Cerebral Lactate Concentration Research Articles

Low oxygen in inspired air causes severe cerebrocortical hypoxia and cell death in the cerebral cortex of awake rats

Type 1 respiratory failure (T1RF) is associated with secondary acute brain injury (sABI). The underlying mechanisms of sABI could include injury to brain cells mediated either by hypoxia or by lung injury-triggered inflammation. To elucidate to what extent T1RF causes hypoxia and a consequent hypoxic injury in the brain in the absence of lung injury, we exposed healthy, conscious Sprague-Dawley rats to 48 h long low partial pressure of O2 in inspired air (PiO2) (7.5–8 % O2 in N2, CO2 < 0.5 %, normal barometric pressure) and measured the partial pressure of oxygen in the premotor cortex (PtO2), cerebral blood flow (CBF), lactate concentrations, and cell death. Low PiO2 significantly affected PtO2, which was 52.3 (SD 2.1) mmHg when PiO2 was normal but declined to 6.4 (SD 3.8) mmHg when PiO2 was low for 1 h. This was accompanied by increased lactate concentrations in plasma, CSF, and premotor cortex. Low PiO2 elevated the number of dead cells in the cerebral cortex from 5.6 (SD 4.8) % (when PiO2 was normal) to 20.5 (SD 4.1) % and 32.37 (SD 6.5) % after 24 h and 48 h exposure to low PiO2, respectively. The Mann-Kendall test could not detect any monotonic increase or decrease in pial blood flow during the 48 h exposure to low PiO2. In summary, our findings suggest that exposure to low PiO2 caused a severe hypoxia in the cerebral cortex, which triggers a massive cell death. Since these conditions mimic T1RF, hypoxic injury could be an important underlying cause of T1RF-induced sABI.

Patients with type 1 diabetes and albuminuria have a reduced brain glycolytic capability that is correlated with brain atrophy.

Patients with type 1 diabetes (T1D) demonstrate brain alterations, including white matter lesions and cerebral atrophy. In this case-control study, we investigated if a reason for this atrophy could be because of diabetes-related complications affecting cerebrovascular or cerebral glycolytic functions. Cerebral physiological dysfunction can lead to energy deficiencies and, consequently, neurodegeneration. We examined 33 patients with T1D [18 females, mean age: 50.8 years (range: 26-72)] and 19 matched healthy controls [7 females, mean age: 45.0 years (range: 24-64)]. Eleven (33%) of the patients had albuminuria. Total brain volume, brain parenchymal fraction, gray matter volume and white matter volume were measured by anatomical MRI. Cerebral vascular and glycolytic functions were investigated by measuring global cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and cerebral lactate concentration in response to the inhalation of hypoxic air (12-14% fractional oxygen) using phase-contrast MRI and magnetic resonance spectroscopy (MRS) techniques. The inspiration of hypoxic air challenges both cerebrovascular and cerebral glycolytic physiology, and an impaired response will reveal a physiologic dysfunction. Patients with T1D and albuminuria had lower total brain volume, brain parenchymal fraction, and gray matter volume than healthy controls and patients without albuminuria. The inhalation of hypoxic air increased CBF and lactate in all groups. Patients with albuminuria had a significantly (p = 0.032) lower lactate response compared to healthy controls. The CBF response was lower in patients with albuminuria compared to healthy controls, however not significantly (p = 0.24) different. CMRO2 was unaffected by the hypoxic challenge in all groups (p > 0.16). A low lactate response was associated with brain atrophy, characterized by reduced total brain volume (p = 0.003) and reduced gray matter volume (p = 0.013). We observed a reduced response of the lactate concentration as an indication of impaired glycolytic activity, which correlated with brain atrophy. Inadequacies in upregulating cerebral glycolytic activity, perhaps from reduced glucose transporters in the brain or hypoxia-inducible factor 1 pathway dysfunction, could be a complication in diabetes contributing to the development of neurodegeneration and declining brain health.

Reproducibility of cerebral blood flow, oxygen metabolism, and lactate and N-acetyl-aspartate concentrations measured using magnetic resonance imaging and spectroscopy.

