Search

Study Objective: Recent experimental evidence identified GABAergic sedation as a possible cause for deprived neuroregeneration and poor outcome after acute brain injury. Patients with aneurysmal subarachnoid hemorrhage are often sedated, and GABAergic sedation, such as midazolam and propofol, is commonly used., Design: Retrospective cohort study based on a prospectively established database., Setting: Single-center neurointensive care unit., Patients: Twenty-nine patients after subarachnoid hemorrhage., Intervention: Noninterventional study., Measurements: The relationship between mean GABAergic sedative dose during the acute phase and outcome after 6 months according to the Glasgow Outcome Scale, and initial Glasgow Coma Scale was investigated., Main Results: Use of GABAergic sedatives was negatively correlated with Glasgow Outcome Scale (r 2 =0.267; P=.008). Administration of sedatives was independent of the initial Glasgow Coma Scale. GABAergic sedatives flunitrazepam, midazolam, and propofol were used differently during the first 10 days after ictus., Conclusion: Administration of GABAergic sedation was associated with an unfavorable outcome after 6 months. To avoid bias (mainly through the indication to use sedation), additional experimental and comparative clinical investigation of, for example, non-GABAergic sedation, and clinical protocols of no sedation is necessary., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Disturbed brain metabolism is a signature of primary damage and/or precipitates secondary injury processes after severe brain injury. Sedatives and analgesics target electrophysiological functioning and are as such well-known modulators of brain energy metabolism. Still unclear, however, is how sedatives impact glucose metabolism and whether they differentially influence brain metabolism in normally active, healthy brain and critically impaired, injured brain. We therefore examined and compared the effects of anesthetic drugs under both critical (<1 mmol/L) and noncritical (>1 mmol/L) extracellular brain glucose levels., Methods: We performed an explorative, retrospective analysis of anesthetic drug administration and brain glucose concentrations, obtained by bedside microdialysis, in 19 brain-injured patients., Result: Our investigations revealed an inverse linear correlation between brain glucose and both the concentration of extracellular glutamate (Pearson r=-0.58, P=0.01) and the lactate/glucose ratio (Pearson r=-0.55, P=0.01). For noncritical brain glucose levels, we observed a positive linear correlation between midazolam dose and brain glucose (P<0.05). For critical brain glucose levels, extracellular brain glucose was unaffected by any type of sedative., Conclusions: These findings suggest that the use of anesthetic drugs may be of limited value in attempts to influence brain glucose metabolism in injured brain tissue.

Objectives: Following traumatic brain injury metabolic stability is impaired. Duration and reversibility of these changes might be important to guide specific interventions., Methods: To characterize temporal and regional changes in cerebral metabolism, 68 male Sprague-Dawley rats were subjected to a focal cortical contusion. Lesion progression and mitochondrial impairment were determined by magnetic resonance imaging (MRI) and triphenyl tetrazolium chloride (TTC) staining, respectively. Metabolic alterations were determined at hours 6 and 24 and day 7 by measuring extracellular glucose, lactate and hypoxanthine levels with microdialysis catheters placed adjacent and distant to the contusion and by quantifying changes in tissue ATP, lactate and glucose using bioluminescence imaging., Results: The cortical lesion reached its maximal extent at hour 24 and remained confined to the ipsilateral hemisphere. In microdialysate, at hour 6, extracellular hypoxanthine and lactate reached maximal values, thereafter hypoxanthine normalized while lactate remained increased. Extracellular glucose reached the highest values at hour 24 and remained elevated. Bioluminescence imaging revealed heterogeneous changes in areas distant to the contusion. No significant changes were found in ATP content. Slightly elevated tissue glucose until 24 hours in the ipsilateral hemisphere was observed. Following a continuous increase, lactate levels were the highest by 6 hours in the ipsilateral cortex and hippocampus., Discussion: CCI is associated with disturbances in energetic metabolism. Metabolic perturbation is not restricted to the early phase and the contusional region following focal cortical contusion, but also involves hippocampus and primarily uninjured parts of the hemisphere.

