A randomized, double-blind trial comparing the effect of two blood pressure targets on global brain metabolism after out-of-hospital cardiac arrest.

PURPOSE: This study aimed to assess the effect of different blood pressure levels on global cerebral metabolism in comatose patients resuscitated from out-of-hospital cardiac arrest (OHCA). METHODS: In a double-blinded trial, we randomly assigned 60 comatose patients following OHCA to low (63 mmHg) or high (77 mmHg) mean arterial blood pressure (MAP). The trial was a sub-study in the Blood Pressure and Oxygenation Targets after Out-of-Hospital Cardiac Arrest-trial (BOX). Global cerebral metabolism utilizing jugular bulb microdialysis (JBM) and cerebral oxygenation (rSO2) was monitored continuously for 96 h. The lactate-to-pyruvate (LP) ratio is a marker of cellular redox status and increases during deficient oxygen delivery (ischemia, hypoxia) and mitochondrial dysfunction. The primary outcome was to compare time-averaged means of cerebral energy metabolites between MAP groups during post-resuscitation care. Secondary outcomes included metabolic patterns of cerebral ischemia, rSO2, plasma neuron-specific enolase level at 48 h and neurological outcome at hospital discharge (cerebral performance category). RESULTS: We found a clear separation in MAP between the groups (15 mmHg, p < 0.001). Cerebral biochemical variables were not significantly different between MAP groups (LPR low MAP 19 (16-31) vs. high MAP 23 (16-33), p = 0.64). However, the LP ratio remained high (> 16) in both groups during the first 30 h. During the first 24 h, cerebral lactate > 2.5 mM, pyruvate levels > 110 µM, LP ratio > 30, and glycerol > 260 µM were highly predictive for poor neurological outcome and death with AUC 0.80. The median (IQR) rSO2 during the first 48 h was 69.5% (62.0-75.0%) in the low MAP group and 69.0% (61.3-75.5%) in the high MAP group, p = 0.16. CONCLUSIONS: Among comatose patients resuscitated from OHCA, targeting a higher MAP 180 min after ROSC did not significantly improve cerebral energy metabolism within 96 h of post-resuscitation care. Patients with a poor clinical outcome exhibited significantly worse biochemical patterns, probably illustrating that insufficient tissue oxygenation and recirculation during the initial hours after ROSC were essential factors determining neurological outcome.

A Prospective Observational Feasibility Study of Jugular Bulb Microdialysis in Subarachnoid Hemorrhage.

BACKGROUND: Cerebral metabolic perturbations are common in aneurysmal subarachnoid hemorrhage (aSAH). Monitoring cerebral metabolism with intracerebral microdialysis (CMD) allows early detection of secondary injury and may guide decisions on neurocritical care interventions, affecting outcome. However, CMD is a regional measuring technique that is influenced by proximity to focal lesions. Continuous microdialysis of the cerebral venous drainage may provide information on global cerebral metabolism relevant for the care of aSAH patients. This observational study aimed to explore the feasibility of jugular bulb microdialysis (JBMD) in aSAH and describe the output characteristics in relation to conventional multimodal monitoring. METHODS: Patients with severe aSAH were included at admission or after in-house deterioration when local clinical guidelines prompted extended multimodal monitoring. Non-dominant frontal CMD, intracranial pressure (ICP), partial brain tissue oxygenation pressure (PbtO2), and cerebral perfusion pressure (CPP) were recorded every hour. The dominant jugular vein was accessed by retrograde insertion of a microdialysis catheter with the tip placed in the jugular bulb under ultrasound guidance. Glucose, lactate, pyruvate, lactate/pyruvate ratio, glycerol, and glutamate were studied for correlation to intracranial measurements. Modified Rankin scale was assessed at 6 months. RESULTS: Twelve adult aSAH patients were monitored during a mean 4.2 ± 2.6 days yielding 22,041 data points for analysis. No complications related to JBMD were observed. Moderate or strong significant monotonic CMD-to-JBMD correlations were observed most often for glucose (7 patients), followed by lactate (5 patients), and pyruvate, glycerol, and glutamate (3 patients). Moderate correlation for lactate/pyruvate ratio was only seen in one patient. Analysis of critical periods defined by ICP > 20, CPP < 65, or PbtO2 < 15 revealed a tendency toward stronger CMD-to-JBMD associations in patients with many or long critical periods. Possible time lags between CMD and JBMD measurements were only identified in 6 out of 60 patient variables. With the exception of pyruvate, a dichotomized outcome was associated with similar metabolite patterns in JBMD and CMD. A nonsignificant tendency toward greater differences between outcome groups was seen in JBMD. CONCLUSIONS: Continuous microdialysis monitoring of the cerebral drainage in the jugular bulb is feasible and safe. JBMD-to-CMD correlation is influenced by the type of metabolite measured, with glucose and lactate displaying the strongest associations. JBMD lactate correlated more often than CMD lactate to CPP, implying utility for detection of global cerebral metabolic perturbations. Studies comparing JBMD to other global measures of cerebral metabolism, e.g., PET CT or Xenon CT, are warranted.