In humans, resting cerebral perfusion, oxygen consumption and energy metabolism demonstrate large intersubject variation regardless of methodology. Whether a similar large variation is also present longitudinally in individual subjects is much less studied, but knowing the time variance in reproducibility is important when designing and interpreting longitudinal follow-up studies examining brain physiology. Therefore, we examined the reproducibility of cerebral blood flow (CBF), global cerebral metabolic rate of oxygen (CMRO2), global arteriovenous oxygen saturation difference (A-V.O2), and cerebral lactate and N-acetyl-aspartate (NAA) concentrations measured using magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques through repeated measurements at 6h, 24h, 7days and several weeks after initial baseline measurements in young healthy adults (N = 26, 13 females, age range 18-35years). Using this setup, we calculated the correlation, limit of agreement (LoA) and within-subject coefficient of variation (CoVWS) between baseline values and the subsequent repeated measurements to examine the longitudinal variation in individual cerebral physiology. CBF and CMRO2 correlated significantly between baseline and all subsequent measurements. The strength of the correlations (R2) and reproducibility metrics (LoA and CoVWS) demonstrated the best reproducibility for the within-day measurements and generally declined with longer time between measurements. Cerebral lactate and NAA concentrations also correlated significantly for all measurements, except between baseline and the 7-day measurement for lactate. Similar to CBF and CMRO2, lactate and NAA demonstrated the best reproducibility for within-day repeated measurements. The gradual decline in reproducibility over time should be considered when designing and interpreting studies on brain physiology, for example, in the evaluation of treatment efficacy.

Human Cerebral Perfusion, Oxygen Consumption, and Lactate Production in Response to Hypoxic Exposure.

Exposure to moderate hypoxia in humans leads to cerebral lactate production, which occurs even when the cerebral metabolic rate of oxygen (CMRO2) is unaffected. We searched for the mechanism of this lactate production by testing the hypothesis of upregulation of cerebral glycolysis mediated by hypoxic sensing. Describing the pathways counteracting brain hypoxia could help us understand brain diseases associated with hypoxia.A total of 65 subjects participated in this study: 30 subjects were exposed to poikilocapnic hypoxia, 14 were exposed to isocapnic hypoxia, and 21 were exposed to carbon monoxide (CO). Using this setup, we examined whether lactate production reacts to an overall reduction in arterial oxygen concentration or solely to reduced arterial oxygen partial pressure. We measured cerebral blood flow (CBF), CMRO2, and lactate concentrations by magnetic resonance imaging and spectroscopy.CBF increased (P < 10−4), whereas the CMRO2 remained unaffected (P > 0.076) in all groups, as expected. Lactate increased in groups inhaling hypoxic air (poikilocapnic hypoxia: n}{}0.0136 frac{mathrm{mmol}/mathrm{L}}{Delta{mathrm{S}}_{mathrm{a}}{mathrm{O}}_2}, P < 10−6; isocapnic hypoxia: n}{}0.0142 frac{mathrm{mmol}/mathrm{L}}{Delta{mathrm{S}}_{mathrm{a}}{mathrm{O}}_2}, P = 0.003) but was unaffected by CO (P = 0.36).Lactate production was not associated with reduced CMRO2. These results point toward a mechanism of lactate production by upregulation of glycolysis mediated by sensing a reduced arterial oxygen pressure. The released lactate may act as a signaling molecule engaged in vasodilation.

252 Non-Invasive Quantification of Human Brain Lactate Concentrations Across Sleep-Wake Cycles

Abstract Introduction Cellular mechanisms underlying changes in small animal brain lactate concentrations have been investigated for more than 70 years and report sharp reductions in lactate (12-35%) during sleep or anesthesia relative to wakefulness. The goal of this study was to investigate alterations in human cerebral lactate concentrations across sleep-wake cycles. Toward this goal, we developed a novel non-invasive methodology, quantified changes in human cerebral lactate during sleep stages, and investigated potential mechanisms associated with changes in lactate. Methods Nine subjects (four females, five males; 21-27 y-o, mean age 24.2 ±2) were sleep deprived overnight, and underwent (5:45~11:00 am) experiments combining simultaneous MR-spectroscopy (MRS) and polysomnography (PSG) in a 3 T MR instrument using a 64-channel head/neck coil. A single voxel MRS (1H-MRS) acquired signals from a volume of interest (12~24 cm3) for every 7.5-s for 88~180-min. Lactate signal intensity was determined from each 7.5-s spectrum, normalized to corresponding water signal, and averaged over 30-s for each PSG epochs. Artifact corrected PSG data were scored for each 30-s epoch using the standard criteria and classified into one of four stages: W, N1, N2 and N3. Group mean lactate levels were quantified using LCModel. Three subjects returned for lactate diffusivity measurements using diffusion-sensitized PRESS MRS sequence. Results Compared to W, group mean lactate levels within each sleep stage showed a reduction of [4.9 ± 4.9] % in N1, [10.4 ± 5.2] % in N2, and [24.0 ± 5.8] % in N3. We observed a significant decrease in lactate apparent diffusion coefficient (ADC) accompanied by reduced brain lactate in sleep compared to wake (P&amp;lt;0.002). There were no differences in ADC values between wake and sleep for H2O, NAA, tCr, or Cho. Conclusion This is the first in-vivo report of alterations in human brain lactate concentrations across sleep-wake cycles. Observed decline in lactate levels during sleep compared to wakefulness is consistent with, and extends results from invasive small animal brain studies first reported more than 70 years ago, and support the notion of altered lactate metabolism and/or increased glymphatic activity in sleeping human brain. Support (if any) The Paul. G. Allen Family Foundation funded the study.

