Evaluating tissue perfusion using labelled water indicator microdialysis in a rat model of haemorrhagic shock

The indicator microdialysis technique with (3)H(2)O was evaluated as a method for assessing local blood flow in skeletal muscle and liver in a rat model of haemorrhagic shock. Microdialysis probes were inserted into the hind limb muscle and liver of 12 rats and perfused with a solution containing (3)H(2)O. Haemorrhagic shock was induced in eight rats by repeated blood withdrawals; four rats were used as a control group. The outflow to inflow (O/I) ratio of water activity, lactate and pyruvate contents in the dialysate were repeatedly measured. The ratio of lactate to pyruvate (L/P) was calculated. There was no correlation between blood loss and O/I ratio (r = 0.323 for liver, r = 0.300 for muscle), between the mean arterial pressure and O/I ratio (r = 0.460 for liver, r = -0.301 for muscle) or between the concentration of lactate and O/I ratio (r = -0.237 for liver, r = 0.454 for muscle). A significant correlation was found between blood loss and lactate concentration in muscle (r = 0.619, p < 0.0001). We suppose that microdialysis with (3)H(2)O cannot be used as a sensitive method to estimate regional blood flow changes during haemorrhagic shock in rats. Measuring lactate, pyruvate and L/P ratio in the microdialysate seems to be a superior method to assess tissue hypoperfusion caused by haemorrhagic shock in rats.     

Effects of epinephrine and norepinephrine on hemodynamics,oxidative metabolism,and organ energetics in endotoxemic rats

OBJECTIVE: To determine whether epinephrine increases lactate concentration in sepsis through hypoxia or through a particular thermogenic or metabolic pathway. DESIGN: Prospective, controlled experimental study in rats. SETTING: Experimental laboratory in a university teaching hospital. INTERVENTIONS: Three groups of anesthetized, mechanically ventilated male Wistar rats received an intravenous infusion of 15 mg/kg Escherichia coli O127:B8 endotoxin. Rats were treated after 90 min by epinephrine ( n=14), norepinephrine ( n=14), or hydroxyethyl starch ( n=14). Three groups of six rats served as time-matched control groups and received saline, epinephrine, or norepinephrine from 90 to 180 degrees min. Mean arterial pressure, aortic, renal, mesenteric and femoral blood flow, arterial blood gases, lactate, pyruvate, and nitrate were measured at baseline and 90 and 180 min after endotoxin challenge. At the end of experiments biopsy samples were taken from the liver, heart, muscle, kidney, and small intestine for tissue adenine nucleotide and lactate/pyruvate measurements. MEASUREMENTS AND RESULTS: Endotoxin induced a decrease in mean arterial pressure and in aortic, mesenteric, and renal blood flow. Plasmatic and tissue lactate increased with a high lactate/pyruvate (L/P) ratio. ATP decreased in liver, kidney, and heart. The ATP/ADP ratio did not change, and phosphocreatinine decreased in all organs. Epinephrine and norepinephrine increased mean arterial pressure to baseline values. Epinephrine increased aortic blood flow while renal blood low decreased with both drugs. Plasmatic lactate increased with a stable L/P ratio with epinephrine and did not change with norepinephrine compared to endotoxin values. Nevertheless epinephrine and norepinephrine when compared to endotoxin values did not change tissue L/P ratios or ATP concentration in muscle, heart, gut, or liver. In kidney both drugs decreased ATP concentration. CONCLUSIONS: Our data demonstrate in a rat model of endotoxemia that epinephrine-induced hyperlactatemia is not related to cellular hypoxia.     

Investigation of the Physiological Basis for Increased Exercise Threshold for Angina Pectoris after Physical Conditioning

Eight patients with coronary heart disease and exertional angina pectoris successfully completed an 11-15 wk program of endurance exercise conditioning. Angina threshold was determined by upright bicycle ergometer exercise and by atrial pacing. The product of heart rate and arterial systolic blood pressure at the exercise angina threshold was higher after conditioning. suggesting that conditioning increased the maximum myocardial O(2) supply during exercise. However, when angina was induced by atrial pacing, heart rate, arterial blood pressure, coronary blood flow, and myocardial O(2) consumption at the angina threshold were the same before and after conditioning. Myocardial lactate extraction during atrial pacing was abnormal in the same five patients before and after conditioning. Conditioning caused no detectable changes in coronary collaterals as judged by coronary arteriograms.The increase in exercise angina threshold appeared to be due to a functional adaptation in either myocardial O(2) supply or the relationship between hemodynamic work and myocardial O(2) consumption. The adaptation was limited to exercise, and did not occur during a different stress to myocardial O(2) supply, atrial pacing.     

