Hugh Richards

Acute systemic erythropoietin therapy to reduce delayed ischemic deficits following aneurysmal subarachnoid hemorrhage: a Phase II randomized, double-blind, placebo-controlled trial: Clinical article

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.

The SILVER (Silver Impregnated Line Versus EVD Randomized trial): a double-blind, prospective, randomized, controlled trial of an intervention to reduce the rate of external ventricular drain infection.

BACKGROUND Cerebrospinal fluid (CSF) infections associated with external ventricular drain (EVD) placement attract major consequences. Silver impregnation of catheters attempts to reduce infection. OBJECTIVE To assess the efficacy of silver catheters against CSF infection. METHODS We performed a randomized, controlled trial involving 2 neurosurgical centers (June 2005 to September 2009). A total of 356 patients requiring an EVD were assessed for eligibility; 325 patients were enrolled and randomized (167 plain, 158 silver); 278 patients were analyzed (140 plain, 138 silver). The primary outcome measure was CSF infection as defined by organisms seen on Gram stain or isolated by culture. Secondary outcome measures included ventriculoperitoneal (VP) shunting. RESULTS There was a significant difference in infection risk between the 2 study arms: 21.4% (30/140) for plain catheters vs 12.3% (17/138) for silver catheters (P = .0427; 95% confidence interval [CI]: 1.015-3.713). Patients who had an EVD infection had more than double the risk of requiring a VP shunt compared with patients without an EVD infection (45.7% [21/46] vs 19.7% [45/229], respectively, P = .0002; 95% CI: 1.766-6.682). There was also a significant difference in VP shunt risk with infection: plain (55.2%; 16/29) vs the silver arm (29.4%; 5/17); P = .0244 (95% CI: 1.144-11.695). A multivariate analysis demonstrated that infection risk was increased by duration of EVD placement (odds ratio: 1.160), spontaneous intracranial hemorrhage (odds ratio 4.958) and decreased by silver catheters (odds ratio: 0.423). CONCLUSION The study provides Class I evidence that silver-impregnated catheters reduce CSF infection.

Hypertonic Saline In Patients With Poor-Grade Subarachnoid Hemorrhage Improves Cerebral Blood Flow, Brain Tissue Oxygen, and pH

Background and Purpose— Delayed cerebral ischemia and infarction due to reduced CBF remains the leading cause of poor outcome after aneurysmal subarachnoid hemorrhage. Hypertonic saline (HS) is associated with an increase in CBF. This study explores whether CBF enhancement with HS in patients with poor-grade subarachnoid hemorrhage is associated with improved cerebral tissue oxygenation. Methods— Continuous monitoring of arterial blood pressure, intracranial pressure, cerebral perfusion pressure, brain tissue oxygen, carbon dioxide, pH, and middle cerebral artery flow velocity was performed in 44 patients. Patients were given an infusion (2 mL/kg) of 23.5% HS. In 16 patients, xenon CT scanning was also performed. CBF in a region surrounding the tissue oxygen sensor was calculated. Data are mean±SD. Results— Thirty minutes postinfusion, a significant increase in arterial blood pressure, cerebral perfusion pressure, flow velocity, brain tissue pH, and brain tissue oxygen was seen together with a decrease in intracranial pressure (P<0.05). Intracranial pressure remained reduced for >300 minutes and flow velocity elevated for >240 minutes. A significant increase in brain tissue oxygen persisted for 240 minutes. Average baseline regional CBF was 33.9±13.5 mL/100 g/min, rising by 20.3%±37.4% (P<0.05) after HS. Patients with favorable outcome responded better to HS in terms of increased CBF, brain tissue oxygen, and pH and reduced intracranial pressure compared with those with an unfavorable outcome. A sustained increase in brain tissue oxygen (beyond 210 minutes) was associated with favorable outcome (P<0.023). Conclusion— HS augments CBF in patients with poor-grade subarachnoid hemorrhage and significantly improves cerebral oxygenation for 4 hours postinfusion. Favorable outcome is associated with an improvement in brain tissue oxygen beyond 210 minutes.

