Mitochondrial function and brain Metabolic Score (BMS) in ischemic Stroke: Evaluation of "neuroprotectants" safety and efficacy.

The initial and significant event developed in ischemic stroke is the sudden decrease in blood flow and oxygen supply to brain tissue, leading to dysfunction of the mitochondria. Many attempts were and are being made to develop new drugs and treatments that will save the ischemic brain, but the efficacy is not optimal and in many patients, irreversible damage to the brain will persist. We review a unique approach to evaluate mitochondrial function and microcirculatory hemodynamic in real time in vivo. Three out of four monitored physiological parameters are integrated into a new Brain Metabolic Score (BMS) calculated in real time and is correlated to Brain Oxygen Balance. The technology was adapted to various experimental as well as clinical situations for monitoring the brain in real time. The developed protocols could be used in testing the efficacy and safety of new drugs in experimental animals. Few models of brain monitoring during partial or complete ischemia were developed and used in naive animals or under brain activation protocols. It was found that mitochondrial function/dysfunction is the major and dominant parameter affecting the calculated Brain Metabolic Score. Using our monitoring system and protocols will provide direct information regarding the ability of the tested brain to provide enough oxygen consumed by the mitochondria in the "resting" or in the "activated" brain in vivo and in real-time. Preliminary studies, indicated that testing the efficacy and safety of new neuroprotectant drugs provided significant results to the R&D studies of ischemic stroke related to mitochondrial function.

Real-time hemodynamic response and mitochondrial function changes with intracarotid mannitol injection.

UNLABELLED: Disruption of blood brain barrier (BBB) is used to enhance chemotherapeutic drug delivery. The purpose of this study was to understand the time course of hemodynamic and metabolic response to intraarterial (IA) mannitol infusions in order to optimize the delivery of drugs for treating brain tumors. PRINCIPAL RESULTS: We compared hemodynamic response, EEG changes, and mitochondrial function as judged by relative changes in tissue NADH concentrations, after intracarotid (IC) infusion of equal volumes of normal saline and mannitol in our rabbit IC drug delivery model. We observed significantly greater, though transient, hyperemic response to IC infusion of mannitol compared to normal saline. Infusion of mannitol also resulted in a greater increase in tissue NADH concentrations relative to the baseline. These hemodynamic, and metabolic changes returned to baseline within 5min of mannitol injection. CONCLUSION: Significant, though transient, changes in blood flow and brain metabolism occur with IA mannitol infusion. The observed transient hyperemia would suggest that intravenous (IV) chemotherapy should be administered either just before, or concurrent with IA mannitol injections. On the other hand, IA chemotherapy should be delayed until the peak hyperemic response has subsided.

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.

Shedding light on mitochondrial function by real time monitoring of NADH fluorescence: I. Basic methodology and animal studies.

Normal mitochondrial function in the process of metabolic energy production is a key factor in maintaining cellular activities. Many pathological conditions in animals, as well as in patients, are directly or indirectly related to dysfunction of the mitochondria. Monitoring the mitochondrial activity by measuring the autofluorescence of NADH has been the most practical approach since the 1950s. This review presents the principles and technological aspects, as well as typical results, accumulated in our laboratory since the early 1970s. We were able to apply the fiber-optic-based NADH fluorometry to many organs monitored in vivo under various pathophysiological conditions in animals. These studies were the basis for the development of clinical monitoring devices as presented in accompanying article. The encouraging experimental results in animals stimulated us to apply the same technology in patients after technological adaptations as described in the accompanying article. Our medical device was approved for clinical use by the FDA.

Shedding light on mitochondrial function by real time monitoring of NADH fluorescence: II: human studies.

Monitoring the mitochondrial function, alone or together with microcirculatory blood flow, volume and hemoglobin oxygenation in patients, is very rare. The integrity of microcirculation and mitochondrial activity is a key factor in keeping normal cellular activities. Many pathological conditions in patients are directly or indirectly related to dysfunction of the mitochondria. Evaluation of mitochondrial activity by measuring the autofluorescence of NADH has been the most practical approach since the 1950s. This review, which accompanies part I, presents the principles and technological aspects of various devices used in order to monitor mitochondrial NADH redox state and tissue viability in patients. In part I, the detailed technological aspects of NADH monitoring were described. Typical results accumulated in our studies since the mid-1990s are presented as well. We were able to apply the fiber optic based NADH fluorometry to several organs monitored in vivo in patients under various pathophysiological conditions.

