Jonathan P. Coles

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.

Incidence and mechanisms of cerebral ischemia in early clinical head injury.

Antemortem demonstration of ischemia has proved elusive in head injury because regional CBF reductions may represent hypoperfusion appropriately coupled to hypometabolism. Fifteen patients underwent positron emission tomography within 24 hours of head injury to map cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), and oxygen extraction fraction (OEF). We estimated the volume of ischemic brain (IBV) and used the standard deviation of the OEF distribution to estimate the efficiency of coupling between CBF and CMRO2. The IBV in patients was significantly higher than controls (67 ± 69 vs. 2 ± 3 mL; P < 0.01). The coexistence of relative ischemia and hyperemia in some patients implies mismatching of perfusion to oxygen use. Whereas the saturation of jugular bulb blood (SjO2) correlated with the IBV (r = 0.8, P < 0.01), SjO2 values of 50% were only achieved at an IBV of 170 ± 63 mL (mean ± 95% CI), which equates to 13 ± 5% of the brain. Increases in IBV correlated with a poor Glasgow Outcome Score 6 months after injury (ρ = −0.6, P < 0.05). These results suggest significant ischemia within the first day after head injury. The ischemic burden represented by this “traumatic penumbra” is poorly detected by bedside clinical monitors and has significant associations with outcome.

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.

Correlation between cerebral blood flow, substrate delivery, and metabolism in head injury: A combined microdialysis and triple oxygen positron emission tomography study

Microdialysis continuously monitors the chemistry of a small focal volume of the cerebral extracellular space. Conversely, positron emission tomography (PET) establishes metabolism of the whole brain, but only for the duration of the scan. The objective of this study was to apply both techniques to head-injured patients simultaneously to assess the relation between microdialysis (glucose, lactate, lactate/pyruvate [L/P] ratio, and glutamate) and PET (cerebral blood flow [CBF], cerebral blood volume, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen) parameters. Microdialysis catheters were inserted into the frontal cerebral cortex and adipose tissue of the anterior abdominal wall of 17 severely head-injured patients. Microdialysis was performed during PET scans, with regions of interest defined by the location of the microdialysis catheter membrane. An intervention (hyperventilation) was performed in 13 patients. The results showed that combining PET and microdialysis to monitor metabolism in ventilated patients is feasible and safe, although logistically complex. There was a significant relation between the L/P ratio and the OEF (Spearman r = 0.69, P = 0.002). There was no significant relation between CBF and the microdialysis parameters. Moderate short-term hyperventilation appeared to be tolerated in terms of brain chemistry, although no areas were sampled by microdialysis where the OEF exceeded 70%. Hyperventilation causing a reduction of the arterial carbon dioxide tension by 0.9 kPa resulted in a significant elevation of the OEF, in association with a reduction in glucose, but no significant elevation in the L/P ratio or glutamate.

Use of T2-weighted magnetic resonance imaging of the optic nerve sheath to detect raised intracranial pressure

IntroductionThe dural sheath surrounding the optic nerve communicates with the subarachnoid space, and distends when intracranial pressure is elevated. Magnetic resonance imaging (MRI) is often performed in patients at risk for raised intracranial pressure (ICP) and can be used to measure precisely the diameter of optic nerve and its sheath. The objective of this study was to assess the relationship between optic nerve sheath diameter (ONSD), as measured using MRI, and ICP.MethodsWe conducted a retrospective blinded analysis of brain MRI images in a prospective cohort of 38 patients requiring ICP monitoring after severe traumatic brain injury (TBI), and in 36 healthy volunteers. ONSD was measured on T2-weighted turbo spin-echo fat-suppressed sequence obtained at 3 Tesla MRI. ICP was measured invasively during the MRI scan via a parenchymal sensor in the TBI patients.ResultsMeasurement of ONSD was possible in 95% of cases. The ONSD was significantly greater in TBI patients with raised ICP (>20 mmHg; 6.31 ± 0.50 mm, 19 measures) than in those with ICP of 20 mmHg or less (5.29 ± 0.48 mm, 26 measures; P < 0.0001) or in healthy volunteers (5.08 ± 0.52 mm; P < 0.0001). There was a significant relationship between ONSD and ICP (r = 0.71, P < 0.0001). Enlarged ONSD was a robust predictor of raised ICP (area under the receiver operating characteristic curve = 0.94), with a best cut-off of 5.82 mm, corresponding to a negative predictive value of 92%, and to a value of 100% when ONSD was less than 5.30 mm.ConclusionsWhen brain MRI is indicated, ONSD measurement on images obtained using routine sequences can provide a quantitative estimate of the likelihood of significant intracranial hypertension.

