Hospitalisation for COVID-19 predicts long lasting cerebrovascular impairment: A prospective observational cohort study.

Human coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has multiple neurological consequences, but its long-term effect on brain health is still uncertain. The cerebrovascular consequences of COVID-19 may also affect brain health. We studied the chronic effect of COVID-19 on cerebrovascular health, in relation to acute severity, adverse clinical outcomes and in contrast to control group data. Here we assess cerebrovascular health in 45 patients six months after hospitalisation for acute COVID-19 using the resting state fluctuation amplitudes (RSFA) from functional magnetic resonance imaging, in relation to disease severity and in contrast with 42 controls. Acute COVID-19 severity was indexed by COVID-19 WHO Progression Scale, inflammatory and coagulatory biomarkers. Chronic widespread changes in frontoparietal RSFA were related to the severity of the acute COVID-19 episode. This relationship was not explained by chronic cardiorespiratory dysfunction, age, or sex. The level of cerebrovascular dysfunction was associated with cognitive, mental, and physical health at follow-up. The principal findings were consistent across univariate and multivariate approaches. The results indicate chronic cerebrovascular impairment following severe acute COVID-19, with the potential for long-term consequences on cognitive function and mental wellbeing.

Brain injury in COVID-19 is associated with dysregulated innate and adaptive immune responses.

COVID-19 is associated with neurological complications including stroke, delirium and encephalitis. Furthermore, a post-viral syndrome dominated by neuropsychiatric symptoms is common, and is seemingly unrelated to COVID-19 severity. The true frequency and underlying mechanisms of neurological injury are unknown, but exaggerated host inflammatory responses appear to be a key driver of COVID-19 severity. We investigated the dynamics of, and relationship between, serum markers of brain injury [neurofilament light (NfL), glial fibrillary acidic protein (GFAP) and total tau] and markers of dysregulated host response (autoantibody production and cytokine profiles) in 175 patients admitted with COVID-19 and 45 patients with influenza. During hospitalization, sera from patients with COVID-19 demonstrated elevations of NfL and GFAP in a severity-dependent manner, with evidence of ongoing active brain injury at follow-up 4 months later. These biomarkers were associated with elevations of pro-inflammatory cytokines and the presence of autoantibodies to a large number of different antigens. Autoantibodies were commonly seen against lung surfactant proteins but also brain proteins such as myelin associated glycoprotein. Commensurate findings were seen in the influenza cohort. A distinct process characterized by elevation of serum total tau was seen in patients at follow-up, which appeared to be independent of initial disease severity and was not associated with dysregulated immune responses unlike NfL and GFAP. These results demonstrate that brain injury is a common consequence of both COVID-19 and influenza, and is therefore likely to be a feature of severe viral infection more broadly. The brain injury occurs in the context of dysregulation of both innate and adaptive immune responses, with no single pathogenic mechanism clearly responsible.

Multivariate profile and acute-phase correlates of cognitive deficits in a COVID-19 hospitalised cohort.

