Jurgens Nortje's research while affiliated with University of Cambridge and other places

Importance Ischemia is an important pathophysiological mechanism after traumatic brain injury (TBI), but its incidence and spatiotemporal patterns are poorly characterized. Objective To comprehensively characterize the spatiotemporal changes in cerebral physiology after TBI. Design, Setting, and Participants This single-center cohort study uses ¹⁵oxygen positron emission tomography data obtained in a neurosciences critical care unit from February 1998 through July 2014 and analyzed from April 2018 through August 2019. Patients with TBI requiring intracranial pressure monitoring and control participants were recruited. Exposures Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral oxygen metabolism (CMRO2), and oxygen extraction fraction. Main Outcomes and Measures Ratios (CBF/CMRO2 and CBF/CBV) were calculated. Ischemic brain volume was compared with jugular venous saturation and brain tissue oximetry. Results A total of 68 patients with TBI and 27 control participants were recruited. Results from 1 patient with TBI and 7 health volunteers were excluded. Sixty-eight patients with TBI (13 female [19%]; median [interquartile range (IQR)] age, 29 [22-47] years) underwent 90 studies at early (day 1 [n = 17]), intermediate (days 2-5 [n = 54]), and late points (days 6-10 [n = 19]) and were compared with 20 control participants (5 female [25%]; median [IQR] age, 43 [31-47] years). The global CBF and CMRO2 findings for patients with TBI were less than the ranges for control participants at all stages (median [IQR]: CBF, 26 [22-30] mL/100 mL/min vs 38 [29-49] mL/100 mL/min; P < .001; CMRO2, 62 [55-71] μmol/100 mL/min vs 131 [101-167] μmol/100 mL/min; P < .001). Early CBF reductions showed a trend of high oxygen extraction fraction (suggesting classical ischemia), but this was inconsistent at later phases. Ischemic brain volume was elevated even in the absence of intracranial hypertension and highest at less than 24 hours after TBI (median [IQR], 36 [10-82] mL), but many patients showed later increases (median [IQR] 6-10 days after TBI, 24 [4-42] mL; across all points: patients, 10 [5-39] mL vs control participants, 1 [0-3] mL; P < 001). Ischemic brain volume was a poor indicator of jugular venous saturation and brain tissue oximetry. Patients’ CBF/CMRO2 ratio was higher than controls (median [IQR], 0.42 [0.35-0.49] vs 0.3 [0.28-0.33]; P < .001) and their CBF/CBV ratio lower (median [IQR], 7.1 [6.4-7.9] vs 12.3 [11.0-14.0]; P < .001), suggesting abnormal flow-metabolism coupling and vascular reactivity. Patients’ CBV was higher than controls (median [IQR], 3.7 [3.4-4.1] mL/100 mL vs 3.0 [2.7-3.6] mL/100 mL; P < .001); although values were lower in patients with intracranial hypertension, these were still greater than controls (median [IQR], 3.7 [3.2-4.0] vs 3.0 [2.7-3.6] mL/100 mL; P = .002), despite more profound reductions in partial pressure of carbon dioxide (median [IQR], 4.3 [4.1-4.6] kPa vs 4.7 [4.3-4.9] kPa; P = .001). Conclusions and Relevance Ischemia is common early, detectable up to 10 days after TBI, possible without intracranial hypertension, and inconsistently detected by jugular or brain tissue oximetry. There is substantial between-patient and within-patient pathophysiological heterogeneity; ischemia and hyperemia commonly coexist, possibly reflecting abnormalities in flow-metabolism coupling. Increased CBV may contribute to intracranial hypertension but can coexist with abnormal CBF/CBV ratios. These results emphasize the need to consider cerebrovascular pathophysiological complexity when managing patients with TBI.

