Tissue Dysoxia Research Articles

Microcirculation-guided resuscitation in sepsis: the next frontier?

Microcirculatory dysfunction plays a key role in the pathogenesis of tissue dysoxia and organ failure in sepsis. Sublingual videomicroscopy techniques enable the real-time non-invasive assessment of microvascular blood flow. Alterations in sublingual microvascular perfusion were detected during sepsis and are associated with poor outcome. More importantly, sublingual videomicroscopy allowed to explore the effects of commonly applied resuscitative treatments in septic shock, such as fluids, vasopressors and inotropes, and showed that the optimization of macro-hemodynamic parameters may not be accompanied by an improvement in microvascular perfusion. This loss of "hemodynamic coherence," i.e., the concordance between the response of the macrocirculation and the microcirculation, advocates for the integration of microvascular monitoring in the management of septic patients. Nonetheless, important barriers remain for a widespread use of sublingual videomicroscopy in the clinical practice. In this review, we discuss the actual limitations of this technique and future developments that may allow an easier and faster evaluation of the microcirculation at the bedside, and propose a role for sublingual microvascular monitoring in guiding and titrating resuscitative therapies in sepsis.

New study gives F to vitamin C treatment in septic ICU patients

New study gives F to vitamin C treatment in septic ICU patients

ArhGEF12 activates Rap1A and not RhoA in human dermal microvascular endothelial cells to reduce tumor necrosis factor-induced leak.

Overwhelming inflammation in the setting of acute critical illness induces capillary leak resulting in hypovolemia, edema, tissue dysoxia, organ failure and even death. The tight junction (TJ)-dependent capillary barrier is regulated by small GTPases, but the specific regulatory molecules most active in this vascular segment under such circumstances are not well described. We set out to identify GTPase regulatory molecules specific to endothelial cells (EC) that form TJs. Transcriptional profiling of confluent monolayers of TJ-forming human dermal microvascular ECs (HDMECs) and adherens junction only forming-human umbilical vein EC (HUVECs) demonstrate ARHGEF12 is basally expressed at higher levels and is only downregulated in HDMECs by junction-disrupting tumor necrosis factor (TNF). HDMECs depleted of ArhGEF12 by siRNA demonstrate a significantly exacerbated TNF-induced decrease in trans-endothelial electrical resistance and disruption of TJ continuous staining. ArhGEF12 is established as a RhoA-GEF in HUVECs and its knock down would be expected to reduce RhoA activity and barrier disruption. Pulldown of active GEFs from HDMECs depleted of ArhGEF12 and treated with TNF show decreased GTP-bound Rap1A after four hours but increased GTP-bound RhoA after 12h. In cell-free assays, ArhGEF12 immunoprecipitated from HDMECs is able to activate both Rap1A and RhoA, but not act on Rap2A-C, RhoB-C, or even Rap1B which shares 95% sequence identity with Rap1A. We conclude that in TJ-forming HDMECs, ArhGEF12selectively activates Rap1A to limit capillary barrier disruption in a mechanism independent of cAMP-mediated Epac1 activation.

Anemia in septic shock: which transfusion thresholds?

Anemia is a frequent condition in intensive care units (ICU), most especially in septic patients. The hemoglobin level is a major determinant of oxygen transport. Red blood cell transfusion represents the main therapeutic of anemia in the ICU, and the only one able to rapidly increase the hemoglobin level in critical care. Overall, about half of septic patients will require red blood cell transfusion in the ICU and after discharge. Interventional randomized studies have demonstrated the safety and possibly a benefit of restrictive transfusion strategies in the ICU. Hence national and international guidelines consistently recommend such restrictive transfusion strategy by using a hemoglobin transfusion threshold of 7 g/dL to maintain a hemoglobin level between 7 and 9 g/dL in critically ill patients including septic patients. However, septic shock exhibits several features likely to modulate the transfusion indications, including the high prevalence of cardiovascular and onco-hematological comorbid conditions, as well as the defining tissue dysoxia. Transfusion indications in septic shock should certainly be based on the current guidelines, but most importantly should urge a personalized decision-making process taking into account an individual assessment of expected benefits and risks of transfusion.

Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65): protocol and statistical analysis plan for a randomised clinical trial

IntroductionVasodilatory hypotension is common among intensive care unit (ICU) patients; vasopressors are considered standard of care. However, optimal mean arterial pressure (MAP) targets for vasopressor titration are unknown. The objective...

Continuous cardiac output assessment or serial echocardiography during septic shock resuscitation?

Septic shock is the leading cause of cardiovascular failure in the intensive care unit (ICU). Cardiac output is a primary component of global oxygen delivery to organs and a sensitive parameter of cardiovascular failure. Any mismatch between oxygen delivery and rapidly varying metabolic demand may result in tissue dysoxia, hence organ dysfunction. Since the intricate alterations of both vascular and cardiac function may rapidly and widely change over time, cardiac output should be measured repeatedly to characterize the type of shock, select the appropriate therapeutic intervention, and evaluate patient’s response to therapy. Among the numerous techniques commercially available for measuring cardiac output, transpulmonary thermodilution (TPT) provides a continuous monitoring with external calibration capability, whereas critical care echocardiography (CCE) offers serial hemodynamic assessments. CCE allows early identification of potential sources of inaccuracy of TPT, including right ventricular failure, severe tricuspid or left-sided regurgitations, intracardiac shunt, very low flow states, or dynamic left ventricular outflow tract obstruction. In addition, CCE has the unique advantage of depicting the distinct components generating left ventricular stroke volume (large cavity size vs. preserved contractility), providing information on left ventricular diastolic properties and filling pressures, and assessing pulmonary artery pressure. Since inotropes may have deleterious effects if misused, their initiation should be based on the documentation of a cardiac dysfunction at the origin of the low flow state by CCE. Experts widely advocate using CCE as a first-line modality to initially evaluate the hemodynamic profile associated with shock, as opposed to more invasive techniques. Repeated assessments of both the efficacy (amplitude of the positive response) and tolerance (absence of side-effect) of therapeutic interventions are required to best guide patient management. Overall, TPT allowing continuous tracking of cardiac output variations and CCE appear complementary rather than mutually exclusive in patients with septic shock who require advanced hemodynamic monitoring.

Central venous-to-arterial PCO2 difference, arteriovenous oxygen content and outcome after adult cardiac surgery with cardiopulmonary bypass: A prospective observational study.

Rapid identification and treatment of tissue hypoxia reaching anaerobiosis (dysoxia) may reduce organ failure and the occurrence of major postoperative complications (MPC) after cardiac surgery. The predictive ability of PCO2-based dysoxia biomarkers, central venous-to-arterial PCO2 difference (ΔPCO2) and ΔPCO2 to arteriovenous oxygen content difference ratio, is poorly studied in this setting. We evaluated the ability of PCO2-based tissue dysoxia biomarkers, blood lactate concentration and central venous oxygen saturation measured 2 h after admission to the ICU as predictors of MPC. A prospective, observational cohort study. Single-centre, academic hospital cardiovascular ICU. We included adult patients undergoing cardiac surgery with cardiopulmonary bypass and measured dysoxia biomarkers at ICU admission, and after 2, 6 and 24 h. The primary endpoint was MPC, a composite of cardiac and noncardiac MPC evaluated in the 48 h following surgery. After univariate analysis of MPC covariates including dysoxia biomarkers measured at 2 h, multivariate logistic regression analyses were performed to identify the association of these biomarkers with MPC for confounders. Areas under the receiver operating characteristic curves were determined for biomarkers which remained independently associated with MPC. MPC occurred in 56.5% of the 308 patients analysed. ΔPCO2, blood lactate concentration and central venous oxygen saturation measured at 2 h, but not ΔPCO2 to arteriovenous oxygen content difference ratio, were significantly associated with MPC. However, only ΔPCO2 was independently associated with MPC after multivariate analysis. The areas under the receiver operating characteristic curves of ΔPCO2 measured at 2 h for MPC prediction was 0.64 (95% CI 0.57 to 0.70, P < 0.001). After cardiac surgery with cardiopulmonary bypass, ΔPCO2 measured 2 h after ICU admission was the only dysoxia biomarker independently associated with MPC, but with limited performance. ClinicalTrials.gov, NCT03107572.