Background: Preliminary evidence has highlighted a possible association between severe COVID-19 and persistent cognitive deficits. Further research is required to confirm this association, determine whether cognitive deficits relate to clinical features from the acute phase or to mental health status at the point of assessment, and quantify rate of recovery. Methods: 46 individuals who received critical care for COVID-19 at Addenbrooke's hospital between 10th March 2020 and 31st July 2020 (16 mechanically ventilated) underwent detailed computerised cognitive assessment alongside scales measuring anxiety, depression and post-traumatic stress disorder under supervised conditions at a mean follow up of 6.0 (± 2.1) months following acute illness. Patient and matched control (N = 460) performances were transformed into standard deviation from expected scores, accounting for age and demographic factors using N = 66,008 normative datasets. Global accuracy and response time composites were calculated (G_SScore & G_RT). Linear modelling predicted composite score deficits from acute severity, mental-health status at assessment, and time from hospital admission. The pattern of deficits across tasks was qualitatively compared with normal age-related decline, and early-stage dementia. Findings: COVID-19 survivors were less accurate (G_SScore=-0.53SDs) and slower (G_RT=+0.89SDs) in their responses than expected compared to their matched controls. Acute illness, but not chronic mental health, significantly predicted cognitive deviation from expected scores (G_SScore (p=​​0.0037) and G_RT (p = 0.0366)). The most prominent task associations with COVID-19 were for higher cognition and processing speed, which was qualitatively distinct from the profiles of normal ageing and dementia and similar in magnitude to the effects of ageing between 50 and 70 years of age. A trend towards reduced deficits with time from illness (r∼=0.15) did not reach statistical significance. Interpretation: Cognitive deficits after severe COVID-19 relate most strongly to acute illness severity, persist long into the chronic phase, and recover slowly if at all, with a characteristic profile highlighting higher cognitive functions and processing speed. Funding: This work was funded by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC), NIHR Cambridge Clinical Research Facility (BRC-1215-20014), the Addenbrooke's Charities Trust and NIHR COVID-19 BioResource RG9402. AH is funded by the UK Dementia Research Institute Care Research and Technology Centre and Imperial College London Biomedical Research Centre. ETB and DKM are supported by NIHR Senior Investigator awards. JBR is supported by the Wellcome Trust (220258) and Medical Research Council (SUAG/051 G101400). VFJN is funded by an Academy of Medical Sciences/ The Health Foundation Clinician Scientist Fellowship. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.

Post-acute blood biomarkers and disease progression in traumatic brain injury.

There is substantial interest in the potential for traumatic brain injury to result in progressive neurological deterioration. While blood biomarkers such as glial fibrillary acid protein (GFAP) and neurofilament light have been widely explored in characterizing acute traumatic brain injury (TBI), their use in the chronic phase is limited. Given increasing evidence that these proteins may be markers of ongoing neurodegeneration in a range of diseases, we examined their relationship to imaging changes and functional outcome in the months to years following TBI. Two-hundred and three patients were recruited in two separate cohorts; 6 months post-injury (n = 165); and >5 years post-injury (n = 38; 12 of whom also provided data ∼8 months post-TBI). Subjects underwent blood biomarker sampling (n = 199) and MRI (n = 172; including diffusion tensor imaging). Data from patient cohorts were compared to 59 healthy volunteers and 21 non-brain injury trauma controls. Mean diffusivity and fractional anisotropy were calculated in cortical grey matter, deep grey matter and whole brain white matter. Accelerated brain ageing was calculated at a whole brain level as the predicted age difference defined using T1-weighted images, and at a voxel-based level as the annualized Jacobian determinants in white matter and grey matter, referenced to a population of 652 healthy control subjects. Serum neurofilament light concentrations were elevated in the early chronic phase. While GFAP values were within the normal range at ∼8 months, many patients showed a secondary and temporally distinct elevations up to >5 years after injury. Biomarker elevation at 6 months was significantly related to metrics of microstructural injury on diffusion tensor imaging. Biomarker levels at ∼8 months predicted white matter volume loss at >5 years, and annualized brain volume loss between ∼8 months and 5 years. Patients who worsened functionally between ∼8 months and >5 years showed higher than predicted brain age and elevated neurofilament light levels. GFAP and neurofilament light levels can remain elevated months to years after TBI, and show distinct temporal profiles. These elevations correlate closely with microstructural injury in both grey and white matter on contemporaneous quantitative diffusion tensor imaging. Neurofilament light elevations at ∼8 months may predict ongoing white matter and brain volume loss over >5 years of follow-up. If confirmed, these findings suggest that blood biomarker levels at late time points could be used to identify TBI survivors who are at high risk of progressive neurological damage.

Is there a broader role for independent mental capacity advocates in critical care? An exploratory study.

