Hypoxic Hypoxia Research Articles

Antihypoxic Activity of Native Humic Acids of Tomsk Lowland Peat

The antihypoxic activity of humic acids of Tomsk lowland peat was studied experimentally. It was established that native humic acids of peat (HAP) had pronounced antihypoxic activity after a preventive intragastric administration to mice, increasing the lifespan of animals and decreasing the lethality under hypobaric hypoxic and histotoxic hypoxia conditions. The discovered antihypoxic properties of HAP were probably due to their protective antioxidant properties, which prevent free-radical injury to cells and organelles under hypoxia conditions.

The effects of ketamine on the immune response in the fetal ovine brain in response to hypoxic hypoxia (877.8)

Fetal hypoxia is a reduction in oxygen supply to the fetus. HH occurs when maternal and fetal partial pressure of oxygen is decreased due to maternal partial ventilatory restriction. Recently, our lab reported that HH increased inflammatory genes in the fetal brain, and KET reduced the expression by microarray analysis. We hypothesized that HH causes an inflammatory reaction in the fetal ovine brain, and KET attenuates this response. We examined fetal ovine brain (n=3‐5/group) where mother and baby were chronically catheterized, and tracheostomy was performed on the ewe. A 50 % decrease in partial pressure of oxygen was induced by administering nitrogen gas directly to the ewe for 30 min. KET was administered intravenously to the fetus 10 min prior to the induction of HH. Brains were collected 24 hrs post HH stimulus, fixated in 4% paraformaldehyde, and then embedded in paraffin blocks for hematoxylin and eosin staining. After tissue examination under light microscope, lymphocytic infiltration, congestion in blood vessels, and the presence of proteinaceous substances were evaluated by a 5‐point scoring criteria in the HH brains. KET produced a decrease in inflammatory response in tissues subjected to HH, and the induction of HH produced a higher inflammatory response when compared to normoxia group (P<0.05, Friedman test). We conclude that KET decreases the level of inflammation in the fetal ovine brain exposed to HH.Grant Funding Source: Supported by NIH grants HD033053 and HD05761 and by the APS STRIDE program.

Ketamine decreases immune gene expression in ovine fetal frontal cortex exposed to acute hypoxic hypoxia (887.5)

Fetal hypoxic hypoxia (HH), a consequence of maternal hypoxia, stimulates glutamatergic neurotransmission. We hypothesize that excitotoxicity induced by HH can be reduced by pretreatment with ketamine (KET), an NMDA receptor antagonist. The objective was to evaluate the genomic response of fetal frontal cortex under HH with KET. KET (3 mg/kg) was administered intravenously to chronically catheterized ovine fetuses (n=3‐5/group; 123±3 d gestation) 10 min prior to 30 min HH. Fetal frontal cortex was collected 24 hrs post‐HH. mRNA was extracted, labeled, and hybridized to ovine Agilent 15.5k microarray. Significant differences in gene expression between control±KET and HH±KET groups were determined by F‐statistics using the limma package for R (P<0.05). Differentially up‐/down‐regulated genes were analyzed by gene ontology and network analysis, identifying statistically significant overrepresentation of biological processes (P<0.05). Significantly up‐/down‐regulated genes: HH: 244/470 and HH+KET: 556/246. There were 120 common genes up‐regulated by HH and down‐regulated by HH+KET. The enriched biological processes for the overlap genes were involved in regulation of immune system processes (TLR2, MYD88, NFKBIA, IL8, IL6R, IL6ST, CD5, CD14, ICAM1, CCL2, CCL4L1). In conclusion, acute HH increased genomic expression of immune pathways in fetal frontal cortex, and ketamine reduced the response suggesting potential therapy for attenuating neuronal hypoxic damage in fetuses and neonates.

Preclinical evidence of mitochondrial nicotinamide adenine dinucleotide as an effective alarm parameter under hypoxia

Early detection of tissue hypoxia in the intensive care unit is essential for effective treatment. Reduced nicotinamide adenine dinucleotide (NADH) has been suggested to be the most sensitive indicator of tissue oxygenation at the mitochondrial level. However, no experimental evidence comparing the kinetics of changes in NADH and other physiological parameters has been provided. The aim of this study is to obtain the missing data in a systematic and reliable manner. We constructed four acute hypoxia models, including hypoxic hypoxia, hypemic hypoxia, circulatory hypoxia, and histogenous hypoxia, and measured NADH fluorescence, tissue reflectance, cerebral blood flow, respiration, and electrocardiography simultaneously from the induction of hypoxia until death. We found that NADH was not always the first onset parameter responding to hypoxia. The order of responses was mainly affected by the cause of hypoxia. However, NADH reached its alarm level earlier than the other monitored parameters, ranging from several seconds to >10 min. As such, we suggest that the NADH can be used as a hypoxia indicator, although the exact level that should be used must be further investigated. When the NADH alarm is detected, the body still has a chance to recover if appropriate and timely treatment is provided.