Coronary Hemodynamics and Regional Myocardial Metabolism in Experimental Aortic Insufficiency

Acute aortic valvular insufficiency was induced in open chest dogs by employing a special intravascular cannula, or by rupturing an aortic valve leaflet. Phasic and mean coronary flow were assessed in some animals, while in others data were obtained on arterial and coronary sinus blood lactate, pyruvate, P(O2), P(CO2), and pH, and on myocardial tissue lactate, pyruvate, and water content in the outer and inner halves of the free wall of the left ventricle. Results showed that in acute aortic insufficiency diastolic coronary flow decreased as a function of aortic diastolic pressure, but systolic coronary flow increased in such proportion that mean coronary flow did not decrease. With moderate reductions in aortic diastolic pressure due to aortic insufficiency, myocardial blood flow was judged to be nutritionally adequate in both the outer and inner regions of the left ventricle. With more severe reductions in aortic diastolic pressure, the inner region exihibited biochemical signs of anaerobic metabolism. The presence of these metabolic changes could be correlated with either of two previously described pressure indexes. These findings suggest that the reduced coronary perfusion pressure and the intramyocardial tissue pressure gradient can be compensated for by autoregulation in some cases of aortic insufficiency, but in others such compensation may be incomplete, in which case oxygen delivery to the subendocardium will be inadequate to meet local tissue oxygen needs.     

Kinetics of adipose tissue microdialysis-derived metabolites in critically ill septic patients: associations with sepsis severity and clinical outcome

Microdialysis (MD) provides the opportunity to monitor tissue metabolic changes. This study aimed to describe the kinetics of MD-derived metabolites during the course of critical sepsis, to assess whether these metabolites are useful in grading sepsis severity, and to investigate their prognostic use. To this end, 54 mechanically ventilated septic patients were prospectively studied, out of which 39 had shock. Upon sepsis onset, an MD catheter was inserted into the subcutaneous adipose tissue of the upper thigh. Dialysate samples were analyzed for glucose, pyruvate, lactate, and glycerol. Sampling was performed six times per day for a maximum of 6 days. The daily mean values of MD measurements were calculated for each patient. Arterial blood was analyzed for glucose, lactate, and glycerol concomitantly with dialysate sampling. Blood glucose and tissue glucose levels along with lactate levels were high during the entire study period. Tissue pyruvate and glycerol were also raised, whereas the lactate-pyruvate ratio was preserved. At study entry, patients with septic shock had higher tissue lactate (3.3 vs. 1.9 mmol/L, P = 0.01) and glycerol (340 vs. 169 μmol/L, P = 0.04) levels compared with those without shock. Nonsurvivors had higher tissue lactate (P = 0.008), glycerol (P = 0.004), and pyruvate (P = 0.002) levels than survivors during the whole observation period. Logistic regression analysis showed that age (odds ratio [OR], 1.075; 95% confidence interval [CI], 1.004-1.150; P = 0.03), Sequential Organ Failure Assessment score on day 1 (OR, 1.550; 95% CI, 1.043-2.312; P = 0.03), and tissue glycerol on day 1 (OR, 1.007; 95% CI, 1.001-1.012; P = 0.01) predicted mortality independently. In conclusion, critical sepsis is characterized by high tissue lactate and pyruvate levels and a preserved lactate-pyruvate ratio, suggesting a nonischemic mechanism for raised blood lactate levels. Septic shock is associated with higher tissue lactate and glycerol levels compared with sepsis without shock. Elevated tissue lactate, pyruvate, and glycerol levels are related to poor clinical outcome, with the latter constituting an independent predictor.     

Abnormal coronary vascular response to exercise in dogs with severe right ventricular hypertrophy.

Measurements of right coronary artery blood flow, aortic and right ventricular (RV) pressures and heart rate were radiotelemetered during strenuous, spontaneous exercise in normal dogs and dogs with severe RV hypertrophy induced by chronic (5-6 mo) pulmonary artery stenosis. With fixed pulmonic stenosis, dogs with RV hypertrophy exhibited a decrease (P less than 0.01) in arterial pressure during exercise. Under these conditions, exercise increased right coronary artery blood flow and decreased right coronary vascular resistance less (P less than 0.05) in dogs with RV hypertrophy compared with normal. This attenuated response of right coronary artery blood flow of dogs with RV hypertrophy was not observed when arterial pressures remained at preexercise values during exercise. However, regardless of changes in arterial pressures during exercise, all dogs with RV hypertrophy demonstrated a striking postexercise coronary hyperemia (P less than 0.01), suggesting a perfusion deficit of the hypertrophied right ventricle during exercise. These results imply a fundamental defect in the ability of the coronary circulation of the severely hypertrophied right ventricle to provide sufficient nutrient supply in the face of elevated metabolic demands of exercise.     