The immunosuppressant drug tacrolimus (FK-506) failed to show an anti-edematous effect despite suppressing pro-inflammatory cytokines in cerebrospinal fluid following focal traumatic brain injury. By questioning the role of the inflammatory response as a pharmacological target, we investigated the effects of FK-506 on immune cell infiltration in brain-injured rats. Following induction of a cortical contusion, male Sprague-Dawley rats received FK-506 or physiological saline intraperitoneally. Brains were removed at 24 h, 72 h or 7 days, respectively. Frozen brain sections (7 microm) were stained immunohistologically for markers of endothelial activation (intercellular adhesion molecule-1--ICAM-1), neutrophil infiltration (His-48), and microglial and macrophage activation (Ox-6; ED-1), respectively. Immunopositive cells were counted microscopically. Contusion volume (CV) was quantified morphometrically 7 days after trauma. Inflammatory response was confined to the ipsilateral cortex and hippocampal formation, predominating in the contusion and pericontusional cortex. Strongest ICAM-1 expression coincided with sustained granulocyte accumulation at 72h which was suppressed by FK-506. Ox-6+ cells prevailing at 72 h were also significantly reduced by FK-506. ED-1+ cells reaching highest intensity at 7 days were significantly attenuated at 72 h. Cortical CV was not influenced. FK-506 significantly decreased post-traumatic local inflammation which, however, was not associated with a reduction in cortical CV. These results question the importance of post-traumatic local immune cell infiltration in the secondary growth of a cortical contusion.

The aim of this open, descriptive and prospective study was to determine if the new monitoring parameter "continuous intracranial compliance (cICC)" decreases with age in patients with traumatic brain injury (TBI). 30 patients with severe and moderate TBI (Glasgow Coma Scale score < or = 10) contributing to a European multicenter study, organized by the Brain-IT group, underwent computerized monitoring of blood pressure, intracranial pressure (ICP), cerebral perfusion pressure and cICC. Regression analyses of individual median ICP and median cICC versus patients' age revealed no significant dependency. Median cICC declined significantly with increasing ICP (when median ICP = 10, 20 and 30 mmHg, cICC = 0.64, 0.56 and 0.42 ml/mmHg respectively, p < 0.05). These three ICP groups were then subdivided according to age (0-20, 21-40, 41-60 and 61-80 years). Median cICC declined with age in both high ICP groups (median ICP = 20,30 mmHg). Percentage cICC values below a set pathological threshold of lower than 0.05 ml/mmHg across the four age groups were 28% (0-20 yrs), 59% (21-40 yrs), 60% (41-60 yrs) and 70% (61-80 yrs) respectively. The observed phenomenon of decreased intracranial volume challenge compensation with advancing age may contribute to the well-known fact of a worse outcome in elderly patients after TBI.

Background: Volatile anesthetics reduce neuronal excitation and cerebral metabolism but can also increase intracellular water accumulation in normal and injured brains. While attenuation of neuronal excitation and glutamate release are beneficial under pathological conditions, any increase in edema formation should be avoided. In the present study we investigated duration-dependent effects of the commonly used isoflurane/nitrous oxide (N2O) anesthesia on EEG activity, specific NMDA receptor binding, extracellular, CSF, and plasma glutamate, and cerebral water content in brain-injured rats subjected to short (30 minutes) or prolonged (4 hours) anesthesia., Methods: Before controlled cortical impact injury (CCI), during prolonged (4-8 hours) or short anesthesia (7.5-8 hours after CCI), and before brain removal, changes in neuronal activity were determined by quantitative EEG analysis and glutamate was measured in arterial plasma. Brains were processed to determine acute and persisting changes in cerebral water content and 125I-Mk801 NMDA receptor binding at 8 and 32 hours after CCI, i.e., immediately or 24 hours after short or prolonged anesthesia. During prolonged anesthesia glutamate was measured via microdialysis within the cortical contusion. CSF was sampled before brain removal., Findings: Prolonged isoflurane (1.8 vol%) anesthesia significantly increased EEG activity, plasma, cortical extracellular, and CSF glutamate, cortical and hippocampal 125I-Mk801 NMDA receptor binding, and cerebral water content in brain-injured rats. These changes were partially reversible within 24 hours after prolonged anesthesia. At 24 hours, CSF glutamate was significantly reduced following long isoflurane anesthesia compared to rats previously subjected to short anesthesia despite an earlier significant increase. Conclusions. The partially reversible increases in EEG activity, 125I-Mk801 NMDA receptor binding, cerebral water content, plasma and CSF glutamate appear important for physiological, pathophysiological, and pharmacological studies requiring prolonged anesthesia with isoflurane. Increases in extracellular cortical and plasma glutamate could contribute to acute aggravation of underlying tissue damage.