Blood oxygenation level dependent, blood volume, and blood flow responses to carbogen and hypoxic hypoxia in 9L rat gliomas as measured by MRI

PurposeTo study vascular responsiveness to hypoxia and hypercarbia together with vessel size index (VSI) in a 9L rat glioma (n = 11) using multimodal MRI.Materials and MethodsVSI was determined using T2 and MRI following AMI‐227 contrast agent. Blood oxygenation level dependent (BOLD) signal response was determined using T2 EPI MRI, blood volume changes using AMI‐227 and blood flow by means of continuous arterial spin labeling.ResultsVSI in the cortex, tumor rim, and core of 2.2 ± 1.0, 18.2 ± 5.4, and 23.9 ± 14.7 μm, respectively, showing a larger average vessel size in glioma than in the brain parenchyma. BOLD and blood volume signal changes to hypoxia and hypercapnia were much more profound in the tumor rim than the core. Hypoxia led to rim BOLD signal change that was larger in amplitude and it attained the low value much faster than either core or brain cortex. The vasculature in the rim appears more responsive to respiratory challenges in terms of volume adaptation than the core. Blood flow values within the gliomas were much lower than in the contralateral brain. Neither hypercarbia nor hypoxia had an effect on the tumor blood flow.ConclusionVascular responses of 9L gliomas to respiratory challenge, in particular hypoxia, are heterogeneous between the core and rim zones, potentially offering a means to classify and separate intratumor tissues with differing hemodynamic characteristics. J. Magn. Reson. Imaging 2014;39:110–119. © 2013 Wiley Periodicals, Inc.

THE INFLUENCE OF EXPERIMENTAL SUBACUTE HYPOBARIC HYPOXIA ON P-GLYCOPROTEIN FUNCTIONAL ACTIVITY

In a study on rabbits the effect of the experimental subacute hypobaric hypoxic hypoxia on the functional activity of ATP-dependent protein transporter P-glycoprotein (Pgp) was studied. Pgp activity was assessed by pharmacokinetic of it’s marker substrate fexofenadine. It was found that 4-hour hypoxic action leads to Pgp induction.

Response to hypoxic provocation in patients with chronic heart failure and its predictive value for central sleep apnea

Introduction Central apneas are usually clustered in periodic sequences in patients with chronic heart failure (CHF) and central sleep apnea (CSA), triggered by destabilizing events. We hypothesized that a provocation with exogenous hypoxic hypoxia may destabilize a system with abnormal gain (controller and plant) enough to trigger visually recognizable central events during wakefulness in those patients. The aim of the study is to investigate the response to hypoxic provocation in patients with CHF and its capability to predict the presence of CSA. Materials and methods Nineteen patients with CHF (age=65.5±7.3, EF=51.9±6.6) have been recruited and subjected to polysomnography and hypoxic provocation. Central apnea-hypopnea index (cAHI)>5 determined the presence of CSA, dividing the patients in 2 groups – with CSA ( n =13, cAHI=29.2±16.2) and CHF without CSA ( n =6, cAHI=4.0±1.6, p 3% were scored for each period and respective indices for apneas and hypopneas (hAHI) and oxygen desaturations (hODI) have been calculated in the classical manner (count per 1h). Results No differences were present between the 2 groups in the prehypoxic period (hAHIpre=27.6±26.7 vs. 16.3±27.3, NS; hODIpre=18.6±23.5 vs. 12.9±17.6, NS; average desaturation (hAvDespre)=2.5±2.4 vs. 2.3±1.9, NS in patients and controls, respectively). Significantly higher values for these parameters were found after the hypoxic provocation in the CHF+CSA group, compared to CHF controls (hAHIpost=54.5±28.8 vs. 18.8±28.8, p =0.022; hODIpost=37.0±23.2 vs. 2.4±4.5, p p =0.007). Exogenous hypoxia provoked significantly more events in the posthypoxic period, compared to baseline values only in CHF+CSA patients (hAHIpre/hAHIpost, p =0.002; hODIpre/hODIpost, p =0.002; hAvDespre/hAvDespost, p =0.008). Strong significant correlation was found between cAHI and hAHI3 (rho=0.553, p =0.05) and hODI3 (rho=0.564, p =0.05). Patients presenting with positive hypoxic provocation test (empirically chosen if hAHIpost>30) had 11.8 times higher odds (95% CI=1.34–105, p =0.026) to have CSA. Conclusion Hypoxic provocation triggers central events during wakefulness in the majority of CHF+CSA patients and may be used as a predictor of the presence and magnitude of CSA in CHF. Acknowledgement The study was financed by the Bulgarian Ministry of Youth and Science.

