Lack of change in the respiratory quotient during oxygen supply dependence in endotoxemic shock: a subanalysis of an experimental controlled study.

OBJECTIVE: To evaluate if the reductions in systemic and renal oxygen consumption are associated with the development of evidence of anaerobic metabolism. METHODS: This is a subanalysis of a previously published study. In anesthetized and mechanically ventilated sheep, we measured the respiratory quotient by indirect calorimetry and its systemic, renal, and intestinal surrogates (the ratios of the venous-arterial carbon dioxide pressure and content difference to the arterial-venous oxygen content difference. The Endotoxemic Shock Group (n = 12) was measured at baseline, after 60 minutes of endotoxemic shock, and after 60 and 120 minutes of fluid and norepinephrine resuscitation, and the values were compared with those of a Control Group (n = 12) without interventions. RESULTS: Endotoxemic shock decreased systemic and renal oxygen consumption (6.3 [5.6 - 6.6] versus 7.4 [6.3 - 8.5] mL/minute/kg and 3.7 [3.3 - 4.5] versus 5.4 [4.6 - 9.4] mL/minute/100g; p < 0.05 for both). After 120 minutes of resuscitation, systemic oxygen consumption was normalized, but renal oxygen consumption remained decreased (6.3 [5.9 - 8.2] versus 7.1 [6.1 - 8.6] mL/minute/100g; p = not significance and 3.8 [1.9 - 4.8] versus 5.7 [4.5 - 7.1]; p < 0.05). The respiratory quotient and the systemic, renal and intestinal ratios of the venous-arterial carbon dioxide pressure and content difference to the arterial-venous oxygen content difference did not change throughout the experiments. CONCLUSION: In this experimental model of septic shock, oxygen supply dependence was not associated with increases in the respiratory quotient or its surrogates. Putative explanations for these findings are the absence of anaerobic metabolism or the poor sensitivity of these variables in detecting this condition.

Lack of change in the respiratory quotient during oxygen supply dependence in endotoxemic shock: a subanalysis of an experimental controlled study / Ausência de alteração no quociente respiratório durante a dependência do suprimento de oxigênio no choque endotoxêmico: subanálise de um estudo experimental controlado

ABSTRACT Objective: To evaluate if the reductions in systemic and renal oxygen consumption are associated with the development of evidence of anaerobic metabolism. Methods: This is a subanalysis of a previously published study. In anesthetized and mechanically ventilated sheep, we measured the respiratory quotient by indirect calorimetry and its systemic, renal, and intestinal surrogates (the ratios of the venous-arterial carbon dioxide pressure and content difference to the arterial-venous oxygen content difference. The Endotoxemic Shock Group (n = 12) was measured at baseline, after 60 minutes of endotoxemic shock, and after 60 and 120 minutes of fluid and norepinephrine resuscitation, and the values were compared with those of a Control Group (n = 12) without interventions. Results: Endotoxemic shock decreased systemic and renal oxygen consumption (6.3 [5.6 - 6.6] versus 7.4 [6.3 - 8.5] mL/minute/kg and 3.7 [3.3 - 4.5] versus 5.4 [4.6 - 9.4] mL/minute/100g; p < 0.05 for both). After 120 minutes of resuscitation, systemic oxygen consumption was normalized, but renal oxygen consumption remained decreased (6.3 [5.9 - 8.2] versus 7.1 [6.1 - 8.6] mL/minute/100g; p = not significance and 3.8 [1.9 - 4.8] versus 5.7 [4.5 - 7.1]; p < 0.05). The respiratory quotient and the systemic, renal and intestinal ratios of the venous-arterial carbon dioxide pressure and content difference to the arterial-venous oxygen content difference did not change throughout the experiments. Conclusion: In this experimental model of septic shock, oxygen supply dependence was not associated with increases in the respiratory quotient or its surrogates. Putative explanations for these findings are the absence of anaerobic metabolism or the poor sensitivity of these variables in detecting this condition.