递增负荷运动下血乳酸丙酮酸的动态变化规律及乳酸阈机制探讨

背景:作者曾提出:“运动中有氧产能过程与当时耗能过程不匹配是代谢发生转变的原因;而丙酮酸转化成乳酸的直接作用是防止丙酮酸在胞浆内堆积,防止其堆积对糖酵解产能过程的抑制,以保证酵解过程的快速供能;这一步生化反应的机制是对畅通糖代谢酵解途径供能速率的调节”的假说。目的:观察补充吸氧对代谢转变有无影响,分别从人体和动物水平上探讨乳酸阈强度(代谢转变时)下代谢转变的机制,验证人体和动物结果的一致性。设计:随机对照观察。单位:河北师范大学体育学院,廊坊师范学院体育系。对象:受试者为24名体育专业本科男生,体质量为(58±4)kg,身高为(175±6)cm,年龄(21±2)岁,二级运动员12人,无等级学生12人;雄性SD大鼠30只。方法:整体实验于2006-04/06河北师范大学体育学院运动生理机能实验室完成。24名学生分为二级运动员组和无等级训练组,各12名,进行递增负荷功率自行车运动;选取30只SD大鼠随机分为负重游泳训练组15只,无负重游泳适应组15只,负重游泳训练组进行递增负荷游泳运动。首先确定人体组与大鼠组各自的代谢转变强度,后在正常吸空气与补充吸氧条件下重复其前一阶段运动。分别在重复运动前及递增负荷运动到乳酸阈强度下,测定人体及大鼠的静脉血氧分压、丙酮酸、乳酸含量。人体组每2min递增负荷50W,大鼠组每2min递增负荷是体质量的1%,直至不能坚持为止。选择递增负荷运动方法,让体内代谢逐步由有氧向无氧代谢过度,确定过度点即乳酸阈强度。通过静脉血氧分压、丙酮酸、乳酸含量的前后对比和补充与否对各指标有无影响,以及人体和动物的结果是否一致,以证明假说的信度和效度。主要观察指标:人体组和大鼠组乳酸阈强度下及补充吸氧前后的静脉血氧分压、丙酮酸、乳酸含量。结果:受试者24名和30只大鼠全部进入结果分析。①人体受试者(两组)和30只大鼠(两组)在递增负荷运动中每级负荷2min末取血所得到的乳酸曲线,明显反映出了血乳酸拐点所对应的代谢转变强度及训练水平的差异,有训练者的血乳酸拐点明显置后。②在乳酸阈强度下,不论是否吸氧,人体组和大鼠组的血乳酸含量与氧分压之间均不相关[(3.61±0.56),(5.43±0.55)mmol/L;(4.46±0.86),(7.80±0.27)kPa,r=0.31,0.31,P>0.05],整个测试过程人体组血氧饱和度均不低于98%;而两组受试血乳酸与血丙酮酸含量之间差异均有非常显著性意义[丙酮酸:(1.04±0.16),(0.91±0.37)mmol/L,P<0.001]。③人体组和大鼠组在重复运动前及乳酸阈强度下,丙酮酸平均值分别是(0.97±0.17),(1.04±0.16)mmol/L;(0.93±0.25),(0.91±0.37)mmol/L。两组受试重复运动前与乳酸阈强度时的血丙酮酸含量差异均无显著性意义(P>0.05)。结论:运动中由有氧向无氧代谢转变时体内不缺氧,补充吸氧对代谢的转变没有影响;丙酮酸不易通过肌细胞膜而乳酸可以通过。实验结果支持丙酮酸转化成乳酸的直接作用是防止丙酮酸在胞浆内堆积的观点。     