Cerebral blood flow response to acute hypoxic hypoxia

Hypoxic hypoxia (inspiratory hypoxia) stimulates an increase in cerebral blood flow (CBF) maintaining oxygen delivery to the brain. However, this response, particularly at the tissue level, is not well characterised. This study quantifies the CBF response to acute hypoxic hypoxia in healthy subjects. A 20-min hypoxic (mean PETo2 = 52 mmHg) challenge was induced and controlled by dynamic end-tidal forcing whilst CBF was measured using pulsed arterial spin labelling perfusion MRI. The rate constant, temporal delay and magnitude of the CBF response were characterised using an exponential model for whole-brain and regional grey matter. Grey matter CBF increased from 76.1 mL/100 g/min (95% confidence interval (CI) of fitting: 75.5 mL/100 g/min, 76.7 mL/100 g/min) to 87.8 mL/100 g/min (95% CI: 86.7 mL/100 g/min, 89.6 mL/100 g/min) during hypoxia, and the temporal delay and rate constant for the response to hypoxia were 185 s (95% CI: 132 s, 230 s) and 0.0035 s–1 (95% CI: 0.0019 s–1, 0.0046 s–1), respectively. Recovery from hypoxia was faster with a delay of 20 s (95% CI: –38 s, 38 s) and a rate constant of 0.0069 s–1 (95% CI: 0.0020 s–1, 0.0103 s–1). R2*, an index of blood oxygenation obtained simultaneously with the CBF measurement, increased from 30.33 s–1 (CI: 30.31 s–1, 30.34 s–1) to 31.48 s–1 (CI: 31.47 s–1, 31.49 s–1) with hypoxia. The delay and rate constant for changes in R2* were 24 s (95% CI: 21 s, 26 s) and 0.0392 s–1 (95% CI: 0.0333 s–1, 0.045 s–1 ), respectively, for the hypoxic response, and 12 s (95% CI: 10 s, 13 s) and 0.0921 s–1 (95% CI: 0.0744 s–1, 0.1098 s–1/) during the return to normoxia, confirming rapid changes in blood oxygenation with the end-tidal forcing system. CBF and R2* reactivity to hypoxia differed between subjects, but only R2* reactivity to hypoxia differed significantly between brain regions. © 2013 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.

Comparative Analysis of Brain Pyruvate Kinase Activity Of White Rats Exposed To Hypoxic Hypoxia During Two Stages Of Prenatal Development

Comparative Analysis of Brain Pyruvate Kinase Activity Of White Rats Exposed To Hypoxic Hypoxia During Two Stages Of Prenatal Development

Resuscitation of patients with septic shock: please “mind the gap”!

Resuscitation of patients with septic shock: please “mind the gap”!

Effect of chronic hypoxic hypoxia on oxidation and glucuronidation of carvedilol in rats

Heart failure is accompanied with tissue (circulatory) hypoxia, and the metabolism of several drugs has been reported to be reduced in heart failure. The aim of this study was to investigate the effect of another type of respiratory hypoxia, hypoxic hypoxia (FiO2 15 % for 24 h followed by FiO2 10 % for 9 days) on the metabolism of carvedilol enantiomers in rats. Oxidation of carvedilol in rat liver microsomes was evaluated in the presence of reduced nicotinamide adenine dinucleotide phosphate, whereas glucuronidation was evaluated in the presence of UDP-glucuronic acid. Both oxidation and glucuronidation activities for two carvedilol enantiomers in hypoxic rat liver microsomes were similar to those in control rat liver microsomes. We also performed pharmacokinetic analysis of carvedilol enantiomers following intraportal infusion in control and hypoxic rats. The mean (±S.E.) portal clearance value of R- and S-carvedilol in control rats was 72 ± 16 and 156 ± 31 ml/min/kg, respectively, whereas that of the R- and S-enantiomers in hypoxic rats was 68 ± 8 and 113 ± 14 ml/min/kg, respectively. These findings indicated that the metabolism of carvedilol enantiomers was not significantly diminished in rats with chronic hypoxic hypoxia, and that other factor(s) besides hypoxia may be responsible for the reduced drug metabolism in heart failure.