Severity of Symptoms of Systemic Inflammatory Response Syndrome and Congestive Heart Failure Caused by Chronic Aortic Stenosis and Its Pharmacological Correction

Systemic inflammatory response syndrome (SIRS) is one of the key accompanied states that worsens severity of congestive heart failure (CHF) and leads refractory CHF to conventional therapy. We investigated whether the cessation of the symptoms and signs of SIRS prevents the progression of the CHF caused by chronic aortic stenosis in rabbits. 8 weeks after induced CHF by left descending coronary artery stenosis, all animals were randomly assigned into 3 groups: control (CG)—without therapy (infusion of 0.9% NaCl); main I— receive mg/kg of Adenocin® dissolved in water for injection i.v., once daily and main II—animals receive 0.25 mg/kg enalapril i.m, furosemide 1.0 mg/kg i.v. (bolus) and pimobendan 0.1 mg/kg i.v. once daily. All animals were euthanized after 14 days of the beginning of treatment. Long-term aortic stenosis leads to a simultaneously developing of CHF, diagnosed by developing cardiac hypertrophy, increased level of BNP and myocardial oedema and SIRS, confirmed by increasing markers and symptoms of endotoxemia, tissue dysoxia and decreasing reserve ability of intrinsic defense systems. Restoration of myocardium redox-potential and level of NAD under treatment with Adenocin® leads unlike combined treatment with enalapril, furosemide and pimobendan to restoration, the regulatory pathways of TNF-α synthesis, cessation of the hypoxic/ischemic, lysosomal dysfunction and free radical-induced damage in myocardium and symptoms of CHF. Potential important link between cellular metabolism (hypoxia/ischemia), endotoxemia and disturbances in intrinsic defense system is the level of redox-potentail, NAD/NADH in myocardium. Influence of oxidized form of NAD-containing positive inotropic drug Adenocin® leads to the decreasing symptoms of CHF and beneficial action occurs on all the key links of SIRS.

Lactate, a useful marker for disease mortality and severity but an unreliable marker of tissue hypoxia/hypoperfusion in critically ill patients.

Early aggressive hemodynamic resuscitation using elevated plasma lactate as a marker is an essential component of managing critically ill patients. Therefore, measurement of blood lactate is recommended to stratify patients based on the need for fluid resuscitation and the risks of multiple organ dysfunction syndrome and death. Hyperlactatemia is common among critically ill patients, and lactate levels and their trend may be reliable markers of illness severity and mortality. Although hyperlactatemia has been widely recognized as a marker of tissue hypoxia/hypoperfusion, it can also result from increased or accelerated aerobic glycolysis during the stress response. Additionally, lactate may represent an important energy source for patients in critical condition. Despite its inherent complexity, the current simplified view of hyperlactatemia is that it reflects the presence of global tissue hypoxia/hypoperfusion with anaerobic glycolysis. This review of hyperlactatemia in critically ill patients focuses on its pathophysiological aspects and recent clinical approaches. Hyperlactatemia in critically ill patients must be considered to be related to tissue hypoxia/hypoperfusion. Therefore, appropriate hemodynamic resuscitation is required to correct the pathological condition immediately. However, hyperlactatemia can also result from aerobic glycolysis, unrelated to tissue dysoxia, which is unlikely to respond to increases in systemic oxygen delivery. Because hyperlactatemia may be simultaneously related to, and unrelated to, tissue hypoxia, physicians should recognize that resuscitation to normalize plasma lactate levels could be over-resuscitation and may worsen the physiological status. Lactate is a reliable indicator of sepsis severity and a marker of resuscitation; however, it is an unreliable marker of tissue hypoxia/hypoperfusion.