Efficacy of antibiotic-impregnated shunt catheters in reducing shunt infection: data from the United Kingdom Shunt Registry

OBJECT In recent years CSF shunt catheters impregnated with rifampicin and clindamycin have been introduced to the United Kingdom (UK) market. These catheters have been shown to be effective in vitro against cultures of Staphylococcus epidermidis. The authors used data collected by the UK Shunt Registry to assess the efficacy of antibiotic-impregnated catheters (AICs) against shunt infection by using a matched-pair study design. METHODS The UK Shunt Registry contains data on nearly 33,000 CSF shunt-related procedures. The authors identified 1139 procedures in which impregnated catheters had been used, and accurate information was known about diagnosis, number of revisions, sex, and age in these cases. The database was ordered chronologically and searched forward and backward for cases with these same characteristics but involving conventional catheters. Matches were found for 994 procedures. RESULTS Among the 994 procedures in which AICs had been used, 30 shunts were subsequently revised because of shunt infection. Among the 994 controls, 47 were subsequently revised for infection (p = 0.048, chi-square test). CONCLUSIONS The UK Shunt Registry does not collect data on causative organisms, and the surgeon is relied on entirely for the diagnosis of infection. However, with the large number of matched pairs evaluated, the authors attempted to reduce bias to a minimum. Their data suggest that AICs have the potential to significantly reduce shunt infections.

Enhancement of cerebral blood flow using systemic hypertonic saline therapy improves outcome in patients with poor-grade spontaneous subarachnoid hemorrhage.

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 x 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.

Uncoupling of Cerebral Blood Flow and Metabolism after Cerebral Contusion in the Rat

Positron emission tomography scans of patients with head injuries often show discrete areas of increased 18F-fluorodeoxyglucose uptake (“hot spots”) when performed hours to days after the initial ictus. Using quantitative autoradiographic methods, the authors have investigated whether cerebral blood flow and glucose metabolism are uncoupled 2 hours after controlled head injury in an animal model, and whether any “hot spots” are accompanied by changes in cerebral glucose concentration. Experiments were performed on 18 anesthetized, ventilated (1.5% halothane in 2:1 nitrous oxide:oxygen) Sprague-Dawley rats weighing 300 to 330 g. A burr hole was made over the left parietal cortex, and all animals received a piston impact on the intact dura (2 mm in diameter, 2.0 m/sec, 2 mm in depth). All animals remained anesthetized and ventilated for a further 2 hours, after which quantitative autoradiography was used to determine either (1) local cerebral blood flow (LCBF) using 14C-iodoantipyrine, (2) local cerebral glucose utilization (LCGU) using 14C-deoxyglucose, or (3) local cerebral glucose content (LCGC) using 14C-methylglucose. Local CBF, LCGU, and LCGC were measured in five regions adjacent to the contusion, and values then were normalized on the contralateral cortex. Normalized LCBF, LCGU, or LCGC varied in parallel in ipsilateral cortex (no change) and in the ischemic core of the contusion (reduced). However, there were marked changes in the patterns observed in the boundary zone (within 1 mm of the contusion). In all six rats used for LCGU measurement, there were discrete areas of high metabolism, whereas in all six rats used for LCBF measurement, flow was universally depressed in the boundary zone. Of the six rats used for LCGC determination, there was a discrete area of high signal in only one. The authors conclude that there are discrete areas of uncoupling of cerebral blood flow and metabolism after head injury within 2 hours of cerebral contusion in the rat that cannot be explained by changes in cerebral glucose content in the majority of animals.

Magnetic field interactions in adjustable hydrocephalus shunts.