Object: The majority of patients with poor-grade subarachnoid hemorrhage (SAH), that is, World Federation of Neurosurgical Societies (WFNS) Grades IV and V, have high morbidity and mortality rates. The objective of this study was to investigate cerebral metabolism in patients with low- compared with high-grade SAH by using bedside microdialysis and to evaluate whether microdialysis parameters are of prognostic value for outcome in SAH., Methods: A prospective investigation was conducted in 149 patients with SAH (mean age 50.9 +/- 12.9 years); these patients were studied for 162 +/- 84 hours (mean +/- standard deviation). Lesions were classified as low-grade SAH (WFNS Grades I-III, 89 patients) and high-grade SAH (WFNS Grade IV or V, 60 patients). After approval by the local ethics committee and consent from the patient or next of kin, a microdialysis catheter was inserted into the vascular territory of the aneurysm after clip placement. The microdialysates were analyzed hourly for extracellular glucose, lactate, lactate/pyruvate (L/P) ratio, glutamate, and glycerol. The 6- and 12-month outcomes according to the Glasgow Outcome Scale and functional disability according to the modified Rankin Scale were assessed. In patients with high-grade SAH, cerebral metabolism was severely deranged compared with those who suffered low-grade SAH, with high levels (p < 0.05) of lactate, a high L/P ratio, high levels of glycerol, and, although not significant, of glutamate. Univariate analysis revealed a relationship among hyperglycemia on admission, Fisher grade, and 12-month outcome (p < 0.005). In a multivariate regression analysis performed in 131 patients, the authors identified four independent predictors of poor outcome at 12 months, in the following order of significance: WFNS grade, patient age, L/P ratio, and glutamate (p < 0.03)., Conclusions: Microdialysis parameters reflected the severity of SAH. The L/P ratio was the best metabolic independent prognostic marker of 12-month outcome. A better understanding of the causes of deranged cerebral metabolism may allow the discovery of therapeutic options to improve the prognosis, especially in patients with high-grade SAH, in the future.

Background and Purpose: Cerebral microdialysis (MD) is discussed as a technique for detection of cerebral ischemia in subarachnoid hemorrhage; however, clinical data on cerebral blood flow (CBF) are limited in these patients. The main objective of this study was to investigate whether pathological MD parameters reflect a reduced regional CBF (rCBF) determined by 15O-H2O PET., Methods: Thirteen subarachnoid hemorrhage patients (age, 48.7+/-15.0 years; World Federation of Neurological Surgeons grade 1 to 5) were studied. Extracellular glucose, lactate, lactate/pyruvate (L/P) ratio, glutamate, and glycerol levels were analyzed hourly. rCBF was determined in the volume of interest of the MD catheter and all vascular territories. MD values were correlated to rCBF on the day of PET. Then, MD concentrations of asymptomatic versus ischemic phases (3-day medians) were analyzed., Results: In symptomatic patients (n=10), rCBF was significantly lower compared with controls (n=3, P=0.048). Glutamate correlated best with rCBF (r=-0.66; P=0.014), followed by glycerol (r=-0.62; P=0.021). The L/P ratio was most sensitive (0.82) and specific (1.0) in indicating symptoms of ischemia, but only during longer periods of ischemia., Conclusions: rCBF correlates best with glutamate, followed by glycerol, whereas the L/P ratio is sensitive only after longer periods of ischemia. Clinically relevant regional metabolic derangements occur already above an rCBF of 20 mL x 100 g(-1).min(-1). Future research should focus on identifying alternative causes of metabolic derangement in subarachnoid hemorrhage patients and optimal treatment management in these patients.