0347: Beneficial cardiovascular effects of O-GlcNAc stimulation in early phase of septic shock

O-GlcNAcylation, a post-translational modification, is the end product of the hexosamine biosynthetic pathway (HBP). Recent studies showed beneficial effects of its increase in acute pathologies, such as hemorrhagic shock. We postulated that increase in total protein OGlcNAcylation at the early phase of septic shock, a systemic inflammation associated with a cardiovascular dysfunction, could improve cardiovascular function and reduce mortality. To induce an endotoxemic shock, rats (n=6-8) received iv either lipopolysaccharide (LPS, 5mg/kg) or saline (CTRL). After 1 h, fluid resuscitation (FR,15mL/kg of colloid, iv) was associated or not with HBP substrate: glucosamine (GlcN, 180mg/kg) or an O-GlcNAcase inhibitor (NButGT, 10mg/kg). Two hours later, echography and mean arterial pressure (MAP) evaluation were performed; blood samples and heart were then collected to evaluate biological parameters (lactate, troponin T) and total O-GlcNAcylation by western-blot. In vivo studies showed an hypotension in LPS restored by FR and treatments (MAP: CTRL 87±1, LPS 73±5*, LPS-FR 93±6#, NButGT 83±5, GlcN 92±4mmHg, *: p<0.01 vs CTRL, #: p<0.01 vs LPS) and a systolic dys-function in LPS with a trend toward an improvement by NButGT and GlcN (ejection fraction: CTRL 80±3, LPS 66±3*, LPS-FR 69±2, NButGT 74±2, GlcN 75±2%, *: p<0.01 vs CTRL). NButGT and GlcN efficiently increased total O-GlcNAc (200 and 300% respectively vs LPS-FR). This effect was associated with a reduced cardiomyocyte insult and tissue dysoxia. At the early phase of septic shock NButGT and GlcN induce an increase in cardiac O-GlcNAcylation leading to improve tissue oxygenation and to reduce cardiac injury. These treatments trend to increase the cardiovascular function. Yet, coming studies will evaluate the effect of NButGT and GlcN on mortality.

Effets des vasoconstricteurs sur la microcirculation

Physiology and animal models often predict microvascular negative effects of excessive vasoconstriction. The following are among them: a drop in capillary pressure (even closure of capillaries), a drop in microvascular haematocrit, a possible drop in flow, a possible decrease in capillary density. In fact, the impact of usual vasoconstrictors is difficult to predict, e.g. norepinephrine is an alpha agonist, which simultaneously increases arteriolar but also venular resistances together with a possible increase in cardiac output by beta stimulation or thanks to preload effect. Concerning norepinephrine and probably terlipressin, the effects on splanchnic, renal and most often sublingual microcirculation are globally either positive or neutral if a deep hypovolemia is treated before perfusion of the drug and if mean arterial pressure goal is below 75 mmHg. Phenylephrine seems deleterious and difficult to use. Vasopressin requires more studies concerning microcirculation. Careful titration and even decrementation of the drugs in case of tissue dysoxia (mottling of the skin, the increase of lactate levels) seems to be common sense.