Autonomic regulation of organ vascular resistances during hypoxemia in the cat

This study aimed to dissect the roles played by the autonomic interoreceptors, the carotid bodies (cbs) and the aortic bodies (abs) on the vascular resistances of several organs in anesthetized, paralyzed, artificially ventilated cats challenged by systemic hypoxemia. Two 15 min challenges stimulated each of 5 animals in two different groups: (1) in the intact group hypoxic hypoxia (10% O2 in N2; HH) stimulated both abs and cbs, increasing neural output to the nucleus tractus solitarius (NTS); (2) in this group carbon monoxide hypoxia (30% O2 in N2 with the addition of CO; COH) stimulated only the abs, increasing neural output to the NTS. (3) In the second group in which their bilateral aortic depressor nerves had been transected only the cbs increased neural output to the NTS during the HH challenge; (4) in this aortic body resected group during COH neither abs nor cbs increased neural traffic to the NTS. CO and 10% O2 reduced Hb saturation to the same level. With the use of radiolabeled microspheres blood flow was measured in a variety of organs. Organ vascular resistance was calculated by dividing the aortic pressure by that organ's blood flow. The spleen and pancreas revealed a vasoconstriction in the face of systemic hypoxemia, thought to be sympathetic nervous system (SNS)-mediated. The adrenals and the eyes vasodilated only when cbs were stimulated. Vasodilation in the heart and diaphragm showed no effect of chemoreceptor stimulated increase in SNS output. Different chemoreceptor involvement had different effects on the organs.

Abstract 4047: A novel in vivo model of breast cancer hypoxia reveals an epithelial-to-mesenchymal transition switch.

Abstract Background: Low levels of oxygen within cells are characteristic of many solid malignant tumors. This phenomenon has been described as an important trigger of tumor invasion and metastasis. Despite the importance of this association between hypoxia and more aggressive cancer phenotypes, experimental models to study the influence of hypoxia in cancer development and progression have been limited to in vitro models and in vivo models based on mice being subject to a systemic hypoxic state or drug-induced hypoxia. These models have provided inconclusive and controversial data. We developed a novel in vivo model of breast cancer hypoxia to study the influence of transitory hypoxia on epithelial to mesenchymal transition (EMT). Methods: 4T1 and 67nr cell lines were engrafted into the kidney cortex of female BALB/c mice. Placing an aneurysm clip on the kidney hilum for 40 minutes, hypoxia was directed to tumor site after 7 days of engraftment. After 14, 21 and 28 (67nr only) days of engraftment, mice were sacrificed and the histological evaluation was used to analyze the morphological changes induced by ischemia in kidney cortex, and to verify the metastatic potential to lungs and liver. Tumors were sampled after 14 days of engraftment for gene expression assay. Real time RT-PCR was performed to analyze the relative expression of Cdh1, Vim, Fn1, Ctnnb1, Jag1, Notch1, Snai2, Sox9, Tgfb1, Twist1, HIF2A, Hif1a and Ca9 genes (TaqMan® Gene Expression Assay) in cell lines and in tumors in the control group and the hypoxia group. TBP and HPRT were used as housekeeping genes and 12 weeks-old normal breast mouse tissue was used as reference. Results: All mice engrafted with 4T1 and 67nr into the renal cortex developed local tumors. We did not observed metastasis to the liver. In 4T1 group, metastases to the lungs were observed only in hypoxia group after 14 days after engraftment. After 21 days, all mice developed lung metastases. In 67nr, metastases to the lungs were observed only in hypoxia group after 28 days after engraftment. According to gene expression analyses, virtually all genes were different expressed after engraftment comparing to cell lines. When comparing the control and hypoxia groups, we observed a significant 2.6 fold and 3.1 fold change in VIM expression, and an 0.51 fold and 0.53 fold change in CDH1 expression in 4T1 and 67nr cell lines, respectively. In 67nr the SLUG expression changed 496 fold and the SLUG/SOX9 ratio changed 4.8-fold. The HIF1A/HIF2A expression ratio increased in 4T1 and 67nr tumors after hypoxia. The expression of TGFB1, TWIST1 and CTNNB1 genes was not significant changed in tumors subjected to hypoxia. Conclusion: hypoxia directed to the tumor site in an in vivo model induces a EMT transition signature and accelerate the metastatic dissemination of murine breast cancer allograft. The expressive increase in SLUG expression suggests this transcription factor is crucial to hypoxia-induced EMT. Citation Format: Daniel G. Tiezzi, Heriton MR Antonio, Renata D. Sicchieri, Cristiane M. Milanezi, Larissa RM Mandarano, Alan A. Coelho, Jurandyr M. de Andrade. A novel in vivo model of breast cancer hypoxia reveals an epithelial-to-mesenchymal transition switch. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4047. doi:10.1158/1538-7445.AM2013-4047