OBJECT Exposing patients with ventricular shunts to magnetic fields and MR imaging procedures poses a significant risk of unintentional changes in shunt settings. Shunt valves can also generate considerable imaging artifacts. The purpose of this study was to determine the magnetic field safety and MR imaging compatibility of 5 adjustable models of hydrocephalus shunts. METHODS The Codman Hakim (regular and with SiphonGuard), Miethke ProGAV, Medtronic Strata, Sophysa Sophy and Polaris programmable valves were tested in a low-intensity magnetic field, and then translational attraction (TA), magnetic torque (MT), and volume of artifacts on T1-weighted spin echo (SE) and gradient echo (GE) pulse sequences in a 3-T MR imaging unit were measured. RESULTS The ProGAV and Polaris valves were immune to unintentional reprogramming by magnetic fields up to 3 T. Other valves randomly changed settings, starting from the intensity of field: Sophy valve 24 mT, Strata valve 30 mT, and both Codman Hakim programmable valves from 42 mT. Shunt performances in the 3-T MR imaging unit are reported in the order of compatibility: 1) Codman Hakim regular, TA = 0.005 N, MT = 0.000 Nm, GE = 30 cm(3), SE = 2 cm(3); 2) Miethke ProGAV, TA = 0.001 N, MT = 1.4 x 10(3) Nm, GE = 231 cm(3), SE = 13 cm(3); 3) Codman Hakim with SiphonGuard, TA = 0.005 N, MT = 2.3 x 10(3) Nm, GE = 233 cm(3), SE = 19 cm(3); 4) Medtronic Strata, TA = 0.27 N, MT = 18.0 x 10(3) Nm, GE = 484 cm(3), SE = 86 cm(3); 5) Sophysa Sophy, TA = 0.82 N, MT = 38.9 x 10(3) Nm, GE = 758 cm(3), SE = 72 cm(3); and 6) Sophysa Polaris, TA = 0.80 N, MT = 39.6 x 10(3) Nm, GE = 954 cm(3), SE = 100 cm(3). CONCLUSIONS All valves, with the exception of the Polaris and ProGAV models, are prone to unintentional reprogramming when exposed to heterogeneous magnetic fields stronger than 40 mT. All tested valves can be considered safe for 3-T MR imaging. All valves generated a distortion of the MR image, especially the GE sequences.

Biological effects of acute pravastatin treatment in patients after aneurysmal subarachnoid hemorrhage : a double-blind, placebo-controlled trial

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.

Critical closing pressure determined with a model of cerebrovascular impedance.

Critical closing pressure (CCP) is the arterial blood pressure (ABP) at which brain vessels collapse and cerebral blood flow (CBF) ceases. Using the concept of impedance to CBF, CCP can be expressed with brain-monitoring parameters: cerebral perfusion pressure (CPP), ABP, blood flow velocity (FV), and heart rate. The novel multiparameter method (CCPm) was compared with traditional transcranial Doppler (TCD) calculations of CCP (CCP1). Digital recordings of ABP, intracranial pressure (ICP), and TCD-based FV from previously published studies of 29 New Zealand White rabbits were reanalyzed. Overall, CCP1 and CCPm showed correlation across wide ranges of ABP, ICP, and PaCO2 (R = 0.93, P < 0.001). Three physiological perturbations were studied: increase in ICP (n = 29) causing both CCP1 and CCPm to increase (P < 0.001 for both); reduction of ABP (n = 10) resulting in decrease of CCP1 (P = 0.006) and CCPm (P = 0.002); and controlled increase of PaCO2 (n = 8) to hypercapnic levels, which decreased CCP1 and CCPm, albeit insignificantly (P = 0.123 and P = 0.306 respectively), caused by a spontaneous significant increase in ABP (P = 0.025). Multiparameter mathematical model of critical closing pressure explains the relationship of CCP on brain-monitoring variables, allowing the estimation of CCP during cases such as hypercapnia-induced hyperemia, where traditional calculations, like CCP1, often reach negative non-physiological values.

Assessing quality of life after traumatic brain injury: examination of the short form 36 health survey.

Measuring health-related quality of life (HRQoL) has an important role in the comprehensive assessment of patient recovery following traumatic brain injury (TBI). We examined the validity of domain and summary scores derived from the Medical Outcomes Survey 36-Item Short Form Health Questionnaire (SF-36) as outcome measures for TBI in a prospective study of 514 patients with a range of functional impairment (Glasgow Outcome Scale-Extended [GOSE] scores 3-8). Item scaling criteria for the eight domain scores were tested and principal component analysis was used to examine if physical and mental component summary scores were valid. External validity was assessed by comparison with GOSE. Mean response, variance, and distribution of the items were largely equivalent, and item-own scale correlations corrected for overlap all exceeded the threshold for equivalent contribution to domain scores and convergent validity. All corrected item-own scale correlations were greater than the respective item-other correlations indicating no scaling failures, and reliability coefficients for the domain scores were high and substantially more than the inter-domain correlations. Overall, criteria for summing items into domain scores were satisfied, and there was a significant relationship of increasing score with more favorable GOSE class across all domains. However, there were floor and/or ceiling effects in four of the eight domains, and principal component analysis of the domain scores demonstrated only a unidimensional structure to the data. We conclude that individual SF-36 domain scores are valid measures of HRQoL in TBI patients, but that the physical and mental component summaries should be interpreted with caution.