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 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) &mgr;mol·100 mL−1·min−1 to 30 (28–36) &mgr;mol·100 mL−1·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.

Analysis of acute traumatic axonal injury using diffusion tensor imaging

Traumatic axonal injury (TAI) contributes significantly to mortality and morbidity following traumatic brain injury (TBI), but is poorly characterized by conventional imaging techniques. Diffusion tensor imaging (DTI) may provide better detection as well as insights into the mechanisms of white matter injury. DTI data from 33 patients with moderate-to-severe TBI, acquired at a median of 32 h postinjury, were compared with data from 28 age-matched controls. The global burden of whole brain white matter injury (GBWMI) was quantified by measuring the proportion of voxels that lay below a critical fractional anisotropy (FA) threshold, identified from control data. Mechanisms of change in FA maps were explored using an Eigenvalue analysis of the diffusion tensor. When compared with controls, patients showed significantly reduced mean FA (p < 0.001) and increased apparent diffusion coefficient (ADC; p = 0.017). GBWMI was significantly greater in patients than in controls (p < 0.01), but did not distinguish patients with obvious white matter lesions seen on structural imaging. It predicted classification of DTI images as head injury with a high degree of accuracy. Eigenvalue analysis showed that reductions in FA were predominantly the result of increases in radial diffusivity (p < 0.001). DTI may help quantify the overall burden of white matter injury in TBI and provide insights into underlying pathophysiology. Eigenvalue analysis suggests that the early imaging changes seen in white matter are consistent with axonal swelling rather than axonal truncation. This technique holds promise for examining disease progression, and may help define therapeutic windows for the treatment of diffuse brain injury.

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

ObjectiveTo directly compare the cerebrovascular effects of norepinephrine and dopamine in patients with acute traumatic brain injury. DesignProspective randomized crossover trial. SettingNeurosciences critical care unit of a university hospital. PatientsTen acutely head-injured patients requiring vasoactive drugs to maintain a cerebral perfusion pressure of 65 mm Hg. InterventionsPatients 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 ResultsMean 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·sec−1, 61.3 ± 22.3 cm·sec−1, and 68.4 ± 24.8 cm·sec−1 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. ConclusionsNorepinephrine may be more predictable and efficient to augment cerebral perfusion in patients with traumatic brain injury.

Defining Ischemic Burden after Traumatic Brain Injury Using 15O PET Imaging of Cerebral Physiology

Whereas postmortem ischemic damage is common in head injury, antemortem demonstration of ischemia has proven to be elusive. Although 15O positron emission tomography may be useful in this area, the technique has traditionally analyzed data within regions of interest (ROIs) to improve statistical accuracy. In head injury, such techniques are limited because of the lack of a priori knowledge regarding the location of ischemia, coexistence of hyperaemia, and difficulty in defining ischemic cerebral blood flow (CBF) and cerebral oxygen metabolism (CMRO2) levels. We report a novel method for defining disease pathophysiology following head injury. Voxel-based approaches are used to define the distribution of oxygen extraction fraction (OEF) across the entire brain; the standard deviation of this distribution provides a measure of the variability of OEF. These data are also used to integrate voxels above a threshold OEF value to produce an ROI based upon coherent physiology rather than spatial contiguity (the ischemic brain volume; IBV). However, such approaches may suffer from poor statistical accuracy, particularly in regions with low blood flow. The magnitude of these errors has been assessed in modeling experiments using the Hoffman brain phantom and modified control datasets. We conclude that this technique is a valid and useful tool for quantifying ischemic burden after traumatic brain injury.