Patterns of cerebral tissue oxygen tension and cytoplasmic redox state in bacterial meningitis.

BACKGROUND: Compromised cerebral energy metabolism is common in patients with bacterial meningitis. In this study, simultaneous measurements of cerebral oxygen tension and lactate/pyruvate ratio were compared to explore whether disturbed energy metabolism was usually caused by insufficient tissue oxygenation or compromised oxidative metabolism of pyruvate indicating mitochondrial dysfunction. SUBJECT AND METHODS: Ten consecutive patients with severe streptococcus meningitis were included in this prospective cohort study. Intracranial pressure, brain tissue oxygen tension (PbtO2 ), and energy metabolism (intracerebral microdialysis) were continuously monitored in nine patients. A cerebral lactate/pyruvate (LP) ratio <30 was considered indicating normal oxidative metabolism, LP ratio >30 simultaneously with pyruvate below lower normal level (70 µmol/L) was interpreted as biochemical indication of ischemia, and LP ratio >30 simultaneously with a normal or increased level of pyruvate was interpreted as mitochondrial dysfunction. The biochemical variables were compared with PbtO2 simultaneously monitored within the same cerebral region. RESULTS: In two cases, the LP ratio was normal during the whole study period and the simultaneously monitored PbtO2 was 18 ± 6 mm Hg. In six cases, interpreted as mitochondrial dysfunction, the simultaneously monitored PbtO2 was 20 ± 6 mm Hg and without correlation with the LP ratio. In one patient, exhibiting a pattern interpreted as ischemia, PbtO2 decreased below 10 mm Hg and a correlation between LP and PbtO2 was observed. CONCLUSION: This study demonstrated that compromised cerebral energy metabolism, evidenced by increased LP ratio, was common in patients with severe bacterial meningitis while not related to insufficient tissue oxygenation.

Biochemical indications of cerebral ischaemia and mitochondrial dysfunction in severe brain trauma analysed with regard to type of lesion.

BACKGROUND: The study focuses on three questions related to the clinical usefulness of microdialysis in severe brain trauma: (1) How frequently is disturbed cerebral energy metabolism observed in various types of lesions? (2) How often does the biochemical pattern indicate cerebral ischaemia and mitochondrial dysfunction? (3) How do these patterns relate to mortality? METHOD: The study includes 213 consecutive patients with severe brain trauma (342 intracerebral microdialysis catheters). The patients were classified into four groups according to the type of lesion: extradural haematoma (EDH), acute subdural haematoma (SDH), cerebral haemorrhagic contusion (CHC) and no mass lesion (NML). Altogether about 150,000 biochemical analyses were performed during the initial 96 h after trauma. RESULTS: Compromised aerobic metabolism occurred during 38 % of the study period. The biochemical pattern indicating mitochondrial dysfunction was more common than that of ischaemia. In EDH and NML aerobic metabolism was generally close to normal. In SDH or CHC it was often severely compromised. Mortality was increased in SDH with impaired aerobic metabolism, while CHC did not exhibit a similar relation. CONCLUSIONS: Compromised energy metabolism is most frequent in patients with SDH and CHC (32 % and 49 % of the study period, respectively). The biochemical pattern of mitochondrial dysfunction is more common than that of ischaemia (32 % and 6 % of the study period, respectively). A correlation between mortality and biochemical data is obtained provided the microdialysis catheter is placed in an area where energy metabolism reflects tissue outcome in a large part of the brain.