Decreasing gut wall glucose as an early marker of impaired intestinal perfusion

OBJECTIVE: The aim of this study was to assess the microcirculatory and metabolic consequences of reduced mesenteric blood flow. DESIGN: Prospective, controlled animal study. SETTING: The surgical research unit of a university hospital. SUBJECTS: A total of 13 anesthetized and mechanically ventilated pigs. INTERVENTIONS: Pigs were subjected to stepwise mesenteric blood flow reduction (15% in each step, n = 8) or served as controls (n = 5). Superior mesenteric arterial blood flow was measured with ultrasonic transit time flowmetry, and mucosal and muscularis microcirculatory perfusion in the small bowel were each measured with three laser Doppler flow probes. Small-bowel intramucosal Pco2 was measured by tonometry, and glucose, lactate (L), and pyruvate (P) were measured by microdialysis. MEASUREMENTS AND MAIN RESULTS: In control animals, superior mesenteric arterial blood flow, mucosal microcirculatory blood flow, intramucosal Pco2, and the lactate/pyruvate ratio remained unchanged. In both groups, mucosal blood flow was better preserved than muscularis blood flow. During stepwise mesenteric blood flow reduction, heterogeneous microcirculatory blood flow remained a prominent feature (coefficient of variation, approximately 45%). A 30% flow reduction from baseline was associated with a decrease in microdialysis glucose concentration from 2.37 (2.10-2.70) mmol/L to 0.57 (0.22-1.60) mmol/L (p < .05). After 75% flow reduction, the microdialysis lactate/pyruvate ratio increased from 8.6 (8.0-14.1) to 27.6 (15.5-37.4, p < .05), and arterial-intramucosal Pco2 gradients increased from 1.3 (0.4-3.5) kPa to 10.8 (8.0-16.0) kPa (p < .05). CONCLUSIONS: Blood flow redistribution and heterogeneous microcirculatory perfusion can explain apparently maintained regional oxidative metabolism during mesenteric hypoperfusion, despite local signs of anaerobic metabolism. Early decreasing glucose concentrations suggest that substrate supply may become crucial before oxygen consumption decreases.     

Jejunal luminal microdialysate lactate in cardiac tamponade--effect of low systemic blood flow on gut mucosa

OBJECTIVE: To assess gut mucosal metabolic response and susceptibility to dysoxia during low systemic blood flow induced by cardiac tamponade. DESIGN: A randomized, controlled animal experiment. SETTING: National laboratory animal center. INTERVENTIONS: Cardiac tamponade was induced in six pigs, while six additional pigs served as controls. In the tamponade group, fluid was injected into the pericardial space to reduce aortic flow, aiming first at a flow of 50 ml/kg per min and then at 30 ml/kg per min. Each step lasted for 60 min. MEASUREMENTS AND RESULTS: We measured luminal lactate by microdialysis and mucosal PCO(2) by tonometry in the mid-jejunum. Aortic and superior mesenteric artery blood flow, arterial and mesenteric venous lactate, pyruvate and ketone bodies and regional lactate exchange were measured. The distribution of aortic blood flow to superior mesenteric artery remained unchanged (baseline 14 (12-16)%; median (interquartile range), stepwise flow reduction 11 (10-17)% and 13 (12-19)%, NS) during reduction of aortic blood flow from 81 (61-95) ml/kg per min to 49 (47-49) ml/kg per min and 23 (21-27) ml/kg per min. Systemic hyperlactatemia developed early, whereas gut luminal lactate increased only after 60 min of hypoperfusion and could be largely explained by arterial hyperlactatemia. Mesenteric venous lactate-to-pyruvate (L/P) ratio increased after 30 min of tamponade, but both venous-arterial lactate and pyruvate gradients turned negative (gut lactate and pyruvate uptake). Mesenteric venous ss-hydroxybutyrate to acetoacetate ratio increased after 60 min. No changes were observed in the controls. CONCLUSIONS: Jejunal mucosal dysoxia and anaerobic metabolism occurs late during low systemic blood flow induced by experimental cardiac tamponade.     

Plasma acetate concentrations during canine haemorrhagic shock.

Acetate, pyruvate, lactate and NEFA concentrations, as well as acid-base-parameters were followed during bleeding, stable hypotension and re-infusion in five dogs. Mean arterial blood pressures were kept at 30 mmHg during the shock phase. An increase in acetate concentrations (P less than 0.01) was found in arterial as well as in venous plasma samples. The maximal mean acetate concentration was 0.19 mmol/l (during reinfusion) as compared to 0.06 mmol/l prior to bleeding. There was no difference between arterial and inferior caval venous concentrations. A definite correlation (r = 0.81, P less than 0.02) was found between blood pyruvate and plasma acetate concentrations. There was no correlation between plasma glucose or NEFA and acetate concentrations or between blood excess lactate and plasma acetate. The plasma acetate accumulation was negligible compared to the concomitant lactate accumulation (1:60), and did not contribute to the metabolic acidosis of shock. The correlation between acetate and pyruvate concentrations may indicate that pyruvate is the main substrate of acetate production in hypovolemic shock.     