RESUMO Objetivo: Avaliar se as reduções do consumo de oxigênio sistêmico e renal estão associadas ao desenvolvimento de evidências de metabolismo anaeróbico. Métodos: Esta é uma subanálise de estudo já publicado. Em ovinos anestesiados e ventilados mecanicamente, medimos o quociente respiratório por calorimetria indireta e seus substitutos sistêmicos, renais e intestinais (as razões entre a diferença de pressão venoarterial do teor de dióxido de carbono e a diferença arteriovenosa do teor de oxigênio). O Grupo Choque Endotoxêmico (n = 12) foi medido inicialmente, após 60 minutos do choque endotoxêmico e após 60 e 120 minutos da ressuscitação com fluidos e norepinefrina, e os valores foram comparados com os do Grupo Controle (n = 12) sem intervenções. Resultados: O choque endotoxêmico diminuiu o consumo de oxigênio sistêmico e renal (6,3 [5,6 - 6,6] versus 7,4 [6,3 - 8,5] mL/minuto/kg e 3,7 [3,3 - 4,5] versus 5,4 [4,6 - 9,4] mL/minuto/100g; p < 0,05 para ambos). Após 120 minutos de ressuscitação, o consumo sistêmico de oxigênio foi normalizado, mas o consumo renal de oxigênio permaneceu reduzido (6,3 [5,9 - 8,2] versus 7,1 [6,1 - 8,6] mL/minuto/100g; p = NS e 3,8 [1,9 - 4,8] versus 5,7 [4,5 - 7,1]; p < 0,05). O quociente respiratório e as razões sistêmica, renal e intestinal entre a diferença na pressão venoarterial do teor de dióxido de carbono e a diferença arteriovenosa do teor de oxigênio não se alteraram ao longo dos experimentos. Conclusão: Nesse modelo experimental de choque séptico, a dependência do suprimento de oxigênio não foi associada a aumentos no quociente respiratório ou em seus substitutos. As explicações possíveis para esses achados são a ausência de metabolismo anaeróbico ou a baixa sensibilidade dessas variáveis na detecção dessa condição.

Microcirculatory effects of rewarming in experimental hemorrhagic shock.

BACKGROUND: Rewarming is a recommended therapy during the resuscitation of hypothermic patients with hemorrhagic shock. In experimental models, however, it increases inflammatory response and mortality. Although microcirculation is potential target of inflammation, the microvascular effects of rewarming during the resuscitation of hemorrhagic shock have not been studied. Our goal was to assess the systemic and microcirculatory effects of an increase in core temperature (T°) during the retransfusion of hemorrhagic shock in sheep. Our hypothesis was that rewarming could hamper microcirculation. METHODS: In anesthetized and mechanically ventilated sheep, we measured systemic, intestinal, and renal hemodynamics and oxygen transport. O2 consumption (VO2) and respiratory quotient were measured by indirect calorimetry. Cortical renal, intestinal villi and sublingual microcirculation were assessed by IDF-videomicroscopy. After basal measurements, hemorrhagic shock was induced and T° was reduced to ~33 °C. After 1 h of shock and hypothermia, blood was retransfused and Ringer lactate solution was administered to prevent arterial hypotension. In the control group (n = 12), T° was not modified, while in the intervention (rewarming) group, it was elevated ~3 °C. Measurements were repeated after 1 h. RESULTS: During shock, both groups showed similar systemic and microvascular derangements. After retransfusion, VO2 remained decreased compared to baseline in both groups, but was lower in the control compared to the rewarming group. Perfused vascular density has a similar behavior in both groups. Compared to baseline, it remained reduced in peritubular (control vs. rewarming group, 13.8 [8.7-17.5] vs. 15.7 [10.1-17.9] mm/mm2, PNS) and villi capillaries (14.7 [13.6-16.8] vs. 16.3 [14.2-16.9] mm/mm2, PNS), and normalized in sublingual mucosa (19.1 [16.0-20.3] vs. 16.6 [14.7-17.2] mm/mm2, PNS). CONCLUSIONS: This is the first experimental study assessing the effect of rewarming on systemic, regional, and microcirculatory perfusion in hypothermic hemorrhagic shock. We found that a 3 °C increase in T° neither improved nor impaired the microvascular alterations that persisted after retransfusion. In addition, sublingual mucosa was less susceptible to reperfusion injury than villi and renal microcirculation.