Pharmacological modulation of the lactate fuelling of neuron by astrocytes after an experimental cardiac arrest in rabbits

Rapid induction of therapeutic hypothermia is known to prevent neurological sequelae after cardiac arrest. Its mechanism of action could involve a preservation of astrocytes function, which are known to fuel neuron with lactate in stress conditions. We investigated whether a specific stimulation of astrocyte metabolism by pyruvate administration could induce lactate release and exacerbate the neuronal death as compared to direct stimulation of neurons by lactate administration. Eighteen rabbits were anesthetized and instrumented for cerebral microdialysis and evaluation of cerebral consumption of O 2 , lactate and glucose. After 10 min of ventricular fibrillation and resuscitation, animals received an intravenous infusion of saline (control group, n = 6), sodium lactate (5 mg/kg/min, Lac group, n = 6) or pyruvate (5 mg/kg/min, Py group, n = 6). Neuronal death was quantified by fluorojade C staining after 240 min of follow-up. After cardiac arrest, cerebral concentration of lactates and glucose increased in all groups, with a concomitant decreased oxygen consumption and increased lactate and glucose consumption. In the Py group, pyruvate was reduced in lactate as suggested by a significant increase in cerebral lactate concentration in Py group vs others (8.0 ± 0.8, 3.5 ± 0.5 vs 4.4 ± 1.2 μmol/L in Py, Lac and Control groups at 30 min post-cardiac arrest, respectively). This led to a greater neuronal death (25 ± 6, 34 ± 6 vs 50 ± 6 dead neurons per field, in Control, Lac and Py groups, respectively), suggesting that astrocyte fuelling with pyruvate is worse than direct neuronal fuelling with lactate. Neuron fuelling with lactate after cardiac arrest is deleterious for neurons. Specific stimulation of astrocytes by pyruvate administration enhances lactate production and worsen the neurological death.

Brain Tissue Oxygen Response as Indicator for Cerebral Lactate Levels in Aneurysmal Subarachnoid Hemorrhage Patients.

Early detection of cerebral ischemia and metabolic crisis is crucial in critically ill subarachnoid hemorrhage (SAH) patients. Variable increases in brain tissue oxygen tension (PbtO2) are observed when the fraction of inspired oxygen (FiO2) is increased to 1.0. The aim of this prospective study was to evaluate whether a 3-minute hyperoxic challenge can identify patients at risk for cerebral ischemia detected by cerebral microdialysis. Twenty consecutive severe SAH patients undergoing continuous cerebral PbtO2 and microdialysis monitoring were included. FiO2 was increased to 1.0 for 3 minutes (the FiO2 challenge) twice a day and PbtO2 responses during the FiO2 challenges were related to cerebral microdialysis-measures, ie, lactate, the lactate-pyruvate ratio, and glycerol. Multivariable linear and logistic regression models were created for each outcome parameter. After predefined exclusions, 274 of 400 FiO2 challenges were included in the analysis. Lower absolute increases in PbtO2 (∆PbtO2) during FiO2 challenges were significantly associated with higher cerebral lactate concentration (P<0.001), and patients were at higher risk for ischemic lactate levels >4 mmol/L (odds ratio 0.947; P=0.04). Median (interquartile range) ∆PbtO2 was 7.1 (4.6 to 12.17) mm Hg when cerebral lactate was >4 mmol/L and 10.2 (15.76 to 14.24) mm Hg at normal lactate values (≤4 mmol/L). Median ∆PbtO2 was significantly lower during hypoxic than during hyperglycolytic lactate elevations (4.6 vs. 10.6 mm Hg, respectively; P<0.001). Lactate-pyruvate ratio and glycerol levels were mainly determined by baseline characteristics. A 3-minute FiO2 challenge is an easy to perform and feasible bedside diagnostic tool in SAH patients. The absolute increase in PbtO2 during the FiO2 challenge might be a useful surrogate marker to estimate cerebral lactate concentrations and might be used to identify patients at risk for impending ischemia.