BACKGROUND: This research explores the current and potential future role of independent mental capacity advocates (IMCAs) in critical care. The Mental Capacity Act (MCA) of 2005 introduced IMCAs as advocates for patients without anyone to represent their best interests, but research suggests that this role is not well understood or implemented. No existing research explores the role of IMCAs in critical care or their potential use when families are judged 'appropriate to act' on the patient's behalf. It is suggested that families may not be best placed to advocate for their sick family member when they themselves are in a state of shock. AIM: To investigate existing levels of knowledge and awareness of the MCA and understanding of the role of IMCAs in critical care as a prelude to considering whether the role of IMCAs might usefully be extended. The concept of 'IMCA clinics' is introduced and explored. DESIGN AND METHODS: A small-scale qualitative study using thematic analysis of 15 interviews across two NHS sites and a survey of IMCA services were undertaken. RESULTS: Some knowledge of the MCA was evident across both study sites, but training on MCA remains unsatisfactory, with confusion about the role of IMCAs and when they should become involved. Overall, participants felt that the broader involvement of IMCAs on a regular basis within critical care could be useful. CONCLUSIONS: There was evidence of good practice when instructing IMCAs, but further work needs to be conducted to ensure that critical care staff are informed about the referral process. It was clear that expanding the role of an advocate warrants further investigation. RELEVANCE TO CLINICAL PRACTICE: Further training on the role of IMCAs within critical care is required, and good practice examples should be shared with other units to improve referral rates to the IMCA service and ensure that vulnerable patients are properly represented.

Parcellating the neuroanatomical basis of impaired decision-making in traumatic brain injury.

Cognitive dysfunction is a devastating consequence of traumatic brain injury that affects the majority of those who survive with moderate-to-severe injury, and many patients with mild head injury. Disruption of key monoaminergic neurotransmitter systems, such as the dopaminergic system, may play a key role in the widespread cognitive dysfunction seen after traumatic axonal injury. Manifestations of injury to this system may include impaired decision-making and impulsivity. We used the Cambridge Gambling Task to characterize decision-making and risk-taking behaviour, outside of a learning context, in a cohort of 44 patients at least six months post-traumatic brain injury. These patients were found to have broadly intact processing of risk adjustment and probability judgement, and to bet similar amounts to controls. However, a patient preference for consistently early bets indicated a higher level of impulsiveness. These behavioural measures were compared with imaging findings on diffusion tensor magnetic resonance imaging. Performance in specific domains of the Cambridge Gambling Task correlated inversely and specifically with the severity of diffusion tensor imaging abnormalities in regions that have been implicated in these cognitive processes. Thus, impulsivity was associated with increased apparent diffusion coefficient bilaterally in the orbitofrontal gyrus, insula and caudate; abnormal risk adjustment with increased apparent diffusion coefficient in the right thalamus and dorsal striatum and left caudate; and impaired performance on rational choice with increased apparent diffusion coefficient in the bilateral dorsolateral prefrontal cortices, and the superior frontal gyri, right ventrolateral prefrontal cortex, the dorsal and ventral striatum, and left hippocampus. Importantly, performance in specific cognitive domains of the task did not correlate with diffusion tensor imaging abnormalities in areas not implicated in their performance. The ability to dissociate the location and extent of damage with performance on the various task components using diffusion tensor imaging allows important insights into the neuroanatomical basis of impulsivity following traumatic brain injury. The ability to detect such damage in vivo may have important implications for patient management, patient selection for trials, and to help understand complex neurocognitive pathways.

Juguloarterial endothelin-1 gradients after severe traumatic brain injury.

BACKGROUND: Endothelin-1 (ET-1) is a potent vasoconstrictor and is thought to be responsible for secondary ischemia and vasogenic edema after traumatic brain injury (TBI). Both CSF and plasma concentrations have been shown to be increased after TBI, but there is little evidence to confirm an intracranial site of production. METHODS: Using paired arterial and jugular venous bulb sampling, we measured arterial and jugular levels of ET-1 and its precursor, big endothelin (Big ET), and calculated juguloarterial (JA) gradients for the first 5 days post-TBI. RESULTS: Arterial levels of both Big ET and ET-1 were maximal on day 1 post-TBI, and decreased thereafter (P < 0.05). Arterial levels of Big ET and ET-1 showed correlation across all 5 days of the study (r(2) = 0.25, P < 0.001). While there was no significant JA gradient for Big ET, significant gradients were observed for ET-1 on days 1-4 post-TBI (P < 0.05). There was no correlation between JA gradients for Big ET and ET-1 (r(2) < 0.1, P > 0.9). These data suggest parenchymal production of ET-1 by brain tissue with spill over into the blood, rather than local intraluminal cleavage of Big ET in the cerebral vasculature. Systemic ET-1 levels and JA gradients of ET-1 were unrelated to the injury severity, APACHE II score, Marshall Grade, the presence of subarachnoid or subdural hemorrhage, or eventual outcome. CONCLUSIONS: These findings confirm the synthesis of Big ET and its cleavage to ET-1 within the brain after TBI. More work is needed to elucidate the pathophysiological role and the outcome impact of ET-1 generation after TBI.