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

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

Towards integrative physiological monitoring of the critically ill: from cardiovascular to microcirculatory and cellular function monitoring at the bedside

Current hemodynamic monitoring of critically ill patients is mainly focused on monitoring of pressure-derived hemodynamic variables related to systemic circulation. Increasingly, oxygen transport pathways and indicators of the presence of tissue dysoxia are now being considered. In addition to the microcirculatory parameters related to oxygen transport to the tissues, it is becoming increasingly clear that it is also important to gather information regarding the functional activity of cellular and even subcellular structures to gain an integrative evaluation of the severity of disease and the response to therapy. Crucial to these developments is the need to provide continuous measurements of the physiological and pathophysiological state of the patient, in contrast to the intermittent sampling of biomarkers. As technological research and clinical investigations into the monitoring of critically ill patients have progressed, an increasing amount of information is being made available to the clinician at the bedside. This complexity of information requires integration of the variables being monitored, which requires mathematical models based on physiology to reduce the complexity of the information and provide the clinician with a road map to guide therapy and assess the course of recovery. In this paper, we review the state of the art of these developments and speculate on the future, in which we predict a physiological monitoring environment that is able to integrate systemic hemodynamic and oxygen-derived variables with variables that assess the peripheral circulation and microcirculation, extending this real-time monitoring to the functional activity of cells and their constituents. Such a monitoring environment will ideally relate these variables to the functional state of various organ systems because organ function represents the true endpoint for therapeutic support of the critically ill patient.

Microdialysis detection of lactate in subcutaneous tissue as a reliable indicator of tissue metabolic disorders in an animal sepsis model

Tissue dysoxia is thought to be a fundamental cause of the organ failure that occurs as a result of shock. Plasma lactate has been frequently measured as an indicator of the state of systemic tissue metabolism. On the other hand, tissue lactate levels can directly indicate a disorder in the state of cytological tissue metabolism. The continuous monitoring of lactate levels in subcutaneous tissue will reflect the state of tissue dysoxia more precisely than levels of lactate in the plasma lactate. We have investigated the differences in the levels of plasma and tissue lactate using a microdialysis (MD) technique in an animal septic shock model. Male 8-week-old Wistar/ST rats were used. We prepared an animal model by injection of lipopolysaccharide (LPS) into the abdominal cavity. LPS was given to 9 animals in the experimental group while physiological saline was given to 6 animals in the control group. A MD probe was used to quantify the lactate levels in the subcutaneous tissue. The mean arterial pressure, blood gas content and lactate levels were measured every 50 min up to 400 min after injection and compared between both groups. The MAP of both groups showed similar changes after injection. Plasma lactate levels in the LPS group showed a significant increase after 100 min and reached a plateau from 150 min to 250 min. Subcutaneous lactate in the LPS group showed a significant increase after 150 min. Subcutaneous pyruvate in the LPS group showed a significant increase after 100 min. The lactate/pyruvate (L/P) ratio in the subcutaneous tissue showed a sustained increase from 300 min in the LPS group. Monitoring plasma lactate levels is useful for the early assessment of anaerobic metabolism before hypotension. Plasma lactate levels did not increase during some periods. This phenomenon was due to the balance between production and utilization. However, tissue lactate showed a chronological increase. These results suggest that the measurement of tissue lactate levels is reliable for assessing local energy metabolic disturbances. Under conditions of septic shock, an increase in lactate levels was found to be a sensitive marker of tissue metabolism disorder.

SvO2 to monitor resuscitation of septic patients: let's just understand the basic physiology

Real-time monitoring of mixed venous oxygen blood saturation (SvO2) or of central venous oxygen blood saturation is often used during resuscitation of septic shock. However, the meaning of these parameters is far from straightforward. In the present commentary, we emphasize that SvO2 - a global marker of tissue oxygen balance - can never be simplistically used as a marker of preload responsiveness, which is an intrinsic marker of cardiac performance. In some septic shock patients, because of profound hypovolemia or myocardial dysfunction, SvO2 can be low but obviously cannot alone indicate whether a fluid challenge would increase cardiac output. In other patients, because of a profound impairment of oxygen extraction capacities, SvO2 can be abnormally high even in patients who are still able to respond positively to fluid infusion. In any case, other reliable dynamic parameters can help to address the important question of fluid responsiveness/unresponsiveness. However, whether fluid administration in fluid responders and high SvO2 would be efficacious to reduce tissue dysoxia in the most injured tissues is still uncertain.

