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.
Adam M. H. Young, Mathew R. Guilfoyle, Helen Fernandes, Matthew R. Garnett, Shruti Agrawal, and Peter J. Hutchinson
There is increasing interest in the use of predictive models of outcome in adult head injury. Two international models have been identified to be reliable modalities for predicting outcome: the Corticosteroid Randomisation After Significant Head Injury (CRASH) model, and the International Mission on Prognosis and Analysis of randomized Controlled Trials in TBI (IMPACT) model. However, these models are designed only to identify outcomes in adult populations.
A retrospective analysis was performed on pediatric patients with severe traumatic brain injury (TBI) admitted to the pediatric intensive care unit (PICU) of Addenbrooke's Hospital between January 2009 and December 2013. The individual risk of 14-day mortality was calculated using the CRASH-Basic and -CT models, and the risk of 6-month mortality calculated using the IMPACT-Core and -Extended (including CT findings) models. Model accuracy was determined by standardized mortality ratio (SMtR; observed/expected deaths), discrimination was evaluated as the area under the receiver operating curve (AUROC), and calibration assessed using the Hosmer-Lemeshow χ2 test.
Ninety-four patients with an average age of 7.3 years were admitted to the PICU with a TBI. The mortality rate was 12.7% at 14 days and at 6 months. For the CRASH-Basic model, the SMtR was 1.42 and both calibration (χ2 = 6.1, p = 0.64) and discrimination (AUROC = 0.92) were good. For the IMPACT-Core model, the SMtR was 1.03 and the model was also well calibrated (χ2 = 8.99, p = 0.34) and had good discrimination (AUROC = 0.85). Poor outcome was observed in 17% of the cohort and identified with the CRASH-Basic and IMPACT-Core models to varying degrees: standardized morbidity ratio = 0.89 vs 0.67, respectively; calibration = 6.5 (χ2) and 0.59 (p value) versus 8.52 (χ2) and 0.38 (p value), respectively; and discrimination (AUROC) = 0.92 versus 0.83, respectively.
Adult head injury models may be applied with sufficient accuracy to identify predictors of morbidity and mortality in pediatric TBI.
Maria Pia Tropeano, Riccardo Spaggiari, Hernán Ileyassoff, Kee B. Park, Angelos G. Kolias, Peter J. Hutchinson, and Franco Servadei
Traumatic brain injury (TBI) is a global public health problem and more than 70% of trauma-related deaths are estimated to occur in low- and middle-income countries (LMICs). Nevertheless, there is a consistent lack of data from these countries. The aim of this work is to estimate the capacity of different and heterogeneous areas of the world to report and publish data on TBI. In addition, we wanted to estimate the countries with the highest and lowest number of publications when taking into account the relative TBI burden.
First, a bibliometric analysis of all the publications about TBI available in the PubMed database from January 1, 2008, to December 31, 2018, was performed. These data were tabulated by country and grouped according to each geographical region as indicated by the WHO: African Region (AFR), Region of the Americas (PAH), South-East Asia Region (SEAR), European Region (EUR), Eastern Mediterranean Region (EMR), and Western Pacific Region (WPR). In this analysis, PAH was further subdivided into Latin America (AMR-L) and North America (AMR-US/Can). Then a “publication to TBI volume ratio” was derived to estimate the research interest in TBI with respect to the frequency of this pathology.
Between 2008 and 2018 a total of 8144 articles were published and indexed in the PubMed database about TBI. Leading WHO regions in terms of contributions were AMR-US/Can with 4183 articles (51.36%), followed by EUR with 2003 articles (24.60%), WPR with 1507 (18.50%), AMR-L with 141 articles (1.73%), EMR with 135 (1.66%), AFR with 91 articles (1.12%), and SEAR with 84 articles (1.03%). The highest publication to TBI volume ratios were found for AMR-US/Can (90.93) and EUR (21.54), followed by WPR (8.71) and AMR-L (2.43). Almost 90 times lower than the ratio of AMR-US/Can were the ratios for AFR (1.15) and SEAR (0.46).
An important disparity currently exists between countries with a high burden of TBI and those in which most of the research is conducted. A call for improvement of data collection and research outputs along with an increase in international collaboration could quantitatively and qualitatively improve the ability of LMICs to ameliorate TBI care and develop clinical practice guidelines.
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, 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, 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.