Acidosis induced by lactate,pyruvate, or HCl increases blood viscosity

PURPOSE: Serum lactate correlates with the severity of disease and the mortality in shock. It is not clear if lactate is only a marker or a mediator of disease. We tested the hypothesis that acidosis induced by lactate and pyruvate affects blood flow properties. MATERIALS AND METHODS: Human blood was incubated with additional lactate (0-50 mmol/L) or pyruvate (0-25 mmol/L) for 1 hour at 37 degrees C. Blood viscosity was measured at high (94.5 s(-1)) and low (0.1 s(-1)) shear rate. Hematocrit was measured with an electronic particle counter as well as centrifugation. RESULTS: A total of 50 mmol/L additional lactate produced acidosis (pH 6.4) and increased whole-blood viscosity at high shear rate (94.5 s(-1): 6.53 +/- 0.51 mPa.s vs 4.94 +/- 0.18 mPa.s for control, n = 5, P <.001) and low shear rate (0.1 s(-1): 93.9 +/- 18.6 mPa.s vs 53.5 +/- 7.7 mPa.s, n = 5, P <.001). Simultaneously, an increased centrifuged hematocrit was observed (about 7% with 50 mmol/L lactate, P <.001), indicating eryth-rocyte swelling. These changes were reversible on removal of lactate. The addition of 25 mmol/L pyruvate also induced acidosis and increased blood viscosity and centrifuged hematocrit. When HCl was used to induce a comparable pH level decrease, a similar increase in blood viscosity and hematocrit were observed. CONCLUSIONS: Pronounced acidosis induced by either lactate, pyruvate, or HCl impairs blood flow properties, which may contribute to the understanding of the pathophysiology of critical illness.     

Treatment of Lactic Acidosis with Dichloroacetate in Dogs

Lactic acidosis is a clinical condition due to accumulation of H(+) ions from lactic acid, characterized by blood lactate levels >5 mM and arterial pH <7.25. In addition to supportive care, treatment usually consists of intravenous NaHCO(3), with a resultant mortality >60%. Dichloroacetate (DCA) is a compound that lowers blood lactate levels under various conditions in both man and laboratory animals. It acts to increase pyruvate oxidation by activation of pyruvate dehydrogenase. We evaluated the effects of DCA in the treatment of two different models of type B experimental lactic acidosis in diabetic dogs: hepatectomy-lactic acidosis and phenformin-lactic acidosis. The metabolic and systemic effects examined included arterial blood pH and levels of bicarbonate and lactate; the intracellular pH (pHi) in liver and skeletal muscle; cardiac index, arterial blood pressure and liver blood flow; liver lactate uptake and extrahepatic splanchnic (gut) lactate production; and mortality. Effects of DCA were compared with those of either NaCl or NaHCO(3). The infusion of DCA and NaHCO(3), delivered equal amounts of volume and sodium, although the quantity of NaHCO(3) infused (2.5 meq/kg per h) was insufficient to normalize arterial pH.In phenformin-lactic acidosis, DCA-treated animals had a mortality of 22%, vs. 89% in those treated with NaHCO(3). DCA therapy increased arterial pH and bicarbonate, liver pHi and cardiac index, with increased liver lactate uptake and a fall in blood lactate. With NaHCO(3) therapy, there were decrements of cardiac index and liver pHi, with an increase in venous pCO(2) and gut production of lactate.Dogs with hepatectomy-lactic acidosis were either treated or pretreated with DCA. Treatment with DCA resulted in stabilization of cardiac index, a fall in blood lactate, and 17% mortality. NaHCO(3) was associated with a continuous decline of cardiac index, rise in blood lactate, and 67% mortality. In dogs pretreated with NaCl, mortality was 33%, but all dogs pretreated with DCA survived. Dogs pretreated with DCA also had lower blood lactate and higher arterial pH and bicarbonate than did those pretreated with NaCl.Thus, in either of two models of type B experimental lactic acidosis, treatment with DCA improves cardiac index, arterial pH, bicarbonate and lactate, and liver pHi. The mortality in dogs with type B lactic acidosis was significantly less in DCA-treated animals than in those treated with other modalities.     