The Effect of Erythropoietin on Microcirculation Perfusion and Tissue Bioenergetics of the Small Intestine in a Hemorrhagic Shock and Resuscitation Rat Model

Erythropoietin (EPO) can exert acute hemodynamic and anti-inflammatory effects in addition to erythropoiesis. We tested the hypothesis that EPO given at resuscitation with saline will improve capillary perfusion and tissue oxygenation in the gut using a hemorrhagic shock model. Sprague-Dawley rats were bled 30 mL/kg to maintain a mean arterial blood pressure of 40 mm Hg for 50 minutes and then randomized to one of four resuscitation groups (n = 6 per group): blood, blood + recombinant human EPO (rHuEPO), saline, and saline + rHuEPO. Intravenous rHuEPO (1,000 U/kg) was given at the start of resuscitation. Intravital microscopy was used to measure perfused capillary density, flow motion of red blood cell (RBC), and tissue NADH fluorescence 60 minutes after resuscitation. Venous oxygenation saturation (Svo2) was also measured in a second experiment. In the blood +/- rHuEPO resuscitation group, the perfused capillary density, RBC flow motion scores, and NADH fluorescence returned to near normal values. The saline + rHuEPO group compared with the saline group demonstrated an increased RBC flow motion score (2.32 vs. 1.60; p < 0.01); however, the perfused capillary density was not significantly increased (23.03 Cap/mm vs. 21.61 Cap/mm; p = 0.40). The saline + rHuEPO group also demonstrated statistically significant lower NADH fluorescence than the saline group after shock following resuscitation (110% +/- 3.64% vs. 122% +/- 4.26%; p < 0.05) suggesting decreased tissue dysoxia. The Svo2 in the saline + rHuEPO group was higher when compared with the saline group (45% vs. 38% by continuous oximetry; 38% vs. 29% by co-oximetry; p < 0.05). Our results suggest that the addition of rHuEPO at the time of saline resuscitation may have beneficial effects in hemorrhagic shock by improving tissue perfusion and decreasing dysoxia in the gut.

Venous-arterial PCO2 difference as an early predictor of organ dysfunction in the ICU

The early identification and scrupulous monitoring of tissue dysoxia can improve the management of critical patient. In this light, the final product of aerobe and anaerobe metabolism (that is, carbon dioxide) can provide useful information on adequacy of tissue perfusion and metabolism [1,2]. The aim of our study was to evaluate whether the venous-arterial PCO2 gradient provides useful information on tissue dysfunction in patients admitted to the ICU.

Effects of various concentrations of inhaled oxygen on tissue dysoxia, oxidative stress, and survival in a rat hemorrhagic shock model

Objective To test the hypothesis that a fractional inspired oxygen (F IO 2) of 1.0 compared to 0.4 during hemorrhagic shock (HS) and fluid resuscitation (FR): mitigates tissue dysoxia; however, enhances the oxidative stress; therefore, offsets the benefit on survival. Methods Thirty rats underwent: HS for 75 min, during which 3.0 mL/100 g of blood was withdrawn, followed by FR for 75 min, during which 1.0 mL/100 g of shed blood and 3.0 mL/100 g of crystalloid solution were infused. Ten rats were randomized into one of three F IO 2 (0.21 vs. 0.4 vs. 1.0) groups, and observed for survival until 72 h in each group. Hemodynamics, liver tissue PO 2 (P TO 2), and, plasma antioxidants levels were also monitored. Results Oxygen inhalation increased mean arterial pressure (MAP) and decreased heart rate (HR) during HS and FR. Liver P TO 2 was less than 10 Torr in all groups throughout HS; while it increased to average 26–35 Torr in oxygen groups during FR, it remained at 10 Torr with F IO 2 0.21 ( P < 0.01). MAP, HR, and P TO 2 did not differ significantly between oxygen groups. Plasma antioxidants levels did not differ among the three groups. All rats treated with oxygen, but eight of 10 rats with F IO 2 0.21 survived up to 72 h (NS). Conclusions Supplemental oxygen does not mitigate tissue dysoxia during HS, but does reduce tissue dysoxia without enhancing oxidative stress during subsequent FR. Increased F IO 2 appears to prolong survival. These beneficial effects of supplemental oxygen do not differ between an F IO 2 of 0.4 and 1.0.