Early metabolic characteristics of lesion and nonlesion tissue after head injury.

We defined lesion and structurally normal regions using magnetic resonance imaging at follow-up in patients recovering from head injury. Early metabolic characteristics in these regions of interest (ROIs) were compared with physiology in healthy volunteers. Fourteen patients with severe head injury had positron emission tomography within 72 h, and magnetic resonance imaging at 3 to 18 months after injury. Cerebral blood flow (CBF), oxygen utilization (CMRO(2)), and oxygen extraction fraction (OEF) were all lower in lesion ROIs, compared with nonlesion and control ROIs (P<0.001); however, there was substantial overlap in physiology. Control ROIs showed close coupling among CBF, blood volume (CBV), and CMRO(2), whereas relationships within lesion and nonlesion ROIs were abnormal. The relationship between CBF and CMRO(2) generally remained coupled but the slope was reduced; that for CBF and OEF was variable; whereas that between CBF and CBV was highly variable. There was considerable heterogeneity between and within patients. Although irreversibly damaged tissue is characterized by marked derangements in physiology, a more detailed analysis shows acute changes in physiology and physiologic relationships within regions of the brain that appear structurally normal at follow-up. Such pathophysiological derangements may result in selective neuronal loss and impact on functional outcome.

Early derangements in oxygen and glucose metabolism following head injury: the ischemic penumbra and pathophysiological heterogeneity.

INTRODUCTION: Conclusive evidence of cerebral ischemia following head injury has been elusive. We aimed to use (15)O and (18)Fluorodeoxyglucose positron emission tomography (PET) to investigate pathophysiological derangements following head injury. RESULTS: Eight patients underwent PET within 24 h of injury to map cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), oxygen extraction fraction (OEF), and cerebral glucose metabolism (CMRglc). Physiological regions of interest (ROI) were generated for each subject using a range of OEF values from very low (<10), low (10-30), normal range (30-50), high (50-70), and critically high (> or =70%). We applied these ROIs to each subject to generate data that would examine the balance between blood flow and metabolism across the injured brain independent of structural injury. DISCUSSION: Compared to the normal range, brain regions with higher OEF demonstrate a progressive CBF reduction (P < 0.01), CMRO2 increase (P < 0.05), and no change in CMRglc, while regions with lower OEF are associated with reductions in CBF, CMRO2, and CMRglc (P < 0.01). Although all subjects demonstrate a decrease in CBF with increases in OEF > 70%, CMRO2 and CMRglc were generally unchanged. One subject demonstrated a reduction in CBF and small fall in CMRO2 within the high OEF region (>70%), combined with a progressive increase in CMRglc. CONCLUSIONS: The low CBF and maintained CMRO2 in the high OEF ROIs is consistent with classical cerebral ischemia and the presence of an 'ischemic penumbra' following early head injury, while the metabolic heterogeneity that we observed suggests significant pathophysiological complexity. Other mechanisms of energy failure are clearly important and further study is required to delineate the processes involved.

Effect of hyperoxia on regional oxygenation and metabolism after severe traumatic brain injury: preliminary findings.