Mitochondrial function and tissue vitality: bench-to-bedside real-time optical monitoring system.

BACKGROUND: The involvement of mitochondria in pathological states, such as neurodegenerative diseases, sepsis, stroke, and cancer, are well documented. Monitoring of nicotinamide adenine dinucleotide (NADH) fluorescence in vivo as an intracellular oxygen indicator was established in 1950 to 1970 by Britton Chance and collaborators. We use a multiparametric monitoring system enabling assessment of tissue vitality. In order to use this technology in clinical practice, the commercial developed device, the CritiView (CRV), is tested in animal models as well as in patients. METHODS AND RESULTS: The new CRV enables the optical monitoring of four different parameters, representing the energy balance of various tissues in vivo. Mitochondrial NADH is measured by surface fluorometry/reflectometry. In addition, tissue microcirculatory blood flow, tissue reflectance and oxygenation are measured as well. The device is tested both in vitro and in vivo in a small animal model and in preliminary clinical trials in patients undergoing vascular or open heart surgery. In patients, the monitoring is started immediately after the insertion of a three-way Foley catheter (urine collection) to the patient and is stopped when the patient is discharged from the operating room. The results show that monitoring the urethral wall vitality provides information in correlation to the surgical procedure performed.

Optically measured NADH concentrations are unaffected by propofol induced EEG silence during transient cerebral hypoperfusion in anesthetized rabbits.

The neuroprotective benefit of intra-operative anesthetics is widely described and routinely aimed to invoke electroencephalographic (EEG) silence in anticipation of transient cerebral ischemia. Previous rat survival studies have questioned an additional benefit from achieving EEG silence during transient global cerebral hypoperfusion. Surgical preparation on twelve New Zealand white rabbits under ketamine-propofol anesthesia, included placement of skull screws for bilateral EEG monitoring, skull shaving for laser Doppler probes, and a 5 mm diameter right temporal craniotomy for the NADH probe. Transient global cerebral hypoperfusion was achieved with bilateral internal carotid artery occlusion and pharmacologically induced systemic hypotension. All animals acted as controls, and had cerebral hypoperfusion under baseline propofol anesthesia with an active EEG. Thereafter, animals were randomized to receive bolus injection of intracarotid (3-5 mg) or intravenous (10-20 mg) 1% propofol to create EEG silence for 1-2 min. The data collected at baseline, peak hypoperfusion, and 5 and 10 min post hypoperfusion was analyzed by repeated measures ANOVA with post hoc Bonferroni-Dunn test. Eleven of the twelve rabbits completed the protocol. Hemodynamics and cerebral blood flow changes were comparable in all the animals. Compared to controls, the increase in NADH during ischemia was unaffected by EEG silence with either intravenous or intraarterial propofol. We failed to observe any significant additional attenuation of the elevation in NADH levels with propofol induced EEG silence during transient global cerebral hypoperfusion. This is consistent with previous rat survival studies showing that EEG silence was not required for full neuroprotective effects of pentothal anesthesia.

Real-time monitoring of spatial and temporal metabolic changes during focal cerebral ischemia in rats.

Focal cerebral ischemia creates a gradual injury, ranging from severe injury in the core towards moderate damage in the penumbra. Disruption of blood supply leads to shortage in oxygen supply, resulting in mitochondrial disruption in the ischemic area. The present work study the mitochondrial function and microcirculatory blood supply in the core and penumbra of the ischemic tissue following different ischemic durations. Focal ischemia was obtained by middle cerebral artery occlusion (MCAO). Monitoring of the brain was conducted using a unique multi-site-multi-parametric (MSMP) monitoring system, which enables real-time, in vivo, simultaneous and continuous monitoring of mitochondrial NADH and CBF. Short sessions of anoxia before ischemia and following reperfusion were used to test the ability of the tissue to respond to such metabolic challenges. Following focal ischemia, CBF levels decreased and NADH levels increased and recovered at reperfusion. These changes were more severe in the core compared to the penumbra. Longer ischemic duration led to an increase in oxygen demand following reperfusion and to vast disruption of blood supply, as seen during short anoxic exposures. In conclusion, the ability of mitochondrial activity and blood supply to recuperate following ischemia, as well as the ability of the tissue to cope with metabolic challenges, varies in the core and the penumbra and depends on ischemic duration. The MSMP monitoring system, used in the current study, can add valuable information regarding the metabolic state of the brain during focal ischemia.

