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Marek Czosnyka, Peter Smielewski, Ivan Timofeev, Andrea Lavinio, Eric Guazzo, Peter Hutchinson and John D. Pickard

✓Many doctors involved in the critical care of head-injured patients understand intracranial pressure (ICP) as a number, characterizing the state of the brain pressure–volume relationships. However, the dynamics of ICP, its waveform, and secondarily derived indices portray useful information about brain homeostasis. There is circumstantial evidence that this information can be used to modify and optimize patients' treatment. Secondary variables, such as pulse amplitude and the magnitude of slow waves, index of compensatory reserve, and pressure–reactivity index (PRx), look promising in clinical practice. The optimal cerebral perfusion pressure (CPP) derived using the PRx is a new concept that may help to avoid excessive use of vasopressors in CPP-oriented therapy. However, the use of secondary ICP indices remains to be confirmed in clinical trials.

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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.

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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.

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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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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.

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Christos Lazaridis, Stacia M. DeSantis, Peter Smielewski, David K. Menon, Peter Hutchinson, John D. Pickard and Marek Czosnyka

Object

Based on continuous monitoring of the pressure reactivity index (PRx), the authors defined individualized intracranial pressure (ICP) thresholds by graphing the relationship between ICP and PRx. These investigators hypothesized that an “ICP dose” based on individually assessed ICP thresholds would correlate more closely with the 6-month outcome when compared with ICP doses derived by the recommended universal thresholds of 20 and 25 mm Hg.

Methods

This study was a retrospective analysis of prospectively collected data from 327 patients with severe traumatic brain injury.

Results

Individualized thresholds were visually identified from graphs of PRx versus ICP; PRx > 0.2 was the cutoff. Intracranial pressure doses were then computed as the cumulative area under the curve above the defined thresholds in graphing ICP versus time. The term “Dose 20” (D20) was used to refer to an ICP threshold of 20 mm Hg; the markers D25 and DPRx were calculated similarly. Separate logistic regression models were fit with death as the outcome and each dose as the predictor, both alone and adjusted for covariates. The discriminative ability of each dose for mortality was assessed by receiver operating characteristic AUC analysis in which 5-fold cross-validation was used. A clearly identifiable PRx-based threshold was possible in 224 patients (68%). The DPRx (AUC 0.81, 95% CI 0.74–0.87) was found to have the highest area under the curve (AUC) over both D20 (0.75, 95% CI 0.68–0.81) and D25 (0.77, 95% CI 0.70–0.83); in the cross-validation model, DPRx remained the best discriminator of mortality (DPRx: AUC 0.77 [95% CI 0.68–0.89]; D20: 0.72 [95% CI 0.66–0.81]; and D25: 0.65 [95% CI 0.56–0.73]).

Conclusions

The authors explored the importance of different ICP thresholds for outcome by calculating patient-specific ICP doses based on the continuous monitoring of cerebrovascular pressure reactivity. They found that these individualized doses of intracranial hypertension were stronger predictors of death than doses derived from the universal thresholds of 20 and 25 mm Hg. The PRx could offer a method that can be directed toward individualizing the ICP threshold.

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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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Magdalena Hiler, Marek Czosnyka, Peter Hutchinson, Marcella Balestreri, Peter Smielewski, Basil Matta and John D. Pickard

Object

The authors explored the relationship between computerized tomography (CT) scan findings and intracranial pressure (ICP) measurements obtained in the first 24 hours of monitoring to identify parameters predicting outcome in patients with severe traumatic brain injury (TBI).

Methods

Intracranial pressure, mean arterial blood pressure, cerebral perfusion pressure (CPP), and pressure reactivity index were measured continuously in 126 patients with severe TBI who were admitted to a neuroscience critical care unit. Mean values in the initial 24 hours of monitoring and in the total period of monitoring were compared with types of injury categorized on the basis of the initial CT scan according to the classification of Marshall, et al., and with Glasgow Outcome Scale scores.

The initial CT scan classification correlated significantly but weakly with ICP measured during the first 24 hours of monitoring (p = 0.036) but not with mean ICP over the total time of intensive care. Both midline shift and the ratio of frontal horn diameter to internal diameter correlated with ICP in the first 24 hours (p < 0.007) and with ICP over the total monitoring period (p < 0.03). Outcome score correlated with initial CT scan findings (p = 0.018), ICP over the total monitoring period (p < 0.0023), pressure reactivity over the total monitoring period (p < 0.0002), and pressure reactivity in the first 24 hours (p < 0.0001) but not with ICP in the first 24 hours. Patients with disturbed pressure reactivity in the first 24 hours after injury had a significantly higher mortality rate than patients with intact pressure reactivity (28.6% compared with 9.5%; p < 0.001).

Conclusions

Patients with severe TBI who have early loss of autoregulation have a worse prognosis. Mean ICP values in patients with diffuse TBI cannot be predicted by using the Marshall CT scan classification.

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Georgios V. Varsos, Angelos G. Kolias, Peter Smielewski, Ken M. Brady, Vassilis G. Varsos, Peter J. Hutchinson, John D. Pickard and Marek Czosnyka

OBJECT

Cerebral blood flow is associated with cerebral perfusion pressure (CPP), which is clinically monitored through arterial blood pressure (ABP) and invasive measurements of intracranial pressure (ICP). Based on critical closing pressure (CrCP), the authors introduce a novel method for a noninvasive estimator of CPP (eCPP).

METHODS

Data from 280 head-injured patients with ABP, ICP, and transcranial Doppler ultrasonography measurements were retrospectively examined. CrCP was calculated with a noninvasive version of the cerebrovascular impedance method. The eCPP was refined with a predictive regression model of CrCP-based estimation of ICP from known ICP using data from 232 patients, and validated with data from the remaining 48 patients.

RESULTS

Cohort analysis showed eCPP to be correlated with measured CPP (R = 0.851, p < 0.001), with a mean ± SD difference of 4.02 ± 6.01 mm Hg, and 83.3% of the cases with an estimation error below 10 mm Hg. eCPP accurately predicted low CPP (< 70 mm Hg) with an area under the curve of 0.913 (95% CI 0.883–0.944). When each recording session of a patient was assessed individually, eCPP could predict CPP with a 95% CI of the SD for estimating CPP between multiple recording sessions of 1.89–5.01 mm Hg.

CONCLUSIONS

Overall, CrCP-based eCPP was strongly correlated with invasive CPP, with sensitivity and specificity for detection of low CPP that show promise for clinical use.