Patients with cerebral lesions run a high risk of developing cerebral hypoxic and ischemic damage due to secondary insults. To minimize the risk of secondary cerebral hypoxia and ischemia, new monitoring techniques of cerebral oxygenation and metabolism have been developed and may help to understand the pathophysiology of secondary brain damage for a better treatment and outcome in critical patients. Cerebral microdialysis is a relatively new technique for measuring brain molecules of the extracellular space. The technical aspects, the interpretation of the commonly measured parameters, the use of the two commonly used oxygenation parameters (jugular venous oxygen saturation and monitoring of brain tissue PO(2) and the microdialysis technique to monitor cerebral metabolism in patients with head injury), subarachnoid hemorrhage, and ischemic stroke are considered. Pitfalls of the techniques and their future potential are discussed.

The objective was to measure metabolic changes monitored by bedside microdialysis during impending and manifest hypoxia in traumatic brain injury. In 41 patients, a PtiO2-catheter (Licox; 1/min) was placed into non-lesioned frontal white matter together with a microdialysis catheter (CMA, hourly). Data were analysed for identification of episodes of impending (PtiO2 < 10 - 15 mmHg > 5 min) and manifest cerebral hypoxia (PtiO2 < 10 mmHg, > 5 min). In 69% of patients hypoxic episodes occurred, most frequently associated with hyperventilation (p < 0.001). During impending hypoxia, glutamate was increased (p = 0.03), while the energy metabolites remained stable. Manifest hypoxia was reflected by significant increases of glutamate (p = 0.007) and lactate (p = 0.044), but normal lactate-pyruvate ratios. We conclude that hyperventilation had a potential adverse effect on cerebral metabolism and was most frequently associated with cerebral hypoxia. A PtiO2 < 10 mmHg can induce metabolic changes with increase of glutamate and lactate. The presence of anaerobic cerebral metabolism probably depends on duration and severity of the hypoxic episode.

Objective: To analyze the time course and changes of cerebral microdialysis parameters after aneurysmal subarachnoid hemorrhage (SAH) in respect to the clinical course (asymptomatic, delayed, and acute ischemic neurologic deficits) to evaluate the method of bedside microdialysis in these patients., Design: Prospective, controlled study during a 3-yr period., Setting: Neurosurgical intensive care unit at a primary level university hospital, supervised and staffed by members of both the department of neurosurgery and the department of anesthesiology and intensive care medicine., Patients: Ninety-seven patients (51 females/21 males; 52 +/- 13 yrs; World Federation of Neurological Surgeons Scale grades 0-5) after aneurysmatic SAH., Measurements and Main Results: A microdialysis catheter (CMA 100) was inserted into the region most likely to be affected by vasospasm directly after aneurysm clipping, connected to a pump, and perfused with Ringer solution (0.3 microL/min). The dialysates were collected hourly and analyzed at the bedside for glucose, lactate, lactate-pyruvate ratio, glutamate, and glycerol (CMA 600). Patients were classified according to clinical presentation as being asymptomatic or having acute (AIND) or delayed (DIND) ischemic neurologic deficits. DIND patients (n = 18) had significantly higher lactate and glutamate concentrations on days 1-8 post-SAH and a higher lactate-pyruvate ratio on days 3-8 post-SAH compared with asymptomatic patients (n = 57; p <.025). Glucose and glycerol levels did not differ in asymptomatic and DIND patients. AIND patients (n = 22) had the worst metabolic pattern: the extracellular glucose concentration was low, whereas the lactate, lactate-pyruvate ratio, glutamate, and glycerol levels were significantly elevated compared with asymptomatic and DIND patients. In 83% of the DIND patients, the changes in metabolites indicative of cerebral ischemia preceded the onset of symptomatic vasospasm. All DIND patients clinically improved in their Glasgow Coma Scale scores with induced hypertension, intentional hypervolemia, and/or hemodilution therapy (p =.01)., Conclusion: Cerebral bedside microdialysis is a safe and promising technique for monitoring (impending) regional cerebral ischemia. The dialysate changes can indicate early the onset of delayed neurologic deterioration and are in good accordance with the clinical course of SAH patients. In the future, this technique may be used to monitor the efficacy of the intensive care therapy of these patients.