Bedside evaluation of cerebral energy metabolism in severe community-acquired bacterial meningitis.

BACKGROUND: Mortality and morbidity have remained high in bacterial meningitis. Impairment of cerebral energy metabolism probably contributes to unfavorable outcome. Intracerebral microdialysis is routinely used to monitor cerebral energy metabolism, and recent experimental studies indicate that this technique may separate ischemia and non-ischemic mitochondrial dysfunction. The present study is a retrospective interpretation of biochemical data obtained in a series of patients with severe community-acquired meningitis. METHODS: Cerebral energy metabolism was monitored in 15 patients with severe community-acquired meningitis utilizing intracerebral microdialysis and bedside biochemical analysis. According to previous studies, cerebral ischemia was defined as lactate/pyruvate (LP) ratio > 30 with intracerebral pyruvate level < 70 µmol L(-1). Non-ischemic mitochondrial dysfunction was defined as LP-ratio > 30 at a normal or increased interstitial concentration of pyruvate (≥ 70 µmol L(-1)). Patients with LP-ratios < 30 were classified as no mitochondrial dysfunction. RESULTS: The biochemical pattern was in 8 patients (10 microdialysis catheters) classified as no mitochondrial dysfunction, in 5 patients classified as non-ischemic mitochondrial dysfunction, and in 2 patients (3 catheters) classified as ischemia. CONCLUSIONS: In patients with severe community-acquired meningitis, compromised cerebral energy metabolism occurs frequently and was diagnosed in 7 out of 15 cases. A biochemical pattern of non-ischemic mitochondrial dysfunction appears to be a more common underlying condition than cerebral ischemia.

Effects of norepinephrine infusion on cerebral energy metabolism during experimental haemorrhagic shock.

BACKGROUND: The use of norepinephrine in the case of life-threatening haemorrhagic shock is well established but widely discussed. The present study was designed to compare the effects of early norepinephrine treatment vs. no treatment on cerebral energy metabolism during haemorrhagic shock. METHODS: Twelve pigs were subjected to haemorrhagic shock, 4 in the control group and 8 in the norepinephrine (NE) group. Following a 60 min baseline period haemorrhagic shock was achieved by bleeding all animals to a pre-defined mean arterial blood pressure (MAP) of approximately 40 mm Hg. When mean arterial pressure had decreased to 40 mmHg NE infusion started in the treatment group. After 90 min, NE infusion stopped, and all pigs were resuscitated with autologous blood and observed for 2.5 h. During the experiment cerebral tissue oxygenation (PbtO2) was monitored continuously and variables reflecting cerebral energy metabolism (glucose, lactate, pyruvate, glutamate, glycerol) were measured by utilizing intracerebral microdialysis. RESULTS: All 12 pigs completed the protocol. NE infusion resulted in significantly higher MAP (p < 0.001). During the shock period lactate/pyruvate (LP) ratio group increased from 20 (15-29) to 66 (38-82) (median (IQR)) in the control group but remained within normal limits in the NE group. The significant increase in LP ratio in the control group remained after resuscitation. After induction of shock PbtO2 decreased markedly in the control group and was significantly lower than in the NE group during the resuscitation phase. CONCLUSION: NE infusion during haemorrhagic shock improved cerebral energy metabolism compared with no treatment.

Bedside interpretation of cerebral energy metabolism utilizing microdialysis in neurosurgical and general intensive care.

