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 pHbt 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 pHbt and PbtO2: 1—low PbtO2/pHbt, 2—low pHbt/normal PbtO2, 3—normal pHbt/low PbtO2, and 4—normal pHbt/PbtO2). Microdialysis values were compared between the groups. The relationship between PbtO2 and lactate/pyruvate (LP) ratio was evaluated at different pHbt 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 PbtO2 (rho = −0.159, P < 0.001) was stronger at low pHbt (rho = −0.201, P < 0.001) and nonsignificant at normal pHbt ( P = 0.993). The state 2 was a significant discriminator of mortality categories ( P = 0.031). Decreased pHbt is associated with impaired metabolism. Measuring pHbt with PbtO2 is a more robust way of detecting metabolic derangements.

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.

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 (PbtO2), 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, PbtO2 and CPP thresholds, with increasing LP ratio in response to decrease in PbtO2 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 PbtO2 < 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, PbtO2, PbtCO2, 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.

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

Pre-operative symptomatic hemisphere CBF was 38 +/- 2 mls/100g/min compared to 40 +/- 3.2 mls/100 g/min in the asymptomatic hemisphere, with the greatest difference observed in the MCA territory (38.6 +/- 2 cf 45.4 +/- 3.2 mls/100g/min). Baseline CBF was not significantly improved post EC/IC bypass. However CVR was significantly improved in the symptomatic hemisphere post-operatively (p = 0.015), with the greatest increase (28%) seen in the MCA territory (p = 0.0105). First, 85% of patients had either an improvement in symptoms or no further symptoms. There was a 93% graft patency and no operative mortality. Low flow EC/IC bypass can improve CVR in patients with symptomatic cerebral ischaemia in the presence of occlusive carotid disease. However, therapy must be individualised, with careful patient selection and minimal surgical morbidity.

Background Microdialysis continuously monitors the chemistry of a small focal volume of the cerebral extracellular space. Positron emission tomography (PET) establishes metabolism of the whole brain but only for the scan’s duration. This study’s objective was to apply these techniques together, in patients with traumatic brain injury, to assess the relationship between microdialysis (extracellular glucose, lactate, pyruvate, and the lactate/pyruvate (L/P) ratio as a marker of anaerobic metabolism) and PET parameters of glucose metabolism using the glucose analogue [ 18 F]-fluorodeoxyglucose (FDG). In particular, we aimed to determine the fate of glucose in terms of differential metabolism to pyruvate and lactate. Materials and methods Microdialysis catheters (CMA70 or CMA71) were inserted into the cerebral cortex of 17 patients with major head injury. Microdialysis was performed during FDG-PET scans with regions of interest for PET analysis defined by the location of the gold-tipped microdialysis catheter. Microdialysate analysis was performed on a CMA600 analyser. Findings There was significant linear relationship between the PET-derived parameter of glucose metabolism (regional cerebral metabolic rate of glucose; CMRglc) and levels of lactate ( r = 0.778, p < 0.0001) and pyruvate ( r = 0.799, p < 0.0001), but not with the L/P ratio. Conclusion The results suggest that in this population of patients, glucose was metabolised to both lactate and pyruvate, but was not associated with an increase in the L/P ratio. This suggests an increase in glucose metabolism to both lactate and pyruvate, as opposed to a shift towards anaerobic metabolism.

Introduction This pilot microdialysis study in acute brain injury patients assessed the relationship between nitric oxide products (total nitrite plus nitrate, termed NOx) and energy-related molecules: glucose, lactate, pyruvate, glutamate and glycerol.

OBJECT Systemic administration of 23.5% hypertonic saline enhances cerebral blood flow (CBF) in patients with poor-grade spontaneous subarachnoid hemorrhage (SAH). Whether the increment of change in CBF correlates with changes in autoregulation of CBF or outcome at discharge remains unknown. METHODS Thirty-five patients with poor-grade spontaneous SAH received 2 ml/kg 23.5% hypertonic saline intravenously, and they underwent bedside transcranial Doppler (TCD) ultrasonography and intracranial pressure (ICP) monitoring. Seventeen of them underwent Xe-enhanced computed tomography (CT) scanning for measuring CBF. Outcome was assessed using the modified Rankin Scale (mRS) at discharge from the hospital. The data were analyzed using repeated-measurement analysis of variance and Dunnett correction. A comparison was made between patients with favorable and unfavorable outcomes using multivariate logistic regression. RESULTS The authors observed a maximum increase in blood pressure by 10.3% (p < 0.05) and cerebral perfusion pressure (CPP) by 21.2% (p < 0.01) at 30 minutes, followed by a maximum decrease in ICP by 93.1% (p < 0.01) at 60 minutes. Changes in ICP and CPP persisted for longer than 180 and 90 minutes, respectively. The results of TCD ultrasonography showed that the baseline autoregulation was impaired on the ipsilateral side of ruptured aneurysm, and increments in flow velocities were higher and lasted longer on the contralateral side (48.75% compared with 31.96% [p = 0.045] and 180 minutes compared with 90 minutes [p < 0.05], respectively). The autoregulation was briefly impaired on the contralateral side during the infusion. A dose-dependent effect of CBF increments on favorable outcome was seen on Xe-CT scans (mRS Score 1-3, odds ratio 1.27 per 1 ml/100 g tissue x min, p = 0.045). CONCLUSIONS Bolus systemic hypertonic saline therapy may be used for reversal of cerebral ischemia to normal perfusion in patients with poor-grade SAH.