Higher physiological vulnerability to hypoxic exposure with advancing age in the human brain

The aging brain is associated with atrophy along with functional and metabolic changes. In this study, we examined age-related changes in resting brain functions and the vulnerability of brain physiology to hypoxic exposure in humans in vivo. Brain functions were examined in 81 healthy humans (aged 18–62 years) by acquisitions of gray and white matter volumes, cerebral blood flow, cerebral oxygen consumption, and concentrations of lactate, N-acetylaspartate, and glutamate+glutamine using magnetic resonance imaging and spectroscopy. We observed impaired cerebral blood flow reactivity in response to inhalation of hypoxic air (p = 0.029) with advancing age along with decreased cerebral oxygen consumption (p = 0.036), and increased lactate concentration (p = 0.009), indicating tissue hypoxia and impaired metabolism. Diminished resilience to hypoxia and consequently increased vulnerability to metabolic stress could be a key part of declining brain health with age. Furthermore, we observed increased resting cerebral lactate concentration with advancing age (p = 0.007), which might reflect inhibited brain clearance of waste products.

Cerebral Lactate Concentration in Neonatal Hypoxic-Ischemic Encephalopathy: In Relation to Time, Characteristic of Injury, and Serum Lactate Concentration.

Cerebral lactate concentration can remain detectable in neonatal hypoxic-ischemic encephalopathy (HIE) after hemodynamic stability. The temporal resolution of regional cerebral lactate concentration in relation to the severity or area of injury is unclear. Furthermore, the interplay between serum and cerebral lactate in neonatal HIE has not been well defined. The study aims to describe cerebral lactate concentration in neonatal HIE in relation to time, injury, and serum lactate. Fifty-two newborns with HIE undergoing therapeutic hypothermia (TH) were enrolled. Magnetic resonance imaging and spectroscopy (MRI + MR spectroscopy) were performed during and after TH at 54.6 ± 15.0 and 156 ± 57.6 h of life, respectively. Severity and predominant pattern of injury was scored radiographically. Single-voxel 1H MR spectra were acquired using short-echo (35 ms) PRESS sequence localized to the basal ganglia (BG), thalamus (Thal), gray matter (GM), and white matter. Cerebral lactate concentration was quantified by LCModel software. Serum and cerebral lactate concentrations were plotted based on age at time of measurement. Multiple comparisons of regional cerebral lactate concentration based on severity and predominant pattern of injury were performed. Spearman's Rho was computed to determine correlation between serum lactate and cerebral lactate concentration at the respective regions of interest. Overall, serum lactate concentration decreased over time. Cerebral lactate concentration remained low for less severe injury and decreased over time for more severe injury. Cerebral lactate remained detectable even after TH. During TH, there was a significant higher concentration of cerebral lactate at the areas of injury and also when injury was more severe. However, these differences were no longer observed after TH. There was a weak correlation between serum lactate and cerebral lactate concentration at the BG (rs = 0.3, p = 0.04) and Thal (rs = 0.35, p = 0.02). However, in infants with moderate-severe brain injury, a very strong correlation exists between serum lactate and cerebral lactate concentration at the BG (rs = 0.7, p = 0.03), Thal (rs = 0.9 p = 0.001), and GM (rs = 0.6, p = 0.04) regions. Cerebral lactate is most significantly different between regions and severity of injury during TH. There is a moderate correlation between serum and cerebral lactate concentration measured in the deep gray nuclei during TH. Differences in injury and altered regional cerebral metabolism may account for these differences.

No evidence for direct effects of recombinant human erythropoietin on cerebral blood flow and metabolism in healthy humans.