The microdialysis technique was initially developed for monitoring neurotransmitters in animals. In 1995 the technique was adopted to clinical use and bedside enzymatic analysis of glucose, pyruvate, lactate, glutamate and glycerol. Under clinical conditions microdialysis has also been used for studying cytokines, protein biomarkers, multiplex proteomic and metabolomic analyses as well as for pharmacokinetic studies and evaluation of blood-brain barrier function. This review focuses on the variables directly related to cerebral energy metabolism and the possibilities and limitations of microdialysis during routine neurosurgical and general intensive care. Our knowledge of cerebral energy metabolism is to a large extent based on animal experiments performed more than 40 years ago. However, the different biochemical information obtained from various techniques should be recognized. The basic animal studies analyzed brain tissue homogenates while the microdialysis technique reflects the variables in a narrow zone of interstitial fluid surrounding the probe. Besides the difference of the volume investigated, the levels of the biochemical variables differ in different compartments. During bedside microdialysis cerebral energy metabolism is primarily reflected in measured levels of glucose, lactate and pyruvate and the lactate to pyruvate (LP) ratio. The LP ratio reflects cytoplasmatic redox-state which increases instantaneously during insufficient aerobic energy metabolism. Cerebral ischemia is characterized by a marked increase in intracerebral LP ratio at simultaneous decreases in intracerebral levels of pyruvate and glucose. Mitochondrial dysfunction is characterized by a moderate increase in LP ratio at a very marked increase in cerebral lactate and normal or elevated levels of pyruvate and glucose. The patterns are of importance in particular for interpretations in transient cerebral ischemia. A new technique for evaluating global cerebral energy metabolism by microdialysis of the draining cerebral venous blood is discussed. In experimental studies it has been shown that pronounced global cerebral ischemia is reflected in venous cerebral blood. Jugular bulb microdialysis has been investigated in patients suffering from subarachnoid hemorrhage, during cardiopulmonary bypass and resuscitation after out of hospital cardiac arrest. Preliminary results indicate that the new technique may give valuable information of cerebral energy metabolism in clinical conditions when insertion of an intracerebral catheter is contraindicated.

Prostacyclin infusion may prevent secondary damage in pericontusional brain tissue.

BACKGROUND: Prostacyclin is a potent vasodilator, inhibitor of leukocyte adhesion, and platelet aggregation, and has been suggested as therapy for cerebral ischemia. A case of focal traumatic brain lesion that was monitored using intracerebral microdialysis, and bedside analysis and display is reported here. When biochemical signs of cerebral ischemia progressed, i.v. infusion of prostacyclin was started. METHODS: Two microdialysis catheters were placed in the penumbra zones surrounding evacuated focal brain contusions. The samples were analyzed for glucose, pyruvate, lactate, glutamate, and glycerol. RESULTS: When biochemical deterioration indicated progressive secondary ischemia (increase in lactate/pyruvate ratio, decrease in glucose, and increase in glutamate levels), continuous infusion of prostacyclin (0.5-1.0 ng kg(-1) min(-1) i.v.) was started. The treatment resulted in an improvement of the lactate/pyruvate ratios and a normalization of the interstitial levels of glucose and glutamate. The glycerol levels remained within normal limits indicating that degradation of cellular membranes had not occurred. CONCLUSION: The above case supports the view that new therapies directed toward protection of the sensitive biochemical penumbra zones surrounding focal brain lesions may be evaluated by intracerebral microdialysis.

Comparison between cerebral tissue oxygen tension and energy metabolism in experimental subdural hematoma.

BACKGROUND: An experimental swine model (n = 7) simulating an acute subdural hematoma (ASDH) was employed (1) to explore the relation between the brain tissue oxygenation (PbtO(2)) and the regional cerebral energy metabolism as obtained by microdialysis, and (2) to define the lowest level of PbtO(2) compatible with intact energy metabolism. METHODS: ASDH was produced by infusion of 7 ml of autologous blood (infusion rate 0.5 ml/min) by a catheter placed subdurally. PbtO(2) and microdialysis probes were placed symmetrically in the injured ("bad-side") and non-injured ("good-side") hemispheres. Intracranial pressure (ICP) was monitored in the "good-side." RESULTS: ICP, cerebral perfusion pressure (CPP), PbtO(2), glucose, lactate, pyruvate, lactate-pyruvate ratio (LP ratio), glutamate, and glycerol were recorded at baseline (60 min) and post trauma (360 min). After the creation of the ASDH, PbtO(2) decreased significantly in both the hemispheres (P < 0.001). No significant difference was found between the sides post trauma. The LP ratio, glutamate, and glycerol in the "bad-side" increased significantly over the "good-side" where the values remained within the normal limits. A PbtO(2) value below approximately 25 mmHg was found to be associated with disturbed energy metabolism in the "bad-side" but not in the "good-side." No correlation was found between the LP ratio and PbtO(2) in either hemisphere. CONCLUSIONS: PbtO(2) monitoring accurately describes tissue oxygenation but does not disclose whether the oxygen delivery is sufficient for maintaining cerebral energy metabolism. Accordingly, it may not be possible to define a threshold level for PbtO(2) below which energy failure and permanent tissue damage occurs.