Cerebral hypoxia and acidosis can follow traumatic brain injury (TBI) and are associated with increased mortality. This study aimed to evaluate a relationship between reduced pH(bt) and disturbances of cerebral metabolism. Prospective data from 56 patients with TBI, receiving microdialysis and Neurotrend monitoring, were analyzed. Four tissue states were defined based on pH(bt) and P(bt)O(2): 1-low P(bt)O(2)/pH(bt), 2-low pH(bt)/normal P(bt)O(2), 3-normal pH(bt)/low P(bt)O(2), and 4-normal pH(bt)/P(bt)O(2)). Microdialysis values were compared between the groups. The relationship between P(bt)O(2) and lactate/pyruvate (LP) ratio was evaluated at different pH(bt) levels. Proportional contribution of each state was evaluated against mortality. As compared with the state 4, the state 3 was not different, the state 2 exhibited higher levels of lactate, LP, and glucose and the state 1-higher LP and reduced glucose (P<0.001). A significant negative correlation between LP and P(bt)O(2) (rho=-0.159, P<0.001) was stronger at low pH(bt) (rho=-0.201, P<0.001) and nonsignificant at normal pH(bt) (P=0.993). The state 2 was a significant discriminator of mortality categories (P=0.031). Decreased pH(bt) is associated with impaired metabolism. Measuring pH(bt) with P(bt)O(2) is a more robust way of detecting metabolic derangements.Journal of Cerebral Blood Flow & Metabolism advance online publication, 12 December 2012; doi:10.1038/jcbfm.2012.186.

Bedside monitoring of cerebral metabolism in traumatic brain injury (TBI) with microdialysis is gaining wider clinical acceptance. The objective of this study was to examine the relationship between the fundamental physiological neuromonitoring modalities intracranial pressure (ICP), cerebral perfusion pressure (CPP), brain tissue oxygen (P(bt)O(2)), and cerebrovascular pressure reactivity index (PRx), and cerebral chemistry assessed with microdialysis, with particular focus on the lactate/pyruvate (LP) ratio as a marker of energy metabolism. Prospectively collected observational neuromonitoring data from 97 patients with TBI, requiring neurointensive care management and invasive cerebral monitoring, were analyzed. A linear mixed model analysis was used to account for individual patient differences. Perilesional tissue chemistry exhibited a significant independent relationship with ICP, P(bt)O(2) and CPP thresholds, with increasing LP ratio in response to decrease in P(bt)O(2) and CPP, and increase in ICP. The relationship between CPP and chemistry depended upon the state of PRx. Within the studied physiological range, tissue chemistry only changed in response to increasing ICP or drop in P(bt)O(2)<1.33 kPa (10 mmHg). In agreement with previous studies, significantly higher levels of cerebral lactate (p<0.001), glycerol (p=0.013), LP ratio (p<0.001) and lactate/glucose (LG) ratio (p=0.003) were found in perilesional tissue, compared to "normal" brain tissue (Mann-Whitney test). These differences remained significant following adjustment for the influences of other important physiological parameters (ICP, CPP, P(bt)O(2), P(bt)CO(2), PRx, and brain temperature; mixed linear model), suggesting that they may reflect inherent tissue properties related to the initial injury. Despite inherent biochemical differences between less-injured brain and "perilesional" cerebral tissue, both tissue types exhibited relationships between established physiological variables and biochemistry. Decreases in perfusion and oxygenation were associated with deteriorating neurochemistry and these effects were more pronounced in perilesional tissue and when cerebrovascular reactivity was impaired.

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. 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. 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). 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.