We evaluated bedside cerebral on-line microdialysis for early detection of cerebral hypoxia in patients with traumatic brain injury. 24 severely head injured patients (Glasgow Coma Score < or = 8) were studied. Patients underwent continuous brain tissue PO2 (PtiO2) monitoring using the LICOX (GMS mbH, Germany) microcatheter device. The catheter was placed into the non-lesioned frontal white matter within 32.2 (7-48) hrs post injury. The microdialysis catheter (CMA 100, Sweden) was placed close to the PtiO2 probe via a 2- or 3-way skull screw, connected to a pump and perfused with Ringer solution (0.3 microliter/min). The microdialysis samples were collected hourly and analyzed at the bedside for glucose, lactate, lactate-pyruvate-ratio and glutamate (CMA 600, Sweden). We identified 252 episodes of impending hypoxia (PtiO2 < 15 mm Hg; 11,810 minutes) and 38 episodes of cerebral hypoxia (PtiO2 < 10 mm Hg; 1996 minutes). Before cerebral hypoxia, glucose decreased significantly. Glutamate was unchanged when no hypoxia or impending hypoxia occurred but increased 3-4 fold before a hypoxic episode appeared. We conclude that early metabolic detection of cerebral hypoxia before a critical decrease in brain tissue PtiO2 is seen and possibly allows earlier changes in treatment (e.g. reduction of hyperventilation therapy).

This study investigates the effect of hypoxic brain tissue PO2 on outcome, and examines the incidence of possible causes for cerebral hypoxia. We studied 35 patients with severe head injury (GCS < or = 8). Age was 33.2 (+/- 11.3) years. Total time of monitoring of PtiO2, intracranial pressure (ICP), cerebral perfusion pressure (CPP), and endtidal PCO2 (ETCO2) was 119.3 (+/- 65.7) hours. Data were continuously recorded by a computer system. Outcome was assessed at discharge and after 6 months post injury. 56% of the patients with more than 300 minutes of PtiO2 < 10 mm Hg died, 22% had an unfavourable outcome, 22% had a favourable outcome. Cerebral hypoxia was associated with intracranial hypertension (ICP > 20 mm Hg) in 11.5 (+/- 15.1)%. CPP was compromised below 60 mm Hg in 16.8 (+/- 23.4)%. Hypocarbia (ETCO2 < 28 mm Hg) was present in 48.0% of the time of PtiO2 < 10 mm Hg. No obvious cause for cerebral hypoxia was found in 45% of the data. These result underscore the association of cerebral hypoxia with poor neurological outcome and stress the meaning of monitoring of PtiO2 as an independent parameter in patients following TBI.

Continuous monitoring of cerebral metabolism would be desirable for early detection of vasospasm in SAH patients. Bedside-microdialysis, a new technique for on-line monitoring of cerebral metabolism, may reflect changes seen in cerebral vasospasm diagnosed by transcranial Doppler sonography (TCD). This report represents the first case of combined TCD monitoring and on-line microdialysis from the brain extracellular fluid in a SAH patient. A 48-year-old woman suffered subarachnoid hemorrhage grade IV according to Hunt and Hess. Angiography revealed an aneurysm of the left carotid artery. The aneurysm was clipped 45 hours after bleeding. The microdialysis catheter was inserted after aneurysm clipping into the white matter of the left temporal lobe. Sampling of microdialysates started immediately, analyzing time for glucose, lactate, pyruvate and glutamate was four minutes. Postoperatively, the patient was doing well and microdialysis and TCD parameters remained within normal range. On the third postoperative day a shift to anaerob metabolism (decrease of glucose, increase of lactate and the lactate-pyruvate ratio up to pathological levels) and an increase in glutamate was observed suggesting insufficient cerebral perfusion. The patient progressively deteriorated clinically. Vasospasm was diagnosed by TCD monitoring 36 hours after onset of ischemic changes monitored by microdialysis. After elevation of mean arterial blood pressure, TCD values and metabolic parameters normalized. Interestingly, the pathological changes in on-line microdialysis preceded the typical increase in blood flow velocity by TCD and the clinical deterioration. Our case suggests, that bedside-microdialysis may be useful for early detection of vasospasm and continuous surveillance of treatment and may be a new guide to treat ischemic neurological deficits following SAH.