OBJECTIVE: To determine the effect of normobaric hyperoxia on cerebral metabolism in patients with severe traumatic brain injury. DESIGN: Prospective clinical investigation. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Eleven patients with severe traumatic brain injury. INTERVENTIONS: Cerebral microdialysis, brain tissue oximetry (PbO2), and oxygen-15 positron emission tomography (15O-PET) were undertaken at normoxia and repeated at hyperoxia (FiO2 increase of between 0.35 and 0.50). MEASUREMENTS AND MAIN RESULTS: Established models were used to image cerebral blood flow, blood volume, oxygen metabolism, and oxygen extraction fraction. Physiology was characterized in a focal region of interest (surrounding the microdialysis catheter) and correlated with microdialysis and oximetry. Physiology was also characterized in a global region of interest (including the whole brain), and a physiologic region of interest (defined using a critical cerebral metabolic rate of oxygen threshold). Hyperoxia increased mean +/- sd PbO2 from 28 +/- 21 mm Hg to 57 +/- 47 mm Hg (p = .015). Microdialysate lactate and pyruvate were unchanged, but the lactate/pyruvate ratio showed a statistically significant reduction across the study population (34.1 +/- 9.5 vs. 32.5 +/- 9.0, p = .018). However, the magnitude of reduction was small, and its clinical significance doubtful. The focal region of interest and global 15O-PET variables were unchanged. "At-risk" tissue defined by the physiologic region of interest, however, showed a universal increase in cerebral metabolic rate of oxygen from a median (interquartile range) of 23 (22-25) micromol x 100 mL(-1) x min(-1) to 30 (28-36) micromol x 100 mL(-1) x min(-1) (p < .01). CONCLUSIONS: In severe traumatic brain injury, hyperoxia increases PbO2 with a variable effect on lactate and lactate/pyruvate ratio. Microdialysis does not, however, predict the universal increases in cerebral metabolic rate of oxygen in at-risk tissue, which imply preferential metabolic benefit with hyperoxia.

Concordant biology underlies discordant imaging findings: diffusivity behaves differently in grey and white matter post acute neurotrauma.

BACKGROUND: Cerebral edema is a common sequelum post traumatic brain injury (TBI). Quantification of the apparent diffusion coefficient (ADC) using diffusion tensor imaging (DTI) may help to characterize the pathophysiology of brain swelling. METHODS: Twenty-two patients with moderate-to-severe TBI underwent magnetic resonance (MR) imaging, including DTI, within five days of injury. The mean ADCs in whole brain white matter, whole brain grey matter and entire brain were calculated and compared to twenty-five controls. FINDINGS: A significant decrease in the grey matter ADC (p < 0.001), significant increase in the white matter ADC (p < 0.001) and no significant change in the whole brain ADC (p = 0.771) was observed. No significant correlation was found between DTI parameters in any of the three regions of interest (ROI) and GCS, time to scan, intracranial pressure (ICP) before and during the time of the scan, cerebral perfusion pressure at time of scan, or Glasgow Outcome Score (GCS). CONCLUSIONS: The decrease in ADC seen in the grey matter is consistent with cytotoxic edema. The increase in ADC in the white matter indicates damage that has led to an overall less restricted diffusion. This study assists in the interpretation of the ADC by showing that the acute changes are different in the whole brain white and grey matter ROIs post TBI.

Variability and fractal analysis of middle cerebral artery blood flow velocity and arterial blood pressure in subarachnoid hemorrhage.

Higher biologic systems operate far from equilibrium resulting in order, complexity, fluctuation of inherent parameters, and dissipation of energy. According to the decomplexification theory, disease is characterized by a loss of system complexity. We analyzed such complexity in patients after subarachnoid hemorrhage (SAH), by applying the standard technique of variability analysis and the novel method of fractal analysis to middle cerebral artery blood flow velocity (FV) and arterial blood pressure (ABP). In 31 SAH -patients, FV (using transcranial Doppler sonography) and direct ABP were measured. The standard deviations (s.d.) and coefficients of variation (CV=relative s.d.) for FV and ABP time series of length 2(10) secs were calculated as measures of variability. The spectral index beta(low) and the Hurst coefficient H(bdSWV) were analyzed as fractal measures. Outcome was assessed 1 year after SAH according to the Glasgow Outcome Scale (GOS). Both FV (beta(low)=2.2+/-0.4, mean+/-s.d.) and ABP (beta(low)=2.3+/-0.4) were classified as nonstationary (fractal Brownian motion) signals. FV showed significantly (P<0.05) higher variability (CV=7.2+/-2.5%) and Hurst coefficient (H(bdSWV)=0.26+/-0.13) as compared with ABP (CV=5.5+/-2.7%, H(bdSWV)=0.19+/-0.11). Better outcome (GOS) correlated significantly (P<0.05) with higher s.d. of FV (Spearman's r(s)=0.51, r(s)(2)=0.26) and ABP (r(s)=0.57, r(s)(2)=0.32), as well as with a higher Hurst coefficient of ABP (r(s)=0.46, r(s)(2)=0.21). Cerebral vasospasm reduced CV of FV, but left H(bdSWV) unchanged. FV and ABP fluctuated markedly despite homeostatic control. A reduced variability of FV and ABP might indicate a loss of complexity and was associated with a less favorable outcome. Therefore, the decomplexification theory of illness may apply to SAH.