There is evidence to suggest that anemia after severe traumatic brain injury (sTBI) is detrimental. However, there is a paucity of evidence supporting the use of transfusion of packed red blood cells in patients with sTBI. To understand the acute effect of packed red blood cell transfusion on cerebral oxygenation and metabolism in patients with sTBI. Prospective clinical study. Addenbrooke's Neurosciences Critical Care Unit, a 21-bed tertiary academic unit. Thirty patients with sTBI. Patients were randomized by computer random number generator to one of three transfusion thresholds: 8, 9, or 10 g/dL. When the patients' hemoglobin concentration fell below their assigned threshold, two units of packed red blood cells were transfused over 2 hours. A 1-hour period of stabilization was observed before final data collection. The primary outcome was change in brain tissue oxygen (Pbto2). Secondary outcomes included dependence of baseline hemoglobin concentration and baseline Pbto2 on the relationship of transfusion and Pbto2, and the effect of transfusion on lactate pyruvate ratio (LPR) and brain pH as markers of cerebral metabolic state. Fifty-seven percent of patients experienced an increase in Pbto2 during the course of the study, whereas in 43% of patients, Pbto2 either did not change or decreased. Multivariable generalized estimating equation analysis revealed change in hemoglobin concentration to significantly and positively associated with change in Pbto2 [0.10 kPa/(g/dL) 95% confidence interval 0.03-0.17, p = 0.003]. Improvement in Pbto2 was not associated with baseline hemoglobin concentration or low Pbto2 (<1 kPa). Fifty-six percent of patients experienced an increase in LPR. No significant relationship between change in LPR or transfusion on pHbt and change in hemoglobin could be demonstrated. Transfusion of packed red blood cells acutely results in improved brain tissue oxygen without appreciable effect on cerebral metabolism. ISRCTN89085577.

The objective was to study the anatomical changes in the pituitary gland following acute moderate or severe traumatic brain injury (TBI). Retrospective, observational, case-control study. Neurosciences Critical Care Unit of a university hospital. Forty-one patients with moderate or severe TBI who underwent magnetic resonance imaging (MRI) during the acute phase (less than seven days) of TBI. MRI scans of 43 normal healthy volunteers were used as controls. None. Patient demographics, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, Injury Severity Score (ISS), post-resuscitation Glasgow Coma Score (GCS), Glasgow Outcome Score (GOS), mean intracranial pressure (ICP), mean cerebral perfusion pressure (CPP), computed tomography (CT) data, pituitary gland volumes and structural lesions in the pituitary on MRI scans. The pituitary glands were significantly enlarged in the TBI group (the median and interquartile range were as follows: cases 672 mm3 (range 601-783 mm3) and controls 552 mm3 (range 445-620 mm3); p value<0.0001). APACHE II, GCS, GOS and ICP were not significantly correlated with the pituitary volume. Twelve of the 41 cases (30%) demonstrated focal changes in the pituitary gland (haemorrhage/haemorrhagic infarction (n=5), swollen gland with bulging superior margin (n=5), heterogeneous signal intensities in the anterior lobe (n=2) and partial transection of the infundibular stalk (n=1). Acute TBI is associated with pituitary gland enlargement with specific lesions, which are seen in approximately 30% of patients. MRI of the pituitary may provide useful information about the mechanisms involved in post-traumatic hypopituitarism.

The aim of this study was to evaluate the effect of ventriculostomy on intracranial pressure (ICP), and related parameters, including cerebrospinal compensation, cerebral oxygenation (PbtO2) and metabolism (microdialysis) in patients with traumatic brain injury (TBI). Twenty-four patients with parenchymal ICP sensors were prospectively included in the study. Ventriculostomy was performed after failure to control ICP with initial measures. Monitoring parameters were digitally recorded before and after ventriculostomy and compared using appropriate tests. In all patients ventriculostomy led to rapid reduction in ICP. Pooled mean daily values of ICP remained < 20mmHg for 72h after ventriculostomy and were lower than before (p < 0.001). In 11 out of 24 patients during the initial 24-h period following ventriculostomy an increase in ICP to values exceeding 20mmHg was observed. In the remaining 13 patients ICP remained stable, allowing reduction in the intensity of treatment. In this group ventriculostomy led to significant improvement in craniospinal compensation (RAP index), cerebral perfusion pressure and PbtO2. Improvement in lactate/pyruvate ratio, a marker of energy metabolism, was correlated with the increase in PbtO2. Ventriculostomy is a useful ICP-lowering manoeuvre, with sustained ICP reduction and related physiological improvements achieved in > 50% of patients.

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. 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. 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). 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.