Effects of Systemic Hypothermia on Microcirculation in Conditions of Hemodynamic Stability and in Hemorrhagic Shock.

INTRODUCTION: Although hypothermia is independently associated with an increased mortality in trauma patients, it might be an effective therapeutic approach for otherwise lethal hemorrhage. The effect of hypothermia on microcirculation, however, has been poorly studied in this setting. Our goal was to characterize the effects of hypothermia on microcirculation in normal conditions and in severe hemorrhagic shock. METHODS: In anesthetized and mechanically ventilated sheep, we measured cardiac output (CO), renal blood flow (RBF), and systemic and renal O2 consumption (VO2). Cortical renal, intestinal villi, and sublingual microcirculation was assessed by IDF-videomicroscopy. After basal measurements, sheep were assigned to hypothermia (n = 12) and normothermia (n = 12) groups. Central temperature was reduced to ∼34°C and maintained at baseline in each group, respectively. Measurements were repeated after 1 h of hemodynamic stable conditions and 1 h of severe hemorrhagic shock. RESULTS: In conditions of hemodynamic stability, the hypothermia group showed lower CO, RBF, and systemic and renal VO2 than the normothermia group. Red blood cell velocity was also lower in renal, villi, and sublingual microvascular beds (836 ±â€Š195 vs. 1,066 ±â€Š162, 916 ±â€Š105 vs. 1051 ±â€Š41, and 970 ±â€Š182 vs. 1,102 ±â€Š49 µm/s, respectively; P < 0.0001 for all). In hemorrhagic shock, most of the microvascular variables were similarly compromised in both the groups. In hypo- and normothermia groups, the percentage of reduction in perfused vascular density was higher in renal than in intestinal and sublingual microcirculation (66 ±â€Š31 vs. 31 ±â€Š23 and 15 ±â€Š15%, and 78 ±â€Š26 vs. 32 ±â€Š37 and 18 ±â€Š21%, P < 0.01 for both). CONCLUSIONS: This is the first experimental study assessing the effect of systemic hypothermia on microcirculation in severe hemorrhagic shock. The main finding was that hypothermia did not hamper additionally the microcirculatory derangements induced by hemorrhagic shock. In addition, renal microcirculation was more susceptible to hemorrhagic shock than villi and sublingual microcirculation.

Effects of fluid and norepinephrine resuscitation in a sheep model of endotoxin shock and acute kidney injury.