Blood oxygenation level dependent, blood volume, and blood flow responses to carbogen and hypoxic hypoxia in 9L rat gliomas as measured by MRI

To study vascular responsiveness to hypoxia and hypercarbia together with vessel size index (VSI) in a 9L rat glioma (n = 11) using multimodal MRI. VSI was determined using T2 and T2* MRI following AMI-227 contrast agent. Blood oxygenation level dependent (BOLD) signal response was determined using T2 EPI MRI, blood volume changes using AMI-227 and blood flow by means of continuous arterial spin labeling. VSI in the cortex, tumor rim, and core of 2.2 ± 1.0, 18.2 ± 5.4, and 23.9 ± 14.7 μm, respectively, showing a larger average vessel size in glioma than in the brain parenchyma. BOLD and blood volume signal changes to hypoxia and hypercapnia were much more profound in the tumor rim than the core. Hypoxia led to rim BOLD signal change that was larger in amplitude and it attained the low value much faster than either core or brain cortex. The vasculature in the rim appears more responsive to respiratory challenges in terms of volume adaptation than the core. Blood flow values within the gliomas were much lower than in the contralateral brain. Neither hypercarbia nor hypoxia had an effect on the tumor blood flow. Vascular responses of 9L gliomas to respiratory challenge, in particular hypoxia, are heterogeneous between the core and rim zones, potentially offering a means to classify and separate intratumor tissues with differing hemodynamic characteristics.

THE EFFECT OF ADVANCE HYPOXIC TRAINING UPON TISSUE OXYGEN TENSION IN THE TUMOR DURING AQUTE HYPOXIA OF DIFFERENT TYPES

The tumors of rats who had not been acclimated to hypoxia subjected to acute hypoxic hypoxia (altitude chamber) as well as blood hypoxia (carbon monoxide) decreased tissue oxygen tension while histotoxic hypoxia (NaCN) on the contrary increased tissue oxygen tension. The tumor acclimated to hypoxia seems to select compensatory mechanisms mostly associated with increased tissue oxygen tension thus taking advantage of lower extent of tissue oxygen tension when subject to acute hypoxic hypoxia than in femoral muscle. All types of acute hypoxias caused a decrease of tissue oxygen tension in the malignancy.

Hypoxic Hypoxia at Moderate Altitudes: Review of the State of the Science

Unpressurized aircraft routinely operate at altitudes where hypoxia may be of concern. A systematic literature review was conducted regarding hypoxic impairment, including mental functions, sensory deficits, and other pertinent research findings that may affect aviation-related duties at moderate altitude (8000 to 15,000 ft/2438 to 4572 m). The results of this review suggest that cognitive and psychomotor deficits may include learning, reaction time, decision-making, and certain types of memory. However, results are difficult to quantify and reliably reproduce. Inconsistency of results may be related to the subtlety of deficits compared to high altitude, differences among individual compensatory mechanisms, variation in methodology or sensitivity of metrics, presence or absence of exercise, heterogeneous neuronal central nervous system (CNS) response, and interindividual variation. Literature regarding hypoxic visual decrements is more consistent. Rod photoreceptors are more susceptible to hypoxia; visual degradation has been demonstrated at 4000 to 5000 ft (1219 to 1524 m) under scotopic and 10,000 ft (3048 m) under photopic conditions. Augmented night vision goggle resolution demonstrates more resilience to mild hypoxic effects than the unaided eye under starlight conditions. Hypocapnia enhances visual sensitivity and contrast discrimination. Hyperventilation with resulting respiratory alkalosis and cerebral vasoconstriction may confound both cognitive/ psychomotor and visual experimental results. Future research should include augmentation of validated neuropsychological metrics (surrogate investigational end points) with actual flight metrics, investigation of mixed gas formulations, contribution of hypocapnic vasoconstrictive effects on hypoxic performance, and further investigation into cellular- and systems-level approaches for heterogeneous CNS response. Research is also required into the contribution of mild-moderate hypoxia in human factors- and spatial disorientation-related mishaps.