A harmful effect of prolonged hyperventilation on outcome has been shown in comatose patients after severe head injury. The purpose of this study was to assess the acute effect of moderate hyperventilation for treatment of intracranial hypertension (ICP < 20 mmHg) on invasively measured brain tissue-PO2 (PtiO2), PCO2 (PtiCO2) and pH (tipH) in severely head injured patients. 15 severely head injured patients (GCS < or = 8) were prospectively studied. Intracranial pressure (ICP), mean arterial blood pressure (MABP), cerebral perfusion pressure (CPP), endtidal CO2 (ETCO2), PtiO2, PtiCO2 and tipH (Paratrend or Licox microsensors) were continuously recorded using multimodal monitoring. Following a baseline period of 15 minutes, patients were hyperventilated for 10 minutes. Arterial blood gas analysis was done before, during and after hyperventilation. At least three hyperventilation maneuvers were performed per patient. For statistical analysis the Friedman test was used. Hyperventilation (paCO2: 32.4 +/- 0.6 to 27.7 +/- 0.5 mmHg) significantly reduced ICP from 25.3 +/- 1.5 to 14.2 +/- 1.9 mmHg (p < 0.01). As a consequence, CPP increased by 9.6 +/- 3.4 mmHg to 76.8 +/- 3.2 mmHg. Brain tissue PCO2 decreased from 37.5 +/- 1.3 to 34.6 +/- 1.2 while tipH increased from 7.13 to 7.16. In all patients, hyperventilation led to a reduction of brain tissue PO2 (PtiO2/Licox: 24.6 +/- 1.4 to 21.9 +/- 1.7 mmHg, n.s.; PtiO2/Paratrend: 35.8 +/- 4.3 to 31.9 +/- 4.0 mmHg, n.s.). In one case hyperventilation even had to be stopped after 7 min because the drop in brain tissue PO2 below 10 mmHg signalized imminent hypoxia. As well known, hyperventilation improves CPP due to a reduction in ICP. However, this does not ameliorate cerebral oxygenation as demonstrated by the decrease in PtiO2. This underlines that hyperventilation should only be used with caution in the treatment of intracranial hypertension.

Cerebral energy metabolism was studied in cats subjected to fluid-percussion brain trauma followed immediately by 30 minutes of controlled hypoventilation for the purpose of simulating a more realistic model of human head injury. The cerebral blood flow (CBF) and cerebral metabolic rates of oxygen (CMRO2) and glucose (CMRGl) were measured, with simultaneous phosphorus-31 magnetic resonance spectroscopy quantifications of cerebral tissue pH, phosphocreatine (PCr), and inorganic phosphate (Pi). Hypoventilation alone did not produce marked changes in CMRGl, tissue pH, or PCr:Pi ratios. When hypoventilation was combined with trauma, marked alterations in CBF, CMRGl, PCr:Pi ratio, and tissue pH were seen, indicating relative ischemia. The alterations of cerebral energy metabolism produced by combining trauma and hypoventilation are more severe than those caused by fluid-percussion trauma alone, and may provide a more realistic model of human head injury.

Clinical and experimental evidence suggests that head injury can cause alterations of cerebral energy metabolism. However, the etiology of this metabolic perturbation is not known. The objective of this study was to determine the effect of fluid-percussion trauma on cerebral energy metabolism. Seven ventilated, chloralose-anesthetized cats were subjected to a 3.2-atm fluid-percussion brain injury. Before and for 8 hours after trauma, continuous phosphorus-3 1 magnetic resonance spectrography was obtained to noninvasively monitor tissue pH, phosphocreatine (PCr), and inorganic phosphate (Pi) levels. Measurement of cerebral blood flow (CBF) by the radioactive microsphere technique and calculation of oxygen and glucose consumption (CMRO2 and CMRG1) were also performed before trauma as well as 30 minutes and 1, 2, 4, and 8 hours after trauma. The data showed a moderate decrease in tissue pH from 7.04 to 6.89 at 30 minutes following trauma with return to control levels by 3 hours posttrauma. During the 8-hour observation period, CBF, CMRO2, and CMRG1 remained at control levels. Tissue PCr and Pi levels were also unchanged. Fluid-percussion trauma at the 3.2-atm level in ventilated cats causes a moderate and transient decrease in tissue pH that returns to control levels after trauma. No other metabolic changes are seen later than 30 minutes posttrauma. This indicates that a mild metabolic disturbance occurs after trauma in the ventilated animal and quickly returns to normal.