The pathophysiology of renal failure in septic shock is complex. Although microvascular dysfunction has been proposed as a mechanism, there are controversial findings about the characteristics of microvascular redistribution and the effects of resuscitation. Our hypothesis was that the normalization of systemic hemodynamics with fluids and norepinephrine fails to improve acute kidney injury. To test this hypothesis, we assessed systemic and renal hemodynamics and oxygen metabolism in 24 anesthetized and mechanically ventilated sheep. Renal cortical microcirculation was evaluated by SDF-videomicroscopy. Shock (n = 12) was induced by intravenous administration of endotoxin. After 60 min of shock, 30 mL/kg of saline solution was infused and norepinephrine was titrated to reach a mean blood pressure of 70 mmHg for 2 h. These animals were compared with a sham group (n = 12). After endotoxin administration, mean blood pressure, cardiac index, and systemic O2 transport and consumption decreased (P < 0.05 for all). Resuscitation improved these variables. Endotoxin shock also reduced renal blood flow and O2 transport and consumption (205[157-293] vs. 131 [99-185], 28.4[19.0-38.2] vs. 15.8[13.5-23.2], and 5.4[4.0-8.8] vs. 3.7[3.3-4.5] mL·min-1·100 g-1, respectively); cortical perfused capillary density (23.8[23.5-25.9] vs. 17.5[15.1-19.0] mm/mm2); and creatinine clearance (62.4[39.2-99.4] vs. 10.7[4.4-23.5] mL/min). After 2 h of resuscitation, these variables did not improve (174[91-186], 20.5[10.8-22.7], and 3.8[1.9-4.8] mL·min-1·100 g-1, 19.9[18.6-22.1] mm/mm2, and 5.9[1.0-11.9] mL/min). In conclusion, endotoxin shock induced severe renal failure associated with decreased renal flow, O2 transport and consumption, and cortical microcirculation. Normalization of systemic hemodynamics with fluids and norepinephrine failed to improve renal perfusion, oxygenation, and function.NEW & NOTEWORTHY This experimental model of endotoxin shock induced severe renal failure, which was associated with abnormalities in renal regional blood flow, microcirculation, and oxygenation. Derangements included the compromise of peritubular microvascular perfusion. Improvements in systemic hemodynamics through fluids and norepinephrine were unable to correct these abnormalities.

Venoarterial PCO2-to-arteriovenous oxygen content difference ratio is a poor surrogate for anaerobic metabolism in hemodilution: an experimental study.

BACKGROUND: The identification of anaerobic metabolism in critically ill patients is a challenging task. Observational studies have suggested that the ratio of venoarterial PCO2 (Pv-aCO2) to arteriovenous oxygen content difference (Ca-vO2) might be a good surrogate for respiratory quotient (RQ). Yet Pv-aCO2/Ca-vO2 might be increased by other factors, regardless of anaerobic metabolism. At present, comparisons between Pv-aCO2/Ca-vO2 and RQ have not been performed. We sought to compare these variables during stepwise hemorrhage and hemodilution. Since anemia predictably produces augmented Pv-aCO2 and decreased Ca-vO2, our hypothesis was that Pv-aCO2/Ca-vO2 might be an inadequate surrogate for RQ. METHODS: This is a subanalysis of a previously published study. In anesthetized and mechanically ventilated sheep (n = 16), we compared the effects of progressive hemodilution and hemorrhage by means of expired gases analysis. RESULTS: There were comparable reductions in oxygen consumption and increases in RQ in the last step of hemodilution and hemorrhage. The increase in Pv-aCO2/Ca-vO2 was higher in hemodilution than in hemorrhage (1.9 ± 0.2 to 10.0 ± 0.9 vs. 1.7 ± 0.2 to 2.5 ± 0.1, P < 0.0001). The increase in Pv-aCO2 was lower in hemodilution (6 ± 0 to 10 ± 1 vs. 6 ± 0 to 17 ± 1 mmHg, P < 0.0001). Venoarterial CO2 content difference and Ca-vO2 decreased in hemodilution and increased in hemorrhage (2.6 ± 0.3 to 1.2 ± 0.1 vs. 2.8 ± 0.2 to 6.9 ± 0.5, and 3.4 ± 0.3 to 1.0 ± 0.3 vs. 3.6 ± 0.3 to 6.8 ± 0.3 mL/dL, P < 0.0001 for both). In hemodilution, Pv-aCO2/Ca-vO2 increased before the fall in oxygen consumption and the increase in RQ. Pv-aCO2/Ca-vO2 was strongly correlated with Hb (R 2 = 0.79, P < 0.00001) and moderately with RQ (R 2 = 0.41, P < 0.0001). A multiple linear regression model found Hb, RQ, base excess, and mixed venous oxygen saturation and PCO2 as Pv-aCO2/Ca-vO2 determinants (adjusted R 2 = 0.86, P < 0.000001). CONCLUSIONS: In hemodilution, Pv-aCO2/Ca-vO2 was considerably increased, irrespective of the presence of anaerobic metabolism. Pv-aCO2/Ca-vO2 is a complex variable, which depends on several factors. As such, it was a misleading indicator of anaerobic metabolism in hemodilution.