The evaluation of nitric oxide involvement in metrazol induced status epilepticus using multiparametric monitoring.

Nitric oxide (NO) has been implicated in the neuronal hyperexcitability hence its involvement in the pathophysiology of epilepsy is clear. However, some studies indicate that NO has anticonvulsant effects while others present its convulsive effects. In the present study we tested the involvement of NO in pentylenetetrazol (Metrazol) induced Status Epilepticus (SE) rats, using the nonspecific inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME) and the neuronal-specific inhibitor, 7-nitroindazole (7N1). The effects of NOS (NO synthase) inhibitors were tested, within the seizures and between them, using the Multiparametric Assembly (MPA) which continuously monitored Cerebral Blood Flow (CBF) by Laser Doppler flowmetry, mitochondrial NADH redox state by the fluorometric technique, extracellular K(+) and H(+) levels using selective mini-electrodes and electrical activity (DC potential and ECoG) using special electrodes. Between seizures a trend of increase in CBF with oxidation of NADH was seen, with no change in K(+) and H(+) extracellular levels. Pre-treatment with L-NAME prevented this trend of increase in CBF whereas the injection of 7NI even decreased CBF between seizures. Within seizures, CBF increased and mitochondrial NADH was oxidized at the first seizures, while in the last seizure NADH was reduced. The use of NOS inhibitors significantly increased the degree of NADH oxidation at the latest convulsions. In conclusion our results demonstrated beneficial effect of NOS inhibitors on the brain cortex under SE induced by Metrazol, implying that they may serve as anticonvulsant drugs.

Mitochondrial function and cerebral blood flow variable responses to middle cerebral artery occlusion.

Middle cerebral artery occlusion (MCAO), which leads to focal cerebral ischemia, serves as an experimental model for brain stroke. There is a large variation in protocols and techniques using the MCAO model, which may affect the outcomes seen in different studies. The current work presents and compares the diverse responses in mitochondrial NADH and cerebral blood flow (CBF) following focal ischemia induced by the MCAO technique. Ninety-six Wistar rats underwent focal cerebral ischemia by MCAO, and monitored in the core and the penumbra using a unique Multi-Site-Multi-Parametric (MSMP) system, which measures mitochondrial NADH using the fluorometric technique, and CBF using laser Doppler flowmetry (LDF). Following MCAO, 58% of the experiments yielded expected responses, namely a decrease in CBF and an increase in NADH. However, 42% of the experiments showed six other profiles of responses, in which CBF, NADH and tissue reflectance (Ref) responded differently. These profiles included: ischemia without reperfusion, death following reperfusion, minor responses in parameters during ischemia, CBF elevation in the penumbra following MCAO, spontaneous early reperfusion and late reperfusion. These results demonstrate that MCAO is a complex model, which may lead to different responses other than the common expected outcomes, i.e. mitochondrial damage and reduced blood flow in both core and penumbra. The MSMP monitoring system may serve as an important tool in early diagnosis of successful focal cerebral ischemia, reducing the percentage of unsuccessful experiments.

Use of NADH fluorescence to determine mitochondrial function in vivo.

Normal mitochondrial function is a critical factor in maintaining cellular homeostasis in various organs of the body. Due to the involvement of mitochondrial dysfunction in many pathological states, the real-time in vivo monitoring of the mitochondrial metabolic state is crucially important. This type of monitoring in animal models as well as in patients provides real-time data that can help interpret experimental results or optimize patient treatment. In this paper we are summarizing the following items: (1) presenting the solid scientific ground underlying nicotine amide adenine dinucleotide (NADH) NADH fluorescence measurements based on published materials. (2) Presenting NADH fluorescence monitoring and its physiological significance. (3) Providing the reader with basic information on the methodologies of the fluorometers reflectometers. (4) Clarifying various factors affecting the monitored signals, including artifacts. (5) Presenting the potential use of monitoring mitochondrial function in vivo for the evaluation of drug development. The large numbers of publications by different groups testify to the valuable information gathered in various experimental conditions. The monitoring of NADH levels in the tissue provides the most important information on the metabolic state of the mitochondria in terms of energy production and intracellular oxygen levels. Although NADH signals are not calibrated in absolute units, their trend monitoring is important for the interpretation of physiological or pathological situations. To better understand the tissue function, the multiparametric approach has been developed where NADH serves as the key parameter to be monitored.

