Comparison of central venous minus arterial carbon dioxide pressure to arterial minus central venous oxygen content ratio and lactate levels as predictors of mortality in critically ill patients: a systematic review and meta-analysis. / Comparação da proporção entre pressão venosa central menos arterial de dióxido de carbono e conteúdo de oxigênio arterial menos venoso central e níveis de lactato como preditores de mortalidade em pacientes críticos: uma revisão sistemática e metanálise.

OBJECTIVE: The central venousarterial carbon dioxide pressure to arterial-central venous oxygen content ratio (Pcv-aCO2/Ca-cvO2) is frequently used as a surrogate for tissue oxygenation. We aimed to identify and synthesize literature and quality of evidence supporting Pcv-aCO2/Ca-cvO2 as a predictor of mortality in critically ill patients compared with lactate. METHODS: We searched several databases for studies measuring Pcv-aCO2/Ca-cvO2 in critically ill patients. Independent investigators performed the article screening and data extraction. A random-effects metaanalysis was performed. Pooled standardized mean differences (SMD) were used to compare the prognostic ability of Pcv-aCO2/Ca-cvO2 and lactate. RESULTS: We initially retrieved 172 studies; 17 were included for qualitative description, and 10 were included for quantitative synthesis. The mean Pcv-aCO2/Ca-cvO2 was higher in nonsurvivors than in survivors (pooled SMD = 0.75; 95%CI 0.34 - 1.17; I2 = 83%), as was the case with lactate levels (pooled SMD = 0.94; 95%CI 0.34 - 1.54; I2 = 92%). Both tests were statistically significant predictors of mortality, albeit with overlapping 95%CIs between them. CONCLUSION: Moderate-quality evidence showed little or no difference in the ability of Pcv-aCO2/Ca-cvO2, compared with lactate, to predict mortality. Nevertheless, our conclusions are limited by the considerable heterogeneity among the studies.PROSPERO registration: CRD42019130387.

OBJETIVO: A proporção entre pressão venosa central menos arterial de dióxido de carbono e conteúdo de oxigênio arterial menos venoso central (Pcv-aCO2/Ca-cvO2) é frequentemente usada como substituta para a oxigenação tecidual. O objetivo deste estudo foi identificar e sintetizar a literatura e a qualidade das evidências que suportam a Pcv-aCO2/Ca-cvO2 como um preditor de mortalidade em comparação com o lactato em pacientes críticos. MÉTODOS: Pesquisamos vários bancos de dados procurando estudos que tivessem medido a Pcv-aCO2/Ca-cvO2 em pacientes críticos. Pesquisadores independentes realizaram a triagem dos artigos e a extração de dados. Uma metanálise de efeitos aleatórios foi realizada. Diferenças médias padronizadas agrupadas foram usadas para comparar a capacidade prognóstica da Pcv-aCO2/Ca-cvO2 e do lactato. RESULTADOS: Inicialmente, obtivemos 172 estudos; 17 foram incluídos para descrição qualitativa, e dez foram incluídos para síntese quantitativa. A média de Pcv-aCO2/Ca-cvO2 foi maior nos não sobreviventes do que nos sobreviventes (diferença média padronizada agrupada de 0,75; IC95% 0,34 - 1,17; I2 = 83%), assim como os níveis de lactato (diferença média padronizada agrupada = 0,94; IC95% 0,34 - 1,54; I2 = 92%). Ambos os testes foram preditores estatisticamente significativos de mortalidade, embora com sobreposição de IC95% entre eles. CONCLUSÃO: Evidências de qualidade moderada mostraram pouca ou nenhuma diferença na capacidade da Pcv-aCO2/Ca-cvO2, em comparação com o lactato, em predizer mortalidade. No entanto, nossas conclusões são limitadas pela considerável heterogeneidade entre os estudos.Registro no PROSPERO: CRD42019130387.