The use of near infrared spectroscopy (NIRS) to evaluate cerebral oxygenation changes has been reported in a variety of medical and neurosurgical conditions. This chapter looks at the application of NIRS during carotid endarterectomy. It demonstrates our own use of this technique in combination with other monitoring modalities. The NIRO 300 is a noninvasive bedside monitor which gives simultaneous measurement of tissue oxygen index (TOI) and hemoglobin concentration changes. The instrument is based on technology employed in the earlier NIRO 500 and a prototype spatially resolved spectrometer. The reliable detection of compromised regional cerebral perfusion therefore plays an important role in the management of patients undergoing carotid surgery. During carotid endarterectomy, segregation of the NIRS signal between intra- and extracranial vascular territories is possible, by staged application of vascular clamps to the external and internal carotid arteries.

Following traumatic brain injury (TBI), cascades of inflammatory processes occur. Laboratory studies implicate the cytokines interleukin-1alpha (IL-1alpha) and IL-1beta in the pathophysiology of TBI and cerebral ischemia, whilst exogenous and endogenous interleukin-1 receptor antagonist (IL-1ra) is neuroprotective. We analyzed IL-1alpha, IL-1beta, and IL-1ra in brain microdialysates (100-kDa membrane) in 15 TBI patients. We also analyzed energy-related molecules (glucose, lactate, pyruvate, glutamate, and the lactate/pyruvate ratio) in these brain microdialysates. Mean of mean (+/-SD) in vitro microdialysis percentage recoveries (extraction efficiencies) were IL-1alpha 19.7+/-7.6%, IL-1beta 23.9+/-10.5%, and IL-1ra 20.9+/-6.3%. In the patients' brain microdialysates, mean of mean cytokine concentrations (not corrected for percentage recovery) were IL-1alpha 5.6+/-14.8 pg/mL, IL-1beta 10.4+/-14.7 pg/mL, and IL-1ra 2796+/-2918 pg/mL. IL-1ra was consistently much higher than IL-1alpha and IL-1beta. There were no significant relationships between IL-1 family cytokines and energy-related molecules. There was a significant correlation between increasing IL-1beta and increasing IL-1ra (Spearman r=0.59, p=0.028). There was also a significant relationship between increasing IL-1ra and decreasing intracranial pressure (Spearman r=-0.57, p=0.041). High concentrations of IL-1ra, and also high IL-1ra/IL-1beta ratio, were associated with better outcome (Mann Whitney, p=0.018 and p=0.0201, respectively), within these 15 patients. It is unclear whether these IL-1ra concentrations are sufficient to antagonize the effects of IL-1beta in vivo. This study demonstrates feasibility of our microdialysis methodology in recovering IL-1 family cytokines for assessing their inter-relationships in the injured human brain, and suggests a neuroprotective role for IL-1ra. It remains to be seen whether exogenous IL-1ra or other agents can be used to manipulate cytokine levels in the brain, for potential therapeutic effect.

OBJECTIVE: To define whether or not direct microscopic closure with or without the use of a vascular patch is advantageous in terms of clinical outcome and late vessel occlusion rates after microsurgical carotid endarterectomy. METHODS: Three hundred thirty-eight elective carotid endarterectomies in 315 patients were randomized to direct arteriotomy or closure with a polyester collagen-coated vascular patch. Ten procedures did not follow the randomization process because of technical difficulties and were excluded. Vessel patency (duplex ultrasound) and outcome were assessed during and immediately after surgery and at 4 and 12 months after surgery. RESULTS: Four-month ultrasound assessment (n = 321) identified five occluded vessels: two in the patch group (n = 149) and three in the direct closure group (n = 172). Six patients in the patch group had died or were significantly disabled at 4 months, compared with five in the direct closure group. At the 12-month assessment (n = 313), eight vessels had occluded: five from the patched group (n = 146) and three from the direct closure group (n = 167). Eight patients in the patch group had died or were significantly disabled, compared with four in the direct closure group. No statistically significant difference between the two groups in terms of vessel occlusion, morbidity, or mortality was seen (P > 0.1). CONCLUSION: No difference in vessel patency and clinical outcome has been identified after microscopic patch angioplasty and direct arteriotomy repair. The authors conclude that there is no benefit from the routine use of patch angioplasty in microscopic carotid endarterectomy.