Erythropoietin (EPO) is expressed in human brain tissue, but its exact role is unknown. EPO may improve the efficiency of oxidative metabolism and has neuroprotective properties against hypoxic injuries in animal models. We aimed to investigate the effect of recombinant human EPO (rHuEPO) administration on healthy cerebral metabolism in humans during normoxia and during metabolic stress by inhalation of 10% O2 hypoxic air. Twenty-four healthy men participated in a two-arm double-blind placebo-controlled trial. rHuEPO was administered as a low dose (5,000 IU) over 4 wk ( n = 12) or as a high dose (500 IU·kg body wt-1·day-1) for three consecutive days ( n = 12). Global cerebral blood flow (CBF) and metabolic rate of glucose (CMRglc) were measured with positron emission tomography. CBF, metabolic rate of oxygen ([Formula: see text]), and cerebral lactate concentration were measured by magnetic resonance imaging and spectroscopy. Low-dose treatment increased hemoglobin and was associated with a near-significant decrease in CBF during baseline normoxia. High-dose treatment caused no change in CBF. Neither treatment had an effect on normoxia CMRglc, [Formula: see text], or lactate concentration or an effect on the cerebral metabolic response to inhalation of hypoxic air. In conclusion, the study found no evidence for a direct effect of rHuEPO on cerebral metabolism. NEW & NOTEWORTHY We demonstrate with magnetic resonance imaging and positron emission tomography that administration of erythropoietin does not have a substantial direct effect on healthy human resting cerebral blood flow or effect on cerebral glucose and oxygen metabolism. Also, administration of erythropoietin did not have a direct effect on the metabolic response to acute hypoxic stress in healthy humans, and a suggested neuroprotective effect from erythropoietin is therefore likely not a direct effect of erythropoietin on cerebral metabolism.

Cerebral blood flow, oxygen metabolism, and lactate during hypoxia in patients with obstructive sleep apnea.

Obstructive sleep apnea (OSA) is associated with increased risk of stroke but the underlying mechanism is poorly understood. We suspect that the normal cerebrovascular response to hypoxia is disturbed in patients with OSA. Global cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and lactate concentration during hypoxia were measured in patients with OSA and matched controls. Twenty-eight patients (82.1% males, mean age 52.3 ± 10.0 years) with moderate-to-severe OSA assessed by partial polysomnography were examined and compared with 19 controls (73.7% males, mean age 51.8 ± 10.1 years). Patients and controls underwent magnetic resonance imaging (MRI) during 35 min of normoxia followed by 35 min inhaling hypoxic air (10%-12% O2). After 3 months of continuous positive airway pressure (CPAP) treatment, 22 patients were rescanned. During hypoxia, CBF significantly increased with decreasing arterial blood oxygen concentration (4.53 mL (blood)/100 g/min per -1 mmol(O2)/L, p < 0.001) in the control group, but was unchanged (0.89 mL (blood)/100 g/min per -1 mmol(O2)/L, p = 0.289) in the patient group before CPAP treatment. The CBF response to hypoxia was significantly weaker in patients than in controls (p = 0.003). After 3 months of CPAP treatment the CBF response normalized, showing a significant increase during hypoxia (5.15 mL (blood)/100 g/min per -1 mmol(O2)/L, p < 0.001). There was no difference in CMRO2 or cerebral lactate concentration between patients and controls, and no effect of CPAP treatment. Patients with OSA exhibit reduced CBF in response to hypoxia. CPAP treatment normalized these patterns.

Microdialysis as a Part of Invasive Cerebral Monitoring During Porcine Septic Shock.

Metabolic changes in critically ill patients with endotoxin-induced septic shock are measured primarily by techniques that afford organ-specific metabolic monitoring based on interstitial fluid samples. The present study was designed to evaluate the role of cerebral microdialysis (MD) as a part of invasive neuromonitoring during endotoxemia in a porcine model. Continuous endotoxin infusion was administered to 7 female pigs and, in addition to hemodynamic monitoring and blood chemistry, interstitial lactate, pyruvate, glucose and glycerol concentrations in muscle, liver, and cerebral tissue were measured via in vivo MD for an observation period of 180 minutes. The cerebral concentrations of lactate and glycerol showed no significant increases, whereas the hepatic and muscular levels rose dramatically under endotoxemia. However, the lactate/pyruvate ratio and especially the lactate/glucose ratio showed a profound and significant increase in brain tissue as well. Cerebral perfusion pressure decreased from 77 to 50 mm Hg without reaching pathologic values. Although our results confirm the special protection of the brain during endotoxemia compared with other organs, early metabolic changes become evident by increasing lactate/pyruvate ratio and lactate/glucose ratio. MD appears to be a suitable additional technique in invasive neuromonitoring for obtaining early information about metabolic deterioration in the brain during septic shock.

