Lactic acidosis during sepsis is related to increased pyruvate production, not deficits in tissue oxygen availability.

OBJECTIVE. The purpose of this study was to quantitate the derangements in intermediary carbohydrate metabolism and oxygen use in severely septic patients in comparison with healthy volunteers. SUMMARY BACKGROUND DATA. It commonly has been assumed that the development of lactic acidosis during sepsis results from a deficit in tissue oxygen availability. Dichloroacetate (DCA), which is known to increase pyruvate oxidation but only when tissue oxygen is available, provides a means to assess the role of hypoxia in lactate production. METHODS. Stable isotope tracer methodology and indirect calorimetry was used to determine the rates of intermediary carbohydrate metabolism and oxygen use in five severely septic patients with lactic acidosis and six healthy volunteers before and after administration of DCA. RESULTS. Oxygen consumption and the rates of glucose and pyruvate production and oxidation were substantially greater (p < 0.05) in the septic patient compared with healthy volunteers. Administration of DCA resulted in a further increase in oxygen consumption and the percentage of glucose and pyruvate directed toward oxidation. Dichloroacetate also decreased glucose and pyruvate production, with a corresponding decrease in plasma lactate concentration. CONCLUSIONS. These findings clearly indicate that the accumulation of lactate during sepsis is not the result of limitations in tissue oxygenation, but is a sequelae to the markedly increased rate of pyruvate production. Furthermore, the substantially higher rate of pyruvate oxidation in the septic patients refutes the notion of a sepsis-induced impairment in pyruvate dehydrogenase activity.     

Improving myocardial metabolic and functional recovery after cardioplegic arrest

The myocardial oxidation of fatty acids and glucose, the predominant substrates for aerobic metabolism, is impaired after cardioplegic arrest for coronary revascularization. Because lactate can be readily metabolized to pyruvate, it may be the preferred substrate for aerobic metabolism after cardioplegic arrest when arterial concentrations are elevated. Nineteen patients undergoing elective coronary revascularization with blood cardioplegia were randomized to receive LOW (nine patients, no exogenous lactate) or HIGH (10 patients, a perioperative infusion of Ringer's lactate) arterial lactate concentrations. Coronary sinus catheterization and lactate labeled with carbon 14 permitted calculation of myocardial oxygen consumption and lactate oxidation which were significantly increased during reperfusion in the group with HIGH arterial lactate concentrations. Atrial pacing at 110 beats/min on cardiopulmonary bypass resulted in myocardial lactate production (suggesting ischemic anaerobic metabolism) in the LOW lactate group, but atrial pacing increased lactate consumption and oxidation in the HIGH lactate group (suggesting increased aerobic metabolism). Systolic function (the relation between end-systolic pressure and volume) as assessed by nuclear ventriculography 3 hours postoperatively was significantly better (p less than 0.05 by analysis of covariance) in the HIGH lactate group. Postoperative myocardial creatine kinase release was significantly lower in the HIGH lactate group, which suggested less perioperative ischemic injury. Lactate was the preferred substrate for myocardial oxidative metabolism after cardioplegic arrest, and the higher arterial lactate concentrations improved myocardial metabolic and functional recovery and reduced perioperative ischemic injury.     

七氟醚与异丙酚对颅内动脉瘤夹闭术患者脑能量代谢影响的比较

目的 比较七氟醚与异丙酚对颅内动脉瘤夹闭术患者脑能量代谢的影响.方法 择期拟行颅内动脉瘤夹闭术的患者68例,ASA分级Ⅱ级或Ⅲ级,年龄22 ～ 62岁,体重52～81 kg,Hunt- Hess 分级Ⅱ或Ⅲ级,采用随机数字表法,将其随机分为2组(n=34):异丙酚组(P组)和七氟醚组(S组).麻醉诱导时P组靶控输注异丙酚,血浆靶控浓度2.0 μg/ml,S组吸入8％七氟醚.麻醉维持时P组靶控输注异丙酚,血浆靶浓度1.5 μg/ml,S组吸入2％七氟醚.于临时阻断前5 min(T0)、临时阻断5 min(T1)、10min(T2)、15 min(T3)、动脉瘤夹闭10 min (T4)、20 min (T5)和40 min (T6)时,收集脑组织微透析液,采用邻苯二甲醛柱前衍生反相高效液相色谱分析法结合荧光法检测微透析液葡萄糖、乳酸和丙酮酸浓度,计算乳酸/丙酮酸比(L/P比).结果 与P组比较,S组T1～ T6时微透析液葡萄糖、乳酸和丙酮酸浓度升高,T2～T4时L/P比降低(P＜0.05).与T0时比较,两组T1～T6时微透析液葡萄糖浓度降低,乳酸浓度升高,T1～T4时丙酮酸浓度降低,T5、T6时丙酮酸浓度升高,T1～T5时L/P比升高(P＜0.05);与T3时比较,两组T～T6时微透析液葡萄糖浓度和丙酮酸浓度升高,L/P比降低,T5、T6时乳酸浓度降低(P＜0.05).结论 七氟醚改善颅内动脉瘤夹闭术患者脑能量代谢的效果优于异丙酚.     