Intestinal and sublingual microcirculation are more severely compromised in hemodilution than in hemorrhage.

The alterations in O2 extraction in hemodilution have been linked to fast red blood cell (RBC) velocity, which might affect the complete release of O2 from Hb. Fast RBC velocity might also explain the normal mucosal-arterial Pco2 (ΔPco2). Yet sublingual and intestinal microcirculation have not been completely characterized in extreme hemodilution. Our hypothesis was that the unchanged ΔPco2 in hemodilution depends on the preservation of villi microcirculation. For this purpose, pentobarbital-anesthetized and mechanically ventilated sheep were submitted to stepwise hemodilution (n = 8), hemorrhage (n = 8), or no intervention (sham, n = 8). In both hypoxic groups, equivalent reductions in O2 consumption (V̇o2) were targeted. Microcirculation was assessed by videomicroscopy, intestinal ΔPco2 by air tonometry, and V̇o2 by expired gases analysis. Although cardiac output and superior mesenteric flow increased in hemodilution, from the very first step (Hb = 5.0 g/dl), villi functional vascular density and RBC velocity decreased (21.7 ± 0.9 vs. 15.9 ± 1.0 mm/mm(2) and 1,033 ± 75 vs. 850 ± 79 µm/s, P < 0.01). In the last stage (Hb = 1.2 g/dl), these variables were lower in hemodiution than in hemorrhage (11.1 ± 0.5 vs. 15.4 ± 0.9 mm/mm(2) and 544 ± 26 vs. 686 ± 70 µm/s, P < 0.01), and were associated with lower intestinal fractional O2 extraction (0.61 ± 0.04 vs. 0.79 ± 0.02, P < 0.01) but preserved ΔPco2 (5 ± 2 vs. 25 ± 4 mmHg, P < 0.01). Therefore, alterations in O2 extraction in hemodilution seemed related to microvascular shunting, not to fast RBC velocity. The severe microvascular abnormalities suggest that normal ΔPco2 was not dependent on CO2 washout by the villi microcirculation. Increased perfusion in deeper intestinal layers might be an alternative explanation.

Systemic and microcirculatory responses to progressive hemorrhage.

OBJECTIVE: To compare systemic hemodynamics with microcirculatory changes at different vascular beds during progressive hemorrhage. SETTING: University-based research laboratory. SUBJECTS: Twelve anesthetized, mechanically ventilated sheep. INTERVENTIONS: Sheep were randomly assigned to HEMORRHAGE or CONTROL group. In the HEMORRHAGE group (n = 8), three stepwise bleedings of 5 ml/kg at 30-min intervals were performed to add up 15 ml/kg. In the CONTROL group (n = 4), sheep had the same surgical preparation but were not bled. MEASUREMENTS AND MAIN RESULTS: Progressive bleeding decreased cardiac output, and superior mesenteric artery blood flow, and systemic and intestinal oxygen transports from the first step of bleeding whereas systemic and intestinal oxygen consumption remained unchanged. Mean arterial blood pressure, arterial pH and base excess, and intramucosal-arterial PCO(2) were only significantly modified in the last step of bleeding. Arterial lactate increased and sublingual, and intestinal serosal and mucosal capillary microvascular flow indexes and red blood cell velocities progressively decreased after the first step of bleeding (3.0 +/- 0.1 vs. 2.3 +/- 0.4, 3.2 +/- 0.2 vs. 2.4 +/- 0.6, 3.0 +/- 0.0 vs. 2.0 +/- 0.2, and 1,082 +/- 29 vs. 977 +/- 79, 1,042 +/- 24 vs. 953 +/- 60, 287 +/- 65 vs. 262 +/- 16 mum/s; P < 0.05 for all). CONCLUSIONS: Alterations in sublingual, intestinal microcirculation, and arterial lactate simultaneously arose from the first step of bleeding. The microcirculatory changes were identified either by semi-quantitative flow index or by quantitative red blood cell velocity measurements.