Comparação da proporção entre pressão venosa central menos arterial de dióxido de carbono e conteúdo de oxigênio arterial menos venoso central e níveis de lactato como preditores de mortalidade em pacientes críticos: uma revisão sistemática e metanálise / Comparison of central venous minus arterial carbon dioxide pressure to arterial minus central venous oxygen content ratio and lactate levels as predictors of mortality in critically ill patients: a systematic review and meta-analysis

RESUMO Objetivo: A proporção entre pressão venosa central menos arterial de dióxido de carbono e conteúdo de oxigênio arterial menos venoso central (Pcv-aCO2/Ca-cvO2) é frequentemente usada como substituta para a oxigenação tecidual. O objetivo deste estudo foi identificar e sintetizar a literatura e a qualidade das evidências que suportam a Pcv-aCO2/Ca-cvO2 como um preditor de mortalidade em comparação com o lactato em pacientes críticos. Métodos: Pesquisamos vários bancos de dados procurando estudos que tivessem medido a Pcv-aCO2/Ca-cvO2 em pacientes críticos. Pesquisadores independentes realizaram a triagem dos artigos e a extração de dados. Uma metanálise de efeitos aleatórios foi realizada. Diferenças médias padronizadas agrupadas foram usadas para comparar a capacidade prognóstica da Pcv-aCO2/Ca-cvO2 e do lactato. Resultados: Inicialmente, obtivemos 172 estudos; 17 foram incluídos para descrição qualitativa, e dez foram incluídos para síntese quantitativa. A média de Pcv-aCO2/Ca-cvO2 foi maior nos não sobreviventes do que nos sobreviventes (diferença média padronizada agrupada de 0,75; IC95% 0,34 - 1,17; I2 = 83%), assim como os níveis de lactato (diferença média padronizada agrupada = 0,94; IC95% 0,34 - 1,54; I2 = 92%). Ambos os testes foram preditores estatisticamente significativos de mortalidade, embora com sobreposição de IC95% entre eles. Conclusão: Evidências de qualidade moderada mostraram pouca ou nenhuma diferença na capacidade da Pcv-aCO2/Ca-cvO2, em comparação com o lactato, em predizer mortalidade. No entanto, nossas conclusões são limitadas pela considerável heterogeneidade entre os estudos. Registro no PROSPERO:CRD42019130387

ABSTRACT Objective: The central venousarterial carbon dioxide pressure to arterial-central venous oxygen content ratio (Pcv-aCO2/Ca-cvO2) is frequently used as a surrogate for tissue oxygenation. We aimed to identify and synthesize literature and quality of evidence supporting Pcv-aCO2/Ca-cvO2 as a predictor of mortality in critically ill patients compared with lactate. Methods: We searched several databases for studies measuring Pcv-aCO2/Ca-cvO2 in critically ill patients. Independent investigators performed the article screening and data extraction. A random-effects metaanalysis was performed. Pooled standardized mean differences (SMD) were used to compare the prognostic ability of Pcv-aCO2/Ca-cvO2 and lactate. Results: We initially retrieved 172 studies; 17 were included for qualitative description, and 10 were included for quantitative synthesis. The mean Pcv-aCO2/Ca-cvO2 was higher in nonsurvivors than in survivors (pooled SMD = 0.75; 95%CI 0.34 - 1.17; I2 = 83%), as was the case with lactate levels (pooled SMD = 0.94; 95%CI 0.34 - 1.54; I2 = 92%). Both tests were statistically significant predictors of mortality, albeit with overlapping 95%CIs between them. Conclusion: Moderate-quality evidence showed little or no difference in the ability of Pcv-aCO2/Ca-cvO2, compared with lactate, to predict mortality. Nevertheless, our conclusions are limited by the considerable heterogeneity among the studies. PROSPERO registration:CRD42019130387

Central venous minus arterial carbon dioxide pressure to arterial minus central venous oxygen content ratio as an indicator of tissue oxygenation: a narrative review. / Proporção entre pressão venosa central menos arterial de dióxido de carbono e conteúdo arterial menos venoso central de oxigênio como indicador de oxigenação tissular: uma revisão narrativa.

