Peter Smielewski

Limbic hypometabolism in Alzheimer's disease and mild cognitive impairment

The neural basis of the amnesia characterizing early Alzheimers disease (AD) remains uncertain. Postmortem pathological studies have suggested early involvement of the mesial temporal lobe, whereas in vivo metabolic studies have shown hypometabolism of the posterior cingulate cortex. Using a technique that combined the anatomic precision of magnetic resonance imaging with positron emission tomography, we found severe reductions of metabolism throughout a network of limbic structures (the hippocampal complex, medial thalamus, mamillary bodies, and posterior cingulate) in patients with mild AD. We then studied a cohort with mild cognitive impairment in whom amnesia was the only cognitive abnormality and found comparable hypometabolism through the same network. The AD and mild cognitive impairment groups were differentiated, however, by changes outside this network, the former showing significant hypometabolism in amygdala and temporoparietal and frontal association cortex, whereas the latter did not. The amnesia of very early AD reflects severe but localized limbic dysfunction.

Use of drains versus no drains after burr-hole evacuation of chronic subdural haematoma: a randomised controlled trial

BACKGROUND Chronic subdural haematoma causes serious morbidity and mortality. It recurs after surgical evacuation in 5-30% of patients. Drains might reduce recurrence but are not used routinely. Our aim was to investigate the effect of drains on recurrence rates and clinical outcomes. METHODS We did a randomised controlled trial at one UK centre between November, 2004, and November, 2007. 269 patients aged 18 years and older with a chronic subdural haematoma for burr-hole drainage were assessed for eligibility. 108 were randomly assigned by block randomisation to receive a drain inserted into the subdural space and 107 to no drain after evacuation. The primary endpoint was recurrence needing redrainage. The trial was stopped early because of a significant benefit in reduction of recurrence. Analyses were done on an intention-to-treat basis. This study is registered with the International Standard Randomised Controlled Trial Register (ISRCTN 97314294). FINDINGS Recurrence occurred in ten of 108 (9.3%) people with a drain, and 26 of 107 (24%) without (p=0.003; 95% CI 0.14-0.70). At 6 months mortality was nine of 105 (8.6%) and 19 of 105 (18.1%), respectively (p=0.042; 95% CI 0.1-0.99). Medical and surgical complications were much the same between the study groups. INTERPRETATION Use of a drain after burr-hole drainage of chronic subdural haematoma is safe and associated with reduced recurrence and mortality at 6 months. FUNDING Academy of Medical Sciences, Health Foundation, and NIHR Biomedical Research Centre (Neurosciences Theme).

Effect of hyperventilation on cerebral blood flow in traumatic head injury: Clinical relevance and monitoring correlates

Objective To investigate the effect of hyperventilation on cerebral blood flow in traumatic brain injury. Design A prospective interventional study. Setting A specialist neurocritical care unit. Patients Fourteen healthy volunteers and 33 patients within 7 days of closed head injury. Interventions All subjects underwent positron emission tomography imaging of cerebral blood flow. In patients, Paco2 was reduced from 36 ± 1 to 29 ± 1 torr (4.8 ± 0.1 to 3.9 ± 0.1 kPa) and measurements repeated. Jugular venous saturation (Sjvo2) and arteriovenous oxygen content differences (AVDO2) were monitored in 25 patients and values related to positron emission tomography variables. Measurements and Main Results The volumes of critically hypoperfused and hyperperfused brain (HypoBV and HyperBV, in milliliters) were calculated based on thresholds of 10 and 55 mL·100g−1·min−1, respectively. Whereas baseline HypoBV was significantly higher in patients (p < .05), baseline HyperBV was similar to values in healthy volunteers. Hyperventilation resulted in increases in cerebral perfusion pressure (p < .0001) and reductions in intracranial pressure (p < .001), whereas Sjvo2 (>50%) and AVDO2 (<9 mL/mL) did not exceed global ischemic thresholds. However, despite these beneficial effects, hyperventilation shifted the cerebral blood flow distribution curve toward the hypoperfused range, with a decrease in global cerebral blood flow (31 ± 1 to 23 ± 1 mL·100g−1·min−1;p < .0001) and an increase in HypoBV (22 [1–141] to 51 [2–428] mL;p < .0001). Hyperventilation-induced increases in HypoBV were apparently nonlinear, with a threshold value between 34 and 38 torr (4.5–5 kPa). Conclusions Hyperventilation increases the volume of severely hypoperfused tissue within the injured brain, despite improvements in cerebral perfusion pressure and intracranial pressure. Significant hyperperfusion is uncommon, even at a time when conventional clinical management includes a role for modest hyperventilation. These reductions in regional cerebral perfusion are not associated with ischemia, as defined by global monitors of oxygenation, but may represent regions of potentially ischemic brain tissue.