Cerebral energy metabolism and microdialysis in neurocritical care.

It is of obvious clinical importance to monitor cerebral metabolism--in particular, cerebral energy metabolism and indicators of cellular damage-online at the bedside. The technique of cerebral microdialysis provides the opportunity for continuous monitoring of metabolic changes in the tissue before they are reflected in peripheral blood chemistry or in systemic physiological parameters. The basic idea of microdialysis is to mimic the function of a blood capillary by positioning a thin dialysis tube in the tissue and to be used to analyze the chemical composition of the interstitial fluid. The biochemical variables used during routine monitoring were chosen to cover important aspects of cerebral energy metabolism (glucose, pyruvate and lactate), to indicate excessive interstitial levels of excitatory transmitter substance (glutamate) and to give indications of degradation of cellular membranes (glycerol). Furthermore, pharmokinetic studies can be conducted using microdialysis. This article discusses technical and physiological aspects of microdialysis, and its clinical applications in brain injury.

Ethyl Pyruvate Increases Post-Ischemic Levels of Mitochondrial Energy Metabolites: A 13C-Labeled Cerebral Microdialysis Study.

Mitochondrial dysfunction after transient cerebral ischemia can be monitored by cerebral microdialysis (CMD) using changes in the lactate and pyruvate concentrations and ratio. Other metabolites associated with mitochondrial (dys)function are, e.g., tricyclic acid (TCA) and purine metabolites. Ethyl pyruvate (EP) is a putative neuroprotectant, supposedly targeting mitochondrial energy metabolism, but its effect on cerebral energy metabolism has never been described using microdialysis. In this study we monitored the metabolic effects of EP in the endothelin-1 (ET-1) rat model using perfusion with 13C-succinate and analysis of endogenous and 13C-labeled metabolites in the dialysates by liquid chromatography-mass spectrometry (LC-MS). Adult Sprague Dawley rats (n = 27 of which n = 11 were included in the study) were subjected to the microdialysis experiments. Microdialysis probes were perfused with 13C-labeled succinate (1 mM), and striatal dialysates were collected at 30 min intervals before induction of the insult, during intracerebral application of ET-1, and during intravenous treatment with either EP (40 mg/kg) or placebo, which was administered immediately after the insult. The rats were subjected to transient cerebral ischemia by unilateral microinjection of ET-1 in the piriform cortex, causing vasoconstriction of the medial cerebral artery. Monitoring was continued for 5 h after reperfusion, and levels of endogenous and 13C-labeled energy metabolites before and after ischemia-reperfusion were compared in EP-treated and control groups. Infarct volumes were assessed after 24 h. In both the EP-treated and placebo groups, ET-1-induced vasoconstriction resulted in a transient depression of interstitial glucose and elevation of lactate in the ipsilateral striatum. In the reperfusion phase, the concentrations of labeled malate, isocitrate, and lactate as well as endogenous xanthine were significantly higher in the EP-group than in the placebo-group: (mean ± SEM) labeled malate: 39.5% ± 14.9, p = 0.008; labeled isocitrate: 134.8% ± 67.9, p = 0.047; labeled lactate: 61% ± 22.0, p = 0.007; and endogenous xanthine: 93.9% ± 28.3, p = 0.0009. In the placebo group, significantly elevated levels of uridine were observed (mean ± SEM) 32.5% ± 12.7, p = 0.01. Infarct volumes were not significantly different between EP-treated and placebo groups, p = 0.4679. CMD labeled with 13C-succinate enabled detection of ischemic induction and EP treatment effects in the ET-1 rat model of transient focal cerebral ischemia. EP administered as a single intravenous bolus in the reperfusion-phase after transient cerebral ischemia increased de novo synthesis of several key intermediate energy metabolites (13C-malate, 13C-isocitrate, and endogenous xanthine). In summary, mitochondria process 13C-succinate more effectively after EP treatment.