The central venous minus arterial carbon dioxide pressure to arterial minus central venous oxygen content ratio (Pcv-aCO2/Ca-cvO2) has been proposed as a surrogate for respiratory quotient and an indicator of tissue oxygenation. Some small observational studies have found that a Pcv-aCO2/Ca-cvO2 > 1.4 was associated with hyperlactatemia, oxygen supply dependency, and increased mortality. Moreover, Pcv-aCO2/Ca-cvO2 has been incorporated into algorithms for tissue oxygenation evaluation and resuscitation. However, the evidence for these recommendations is quite limited and of low quality. The goal of this narrative review was to analyze the methodological bases, the pathophysiologic foundations, and the experimental and clinical evidence supporting the use of Pcv-aCO2/Ca-cvO2 as a surrogate for respiratory quotient. Physiologically, the increase in respiratory quotient secondary to critical reductions in oxygen transport is a life-threatening and dramatic event. Nevertheless, this event is easily noticeable and probably does not require further monitoring. Since the beginning of anaerobic metabolism is indicated by the sudden increase in respiratory quotient and the normal range of respiratory quotient is wide, the use of a defined cutoff of 1.4 for Pcv-aCO2/Ca-cvO2 is meaningless. Experimental studies have shown that Pcv-aCO2/Ca-cvO2 is more dependent on factors that modify the dissociation of carbon dioxide from hemoglobin than on respiratory quotient and that respiratory quotient and Pcv-aCO2/Ca-cvO2 may have distinct behaviors. Studies performed in critically ill patients have shown controversial results regarding the ability of Pcv-aCO2/Ca-cvO2 to predict outcome, hyperlactatemia, microvascular abnormalities, and oxygen supply dependency. A randomized controlled trial also showed that Pcv-aCO2/Ca-cvO2 is useless as a goal of resuscitation. Pcv-aCO2/Ca-cvO2 should be carefully interpreted in critically ill patients.

Proporção entre pressão venosa central menos arterial de dióxido de carbono e conteúdo arterial menos venoso central de oxigênio como indicador de oxigenação tissular: uma revisão narrativa / Central venous minus arterial carbon dioxide pressure to arterial minus central venous oxygen content ratio as an indicator of tissue oxygenation: a narrative review

RESUMO A proporção entre pressão venosa central menos arterial de dióxido de carbono e conteúdo de oxigênio arterial menos venoso central (Pcv-aCO2/Ca-cvO2) foi proposta como marcador substituto para quociente respiratório e indicador de oxigenação tissular. Alguns pequenos estudos observacionais identificaram que Pcv-aCO2/Ca-cvO2 acima de 1,4 se associa com hiperlactatemia, dependência de suprimento de oxigênio e maior mortalidade. Mais ainda, a Pcv-aCO2/Ca-cvO2 foi incorporada a algoritmos para avaliação da oxigenação tissular e ressuscitação. Contudo, a evidência para estas recomendações é bastante limitada e de baixa qualidade. O objetivo desta revisão narrativa foi analisar as bases metodológicas, os fundamentos fisiopatológicos e a evidência experimental e clínica para dar suporte à utilização da Pcv-aCO2/Ca-cvO2 como marcador substituto para quociente respiratório. De um ponto de vista fisiopatológico, o aumento do quociente respiratório secundariamente a reduções críticas no transporte de oxigênio é um evento dramático e com risco à vida. Entretanto, este evento é facilmente observável e provavelmente não demandaria maiores monitoramentos. Visto que o início do metabolismo anaeróbico é indicado pelo aumento súbito do quociente respiratório e que a faixa normal do quociente respiratório é ampla, o uso do ponto de corte definido como 1,4 para Pcv-aCO2/Ca-cvO2 não faz sentido. Estudos experimentais demonstraram que a Pcv-aCO2/Ca-cvO2 é mais dependente de fatores que modificam a dissociação do dióxido de carbono da hemoglobina do que do quociente respiratório, e o quociente respiratório e Pcv-aCO2/Ca-cvO2 podem ter comportamentos distintos. Estudos conduzidos em pacientes críticos demonstraram resultados controvertidos com relação à capacidade da Pcv-aCO2/Ca-cvO2 para predizer o desfecho, hiperlactatemia, anomalias microvasculares e dependência de suprimento de oxigênio. Um estudo randomizado controlado também demonstrou que a Pcv-aCO2/Ca-cvO2 é inútil como alvo para ressuscitação. A Pcv-aCO2/Ca-cvO2 deve ser interpretada com cautela em pacientes críticos.