Beta EEG reflects sensory processing in active wakefulness and homeostatic sleep drive in quiet wakefulness.

Markers of sleep drive (<10Hz; slow-wave activity and theta) have been identified in the course of slow-wave sleep and wakefulness. So far, higher frequencies in the waking electroencephalogram have not been examined thoroughly as a function of sleep drive. Here, electroencephalogram dynamics were measured in epochs of active wake (wake characterized by high muscle tone) or quiet wake (wake characterized by low muscle tone). It was hypothesized that the higher beta oscillations (15-35Hz, measured by local field potential and electroencephalography) represent fundamentally different processes in active wake and quiet wake. In active wake, sensory stimulation elevated beta activity in parallel with gamma (80-90Hz) activity, indicative of cognitive processing. In quiet wake, beta activity paralleled slow-wave activity (1-4Hz) and theta (5-8Hz) in tracking sleep need. Cerebral lactate concentration, a measure of cerebral glucose utilization, increased during active wake whereas it declined during quiet wake. Mathematical modelling of state-dependent dynamics of cortical lactate concentration was more precisely predictive when quiet wake and active wake were included as two distinct substates rather than a uniform state of wakefulness. The extent to which lactate concentration declined in quiet wake and increased in active wake was proportionate to the amount of beta activity. These data distinguish quiet wake from active wake. Quiet wake, particularly when characterized by beta activity, is permissive to metabolic and electrophysiological changes that occur in slow-wave sleep. These data urge further studies on state-dependent beta oscillations across species.

Acute hypoxia increases the cerebral metabolic rate – a magnetic resonance imaging study

The aim of the present study was to examine changes in cerebral metabolism by magnetic resonance imaging of healthy subjects during inhalation of 10% O2 hypoxic air. Hypoxic exposure elevates cerebral perfusion, but its effect on energy metabolism has been less investigated. Magnetic resonance imaging techniques were used to measure global cerebral blood flow and the venous oxygen saturation in the sagittal sinus. Global cerebral metabolic rate of oxygen was quantified from cerebral blood flow and arteriovenous oxygen saturation difference. Concentrations of lactate, glutamate, N-acetylaspartate, creatine and phosphocreatine were measured in the visual cortex by magnetic resonance spectroscopy. Twenty-three young healthy males were scanned for 60 min during normoxia, followed by 40 min of breathing hypoxic air. Inhalation of hypoxic air resulted in an increase in cerebral blood flow of 15.5% (p = 0.058), and an increase in cerebral metabolic rate of oxygen of 8.5% (p = 0.035). Cerebral lactate concentration increased by 180.3% (), glutamate increased by 4.7% () and creatine and phosphocreatine decreased by 15.2% (p). The N-acetylaspartate concentration was unchanged (p = 0.36). In conclusion, acute hypoxia in healthy subjects increased perfusion and metabolic rate, which could represent an increase in neuronal activity. We conclude that marked changes in brain homeostasis occur in the healthy human brain during exposure to acute hypoxia.

Combined administration of hyperbaric oxygen and hydroxocobalamin improves cerebral metabolism after acute cyanide poisoning in rats

Hyperbaric oxygen therapy (HBOT) or intravenous hydroxocobalamin (OHCob) both abolish cyanide (CN)-induced surges in interstitial brain lactate and glucose concentrations. HBOT has been shown to induce a delayed increase in whole blood CN concentrations, whereas OHCob may act as an intravascular CN scavenger. Additionally, HBOT may prevent respiratory distress and restore blood pressure during CN intoxication, an effect not seen with OHCob administration. In this report, we evaluated the combined effects of HBOT and OHCob on interstitial lactate, glucose, and glycerol concentrations as well as lactate-to-pyruvate ratio in rat brain by means of microdialysis during acute CN poisoning. Anesthetized rats were allocated to three groups: 1) vehicle (1.2 ml isotonic NaCl intra-arterially); 2) potassium CN (5.4 mg/kg intra-arterially); 3) potassium CN, OHCob (100 mg/kg intra-arterially) and subsequent HBOT (284 kPa in 90 min). OHCob and HBOT significantly attenuated the acute surges in interstitial cerebral lactate, glucose, and glycerol concentrations compared with the intoxicated rats given no treatment. Furthermore, the combined treatment resulted in consistent low lactate, glucose, and glycerol concentrations, as well as in low lactate-to-pyruvate ratios compared with CN intoxicated controls. In rats receiving OHCob and HBOT, respiration improved and cyanosis disappeared, with subsequent stabilization of mean arterial blood pressure. The present findings indicate that a combined administration of OHCob and HBOT has a beneficial and persistent effect on the cerebral metabolism during CN intoxication.