Effects of the correction of renal anaemia by erythropoietin on physiological changes during exercise

Abstract. The effects of treating the anaemia of end-stage renal failure with erythropoietin were studied in nine dialysis patients. The increase in haemoglobin concentration (by 59% from 7.0 ± 1.2 to 11.1 ± 1.1 g dl^-1) was associated with increases in exercise duration (by 41%) and maximum oxygen consumption (by 34%). Treatment reduced resting heart rate but did not significantly alter heart rate at maximum exercise, nor resting or exercise blood pressure. Resting arterial potassium concentrations were slightly increased after treatment, but they increased similarly in relation to minute ventilation during exercise. Lactic acidaemia developed during exercise at both levels of haemoglobin, and was accompanied by similar reductions in arterial pH and bicarbonate levels but constant Pao₂ and Paco₂. Ventilation was coupled to the metabolic rate of carbon dioxide production, ventilatory dead-space and arterial Pco₂ before and after treatment of anaemia, the ventilatory requirement for carbon dioxide elimination being unchanged. Treatment of anaemia did not alter resting arterial lactate concentration; the concentration of lactate at maximum exercise was increased slightly following treatment but this increase did not reach statistical significance. The rate of increase in arterial lactate concentration as a function of oxygen consumption, assessed both with respect to the 'lactate threshold' and 'lactate slope index', was significantly delayed by treatment. Treatment of anaemia also delayed the 'anaerobic threshold', and there was good correlation between lactate and anaerobic thresholds. Treatment of renal anaemia by erythropoietin thus results in improved tissue oxygen supply during exercise, reflected by delay in the onset of lactic acidaemia.     

Comparison of Cardiac Output Responses to 2,4-Dinitrophenol-Induced Hypermetabolism and Muscular Work

Both electrically induced exercise and infusion of 2,4-dinitrophenol (DNP) increased oxygen consumption and tissue metabolism in chloralose-anesthetized dogs. Cardiac output increased with oxygen consumption at the same rate in both experimental conditions. The increase in cardiac output induced by exercise was, as expected, accompanied by increases in both lactate-to-pyruvate ratio and "excess lactate" in arterial blood. However, these parameters did not increase after DNP infusion until the rate of oxygen consumption had increased four- to fivefold, perhaps due to facilitation of mitochondrial electron transport by DNP. Anaerobic tissue metabolism therefore probably did not contribute significantly to increased cardiac output during the mild-to-moderate tissue hypermetabolism induced by DNP. The increased cardiac output may have been the result of metabolic changes common to both exercise and DNP infusion; muscular activity alone may not have been the primary determinant of the cardiac output response during exercise.     

Depletion of lactate by dichloroacetate reduces cardiac efficiency after hemorrhagic shock

We have demonstrated previously that dichloroacetate (DCA) treatment in rodents ameliorates, via activation of the pyruvate dehydrogenase complex, the cardiovascular depression observed after hemorrhagic shock. To explore the mechanism of this effect, we administered DCA in a large animal model of hemorrhagic shock. Mongrel hounds were anesthetized with 1.5% isoflurane and were measured for hemodynamics, myocardial contractility, and myocardial substrate utilization. They were hemorrhaged to a mean arterial pressure of 35 mm Hg for 90 min or until arterial lactate levels reached 7.0 mM (1137 +/- 47 mL or 49 +/- 2% total blood volume). Animals were chosen at random to receive DCA dissolved in water or an equal volume of saline at the onset of resuscitation. Two-thirds of the shed blood volume was returned immediately after giving an equivalent volume of saline. Two hours after the onset of resuscitation, mean arterial pressure was not different between DCA and control groups (79 +/- 3 vs. 82 +/- 3 mm Hg, respectively). Arterial lactate levels were significantly reduced by DCA (0.5 +/- 0.06 vs. 2.0 +/- 0.2 mM). However, DCA treatment was associated with a decreased stroke volume index (0.56 +/- 0.06 vs. 0.82 +/- 0.08 mL/kg/beat) and a decreased myocardial efficiency (19 vs. 41 L x mm Hg/mL/100 g tissue). During resuscitation by DCA, myocardial lactate consumption was reduced (21.4 +/- 3.7 vs. 70.7 +/- 16.3 micromole/min/100 g tissue) despite a three-fold increase in myocardial pyruvate dehydrogenase activity, while free fatty acid levels actually began to rise. Although increased lactate oxidation should be beneficial during resuscitation, we propose that DCA treatment led to a deprivation of myocardial lactate supply, which reduced net myocardial lactate oxidation, thus compromising myocardial function during resuscitation from hemorrhagic shock.     