Continuous determination of optimal cerebral perfusion pressure in traumatic brain injury

Objectives: We have sought to develop an automated methodology for the continuous updating of optimal cerebral perfusion pressure (CPPopt) for patients after severe traumatic head injury, using continuous monitoring of cerebrovascular pressure reactivity. We then validated the CPPopt algorithm by determining the association between outcome and the deviation of actual CPP from CPPopt. Design: Retrospective analysis of prospectively collected data. Setting: Neurosciences critical care unit of a university hospital. Patients: A total of 327 traumatic head-injury patients admitted between 2003 and 2009 with continuous monitoring of arterial blood pressure and intracranial pressure. Measurements and Main Results: Arterial blood pressure, intracranial pressure, and CPP were continuously recorded, and pressure reactivity index was calculated online. Outcome was assessed at 6 months. An automated curve fitting method was applied to determine CPP at the minimum value for pressure reactivity index (CPPopt). A time trend of CPPopt was created using a moving 4-hr window, updated every minute. Identification of CPPopt was, on average, feasible during 55% of the whole recording period. Patient outcome correlated with the continuously updated difference between median CPP and CPPopt (chi-square = 45, p < .001; outcome dichotomized into fatal and nonfatal). Mortality was associated with relative “hypoperfusion” (CPP < CPPopt), severe disability with “hyperperfusion” (CPP > CPPopt), and favorable outcome was associated with smaller deviations of CPP from the individualized CPPopt. While deviations from global target CPP values of 60 mm Hg and 70 mm Hg were also related to outcome, these relationships were less robust. Conclusions: Real-time CPPopt could be identified during the recording time of majority of the patients. Patients with a median CPP close to CPPopt were more likely to have a favorable outcome than those in whom median CPP was widely different from CPPopt. Deviations from individualized CPPopt were more predictive of outcome than deviations from a common target CPP. CPP management to optimize cerebrovascular pressure reactivity should be the subject of future clinical trial in severe traumatic head-injury patients.

Cerebral extracellular chemistry and outcome following traumatic brain injury: a microdialysis study of 223 patients

Secondary insults can adversely influence outcome following severe traumatic brain injury. Monitoring of cerebral extracellular chemistry with microdialysis has the potential for early detection of metabolic derangements associated with such events. The objective of this study was to determine the relationship between the fundamental biochemical markers and neurological outcome in a large cohort of patients with traumatic brain injury. Prospectively collected observational neuromonitoring data from 223 patients were analysed. Monitoring modalities included digitally recorded intracranial pressure, cerebral perfusion pressure, cerebrovascular pressure reactivity index and microdialysis markers glucose, lactate, pyruvate, glutamate, glycerol and the lactate/pyruvate ratio. Outcome was assessed using the Glasgow Outcome Scale at 6 months post-injury. Patient-averaged values of parameters were used in statistical analysis, which included univariate non-parametric methods and multivariate logistic regression. Monitoring with microdialysis commenced on median (interquartile range) Day 1 (1-2) from injury and median (interquartile range) duration of monitoring was 4 (2-7) days. Averaged over the total monitoring period levels of glutamate (P = 0.048), lactate/pyruvate ratio (P = 0.044), intracranial pressure (P = 0.006) and cerebrovascular pressure reactivity index (P = 0.01) were significantly higher in patients who died. During the initial 72 h of monitoring, median glycerol levels were also higher in the mortality group (P = 0.014) and median lactate/pyruvate ratio (P = 0.026) and lactate (P = 0.033) levels were significantly lower in patients with favourable outcome. In a multivariate logistic regression model (P < 0.0001), which employed data averaged over the whole monitoring period, significant independent positive predictors of mortality were glucose (P = 0.024), lactate/pyruvate ratio (P = 0.016), intracranial pressure (P = 0.029), cerebrovascular pressure reactivity index (P = 0.036) and age (P = 0.003), while pyruvate was a significant independent negative predictor of mortality (P = 0.004). The results of this study suggest that extracellular metabolic markers are independently associated with outcome following traumatic brain injury. Whether treatment-related improvement in biochemistry translates into better outcome remains to be established.