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

Impulsivity, reward sensitivity, and decision-making in subarachnoid hemorrhage survivors.

Subarachnoid hemorrhage (SAH) survivors often report psychosocial and emotional changes, including a diminished capacity for decision making. However, systematic investigations into the nature of the changes have been limited to those patients surviving SAH secondary to aneurysms of the anterior communicating artery. This study aimed to explore the nature of decision making in survivors of SAH secondary to aneurysms of the middle cerebral or posterior communicating artery using a series of computerized tasks. Twenty SAH survivors and 20 matched controls completed a battery of computerized decision-making tasks. These included tasks examining an individual's ability to make probabilistic choices and risk-taking behavior, as well as tasks examining aspects of impulsivity. The results revealed two key patterns of abnormal decision-making behavior in the SAH survivors: altered sensitivity to both reward and punishment, and impulsive responding. These complex deficits may contribute to difficulties in daily living resulting from apathy, poor judgment, or inhibition in SAH survivors.

Cognitive reserve as a resilience factor against depression after moderate/severe head injury.

Depression is one of the most frequently reported and distressing residual complaints in survivors of head injury. Studies investigating the pattern of neuropathology associated with depression post head injury have found little consistency. One explanation for this is that cognitive reserve "protects" against depression either through more efficient processing or more effective compensation. An alternative explanation is that previous studies have used relatively gross measures of lesion location, and variable inclusion criteria and times between scan and injury. This study explored these possibilities in a cohort of survivors of moderate-severe head injury at least 6 months post-injury. Volunteers completed neuropsychological assessments and structural magnetic resonance imaging (MRI) scans. A significant difference between depressed and non-depressed survivors was found, with higher intelligence associated with lower rates of depression. No significant anatomical differences were found between depressed and non-depressed survivors. These results suggest that premorbid intelligence may provide a resilience factor against depression in head injury survivors.

Effect of cerebral perfusion pressure augmentation on regional oxygenation and metabolism after head injury.

OBJECTIVE: In this study we have used O positron emission tomography, brain tissue oxygen monitoring, and cerebral microdialysis to assess the effects of cerebral perfusion pressure augmentation on regional physiology and metabolism in the setting of traumatic brain injury. DESIGN: Prospective interventional study. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Eleven acutely head-injured patients requiring norepinephrine to maintain cerebral perfusion pressure. INTERVENTIONS: Using positron emission tomography, we have quantified the response to an increase in cerebral perfusion pressure in a region of interest around a brain tissue oxygen sensor (Neurotrend) and microdialysis catheter. Oxygen extraction fraction and cerebral blood flow were measured with positron emission tomography at a cerebral perfusion pressure of approximately 70 mm Hg and approximately 90 mm Hg using norepinephrine to control cerebral perfusion pressure. All other aspects of physiology were kept stable. MEASUREMENTS AND MAIN RESULTS: Cerebral perfusion pressure augmentation resulted in a significant increase in brain tissue oxygen (17 +/- 8 vs. 22 +/- 8 mm Hg; 2.2 +/- 1.0 vs. 2.9 +/- 1.0 kPa, p < .001) and cerebral blood flow (27.5 +/- 5.1 vs. 29.7 +/- 6.0 mL/100 mL/min, p < .05) and a significant decrease in oxygen extraction fraction (33.4 +/- 5.9 vs. 30.3 +/- 4.6 %, p < .05). There were no significant changes in any of the microdialysis variables (glucose, lactate, pyruvate, lactate/pyruvate ratio, glycerol). There was a significant linear relationship between brain tissue oxygen and oxygen extraction fraction (r = .21, p < .05); the brain tissue oxygen value associated with an oxygen extraction fraction of 40% (the mean value for oxygen extraction fraction in normal controls) was 14 mm Hg (1.8 kPa). The cerebral perfusion pressure intervention resulted in a greater percentage increase in brain tissue oxygen than the percentage decrease in oxygen extraction fraction; this suggests that the oxygen gradients between the vascular and tissue compartments were reduced by the cerebral perfusion pressure intervention. CONCLUSIONS: Cerebral perfusion pressure augmentation significantly increased levels of brain tissue oxygen and significantly reduced regional oxygen extraction fraction. However, these changes did not translate into predictable changes in regional chemistry. Our results suggest that the ischemic level of brain tissue oxygen may lie at a level below 14 mm Hg (1.8 kPa); however, the data do not allow us to be more specific.