Moderately prolonged permissive hypotension results in reversible metabolic perturbation evaluated by intracerebral microdialysis - an experimental animal study.

BACKGROUND: Damage control resuscitation (DCR) and damage control surgery (DCS) is the main strategy in patients with uncontrollable hemorrhagic shock. One aspect of DCR is permissive hypotension. However, the duration of hypotension that can be tolerated without affecting the brain is unknown. In the present study we investigate the effect of 60 min severe hypotension on the brain's energy metabolism and seek to verify earlier findings that venous cerebral blood can be used as a marker of global cerebral energy state. MATERIAL AND METHODS: Ten pigs were anaesthetized, and vital parameters recorded. Microdialysis catheters were placed in the left parietal lobe, femoral artery, and superior sagittal sinus for analysis of lactate, pyruvate, glucose, glycerol, and glutamate. Hemorrhagic shock was induced by bleeding the animal until mean arterial pressure (MAP) of 40 mmHg was achieved. After 60 min the pigs were resuscitated with autologous blood and observed for 3 h. RESULTS: At baseline the lactate to pyruvate ratios (LP ratio) in the hemisphere, artery, and sagittal sinus were (median (interquartile range)) 13 (8-16), 21 (18-24), and 9 (6-22), respectively. After induction of hemorrhagic shock, the LP ratio from the left hemisphere in 9 pigs increased to levels indicating a reversible perturbation of cerebral energy metabolism 19 (12-30). The same pattern was seen in LP measurements from the femoral artery 28 (20-35) and sagittal sinus 22 (19-26). At the end of the experiment hemisphere, artery and sinus LP ratios were 16 (10-23), 17 (15-25), and 17 (10-27), respectively. Although hemisphere and sinus LP ratios decreased, they did not reach baseline levels (p < 0.05). In one pig hemisphere LP ratio increased to a level indicating irreversible metabolic perturbation (LP ratio > 200). CONCLUSION: During 60 min of severe hypotension intracerebral microdialysis shows signs of perturbations of cerebral energy metabolism, and these changes trend towards baseline values after resuscitation. Sagittal sinus microdialysis values followed hemisphere values but were not distinguishable from systemic arterial values. Venous (jugular bulb) microdialysis might have a place in monitoring conditions where global cerebral ischemia is a risk.

Cyclosporin A ameliorates cerebral oxidative metabolism and infarct size in the endothelin-1 rat model of transient cerebral ischaemia.

Cerebral microdialysis can be used to detect mitochondrial dysfunction, a potential target of neuroprotective treatment. Cyclosporin A (CsA) is a mitochondrial stabiliser that in a recent clinical stroke trial showed protective potential in patients with successful recanalisation. To investigate specific metabolic effects of CsA during reperfusion, and hypothesising that microdialysis values can be used as a proxy outcome measure, we assessed the temporal patterns of cerebral energy substrates related to oxidative metabolism in a model of transient focal ischaemia. Transient ischaemia was induced by intracerebral microinjection of endothelin-1 (150 pmol/15 µL) through stereotaxically implanted guide cannulas in awake, freely moving rats. This was immediately followed by an intravenous injection of CsA (NeuroSTAT; 15 mg/kg) or placebo solution during continuous microdialysis monitoring. After reperfusion, the lactate/pyruvate ratio (LPR) was significantly lower in the CsA group vs placebo (n = 17, 60.6 ± 24.3%, p = 0.013). Total and striatal infarct volumes (mm3) were reduced in the treatment group (n = 31, 61.8 ± 6.0 vs 80.6 ± 6.7, p = 0.047 and 29.9 ± 3.5 vs 41.5 ± 3.9, p = 0.033). CsA treatment thus ameliorated cerebral reperfusion metabolism and infarct size. Cerebral microdialysis may be useful in evaluating putative neuroprotectants in ischaemic stroke.