Mechanisms of tissue hypercarbia in sepsis

Intramucosal acidosis, that it is to say, an increased intramucosal-arterial PCO2 difference, is a common finding in clinical and experimental sepsis. Nevertheless, the physiologic significance of increases in tissue PCO2 is controversial, since CO2 can be generated by both aerobic and anaerobic biochemical processes. PCO2 can rise after buffering of protons produced in the hydrolysis of high-energy phosphate compounds by bicarbonate, or after the anaerobic production of acids, like lactate. In this case, it could represent tissue dysoxia. Alternatively, an increase in tissue PCO2 could denote hypoperfusion and diminished removal of the CO2 produced during the oxidation of pyruvate. In this last situation, aerobic metabolism might be preserved. In the present review, we discuss the physiologic mechanisms that determine tissue and venous hypercarbia during the three classic forms of hypoxia: stagnant, hypoxic and anemic hypoxia. The results of experimental studies suggest that tissue minus arterial and venoarterial PCO2 gradients primarily reflect alterations in tissue perfusion. These conclusions are further confirmed by a mathematical model of CO2 transport. In sepsis, however, tissue hypercarbia might develop despite normal or high cardiac output. This phenomenon has been initially interpreted as secondary to alterations in energetic metabolism, the so-called cytopathic hypoxia. Yet, new evidences show that the underlying mechanism to tissue hypercarbia in sepsis might be due to severe microcirculatory derangements. In summary, experimental results support the hypothesis that increases in tissue and venous CO2 are insensitive markers of tissue dysoxia, and merely reflect vascular hypoperfusion.

Changes in oxyhemoglobin dissociation curve in intrabdominal organs during pig experimental orthotopic liver transplantation

Liver transplantation has become a gold standard treatment for irreversible liver disease. Conventional measures of oxygenation are inadequate to understand the dynamics of regional oxygen metabolism during liver transplantation because they represent global markers of tissue dysoxia. Therefore, the addition of an assessment of the hemoglobin O(2) binding capacity can give a better insight into systemic and regional tissue oxygenation and can reflect a more accurate estimation of oxygen release to the tissues than can the hemoglobin, the PaO(2) and SaO(2) alone. This prospective study was designed to evaluate possible alterations in the oxyhemoglobin dissociation curve of vital end organs (small bowel, liver, and kidney) in an experimental liver transplantation model. Fifteen pigs with body weights ranging from 25 to 30 kg were used for the study. Five healthy pigs underwent a sham operation under general anesthesia (group A-control). Ten pigs underwent orthotopic liver transplantation (OLT). Five of them were healthy (group B), whereas the other five were in acute liver failure, which had been surgically induced (group C). Systemic arterial blood pressure, cardiac index, and pulmonary and systemic vascular resistance indexes were measured. Venous blood gas analysis was also performed from pulmonary artery, superior mesenteric, hepatic, and renal veins at well-defined timepoints during the course of the OLT. A statistically significant (P < 0.05) decrease of P(50) in groups B and C compared with group A was observed 30 minutes after reperfusion in the systemic circulation, hepatic, and renal veins. This coincided with a decrease in animal temperature 30 minutes after reperfusion. Regarding group C, after reperfusion of the newly transplanted liver there was a significant increase of P(50) in the small bowel in comparison to baseline values. In conclusion, these changes in P(50) may suggest the occurrence of abnormal tissue oxygenation after reperfusion.