Temporal dynamics of lactate concentration in the human brain during acute inspiratory hypoxia

To demonstrate the feasibility of measuring the temporal dynamics of cerebral lactate concentration and examine these dynamics in human subjects using magnetic resonance spectroscopy (MRS) during hypoxia. A respiratory protocol consisting of 10-minute baseline normoxia, 20-minute inspiratory hypoxia, and ending with 10-minute normoxic recovery was used, throughout which lactate-edited MRS was performed. This was repeated four times in three subjects. A separate session was performed to measure blood lactate. Impulse response functions using end-tidal oxygen and blood lactate as system inputs and cerebral lactate as the system output were examined to describe the dynamics of the cerebral lactate response to a hypoxic challenge. The average lactate increase was 20% ± 15% during the last half of the hypoxic challenge. Significant changes in cerebral lactate concentration were observed after 400 seconds. The average relative increase in blood lactate was 188% ± 95%. The temporal dynamics of cerebral lactate concentration was reproducibly demonstrated with 200-second time bins of MRS data (coefficient of variation 0.063 ± 0.035 between time bins in normoxia). The across-subject coefficient of variation was 0.333. The methods for measuring the dynamics of the cerebral lactate response developed here would be useful to further investigate the brain's response to hypoxia.

Therapeutic hypothermia after cardiac arrest – cerebral perfusion and metabolism during upper and lower threshold normocapnia

BackgroundDuring cardiac arrest and after successful resuscitation a continuum of ischaemia-reperfusion injury develops. Mild hypothermia exerts protective effects in the postresuscitation phase but also alters CO2 production and solubility, which may lead to deleterious effects if overlooked when adjusting the ventilation of the resuscitated patient. Using a multimodality approach, the effects of different carbaemic states on cerebral perfusion and metabolism were evaluated during therapeutic hypothermia. MethodsEight comatose survivors of prehospital cardiac arrest were cooled to 33°C for 24h and underwent a 60min phase of interventional lower threshold normocapnia according to temperature non-corrected pCO2 (4.2kPa) and higher threshold normocapnia according to corrected pCO2 (6.0kPa) in a random order. Prior to, during and after each phase, cerebral perfusion and metabolites via a microdialysis catheter were measured. ResultsDuring upper-threshold pCO2, an increase in middle cerebral artery mean flow velocity (MFV) and jugular bulb oxygen saturation (jSvO2) were observed with a concomitant decrease in cerebral lactate concentration. Lower threshold normocapnia was associated with a decrease in MFV in most patients. In all patients jSvO2 decreased but no change in cerebral lactate was observed. In seven patients jSvO2 decreased below 55%. These changes were not reflected to intracranial pressure or cerebral oximetry. ConclusionsDuring induced hypothermia, lower threshold normocapnia was associated with decreased cerebral perfusion/oxygenation but not reflected to interstitial metabolites. Upper threshold pCO2 increased cerebral perfusion and reduced cerebral lactate. Vigilance over the ventilatory and CO2 analysis regimen is mandatory during mild hypothermia.