The effect of glucose administration on carbohydrate metabolism after head injury

The role of intravenous infusion of glucose in limiting ketogenesis and the effect of glucose on cerebral metabolism following severe head injury were studied in 21 comatose patients. The patients were randomly assigned to alimentation with or without glucose. Systemic protein wasting, arterial concentrations of energy substrates, and cerebral metabolism of these energy substrates were monitored for 5 days postinjury. Both groups were in negative nitrogen balance, and had wasting of systemic proteins despite substantial protein intake. Blood and cerebrospinal fluid (CSF) glucose concentrations were highest on Day 1, but remained higher than normal fasting levels on all days of study, even in the patients who received no exogenous glucose. Although there were no differences in blood or CSF glucose concentrations in the two groups of patients, the glucose group had higher plasma insulin levels, with a mean +/- standard deviation of 14.8 +/- 7.3 microU/ml compared to 10.3 +/- 4.2 microU/ml in the saline group. The blood concentrations of beta-hydroxybutyrate, acetoacetate, pyruvate, glycerol, and the free fatty acids were higher in the saline group than in the glucose group. Cerebral oxygen consumption was similar in the two groups, while the cerebral metabolism of glucose and of the ketone bodies was dependent on whether glucose was administered. In the glucose group, glucose was the only energy substrate utilized by the brain. In the saline group, the ketone bodies beta-hydroxybutyrate and acetoacetate replaced glucose to the extent of 16% of the brain's total energy production. Cerebral lactate production and CSF lactate concentration were lower in the saline group. These studies suggest that administration of glucose during the early recovery period of severe head injury is a major cause of suppressed ketogenesis, and may increase production of lactic acid by the traumatized brain by limiting the availability of nonglycolytic energy substrates.     

Acute dichloroacetate administration increases skeletal muscle free glutamine concentrations after burn injury.

OBJECTIVE: To investigate the hypothesis that the stimulation of pyruvate oxidation by dichloroacetate (DCA) administration would increase the level of intramuscular glutamine in severely burned patients. SUMMARY BACKGROUND DATA: The level of intramuscular glutamine decreases in response to severe injury, and the rate of intramuscular glycolysis and pyruvate oxidation is elevated. Intramuscular glutamine concentrations have been correlated to muscle protein synthesis. METHODS: Six studies were conducted on five patients with burns >40% total body surface area. Patients were studied in the fed state during an 8-hour stable isotope infusion. After 5 hours, DCA (30 mg/kg) was administered for 30 minutes. RESULTS: Analysis of muscle biopsy samples taken at 5 and 8 hours of the study revealed a 32% increase in intracellular glutamine levels after DCA administration. Increased intracellular glutamine concentrations did not affect skeletal muscle protein synthesis as determined by a three-pool arteriovenous model or by the direct incorporation of isotope into skeletal muscle protein. DCA administration resulted in a decrease in plasma lactate but no change in alanine de novo synthesis or intracellular concentration. CONCLUSIONS: These results suggest that acute DCA administration can increase intramuscular glutamine concentration, but that this acute elevation does not affect muscle protein metabolism.     

Alterations in cerebral availability of metabolic substrates after severe head injury

Cerebral and systemic metabolism of oxygen, glucose, lactate, pyruvate, beta-hydroxybutyrate, acetoacetate, and amino acids were studied in 27 comatose patients during the first 7 days after a head injury. Systemic oxygen consumption was elevated initially and gradually returned toward normal over the week of study. In contrast, cerebral oxygen consumption was depressed and decreased further over the week of study. Cardiac output and cerebral blood flow were increased with respect to systemic and cerebral metabolic requirements, and remained elevated for the entire week of study. Systemic hyperglycemia and lactic acidosis were present. The injured brain often made a sizeable contribution to the lactic acidosis. The arterial concentrations of pyruvate, beta-hydroxybutyrate and acetoacetate were low. The early postinjury arterial amino acid profile was typically an increased level of alanine, taurine, glutamic acid, and a reduced concentration of valine, leucine, isoleucine, threonine, serine, ornithine, and arginine. At 3-4 days postinjury, as the early abnormalities were returning toward normal, glutamine, lysine, phenylalanine, tyrosine, and methionine became elevated. These late increases in amino acids occurred at the time of the peak in plasma catecholamine concentrations. The net cerebral flux of amino acids followed the same general pattern of evolution over time as did the arterial concentration of amino acids. On days when the availability of the individual amino acid was increased, the net cerebral flux tended to be positive; when the availability was decreased, the net cerebral flux was zero or there was a net efflux of the amino acid. There was a significant linear relationship between the arterial concentration and the net flux of 13 of the 17 amino acids studied. Unlike the fasting state in normal man, in which beta-hydroxybutyrate and acetoacetate are important metabolic substrates, cerebral metabolism after head injury is almost totally dependent upon the aerobic and anaerobic metabolism of glucose. This is at least in part due to injury-induced limitations in the variety of substrates that are available for the brain to extract.     