Persistent villi hypoperfusion explains intramucosal acidosis in sheep endotoxemia.

OBJECTIVE: To test the hypothesis that persistent villi hypoperfusion explains intramucosal acidosis after endotoxemic shock resuscitation. DESIGN: Controlled experimental study. SETTING: University-based research laboratory. SUBJECTS: A total of 14 anesthetized, mechanically ventilated sheep. INTERVENTIONS: Sheep were randomly assigned to endotoxin (n = 7) or control groups (n = 7). The endotoxin group received 5 microg/kg endotoxin, followed by 4 microg x kg(-1) x hr(-1) for 150 mins. After 60 mins of shock, hydroxyethylstarch resuscitation was given to normalize oxygen transport for an additional 90 mins. MEASUREMENTS AND MAIN RESULTS: Endotoxin infusion decreased mean arterial blood pressure, cardiac output, and superior mesenteric artery blood flow (96 +/- 10 vs. 51 +/- 20 mm Hg, 145 +/- 30 vs. 90 +/- 30 mL x min(-1) x kg(-1), and 643 +/- 203 vs. 317 +/- 93 mL x min(-1) x kg(-1), respectively; p < .05 vs. basal), whereas it increased intramucosal-arterial PCO2 (deltaPCO2) and arterial lactate (3 +/- 3 vs. 14 +/- 8 mm Hg, and 1.5 +/- 0.5 vs. 3.7 +/- 1.3 mmol/L; p < .05). Sublingual, and serosal and mucosal intestinal microvascular flow indexes, and the percentage of perfused ileal villi were reduced (3.0 +/- 0.1 vs. 2.3 +/- 0.4, 3.2 +/- 0.2 vs. 2.4 +/- 0.6, 3.0 +/- 0.0 vs. 2.0 +/- 0.2, and 98% +/- 3% vs. 76% +/- 10%; p < .05). Resuscitation normalized mean arterial blood pressure (92 +/- 13 mm Hg), cardiac output (165 +/- 32 mL x min(-1) x kg(-1)), superior mesenteric artery blood flow (683 +/- 192 mL x min(-1) x kg(-1)), and sublingual and serosal intestinal microvascular flow indexes (2.8 +/- 0.5 and 3.5 +/- 0.7). Nevertheless, deltaPCO2, lactate, mucosal intestinal microvascular flow indexes, and percentage of perfused ileal villi remained altered (10 +/- 6 mm Hg, 3.7 +/- 0.9 mmol/L, 2.3 +/- 0.4, and 78% +/- 11%; p < .05). CONCLUSIONS: In this model of endotoxemia, fluid resuscitation corrected both serosal intestinal and sublingual microcirculation but was unable to restore intestinal mucosal perfusion. Intramucosal acidosis might be due to persistent villi hypoperfusion.

Effects of levosimendan and dobutamine in experimental acute endotoxemia: a preliminary controlled study.