Mitochondrial function and energy metabolism in cancer cells: past overview and future perspectives.

The involvements of energy metabolism aspects of mitochondrial dysfunction in cancer development, proliferation and possible therapy, have been investigated since Otto Warburg published his hypothesis. The main published material on cancer cell energy metabolism is overviewed and a new unique in vivo experimental approach that may have significant impact in this important field is suggested. The monitoring system provides real time data, reflecting mitochondrial NADH redox state and microcirculation function. This approach of in vivo monitoring of tissue viability could be used to test the efficacy and side effects of new anticancer drugs in animal models. Also, the same technology may enable differentiation between normal and tumor tissues in experimental animals and maybe also in patients.

Nitrite-induced improved blood circulation associated with an increase in a pool of RBC-NO with no bioactivity.

The reduction of nitrite by RBCs producing NO can play a role in regulating vascular tone. This hypothesis was investigated in rats by measuring the effect of nitrite infusion on mean arterial blood pressure (MAP), cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in conjunction with the accumulation of RBC-NO. The nitrite infusion reversed the increase in MAP and decrease in CBF produced by L-NAME inhibition of e-NOS. At the same time there was a dramatic increase in RBC-NO. Correlations of RBC-NO for individual rats support a role for the regulation of vascular tone by this pool of NO. Furthermore, data obtained prior to treatment with L-NAME or nitrite are consistent with a contribution of RBC reduced nitrite in regulating vascular tone even under normal conditions. The role of the RBC in delivering NO to the vasculature was explained by the accumulation of a pool of bioactive NO in the RBC when nitrite is reduced by deoxygenated hemoglobin chains. A comparison of R and T state hemoglobin demonstrated a potential mechanism for the release of this NO in the T-state present at reduced oxygen pressures when blood enters the microcirculation. Coupled with enhanced hemoglobin binding to the membrane under these conditions the NO can be released to the vasculature.

Effects of anesthesia on brain mitochondrial function, blood flow, ionic and electrical activity monitored in vivo.

Thiopental, a well-known barbiturate, is often used in patients who are at high risk of developing cerebral ischemia, especially during brain surgery. Although barbiturates are known to affect a variety of processes in the cerebral cortex, including oxygen consumption by the mitochondria, the interrelation between mitochondrial function and anesthetics has not been investigated in detail under in vivo conditions. The aim of this study was to examine the effects of thiopental on brain functions in normoxia and under partial or complete ischemia. The use of the multiparametric monitoring system permitted simultaneous measurements of microcirculatory blood flow, NADH fluorescence, tissue reflectance, and ionic and electrical activities of the cerebral cortex. Thiopental caused a significant, dose-dependent decrease in blood flow and a significant decrease in extracellular levels of potassium, with no significant changes in NADH levels in normoxic and ischemic rats. Following complete ischemia (death), the increase in the reflectance was significantly smaller in the anesthetized normoxic group versus the awake normoxic group. The time until the secondary increase in reflectance, seen in death, was significantly shorter in the anesthetized ischemic group. In conclusion, it seems that the protective effect of thiopental occurs only under partial ischemia and not under complete ischemia.

Brain oxygen balance under various experimental pathophysiologycal conditions.

Normally, brain tissue copes with negative oxygen balance by increasing cerebral blood flow (CBF). We examined the effects of increasing oxygen demand, by inducing spreading depression (SD) under various oxygen balance states, on brain O2 balance. The Tissue Vitality Monitoring System was used, which enables real time simultaneous in vivo monitoring of CBF, mitochondrial NADH and tissue HbO2 from the same region of the cerebral cortex. SD was induced during normoxia, hypoxia, hyperoxia, ischemia, and in normal and ischemic brain after systemic epinephrine administration. Under normoxia, hyperoxia and ischemia & epinephrine, the compensation of energy demand induced by SD, was carried out by increasing CBF. The higher oxygen delivery under hyperoxia and epinephrine did not change the pattern of recovery from SD as compared to normoxia, whereas in the ischemic and hypoxic brain, the recovery from SD was prolonged, indicating a lake in oxygen delivery. Epinephrine infusion in the ischemic rat, decreased oxyhemoglobin utilization during SD, indicating that tissue oxygen balance improves even under higher oxygen demand induced by SD.