Does induced hypertension reduce cerebral ischaemia within the traumatized human brain?

Recent changes in published guidelines for the management of patients with severe head injury are based on data showing that aggressive maintenance of cerebral perfusion pressure (CPP) can worsen outcome due to extracranial complications of therapy. However, it remains unclear whether CPP augmentation could reduce cerebral ischaemia, a finding which might prompt the search for CPP augmentation protocols that avoid these extracranial complications. We studied 10 healthy volunteers and 20 patients within 6 days of closed head injury. All subjects underwent imaging of cerebral blood flow (CBF), blood volume (CBV), oxygen metabolism (CMRO2) and oxygen extraction fraction (OEF) using 15O PET. In addition, for patients, the EEG power ratio index (PRI), burst suppression ratio and somatosensory evoked potentials (SEP) were obtained and CPP was increased from 68 +/- 4 to 90 +/- 4 mmHg using an infusion of norepinephrine and measurements were repeated. Following elevation of CPP, CBF and CBV were increased and CMRO2 and OEF were reduced (P < 0.001 for all comparisons). Regions with a reduction in CMRO2 were associated with the greatest reduction in OEF (r2 = 0.3; P < 0.0001). Although CPP elevation produced a significant fall in the ischaemic brain volume (IBV) (from 15 +/- 16 to 5 +/- 4 ml; P < 0.01) and improved flow metabolism coupling, the IBV was small and clinically insignificant in the majority of these patients. However, the reduction in IBV was directly related to the baseline IBV (r2 = 0.97; P < 0.001) and patients with large baseline IBV showed substantial and clinically significant reductions. CPP augmentation increased the EEG PRI (5.0 +/- 1.5 versus 4.3 +/- 1.4, P < 0.01), implying an overall decrease in neural activity, but these changes did not correlate with the reduction in CMRO2 and there was no change in SEP cortical amplitude (N20-P27). These data provide support for recent changes in recommended CPP levels for head injury management across populations of patients with significant head injury. However, they do not provide guidance on whether the intervention may be more appropriate at earlier stages after injury, or in patients selected because of high baseline IBV. It also remains unclear whether CPP values below 65 mmHg can be safely used in this population. Clarification of the significance of a reduction in CMRO2 and neuronal electrical function will require further study.

Sustained moderate reductions in arterial CO2 after brain trauma time-course of cerebral blood flow velocity and intracranial pressure.

OBJECTIVE: In healthy volunteers cerebral blood flow starts to recover towards baseline within a few minutes of continued hyperventilation due to normalisation of perivascular pH. We investigated the time-course of changes in middle cerebral artery mean flow velocity (FVm) and intracranial pressure (ICP) in head-injured patients during sustained moderate reductions in arterial partial pressure of CO(2) (PaCO(2)). DESIGN: Observational study. PATIENTS: Twenty-seven sedated, mechanically ventilated patients with severe head injury. INTERVENTIONS: Measurements were made during and after routine determination of CO(2)-reactivity: an acute 20% increase in respiratory minute volume was followed by a 10-min stabilisation period and 50 min of continued moderate hyperventilation at a constant PaCO(2) (>3.5 kPa). MEASUREMENTS AND RESULTS: FVm was monitored with transcranial Doppler, ICP was monitored with intraparenchymal probes. During the 50-min period with stable PaCO(2) FVm increased in 36% of patients. All other patients showed a decline in FVm over the same time period. Overall FVm recovery was -0.03+/-0.14%.min(-1). The time-course of ICP changes was significantly different from that of FVm, with ICP reaching its lowest value earlier than FVm (23+/-12 vs 37+/-20 min; P = 0.001) and returning more rapidly towards baseline than FVm (0.23+/-0.23 vs -0.03+/-0.14%.min(-1); P< 0.0001). CONCLUSIONS: Head-injured patients may adapt differently to hyperventilation than healthy volunteers. Potentially harmful reductions in cerebral blood flow may persist beyond the duration of useful ICP reduction.

