension therapy on the progression of unruptured intracranial aneurysms.

Methods

Nineteen patients with a mean age of 56 years (range 38–76 years) were recruited for this study. All patients had confirmed intracranial aneurysms. A double-blind, randomized, crossover study was performed using perindopril, irbesartan, isosorbide mononitrate, and a placebo. Blood pressure and pulse pressure waveforms were assessed at the end of each 4-week treatment period.

Perindopril and irbesartan were well tolerated. For all measured parameters except heart rate (p = 0.03), no significant difference between baseline and placebo was identified. Each drug when compared with placebo reduced peripheral arterial blood pressure. Perindopril significantly decreased mean blood pressure by 10 mm Hg (p = 0.004), irbesartan by 9 mm Hg (p = 0.004), and isosorbide mononitrate by 13 mm Hg (p = 0.005).

The administration of each drug effected a significant reduction in the carotid artery augmentation index (AIX) compared with baseline values (perindopril p = 0.01, irbesartan p = 0.0002, and isosorbide mononitrate p = 0.03). There was also a significant difference in the AIX between irbesartan and the placebo (p = 0.05). Compared with the placebo, there was a significant difference in AIX (adjusted for heart rate) following the administration of irbesartan (p = 0.003) and isosorbide mononitrate (p = 0.01), but not with perindopril (p = 0.17).

Conclusions

Irbesartan appears to be the most effective treatment for the combined suppression of blood pressure and AIX in patients with intracranial aneurysms and has a high degree of patient tolerance.

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Peter J. Kirkpatrick, Pietr Smielewski, Peter C. Whitfield, Marik Czosnyka, David Menon, and John D. Pickard

✓ Near-infrared spectroscopy was used to monitor changes in the cerebral oxygenation state in 13 patients during carotid endarterectomy. Variations in the levels of the chromophores (oxygenated hemoglobin (HbO2), deoxygenated hemoglobin (Hb), and oxidized cytochrome (CytO2)), and the total hemoglobin content (tHb) were compared with changes in middle cerebral artery flow velocity measured using transcranial Doppler ultrasonography. Of eight patients who showed a fall in flow velocity on application of the internal carotid artery cross-clamp, seven demonstrated a rapid and closely correlated fall in HbO2 signal, and an increase in Hb. Levels of CytO2 and tHb remained unchanged. During endarterectomy, recovery of the HbO2 and Hb levels toward preclamp baseline values occurred in three of these patients. Intraoperative shunts accelerated recovery of HbO2 and Hb signals in two of three individuals. Release of the internal carotid cross-clamp resulted in a rapid increase in HbO2 and decrease in Hb signal in those patients in whom spontaneous recovery had not occurred; in five instances, a hyperemia evolved with raised flow velocity and HbO2 to above baseline values. Cross-clamping and subsequent reperfusion of the external carotid artery had no effect on any parameter measured. The authors conclude that near-infrared spectroscopy can register changes in cerebral oxygenation during carotid endarterectomy without significant contamination from extracranial tissues.

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Marek Czosnyka, Basil F. Matta, Piotr Smielewski, Peter J. Kirkpatrick, and John D. Pickard

Object. The authors studied the reliability of a new method for noninvasive assessment of cerebral perfusion pressure (CPP) in head-injured patients in which mean arterial blood pressure (ABP) and transcranial Doppler middle cerebral artery mean and diastolic flow velocities are measured.

Methods. Cerebral perfusion pressure was estimated (eCPP) over periods of continuous monitoring (20 minutes—2 hours, 421 daily examinations) in 96 head-injured patients (Glasgow Coma Scale score < 13) who were admitted to the intensive care unit. All patients were sedated, paralyzed, and ventilated. The eCPP and the measured CPP (ABP minus intracranial pressure, measured using an intraparenchymal microsensor) were compared.

The correlation between eCPP and measured CPP was r = 0.73; p < 10−6. In 71% of the examinations, the estimation error was less than 10 mm Hg and in 84% of the examinations, the error was less than 15 mm Hg. The method had a high positive predictive power (94%) for detecting low CPP (< 60 mm Hg). The eCPP also accurately reflected changes in measured CPP over time (r > 0.8; p < 0.001) in situations such as plateau and B waves of intracranial pressure, arterial hypotension, and refractory intracranial hypertension. A good correlation was found between the average measured CPP and eCPP when day-by-day variability was assessed in a group of 41 patients (r = 0.71).

Conclusions. Noninvasive estimation of CPP by using transcranial Doppler ultrasonography may be of value in situations in which monitoring relative changes in CPP is required without invasive measurement of intracranial pressure.

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Peter J. Kirkpatrick, Piotr Smielewski, Marek Czosnyka, David K. Menon, and John D. Pickard

✓ A multimodality recording system was used in 14 ventilated patients with closed head injury to assess the potential use of near-infrared spectroscopy (NIRS) in the neurointensive care unit. Signals of intracranial pressure, cerebral perfusion pressure, peripheral oxygen saturation, jugular venous saturation, and NIRS-derived changes in the chromophores of oxy- and deoxyhemoglobin were digitized and recorded. After a review of 886 hours of continuous monitoring, 376 hours were considered free from artifact and were entered for final analysis. In nine of the patients 38 events were recorded that demonstrated clear changes in cerebral perfusion pressure accompanied by hemodynamic changes in middle cerebral artery flow velocity (transcranial Doppler) and cortical perfusion (laser Doppler flowmetry). Near-infrared spectroscopy showed correlated changes in 37 events (97%) whereas jugular venous saturation monitoring registered only 20 (53%). There was associated peripheral oxygen desaturation in eight cases (21%), intracranial hypertension in 10 (26%), and cerebral hyperemia in eight (21%). The remaining 12 events (32%) appeared to be complex changes of uncertain origin. Iatrogenic factors were identified as causative in 14 cases (37%). The potential application of NIRS in adults and the importance of using multiple parameter recording systems in the interpretation of cerebral events are discussed.