Renal viability evaluated by the multiprobe assembly: a unique tool for the assessment of renal ischemic injury.

BACKGROUND: One of the major causes of transplanted organs' dysfunction is ischemia-reperfusion injury, where mitochondrial dysfunction is the primary contributor to cell damage. Mitochondrial NADH fluorescence reliably describes intracellular oxygen deficiency and mitochondrial function. Therefore, its monitoring at the tissue level, together with other physiological parameters, can serve to evaluate tissue vitality. METHODS: The multiprobe assembly (MPA) enabled the assessment of renal blood flow (RBF) using laser Doppler flowmetry, mitochondrial NADH redox state using the fluorometric technique, and ionic homeostasis using specific mini-electrodes (K(+) and H(+)). The MPA was utilized in two rat groups in which ischemia was induced for a period of 25-30 min (group 1) or for 60 min (group 2), and RBF and NADH were also monitored in a group of rats that underwent a complete kidney ischemia 24 h before the monitoring - a well-known model of acute renal failure. RESULTS: During ischemia, the RBF was completely abolished, NADH and extracellular potassium levels increased, and extracellular pH decreased. Immediately after the reperfusion, full recovery was observed; however, in the rats undergoing 60-min ischemia followed by 24-hour reperfusion, the tissue hemodynamic and mitochondrial functions were significantly impaired. CONCLUSION: This study demonstrates the advantage of using the MPA for real-time evaluation of kidney physiological state, which may serve as a practical instrument for the evaluation of graft viability during transplantation procedures.

Real-time monitoring of mitochondrial NADH and microcirculatory blood flow in the spinal cord.

STUDY DESIGN: We developed a real-time, in vivo monitoring system for the evaluation of spinal cord viability in rats during spinal cord ischemia. OBJECTIVE: The aim of the present study was to apply a real-time multiparametric monitoring system in a rat spinal cord model exposed to ischemia or mechanical compression. SUMMARY OF BACKGROUND DATA: The evaluation of spinal cord integrity during spine surgeries is highly important, as it enhances the potential to prevent secondary irreversible damage to the spinal cord tissue. Mitochondrial NADH redox state is the most sensitive parameter for tissue oxygenation state and, together with microcirculatory blood flow, can estimate the metabolic status of the spinal cord tissue. METHODS: We applied the Tissue Vitality Monitoring System (TVMS) that includes optical fibers for the simultaneous monitoring of the spinal cord blood flow (SCBF) using laser Doppler flowmetry, and the mitochondrial NADH fluorescence using the fluorometric technique. Additionally, systemic arterial blood pressure was measured. Two models involving the interruption of the spinal blood flow were tested: the occlusion of the abdominal aorta (ischemia) and spine mechanical compression. RESULTS: The results clearly demonstrated the link between the level of ischemia and the viability state of the spinal tissue. When SCBF decreased, in both experimental models, mitochondrial NADH was elevated, while reperfusion was associated with NADH oxidation. Nevertheless, during the recovery phase, even though SCBF significantly increased (became hyperemic), no further oxidation of NADH was observed. CONCLUSION: The monitoring of the mitochondrial function together with SCBF by the TVMS reflects the viability of the spinal cord tissue and, together with the conventional monitoring techniques, may help to evaluate the spine conditions, especially under surgical procedures involving the deterioration of the spinal cord blood supply.

Real-time multi-site multi-parametric monitoring of rat brain subjected to traumatic brain injury.