ABSTRACT The central venous minus arterial carbon dioxide pressure to arterial minus central venous oxygen content ratio (Pcv-aCO2/Ca-cvO2) has been proposed as a surrogate for respiratory quotient and an indicator of tissue oxygenation. Some small observational studies have found that a Pcv-aCO2/Ca-cvO2 > 1.4 was associated with hyperlactatemia, oxygen supply dependency, and increased mortality. Moreover, Pcv-aCO2/Ca-cvO2 has been incorporated into algorithms for tissue oxygenation evaluation and resuscitation. However, the evidence for these recommendations is quite limited and of low quality. The goal of this narrative review was to analyze the methodological bases, the pathophysiologic foundations, and the experimental and clinical evidence supporting the use of Pcv-aCO2/Ca-cvO2 as a surrogate for respiratory quotient. Physiologically, the increase in respiratory quotient secondary to critical reductions in oxygen transport is a life-threatening and dramatic event. Nevertheless, this event is easily noticeable and probably does not require further monitoring. Since the beginning of anaerobic metabolism is indicated by the sudden increase in respiratory quotient and the normal range of respiratory quotient is wide, the use of a defined cutoff of 1.4 for Pcv-aCO2/Ca-cvO2 is meaningless. Experimental studies have shown that Pcv-aCO2/Ca-cvO2 is more dependent on factors that modify the dissociation of carbon dioxide from hemoglobin than on respiratory quotient and that respiratory quotient and Pcv-aCO2/Ca-cvO2 may have distinct behaviors. Studies performed in critically ill patients have shown controversial results regarding the ability of Pcv-aCO2/Ca-cvO2 to predict outcome, hyperlactatemia, microvascular abnormalities, and oxygen supply dependency. A randomized controlled trial also showed that Pcv-aCO2/Ca-cvO2 is useless as a goal of resuscitation. Pcv-aCO2/Ca-cvO2 should be carefully interpreted in critically ill patients.

Effects of short-term hyperoxia on sytemic hemodynamics, oxygen transport, and microcirculation: An observational study in patients with septic shock and healthy volunteers.

PURPOSE: To characterize the microvascular effects of a brief period of hyperoxia, in patients with septic shock and in healthy volunteers. MATERIALS AND METHODS: In 20 patients with septic shock, we assessed systemic hemodynamics, sublingual microcirculation by SDF-videomicroscopy, and skin perfusion by capillary refill time (CRT), central-peripheral temperature (ΔT°), and perfusion index. Measurements were performed at baseline and after 5 min of inspired oxygen fraction of 1.00. Additionally, we studied 8 healthy volunteers, in whom hyperoxia was prolonged to 30 min. RESULTS: In septic patients, hyperoxia increased mean arterial pressure and systemic vascular resistance, but cardiac output remained unchanged. The only significant change in sublingual microcirculation was a decreased heterogeneity flow index (1.03 [1.01-1.07] vs 1.01 [0.34-1.05], P = .002). Perfused vascular density (13.1 [12.0-15.0] vs 14.0 [12.2-14.8] mm/mm2, P = .21) and the other sublingual microvascular variables were unmodified. CRT and ΔT° did not change but perfusion index slightly decreased. In healthy volunteers, sublingual microcirculation and skin perfusion were stable. CONCLUSIONS: Short-term hyperoxia induced systemic cardiovascular changes but was not associated with noticeable derangement in sublingual microcirculation and skin perfusion. Nevertheless, longer exposures to hyperoxia might have produced different results.

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.

Severe abnormalities in microvascular perfused vessel density are associated to organ dysfunctions and mortality and can be predicted by hyperlactatemia and norepinephrine requirements in septic shock patients.

PURPOSE: The aims of this study are to determine the general relationship of perfused vessel density (PVD) to mortality and organ dysfunctions and to explore if patients in the lowest quartile of distribution for this parameter present a higher risk of bad outcome and to identify systemic hemodynamic and perfusion variables that enhances the probability of finding a severe underlying microvascular dysfunction. MATERIALS AND METHODS: This is a retrospective multicenter study including 122 septic shock patients participating in 7 prospective clinical trials on which at least 1 sublingual microcirculatory assessment was performed during early resuscitation. RESULTS: Perfused vessel density was significantly related to organ dysfunctions and mortality, but this effect was largely explained by patients in the lowest quartile of distribution for PVD (P = .037 [odds ratio {OR}, 8.7; 95% confidence interval {CI}, 1.14-66.78] for mortality). Hyperlactatemia (P < .026 [OR, 1.23; 95% CI, 1.03-1.47]) and high norepinephrine requirements (P < .019 [OR, 7.04; 95% CI, 1.38-35.89]) increased the odds of finding a severe microvascular dysfunction. CONCLUSIONS: Perfused vessel density is significantly related to organ dysfunctions and mortality in septic shock patients, particularly in patients exhibiting more severe abnormalities as represented by the lowest quartile of distribution for this parameter. The presence of hyperlactatemia and high norepinephrine requirements increases the odds of finding a severe underlying microvascular dysfunction during a sublingual microcirculatory assessment.

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.