OBJECTIVE: To test the hypothesis that levosimendan increases systemic and intestinal oxygen delivery (DO(2)) and prevents intramucosal acidosis in septic shock. DESIGN: Prospective, controlled experimental study. SETTING: University-based research laboratory. SUBJECTS: Nineteen anesthetized, mechanically ventilated sheep. INTERVENTIONS: Endotoxin-treated sheep were randomly assigned to three groups: control (n=7), dobutamine (10 microg/kg/min, n=6) and levosimendan (100 microg/kg over 10 min followed by 100 microg/kg/h, n=6) and treated for 120 min. MEASUREMENTS AND MAIN RESULTS: After endotoxin administration, systemic and intestinal DO(2) decreased (24.6+/-5.2 vs 15.3+/-3.4 ml/kg/min and 105.0+/-28.1 vs 55.8+/-25.9 ml/kg/min, respectively; p<0.05 for both). Arterial lactate and the intramucosal-arterial PCO(2) difference (DeltaPCO(2)) increased (1.4+/-0.3 vs 3.1+/-1.5 mmHg and 9+/-6 vs 23+/-6 mmHg mmol/l, respectively; p<0.05). Systemic DO(2) was preserved in the dobutamine-treated group (22.3+/-4.7 vs 26.8+/-7.0 ml/min/kg, p=NS) but intestinal DO(2) decreased (98.9+/-0.2 vs 68.0+/-22.9 ml/min/kg, p<0.05) and DeltaPCO(2) increased (12+/-5 vs 25+/-11 mmHg, p<0.05). The administration of levosimendan prevented declines in systemic and intestinal DO(2) (25.1+/-3.0 vs 24.0+/-6.3 ml/min/kg and 111.1+/-18.0 vs 98.2+/-23.1 ml/min/kg, p=NS for both) or increases in DeltaPCO(2) (7+/-7 vs 10+/-8, p=NS). Arterial lactate increased in both the dobutamine and levosimendan groups (1.6+/-0.3 vs 2.5+/-0.7 and 1.4+/-0.4 vs. 2.9+/-1.1 mmol/l, p=NS between groups). CONCLUSIONS: Compared with dobutamine, levosimendan increased intestinal blood flow and diminished intramucosal acidosis in this experimental model of sepsis.

Effects of levosimendan in normodynamic endotoxaemia: a controlled experimental study.

OBJECTIVES: Levosimendan is an inotropic and vasodilator drug that has proved to be useful in cardiogenic shock. Pretreatment with levosimendan in experimental hypodynamic septic shock in pigs has shown valuable effects in oxygen transport. Our goal was to assess the effects of levosimendan in a normodynamic model of endotoxaemia. METHODS: Twelve sheep were anaesthetized and mechanically ventilated. After taking basal haemodynamic and oxygen transport measurements, sheep were assigned to two groups during 120 min: (1) endotoxin (5 microg/kg endotoxin); (2) levosimendan (5 microg/kg endotoxin plus levosimendan 200 microg/kg followed by 200 microg/kg/h). Both groups received hydration of 20 ml/kg/h of saline solution. RESULTS: In the endotoxin group, cardiac output, intestinal blood flow and systemic and intestinal oxygen transports and consumptions (DO(2) and VO(2)) remained unchanged. In the levosimendan group, systemic and intestinal DO(2) were significantly higher than in the endotoxin group. Because stroke volume did not change (basal versus 120': 0.9+/-0.1 ml/kg versus 0.9+/-0.2 ml/kg, p=0.3749), the elevation in cardiac output by levosimendan (145+/-17 ml/min/kg versus 198+/-16 ml/min/kg, p=0.0096) was related to an increased heart rate (159+/-32 beats l/min versus 216+/-19 beats l/min, p=0.0037). Levosimendan precluded the development of gut intramucosal acidosis at 120' (endotoxin versus levosimendan, ileal intramucosal-arterial PCO(2) difference: 19+/-4 Torr versus 10+/-4 Torr, p=0.0025). However, levosimendan decreased mean arterial blood pressure (99+/-20 Torr versus 63+/-13 Torr, p=0.0235) and increased blood lactate levels (2.4+/-0.9 mmol/l versus 4.8+/-1.5 mmol/l, p=0.0479). All p-values are differences in specific points (paired or unpaired t-test with Bonferroni correction) after two-way repeated measures ANOVA. A p-value<0.05 was considered significant. CONCLUSIONS: Levosimendan improved oxygen transport and prevented the development of intramucosal acidosis in this experimental model of endotoxaemia. However, systemic hypotension and lactic acidosis occurred. Additional studies are needed to show if different doses and timing of levosimendan administration in septic shock might improve gut perfusion without adverse effects.