Pulmonary lactate release in patients with acute lung injury is not attributable to lung tissue hypoxia

OBJECTIVE: To determine whether pulmonary lactate production in patients with acute lung injury is attributable to lung tissue hypoxia. DESIGN: Prospective, controlled, clinical study. SETTING: A multidisciplinary university intensive care unit in a general hospital. PATIENTS: Seventy consecutive critically ill patients requiring mechanical ventilation and invasive hemodynamic monitoring. Of these patients, 18 had no acute lung injury (no ALI); 33 had acute lung injury (ALI) (Lung Injury Score [LIS] < or =2.5); and 19 had acute respiratory distress syndrome (ARDS) (LIS >2.5). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After hemodynamic measurements, lactate and pyruvate concentrations were assessed in simultaneously drawn arterial (a) and mixed venous (v) blood samples. Pulmonary lactate release was calculated as the product of transpulmonary a-v lactate difference (L[a-v]) times the cardiac index. Two indices of anaerobic metabolism of the lung, i.e., the transpulmonary a-v difference of lactate pyruvate ratio (L/P[a-v]) and excess lactate formation across the lungs (XL), were calculated. L(a-v) and pulmonary lactate release were higher in patients with ARDS than in the other groups (p<.001), and they were also higher in patients with ALI compared with patients with no ALI (p<.001). In patients with ALI and ARDS (n = 52), pulmonary lactate release correlated significantly with LIS (r2 = .14, p<.01) and venous admixture (r2 = .13, p<.01). When all patients were lumped together (n = 70), pulmonary lactate release directly correlated with LIS (r2 = .30, p<.001), venous admixture (r2 = .26, p<.001), and P(A-a)O2 (r2 = .14, p<.01). Neither L/P(a-v) nor XL was significantly different among the three groups. CONCLUSION: The lungs of patients with ALI produce lactate that is proportional to the severity of lung injury. This lactate production does not seem to be attributable to lung tissue hypoxia.     

Blood metabolite data in response to maximal exercise in healthy subjects

Maximal exercise test with gas exchange measurement evaluates exercise capacities with maximal oxygen uptake (VO(2) max) measurement. Measurements of lactate (L), lactate/pyruvate ratio (L/P) and ammonium (A) during rest, exercise and recovery enhance interpretative power of maximal exercise by incorporating muscular metabolism exploration. Maximal exercise test with gas exchange measurement is standardized in cardiopulmonary evaluations but, no reference data of blood muscular metabolites are available to evaluate the muscular metabolism. We determined normal values of L, L/P and A during a standardized maximal exercise and recovery in 48 healthy sedentary volunteers and compared with results obtained in four patients with exercise intolerance and a mitochondrial disease. In healthy subjects, L, L/P and A rose during exercise. In 98% of them L, L/P or A decreased between the fifth and the fifteenth minutes of recovery. In mitochondrial patients, VO(2) max was normal or low, and L, L/P and A had the same evolution as normal subjects or showed no decrease during recovery. We gave normal L, L/P and A values, which establish references for a maximal exercise test with muscular metabolism exploration. This test is helpful for clinicians in functional evaluation, management and treatment of metabolic myopathy and would be a useful tool in diagnosis of metabolic myopathy.     

动—静脉血PH和二氧化碳分压差监测组织氧合的实验研究

研究家兔（ｎ＝１０）急性失血过程中组织供氧量（ＤＯ２）、动脉混合静脉血（ＡＶ）ｐＨ和ＰＣＯ２差的关系，并与血乳酸浓度改变相比较。结果发现，随心输出量（Ｑ）降低，ＡＶｐＨ、ＡＶＨ＋、ＡＶＰＣＯ２进行性增大，血乳酸浓度逐渐升高。失血量和ＡＶｐＨ、ＡＶＨ＋、ＡＶＰＣＯ２以及血乳酸浓度呈双相关系，三者拐折点基本相同。因此，前期相当于“组织耗氧（ＶＯ２）不依赖ＤＯ２”期，即ＶＯ２不随ＤＯ２增减而改变；后期相当于“ＶＯ２依赖ＤＯ２”期，即ＶＯ２随ＤＯ２增减，拐折点相当于临界供氧量（ＤＯ２ｃｒｉｔ）。ＡＶｐＨ和ＡＶＰ－ＣＯ２突然增大提示“ＶＯ２依赖ＤＯ２，即组织缺氧的开始。提示：ＡＶｐＨ和ＡＶＰＣＯ２迅速增大主要与缺氧组织Ｈ＋和ＣＯ２生成增加有关，因此是组织缺氧的可靠指标     