Neurovascular Uncoupling under Mild Hypoxic Hypoxia: An EEG–fMRI Study in Rats

The effects of oxygen availability on neurovascular coupling were investigated using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI), in addition to the monitoring of physiological parameters, in 16 α-chloralose-anesthetized rats. Mild hypoxic hypoxia (oxygen saturation=83.6±12.1%) induced significant reductions in fMRI responses (P<0.05) to electrical stimulation in the forepaw, but EEG responses remained unchanged. In addition, the changes in oxygen saturation were linearly correlated with the changes in the fMRI responses. These data further emphasize the importance of oxygen availability, which may regulate neurovascular coupling via the oxygen-dependent enzymatic synthesis of messenger molecules.

The effects of a short peptide on neurodegenerative processes in rats that are subjected to prenatal hypoxia

We studied the effects of the tripeptide pinealon (Lys-Glu-Arg) on behavior and caspase-3 activity in the brain of 21-day-old rats that were subjected to prenatal hypoxia. We found that administration of pinealon to females during the entire course of pregnancy increased the survival of newborn rat rats that were subjected to prenatal hypoxia. In these rats, at the age of 21 days the activity of caspase-3 in brain structures was significantly lower as compared to rats that were not treated with pinealon during the pregnancy period. This was probably a cause of the less expressed cognitive deficit in these rats. Hypoxic hypoxia during the prefetal or fetal periods had worse effects on cognitive functions and rat survival.

Antihypoxic and Antioxidant Effects of Exogenous Succinic Acid and Aminothiol Succinate-Containing Antihypoxants

Pronounced antihypoxic and antioxidant effects of preventive injection of succinic acid, aminothiol antihypoxants gutimine and amtizol, and succinate-containing aminothiol antihypoxants gutimine succinate and amtizol succinate to Wistar rats with acute hypoxic hypoxia have been demonstrated. Exogenous succinic acid was inferior to aminothiol compounds by antihypoxic effect, but superior to them by its effect on the level of LPO products. Succinate in the aminothiol molecule modulated the intensity of their antihypoxic and antioxidant effects. It did not modulate the antihypoxic activity of amtizol, but reduced the antihypoxic effect of gutimine, presumably because of the physicochemical characteristics of aminothiols. Comparison of the intensities of antihypoxic and antioxidant effects of the studied drugs showed no direct relationship between these effects.

Oxygen transport and mitochondrial function in porcine septic shock, cardiogenic shock, and hypoxaemia

The relevance of tissue oxygenation in the pathogenesis of organ dysfunction during sepsis is controversial. We compared oxygen transport, lactate metabolism, and mitochondrial function in pigs with septic shock, cardiogenic shock, or hypoxic hypoxia. Thirty-two anaesthetized, ventilated pigs were randomized to faecal peritonitis (P), cardiac tamponade (CT), hypoxic hypoxia (HH) or controls. Systemic and regional blood flows, lactate, mitochondrial respiration, and tissue hypoxia-inducible factor 1 alpha (HIF-1α) were measured for 24 h. Mortality was 50% in each intervention group. While systemic oxygen consumption (VO(2) ) was maintained in all groups, hepatic VO(2) tended to decrease in CT [0.84 (0.5-1.3) vs. 0.42 (0.06-0.8)/ml/min/kg; P = 0.06]. In P, fractional hepatic, celiac trunk, and portal vein blood flows, and especially renal blood flow [by 46 (14-91)%; P = 0.001] decreased. In CT, renal blood flow [by 50.4 (23-81)%; P = 0.004] and in HH, superior mesenteric blood flow decreased [by 38.9 (16-100)%, P = 0.009]. Hepatic lactate influx increased > 100% in P and HH, and > 200% in CT (all P < 0.02). Hepatic lactate uptake remained unchanged in P and HH and converted to release in CT. Mitochondrial respiration remained normal. Muscle adenosine triphosphate (ATP) concentrations decreased in P (5.9 ± 1.4 μmol/g wt vs. 2.8 ± 2.7 μmol/g wt, P = 0.04). HIF-1α expression was not detectable in any group. We conclude that despite shock and renal hypoperfusion, tissue hypoxia is not a major pathophysiological issue in early and established faecal peritonitis. The reasons for reduced skeletal muscle tissue ATP levels in the presence of well-preserved in-vitro muscle mitochondrial respiration should be further investigated.