Real-Time Continuous Monitoring of Cerebral Blood Flow Autoregulation Using Near-Infrared Spectroscopy in Patients Undergoing Cardiopulmonary Bypass

Background and Purpose— Individualizing mean arterial blood pressure targets to a patients cerebral blood flow autoregulatory range might prevent brain ischemia for patients undergoing cardiopulmonary bypass (CPB). This study compares the accuracy of real-time cerebral blood flow autoregulation monitoring using near-infrared spectroscopy with that of transcranial Doppler. Methods— Sixty adult patients undergoing CPB had transcranial Doppler monitoring of middle cerebral artery blood flow velocity and near-infrared spectroscopy monitoring. The mean velocity index (Mx) was calculated as a moving, linear correlation coefficient between slow waves of middle cerebral artery blood flow velocity and mean arterial blood pressure. The cerebral oximetry index was calculated as a similar coefficient between slow waves of cerebral oximetry and mean arterial blood pressure. When cerebral blood flow is autoregulated, Mx and cerebral oximetry index vary around zero. Loss of autoregulation results in progressively more positive Mx and cerebral oximetry index. Results— Mx and cerebral oximetry index showed significant correlation (r=0.55, P<0.0001) and good agreement (bias, 0.08±0.18, 95% limits of agreement: −0.27 to 0.43) during CPB. Autoregulation was disturbed in this cohort during CPB (average Mx 0.38, 95% CI 0.34 to 0.43). The lower cerebral blood flow autoregulatory threshold (defined as incremental increase in Mx >0.45) during CPB ranged from 45 to 80 mm Hg. Conclusions— Cerebral blood flow autoregulation can be monitored continuously with near-infrared spectroscopy in adult patients undergoing CPB. Real-time autoregulation monitoring may have a role in preventing injurious hypotension during CPB. Clinical Trials Registration— at www.clinicaltrials.gov (NCT00769691).

Hyperventilation following head injury : Effect on ischemic burden and cerebral oxidative metabolism

Objective:To determine whether hyperventilation exacerbates cerebral ischemia and compromises oxygen metabolism (CMRO2) following closed head injury. Design:A prospective interventional study. Setting:A specialist neurocritical care unit. Patients:Ten healthy volunteers and 30 patients within 10 days of closed head injury. Interventions:Subjects underwent oxygen-15 positron emission tomography imaging of cerebral blood flow, cerebral blood volume, CMRO2, and oxygen extraction fraction. In patients, positron emission tomography studies, somatosensory evoked potentials, and jugular venous saturation (SjO2) measurements were obtained at Paco2 levels of 36 ± 3 and 29 ± 2 torr. Measurements and Main Results:We estimated the volume of ischemic brain and examined the efficiency of coupling between oxygen delivery and utilization using the sd of the oxygen extraction fraction distribution. We correlated CMRO2 to cerebral electrophysiology and examined the effects of hyperventilation on the amplitude of the cortical somatosensory evoked potential response. Patients showed higher ischemic brain volume than controls (17 ± 22 vs. 2 ± 3 mL; p ≤ .05), with worse matching of oxygen delivery to demand (p < .001). Hyperventilation consistently reduced cerebral blood flow (p < .001) and resulted in increases in oxygen extraction fraction and ischemic brain volume (17 ± 22 vs. 88 ± 66 mL; p < .0001), which were undetected by SjO2 monitoring. Mean CMRO2 was slightly increased following hyperventilation, but responses were extremely variable, with 28% of patients demonstrating a decrease in CMRO2 that exceeded 95% prediction intervals for zero change in one or more regions. CMRO2 correlated with cerebral electrophysiology, and cortical somatosensory evoked potential amplitudes were significantly increased by hyperventilation. Conclusions:The acute cerebral blood flow reduction and increase in CMRO2 secondary to hyperventilation represent physiologic challenges to the traumatized brain. These challenges exhaust physiologic reserves in a proportion of brain regions in many subjects and compromise oxidative metabolism. Such ischemia is underestimated by common bedside monitoring tools and may represent a significant mechanism of avoidable neuronal injury following head trauma.

Assessment of Cerebrovascular Autoregulation in Head-Injured Patients: A Validation Study

Background and Purpose— Cerebrovascular autoregulation is frequently measured in head-injured patients. We attempted to validate 4 bedside methods used for assessment of autoregulation. Methods— PET was performed at a cerebral perfusion pressure (CPP) of 70 and 90 mm Hg in 20 patients. Cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRo2) were determined at each CPP level. Patients were sedated with propofol and fentanyl. Norepinephrine was used to control CPP. During PET scanning, transcranial Doppler (TCD) flow velocity in the middle cerebral artery was monitored, and the arterio-jugular oxygen content difference (AJDo2) was measured at each CPP. Autoregulation was determined as the static rate of autoregulation based on PET (SRORPET) and TCD (SRORTCD) data, based on changes in AJDo2, and with 2 indexes based on the relationship between slow waves of CPP and flow velocity (mean velocity index, Mx) and between arterial blood pressure and intracranial pressure (pressure reactivity index, PRx) Results— We found significant correlations between SRORPET and SRORTCD (r2=0.32; P <0.01) and between SRORPET and PRx (r2=0.31; P <0.05). There were no significant associations between PET data and autoregulation as assessed by changes in AJDo2. Global CMRo2 was significantly lower at the higher CPP (P <0.01). Conclusions— Despite some variability, SRORTCD and PRx may provide useful approximations of autoregulation in head-injured patients. At least with our methods, CMRo2 changes with the increase in CPP; hence, flow-metabolism coupling may affect the results of autoregulation testing.