Lactic acidosis as a complication of β-adrenergic aerosols

Lactic acidosis is a marker of tissue hypoperfusion and impairs oxygen delivery. High lactate levels are associated with altered systemic hemodynamics, tissue hypoperfusion, and altered cellular metabolism. Increased lactate levels have also been reported as a complication of β-adrenergic agents administered during asthma therapy. A 49-year-old woman with a prior diagnosis of asthma presented to the emergency department in respiratory distress. She immediately received, in 2 hours, 4 bronchodilator aerosols (ipratropium bromide 0.5 mg/2 mL and terbutaline 5 mg/2 mL) and methylprednisolone intravenous (120 mg). After these 4 aerosols, she was still dyspneic. First, arterial blood gases (pH 7.38; PCO2, 3.92 kPa; HCO3, 19.2 mmol/L) and arterial lactate (lactate, 7.96 mmol/L) were performed with a second series of 4 aerosols. Second, arterial blood gases (pH 7.29; PCO2, 4.01 kPa; HCO3, 15.4 mmol/L) and arterial lactate (lactate, 10.47 mmol/L) were performed at the end of the second series of aerosols. There was no hypoxemia, no inadequate cardiac output state, no anemia, no sepsis, and no use of biguanides. Previous studies have suggested that administration of β agonists can lead to lactic acidemia in the absence of hypoxia or shock, but it is the highest level of lactate that we found in the literature. In sepsis and shock, lactic acidosis is used as a marker of disease severity. In this case, it is not necessarily the sign of an immediate gravity.     

Evolution of lactate/pyruvate and arterial ketone body ratios in the early course of catecholamine-treated septic shock

OBJECTIVES: To measure arterial lactate/pyruvate (L/P) and arterial ketone body ratios as reflection of cytoplasmic and mitochondrial redox state at different stages of catecholamine-treated septic shock and compare them with normal and pathologic values obtained in patients in shock who have decreased oxygen transport (cardiogenic shock), and to assess the relationship between the time course of lactate, L/P ratio, and mortality in septic shock. DESIGN: Prospective, observational human study. SETTING: A university intensive care unit. PATIENTS: Sixty consecutive adult patients who developed septic shock and lactic acidosis requiring the administration of vasopressors. Twenty patients in the intensive care unit without shock, sepsis, and hypoxia and with normal lactate values and 10 patients with cardiogenic shock were also studied. MEASUREMENTS: Hemodynamic measurements, arterial and mixed venous blood gases, arterial lactate and pyruvate concentrations, and arterial ketone body ratio were measured within 4 hrs after the introduction of catecholamine and 24 hrs later. MAIN RESULTS: Fifteen patients (25%) died within the first 24 hrs of septic shock, and these early fatalities had a higher blood lactate (12.2+/-3 versus 4.6+/-1.3 mmol/L; p<.01) concentration and a higher L/P ratio (37+/-4 versus 20+/-1; p<.01) than those who died later. No difference was found for arterial ketone body ratio (0.41+/-0.1 versus 0.50+/-0.06). Forty-five patients survived >24 hrs including 25 survivors and 20 nonsurvivors. Although there was no difference between survivors and nonsurvivors in initial lactate concentration (4.1+/-0.4 and 4.6+/-0.3, respectively), L/P ratio (19+/-1 and 20+/-1, respectively), and arterial ketone body ratio (0.5+/-0.06 and 0.52+/-0.07, respectively), blood lactate and L/P ratio significantly decreased during the first 24 hrs in the survivors (2.8+/-0.4 and 14+/-1, respectively; p<.05). and were stable in the nonsurvivors (4+/-0.3 and 22+/-1, respectively) Although returning to normal values after 24 hrs in survivors and nonsurvivors, arterial ketone body ratio was higher in survivors (1.72+/-0.17 versus 1.09+/-0.15; p<.05). Lactate and L/P ratio were closely correlated (r2 = .8, p<.0001). In the cardiogenic shock group, lactate concentration was 4+/-1 mmol/L, L/P ratio was 40+/-6, and arterial ketone body ratio was 0.2+/-0.05. The mortality rate was 60%. CONCLUSIONS: The main result of the present study is that hemodynamically unstable patients with sepsis needing catecholamine therapy had a lactic acidosis with an elevated L/P ratio and a decreased arterial ketone body ratio, suggesting a decrease in cytoplasmic and mitochondrial redox state. The duration of lactic acidosis is associated with the development of multiple organ failure and death.