INTRODUCTION: Traumatic brain injury (TBI) is one of the major causes of death in the world, with at least ten million serious traumatic brain injuries occurring annually; nevertheless, the pathophysiologic events taking place immediately after the injury are not yet fully known. OBJECTIVE: To study the effects of TBI on brain hemodynamic, metabolic and ionic homeostasis using the multi-parametric monitoring system. This system enables real-time monitoring of cerebral blood flow (CBF), mitochondrial NADH redox state, extracellular levels of K+, H+, DC potential, ECoG and ICP. METHODS: In order to find the best brain location for the monitoring device in relation to the fluid percussion injury site, we used the multi-site multi-parametric monitoring system. Two groups of rats were connected to four monitoring probes at four different locations near the injury site, two in each hemisphere. We monitored CBF, NADH redox state, tissue reflectance and DC steady potential in each of the four sites. RESULTS: Under anoxia, the initial CBF decrease was followed by an increase, NADH level increased, the reflectance decreased and dc potential showed a biphasic response, in all 4 locations. However, following fluid percussion injury, there was a significant variability in the responses in each of the 4 monitored locations. CONCLUSION: The advantage of the multi-parametric-monitoring approach for enhanced understanding of the injured brain was indicated. Moreover, we showed that contralateral monitoring of the injured brain gives good indication for the events taking place following fluid percussion brain injury.

Minimally invasive real time monitoring of mitochondrial NADH and tissue blood flow in the urethral wall during hemorrhage and resuscitation.

BACKGROUND: The ideal endpoint of resuscitation after severe hemorrhage should indicate not only that optimal oxygen delivery has been achieved, but also that oxygen utilization has been restored. A modified Foley catheter for simultaneous assessment of microcirculatory blood flow (TBF) and mitochondrial NADH in the urethral wall was used in the female swine. We hypothesized that changes in mitochondrial NADH and TBF are associated with impaired energy metabolism in the urethra and that these changes correlate with impaired tissue perfusion in the bladder during shock and resuscitation. MATERIAL/METHODS: Female swine n=5 underwent laparotomy. TBF was measured by a laser Doppler flowmeter. Mitochondrial function was evaluated by measuring NADH fluorescence in vivo. Multiparameter sensors (pH, pCO2 and pO2) were placed in the bladder mucosa (BM), and in the skeletal muscle (Sk). Animals underwent hemorrhage and their MAP was maintained at 40 mm Hg by appropriate infusing or withdrawing of blood for 10 min. Animals were resuscitated and observed for 20 min. RESULTS: Urethral NADH increased during shock and recovered during resuscitation, while TBF showed an opposite effect (r(2)=0.74). Skeletal muscle and bladder pO2 decreased during shock (p<0.01) and recovered after resuscitation. NADH increased significantly (p<0.05) during shock and decreased after resuscitation. CONCLUSIONS: Changes in TBF and NADH in the urethral mucosa represent novel markers for the energetic state of the tissue. They could be measured in vivo by a minimally invasive approach and thus could provide important information on the end-points of resuscitation in hemorrhagic shock.

Can the "brain-sparing effect" be detected in a small-animal model?

BACKGROUND: Under O(2) imbalance in the body, blood redistribution occurs between more vital organs and less vital organs. This response is defined as the "brain-sparing effect". The study's aim was to develop a new rat model for simultaneous real-time monitoring of tissue viability in a highly vital organ, the brain, and a less vital organ, the small intestine, under various metabolic perturbations and emergency-like situations. MATERIAL/METHODS: The cerebral cortex and intestinal serosa were exposed in anesthetized rats and a multi-site multi-parametric (MSMP) monitoring system was connected to both. Tissue blood flow (TBF) was monitored using laser Doppler flowmetry and mitochondrial function by NADH fluorometry. The perturbations performed were anoxia (30 sec) and 20 minutes of hypoxia, hypercapnia, or hyperoxia. RESULTS: Under oxygen deficiency, cerebral blood flow (CBF) increased (315+/-53% in anoxia and 140+/-12% in hypoxia), whereas intestinal blood flow decreased (60+/-11% in anoxia and 56+/-13% in hypoxia). Mitochondrial NADH significantly increased in both organs (119+/-2.8% and 151+/-14% in the brain and intestine, respectively). Under hyperoxia, NADH was oxidized in both organs (up to 9% change). Hypercapnia led to an increase in CBF (143+/-11%) and oxidation of mitochondrial NADH (by 10%), with no significant changes in the intestine. CONCLUSIONS: The two organs respond significantly differently to lack of O(2) by activating the sympathetic nervous system. Monitoring less vital organs may indicate an early response to emergency situations. Therefore, a less vital organ could be used as a surrogate organ to be monitored in order to spare the brain.