Cerebral Glutamine Concentration and Lactate–Pyruvate Ratio in Patients with Acute Liver Failure

Hyperammonemia causes brain edema and high intracranial pressure (ICP) in acute liver failure (ALF) by accumulation of glutamine in brain. Since a high-level glutamine may compromise mitochondrial function, the aim of this study was to determine if the lactate-pyruvate ratio is associated with a rise in the glutamine concentration and ICP. In 13 patients with ALF (8F/5M; median age 46 (range 18-66) years) the cerebral extracellular concentrations of glutamine, lactate, and pyruvate were measured by in vivo brain microdialysis together with ICP and cerebral perfusion pressure (CPP). The cerebral glutamine concentration was 4,396 (1,011-9,712) microM, lactate 2.15 (1.1-4.45) mM, and pyruvate 101 (43-255) microM. The lactate-pyruvate ratio was 21 (16-40), ICP 20 (2-28) mmHg, and CPP 72 (56-115) mmHg. Cerebral glutamine concentration correlated with the lactate-pyruvate ratio (r = 0.89, P < 0.05). Also the ICP, but not CPP, correlated to the lactate-pyruvate ratio (r = 0.64, P < 0.05). ICP and the cerebral glutamine concentration in patients with ALF correlate to the lactate-pyruvate ratio. Since CPP was sufficient in all patients the rise in lactate-pyruvate ratio indicates that accumulation of glutamine compromises mitochondrial function and causes intracranial hypertension.

Comparison of terlipressin and noradrenalin on cerebral perfusion, intracranial pressure and cerebral extracellular concentrations of lactate and pyruvate in patients with acute liver failure in need of inotropic support

Volume expansion and inotropic support with catecholamines are sometimes insufficient to ensure adequate blood pressure and cerebral perfusion in acute liver failure (ALF). The aim of this study was to determine if terlipressin increases cerebral perfusion, cerebral concentration of lactate and intracranial pressure (ICP), and to compare the effect with that of noradrenalin (NA). Ten patients (median age 42.5 yr; range 15-66; 5 women) who needed inotropic support and had an ICP and a cerebral microdialysis catheter placed had concomitant recording of cerebral perfusion pressure (CPP), cerebral perfusion (using transcranial Doppler sonography (V(mean))) and ICP. Also cerebral extracellular concentration of lactate ([lactate]ec) and pyruvate ([pyruvate]ec) was collected before and after an increase in the NA infusion rate and/or i.v.-injection of 1mg terlipressin. Both NA and terlipressin increased CPP and V(mean) (p<0.01). Also ICP increased during NA infusion (p<0.01) but not after terlipressin. The cerebral [lactate]ec decreased after terlipressin injection from 2.34 (1.52-8.38) to 1.99 (0.03-4.83)mmol/l (p=0.027) but not during NA infusion (2.83 (1.53-7.11)mmol/l). The [lactate]ec to [pyruvate]ec ratio remained unchanged in both the NA group (20.7 (13.2-40.0)) and terlipressin group (22.2 (10.5-30.0)). This study shows that terlipressin increases CPP and cerebral perfusion with little influence upon ICP and cerebral [lactate]ec in ALF patients. These findings indicate that terlipressin may be valuable, as an additive treatment to NA infusion to secure brain viability.

Lack of utility of arteriojugular venous differences of lactate as a reliable indicator of increased brain anaerobic metabolism in traumatic brain injury

Ischemic lesions are highly prevalent in patients with traumatic brain injuries (TBIs) and are the single most important cause of secondary brain damage. The prevention and early treatment of these lesions is the primary aim in the modem treatment of these patients. One of the most widely used monitoring techniques at the bedside is quantification of brain extracellular level of lactate by using arteriojugular venous differences of lactate (AVDL). The purpose of this study was to determine the sensitivity, specificity, and predictive value of AVDL as an indicator of increases in brain lactate production in patients with TBIs. Arteriojugular venous differences of lactate were calculated every 6 hours using samples obtained though a catheter placed in the jugular bulb in 45 patients with diffuse head injuries (57.8%) or evacuated brain lesions (42.2%). Cerebral lactate concentration obtained with a 20-kD microdialysis catheter implanted in undamaged tissue was used as the de facto gold standard. Six hundred seventy-three AVDL determinations and cerebral microdialysis samples were obtained simultaneously; 543 microdialysis samples (81%) showed lactate values greater than 2 mmol/L, but only 21 AVDL determinations (3.1%) showed an increase in brain lactate. No correlation was found between AVDL and cerebral lactate concentration (p = 0.014, p = 0.719). Arteriojugular venous differences of lactate had a sensitivity and specificity of 3.3 and 97.7%, respectively, with a false-negative rate of 96.7% and a false-positive rate of 2.3%. Arteriojugular venous differences of lactate do not reliably reflect increased cerebral lactate production and consequently are not reliable in ruling out brain ischemia in patients with TBIs. The clinical use of this monitoring method in neurocritical care should be reconsidered.