Diffusion limited oxygen delivery following head injury.

OBJECTIVE: To use a range of techniques to explore diffusion limitation as a mechanism of cellular hypoxia in the setting of head injury. DESIGN: A prospective interventional study. SETTING: A specialist neurocritical care unit. PATIENTS: Thirteen patients within 7 days of closed head injury underwent imaging studies. Tissue for ultrastructural studies was obtained from a cohort of seven patients who required surgery. INTERVENTIONS: Cerebral tissue PO2 (PtO2) was obtained using a multiple-variable sensor, and images of oxygen extraction fraction (OEF), derived from positron emission tomography, were used to calculate cerebral venous PO2 (PvO2). These data were used to derive the PvO2-PtO2 gradient in a region of interest around the sensor, which provided a measure of the efficiency of microvascular oxygen delivery. Measurements were repeated after PaCO2 was reduced from 37 +/- 3 to 29 +/- 3 torr (4.9 +/- 0.4 to 3.9 +/- 0.4 kPa) to assess the ability of the microvasculature to increase oxygen unloading during hypocapnia-induced hypoperfusion. Pericontusional tissue was submitted to electron microscopy to illustrate the structural correlates of physiologic findings. MEASUREMENTS AND MAIN RESULTS: Tissue regions with hypoxic levels of PtO2 (<10 torr) had similar levels of PvO2 compared with nonhypoxic areas and hence displayed larger PvO2-PtO2 gradients (27 +/- 2 vs. 9 +/- 8 torr, p <.001). Despite similar cerebral blood flow reductions with hyperventilation, hypoxic regions achieved significantly smaller OEF increases compared with normoxic regions (7 +/- 5 vs. 16 +/- 6 %, p <.05). Pericontusional tissue showed varying degrees of endothelial swelling, microvascular collapse, and perivascular edema. CONCLUSIONS: Increased diffusion barriers may reduce cellular oxygen delivery following head injury and attenuate the ability of the brain to increase oxygen extraction in response to hypoperfusion. Global or regional OEF underestimates tissue hypoxia due to such mechanisms.

Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients.

OBJECTIVE: To directly compare the cerebrovascular effects of norepinephrine and dopamine in patients with acute traumatic brain injury. DESIGN: Prospective randomized crossover trial. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Ten acutely head-injured patients requiring vasoactive drugs to maintain a cerebral perfusion pressure of 65 mm Hg. INTERVENTIONS: Patients were randomized to start the protocol with either norepinephrine or dopamine. Using an infusion of the allocated drug, cerebral perfusion pressure was adjusted to 65 mm Hg. After 20 mins of data collection, cerebral perfusion pressure was increased to 75 mm Hg by increasing the infusion rate of the vasoactive agent. After 20 mins of data collection, cerebral perfusion pressure was increased to 85 mm Hg and again data were collected for 20 mins. Subsequently, the infusion rate of the vasoactive drug was reduced until a cerebral perfusion pressure of 65 mm Hg was reached and the drug was exchanged against the other agent. The protocol was then repeated. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure and intracranial pressure were monitored and cerebral blood flow was estimated with transcranial Doppler. Norepinephrine led to predictable and significant increases in flow velocity for each step increase in cerebral perfusion pressure (57.5+/-19.9 cm x sec, 61.3+/-22.3 cm x sec, and 68.4+/-24.8 cm x sec at 65, 75, and 85 mm Hg, respectively; p <.05 for all three comparisons), but changes with dopamine were variable and inconsistent. There were no differences between absolute values of flow velocity or intracranial pressure between the two drugs at any cerebral perfusion pressure level. CONCLUSIONS: Norepinephrine may be more predictable and efficient to augment cerebral perfusion in patients with traumatic brain injury.