Background and Purpose-To date, the clinical application of near infrared spectroscopy in the adult brain has been limited. The NIRO 300 (Hamamatsu Photonics) provides a continuous measurement of tissue oxygen index (TOI) using spatially resolved spectroscopy. Although TOI reflects cerebral oxygenation to a high degree of sensitivity and specificity, to become a useful clinical tool, thresholds for cerebral ischemia need to be defined. This study has attempted to identify a quantifiable TOI threshold for ischemia in the adult brain.Methods-One hundred sixty-seven patients undergoing carotid endarterectomy were studied. The NIRO 300 was incorporated into an established multimodal monitoring system enabling observations of cerebral hemodynamic changes under highly controlled conditions. Changes in TOI (%Delta TOI) on clamping the internal carotid artery were compared with intracranial blood flow (middle cerebral artery flow velocity) and cerebral function monitoring to identify and quantify periods of cerebral ischemia.Results-Significant correlation was seen between changes in middle cerebral artery flow velocity and Delta TOI on clamping (r=0.74, P=0.0001). Thirty-one patients showed cerebral ischemia on internal carotid artery clamping as defined by a sustained fall in cerebral function monitoring. A threshold for %Delta TOI of -13 was identified, above which no patients showed any evidence of ischemia on clamping. This threshold provided 100% sensitivity and 93.2% specificity for patients satisfying the preset criteria for cerebral ischemia.Conclusions-These data demonstrate the potential to identify TOI-quantified thresholds for cerebral ischemia in the adult brain and thus improve the clinical use of near infrared spectroscopy. Our observations have defined a drop in TOI (13%) that can be adopted as a threshold for severe cerebral ischemia with high sensitivity and specificity.

OBJECTIVE:To assess the impact of carotid endarterectomy on blood pressure homeostasis and baroreflex function, with particular reference to the presence or absence of significant contralateral carotid artery disease, we conducted a prospective study in 80 patients with symptomatic extracranial carotid disease undergoing carotid endarterectomy in a regional teaching hospital over 2 years.METHODS:Patients were divided into two groups: the control group (n = 37) had no significant contralateral carotid disease; patients in the diseased group (n = 23) had either >70% stenosis or occlusion of the contralateral carotid artery. Seventeen patients with abnormal heart rhythms, poor quality recordings, or with intermediate degrees of contralateral carotid stenosis were excluded. Three patients who had previously undergone contralateral carotid endarterectomy were separately evaluated. Atheromatous plaque was removed from carotid lumen and the baroreflex mechanism received direct intraoperative stimulation before and after carotid endarterectomy. The main outcome measures were (1) the hemodynamic response to the carotid endarterectomy, baroreflex sensitivity, and operating set point (the resting blood pressure, which the baroreflex mechanism maintains) before and after removal of the atheromatous plaque, and (2) the responsiveness of the ipsilateral baroreceptor mechanism to direct stimulation. The impact of the presence of contralateral carotid stenosis on these variables was also evaluated.RESULTS:Patients in the two groups were comparable for preoperative demographic, medication, and hemodynamic variables. Carotid endarterectomy led to a rise in mean arterial pressure from 81.3 +/- 3.9 mm Hg to 103.5 +/- 4.6 mm Hg ( P < .00001) and from 87.6 +/- 4.3 mm Hg to 94.0 +/- 4.5 mm Hg ( P < .003) in the diseased and control groups, respectively. The magnitude of blood pressure response was significantly greater in the diseased group than in the control group ( P < .00001). This hypertensive shift was not accompanied by the expected fall in heart rate. Direct baroreflex stimulation prior to carotid endarterectomy caused a significantly greater response in the diseased group, suggesting sensitization of the ipsilateral carotid baroreceptor in the presence of contralateral carotid disease. Furthermore, the baroreflex response was obliterated after endarterectomy. There were significant reductions in baroreflex sensitivity and a hypertensive shift in the operating set point, the magnitude of which was significantly greater in patients with contralateral carotid disease.CONCLUSIONS:Carotid endarterectomy impairs blood pressure homeostasis through surgical destruction of the ipsilateral carotid baroreflex mechanism. Patients with contralateral carotid stenosis have a reduced baroreflex reserve and show greater baroreflex dysfunction and hemodynamic instability after endarterectomy. These patients are at greater risk of postendarterectomy complications and should be monitored closely.