Effect of decompressive craniectomy on intracranial pressure and cerebrospinal compensation following traumatic brain injury

OBJECTIVE Decompressive craniectomy is an advanced treatment option for intracranial pressure (ICP) control in patients with traumatic brain injury. The purpose of this study was to evaluate the effect of decompressive craniectomy on ICP and cerebrospinal compensation both within and beyond the first 24 hours of craniectomy. METHODS This study was a retrospective analysis of the physiological parameters from 27 moderately to severely head-injured patients who underwent decompressive craniectomy for progressive brain edema. Of these, 17 patients had undergone prospective digital recording of ICP with estimation of ICP waveform-derived indices. The pressure-volume compensatory reserve (RAP) index and the cerebrovascular pressure reactivity index (PRx) were used to assess those parameters. The values of parameters prior to and during the 72 hours after decompressive craniectomy were included in the analysis. RESULTS Decompressive craniectomy led to a sustained reduction in median (interquartile range) ICP values (21.2 mm Hg [18.7; 24.2 mm Hg] preoperatively compared with 15.7 mm Hg [12.3; 19.2 mm Hg] postoperatively; p = 0.01). A similar improvement was observed in RAP. A significantly lower mean arterial pressure (MAP) was needed after decompressive craniectomy to maintain optimum cerebral perfusion pressure (CPP) levels, compared with the preoperative period (99.5 mm Hg [96.2; 102.9 mm Hg] compared with 94.2 mm Hg [87.9; 98.9 mm Hg], respectively; p = 0.017). Following decompressive craniectomy, the PRx had positive values in all patients, suggesting acquired derangement in pressure reactivity. CONCLUSIONS In this study, decompressive craniectomy led to a sustained reduction in ICP and improvement in cerebral compliance. Lower MAP levels after decompressive craniectomy are likely to indicate a reduced intensity of treatment. Derangement in cerebrovascular pressure reactivity requires further studies to evaluate its significance and influence on outcome.

Can Cerebrovascular Reactivity Be Measured With Near-Infrared Spectroscopy?

BACKGROUND AND PURPOSE We used near-infrared spectroscopy (NIRS) to monitor the cerebral oxygenation changes during CO2 reactivity tests. METHODS Fifty healthy volunteers were examined (age range, 19 to 68 years). The monitored parameters were as follows: transcranial Doppler (TCD) time-averaged middle cerebral artery flow velocity end-tidal CO2 (EtCO2); change in concentration of cerebral oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), and total hemoglobin; mean arterial blood pressure; peripheral arterial oxygen saturation (SaO2); and extracranial tissue perfusion with the use of cutaneous laser-Doppler flowmetry. The examination protocol included both hypercapnia and hypocapnia. The cerebrovascular reactivity indexes were calculated as follows: TCD, relative change in flow velocity per 1 kPa increase in EtCO2; NIRS, absolute change in HbO2, Hb, and total hemoglobin concentration (micromoles per liter) per 1 kPa increase in EtCO2. RESULTS Mean middle cerebral artery flow velocity was found to be 58 cm/s at a mean baseline EtCO2 of 4.7 kPa. Mean cerebrovascular reactivities were as follows: TCD, 24%/kPa (SEM, 1.1); HbO2, 2.06 mumol/L per kilopascal (SEM, 0.08); Hb, -0.63 mumol/L per kilopascal (SEM, 0.09); and total hemoglobin concentration, 1.44 mumol/L per kilopascal (SEM, 0.1). Statistical analysis revealed significant correlation between reactivities calculated with the use of NIRS and TCD (P < .001). Although some fluctuations were observed in SaO2 and laser-Doppler flux, they were not correlated with either EtCO2 or NIRS. CONCLUSIONS NIRS signal changes in HbO2, Hb, and total hemoglobin concentration are very sensitive to alterations in EtCO2, which are largely independent of extracranial tissue perfusion. NIRS may be developed as an alternative method for testing cerebrovascular reactivity and may be of particular clinical importance when the ultrasound window is poor.