In Vivo Microdialysis of Endogenous and 13C-labeled TCA Metabolites in Rat Brain: Reversible and Persistent Effects of Mitochondrial Inhibition and Transient Cerebral Ischemia.

Cerebral micro-dialysis allows continuous sampling of extracellular metabolites, including glucose, lactate and pyruvate. Transient ischemic events cause a rapid drop in glucose and a rise in lactate levels. Following such events, the lactate/pyruvate (L/P) ratio may remain elevated for a prolonged period of time. In neurointensive care clinics, this ratio is considered a metabolic marker of ischemia and/or mitochondrial dysfunction. Here we propose a novel, sensitive microdialysis liquid chromatography-mass spectrometry (LC-MS) approach to monitor mitochondrial dysfunction in living brain using perfusion with 13C-labeled succinate and analysis of 13C-labeled tricarboxylic acid cycle (TCA) intermediates. This approach was evaluated in rat brain using malonate-perfusion (10-50 mM) and endothelin-1 (ET-1)-induced transient cerebral ischemia. In the malonate model, the expected changes upon inhibition of succinate dehydrogenase (SDH) were observed, i.e., an increase in endogenous succinate and decreases in fumaric acid and malic acid. The inhibition was further elaborated by incorporation of 13C into specific TCA intermediates from 13C-labeled succinate. In the ET-1 model, increases in non-labeled TCA metabolites (reflecting release of intracellular compounds) and decreases in 13C-labeled TCA metabolites (reflecting inhibition of de novo synthesis) were observed. The analysis of 13C incorporation provides further layers of information to identify metabolic disturbances in experimental models and neuro-intensive care patients.

Copenhagen Head Injury Ciclosporin Study: A Phase IIa Safety, Pharmacokinetics, and Biomarker Study of Ciclosporin in Severe Traumatic Brain Injury Patients.

Traumatic brain injury (TBI) contributes to almost one third of all trauma-related deaths, and those that survive often suffer from long-term physical and cognitive deficits. Ciclosporin (cyclosporine, cyclosporin A) has shown promising neuroprotective properties in pre-clinical TBI models. The Copenhagen Head Injury Ciclosporin (CHIC) study was initiated to establish the safety profile and pharmacokinetics of ciclosporin in patients with severe TBI, using a novel parenteral lipid emulsion formulation. Exploratory pharmacodynamic study measures included microdialysis in brain parenchyma and protein biomarkers of brain injury in the cerebrospinal fluid (CSF). Sixteen adult patients with severe TBI (Glasgow Coma Scale 4-8) were included, and all patients received an initial loading dose of 2.5 mg/kg followed by a continuous infusion for 5 days. The first 10 patients received an infusion dosage of 5 mg/kg/day whereas the subsequent 6 patients received 10 mg/kg/day. No mortality was registered within the study duration, and the distribution of adverse events was similar between the two treatment groups. Pharmacokinetic analysis of CSF confirmed dose-dependent brain exposure. Between- and within-patient variability in blood concentrations was limited, whereas CSF concentrations were more variable. The four biomarkers, glial fibrillary acidic protein, neurofilament light, tau, and ubiquitin carboxy-terminal hydrolase L1, showed consistent trends to decrease during the 5-day treatment period, whereas the samples taken on the days after the treatment period showed higher values in the majority of patients. In conclusion, ciclosporin, as administered in this study, is safe and well tolerated. The study confirmed that ciclosporin is able to pass the blood-brain barrier in a TBI population and provided an initial biomarker-based signal of efficacy.

Insulin, intracerebral glucose and bedside biochemical monitoring utilizing microdialysis.

Following subarachnoid hemorrhage, hyperglycemia is strongly associated with complications and with impaired neurological recovery. Targeted insulin therapy for glycemic control might, on the contrary, have harmful effects by causing too low cerebral glucose levels. The study published by Schlenk and colleagues in the previous issue of Critical Care shows that insulin caused a significant decrease in the interstitial cerebral glucose concentration although the blood glucose level remained unaffected. Since several studies utilizing various analytical techniques have shown that cerebral blood flow and cerebral glucose uptake and metabolism are insulin-independent processes, the observation remains unexplained.