While cerebral ischaemia contributes significantly to secondary brain injury following trauma, there are no data on critical thresholds of brain tissue pO2 (PbO2) for metabolic compromise. The aim of this study was to identify ischaemic thresholds for changes in brain tissue lactate concentrations and lactate/pyruvate ratio. Eleven patients with severe traumatic brain injury, with brain tissue oxygen tension (NeurotrendTM) and microdialysis monitoring in place, were studied within the first 4 days following injury, over 4 h epochs during which physiology was carefully monitored and stabilised as part of a protocol involving transfusion of red cells. All patients were managed according to the Addenbrooke's Hospital Neuro-critical Care Unit head injury algorithm. Data for brain PbO2, and microdialysate glucose, lactate and pyruvate were measured over 20-minute intervals. Relationships between PbO2 and brain lactate level as well as lactate/pyruvate ratio were examined, and the significance of relationships assessed using non-parametric statistical methods. The eleven patients had a mean age of 34 years (range: 17 – 64), a median post-resuscitation GCS of 9 (range: 4 – 13) and 55% were female. Seven patients had the monitors placed in structurally normal-appearing tissue on CT scan, while in four patients the monitors were in abnormal tissue. Pooled mean ( standard deviation) PbO2 was 2.15 1.3 kPa, lactate 2.77 1.58 mmol/l, pyruvate 105 52 mol/l, and L/P ratio 26.6 5.4. There were no significant differences between normal and abnormal tissue, but PbO2 was less than 1 kPa only in abnormal tissue. Fitting with a Lowess function appeared to show an inflection point for increases in lactate at PbO2 below 1.5 kPa (Fig 1;). While the relationship between PbO2 and L/P ratio was also statistically significant (Spearman-Rank : - 0.358, p < 0.001), clear PbO2 threshold levels were less well defined. Brain tissue oxygen displays a threshold at about 1.5 kPa below which brain lactate increases in abnormal tissue. The absence of clear increases in L/P ratio below this threshold raises the possibility that brain lactate elevation in these areas may not entirely be due to tissue hypoxia. As PbO2 in normal tissue did not drop below 1 kPa, our data may be less representative of physiology in these areas. Further investigation is required in patients with low PbO2.

The technique of near infrared spectroscopy (NIRS) is based on the principle of light attenuation by the chromophores oxyhaemoglobin (HbO2), deoxyhaemoglobin (Hb) and cytochrome oxidase. Changes in the detected light levels can therefore represent changes in concentrations of these chromophores. Clinical use of NIRS in the brain has been well established in neonates where transillumination is possible. While it has become a useful research tool for monitoring the adult brain, clinical application has been hampered by the fact that it must be applied in reflectance mode. This has resulted in a number of concerns, most significantly the issue of signal contamination by the extracranial tissue layers. Algorithms have been applied to try to overcome this problem, and techniques such as time resolved, phase resolved and spatially resolved spectroscopy have been developed. There has been renewed interest in NIRS as an easy to use, non-invasive technique for measuring tissue oxygenation in the adult brain. Recent technical advances have led to the development of compact, portable instruments that detect changes in optical attenuation of several wavelengths of light. Near infrared spectroscopy is an evolving technology that holds significant potential for technical advancement. In particular, NIRS shows future promise as a clinical tool for bedside cerebral blood flow measurements and as a cerebral imaging modality for mapping structure and function.

OBJECTIVE:To compare the effects of a cerebral perfusion pressure (CPP) intervention achieved with dopamine and norepinephrine after severe head injury.DESIGN:Prospective, controlled, trial.SETTING:Neurosciences critical care unit.PATIENTS:Eleven patients with a head injury, requiring dopamine or norepinephrine infusions to support CPP.INTERVENTION:Cerebral tissue gas measurements were recorded using a multimodal sensor, and regional chemistry was assessed using microdialysis. Patients received in, randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 65 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 85 mmHg. Data were then acquired using the second agent. Haemodynamic measurements and measurements of cerebral physiology were made during each period.MEASUREMENTS AND RESULTS:The CPP augmentation with norepinephrine, but not with dopamine, resulted in a significant reduction in arterial-venous oxygen difference (37+/-11 vs 33+/-12 ml/l) and a significant increase in brain tissue oxygen (2.6+/-1.1 vs 3.0+/-1.1 kPa). The CPP intervention did not significantly affect intracranial pressure. There were no significant differences between norepinephrine and dopamine on cerebral oxygenation or metabolism either at baseline or following a CPP intervention; however, the response to a CPP intervention with dopamine seemed to be more variable than the response achieved with norepinephrine.CONCLUSIONS:If CPP is to be raised to a level higher than 65-70 mmHg, then it is important to recognise that the response to the intervention may be unpredictable and that the vasoactive agent used may be of importance.