Carbohydrate metabolism in potassium-depleted rats

Carbohydrate metabolism was examined in different organs of rats with dietary potassium deprivation for 4 weeks. Thereafter, a 24- or 48-hour starvation period caused a significant decrease of skeletal muscle and liver glycogen content in K+-depleted (KD) rats, whereas kidney glycogen concentration increased and heart glycogen remained unchanged. In contrast, liver glucose concentration was significantly higher in starved KD animals without changes in muscle, heart, and kidney glucose concentrations. Potassium depletion caused a highly significant decrease of plasma and muscle potassium concentrations, metabolic alkalosis, reduced plasma insulin, and increased creatine phosphokinase levels. Blood lactate, pyruvate, and oxoglutarate levels were significantly enhanced in fasted KD rats, whereas blood citrate, beta-hydroxybutyrate, and glucose concentrations were unchanged. Blood acetoacetate level, however, was significantly reduced following potassium depletion. Therefore, beta-hydroxybutyrate/acetoacetate ratio increased significantly, whereas lactate/pyruvate ratio was not influenced. Our results clearly indicate impaired carbohydrate metabolism in potassium-depleted rats.     

Isotopic evaluation of the metabolism of pyruvate and related substrates in normal adult volunteers and severely burned children: effect of dichloroacetate and glucose infusion

In this study we have assessed the hypothesis that there is a postreceptor defect in glucose metabolism that makes the severely burned patient unable to oxidize glucose efficiently as an energy source. The intracellular pyruvate pool was labeled by the infusion of 3-13C-lactate, and expired CO2 production and isotopic enrichment of both pyruvate and CO2 were determined to calculate the rate of pyruvate production and oxidation. 6,6-d2-Glucose and 15N-alanine were infused simultaneously to relate pyruvate kinetics and oxidation to glucose and alanine kinetics. Five normal volunteers and 10 severely burned patients (mean of 80% +/- 5% body surface burned) were studied in the basal state and during continuous (unlabeled) glucose infusion. Also, the effect of dichloroacetate, which normally stimulates pyruvate dehydrogenase activity, was assessed in both volunteers and patients. The burned patients had many of the classic metabolic responses to severe injury, including significant increases in resting energy expenditure, glucose production, and alanine release from protein breakdown. However, rather than being inhibited, the rate of pyruvate oxidation was increased approximately 300% in burned patients. Although the patients had an elevated mean concentration of lactate, stemming from increased lactate production, no deficit in pyruvate dehydrogenase activity was evident. Rather, the high rate of lactate production was apparently a consequence of the high rate of glycolysis. On the other hand, the direct pathway for synthesis of glycogen from infused glucose appeared to be impaired in burned patients. In both volunteers and patients, dichloroacetate stimulated the percent of pyruvate directed to oxidation, thereby reducing the conversion of pyruvate to other fates, including lactate. However, because there was no deficit in pyruvate dehydrogenase activity in the patients compared with normal volunteers before dichloroacetate treatment, no unique effect of dichloroacetate on glucose or protein kinetics was observed in burned patients. From these results we conclude that if there is a postreceptor defect in glucose metabolism in burned patients, it involves the pathway of direct glycogen synthesis and not the pathway of oxidation.     

Effects of insulin deprivation and replacement on in vivo subcutaneous adipose tissue substrate metabolism in humans

The effects of insulin deprivation and replacement on adipose tissue metabolism were investigated in vivo with microdialysis in nine insulin-dependent diabetic patients with no residual insulin secretion. Dialysis probes, implanted in abdominal subcutaneous fat, were continuously perfused, and tissue dialysate concentrations of glycerol (lipolysis index), glucose, lactate, and pyruvate were determined. Comparisons were made with respective metabolite levels in venous plasma. After termination of intravenous insulin infusion, free insulin in plasma fell from 130 to 70 pM. At the same time, glucose levels in plasma and adipose tissue rose in parallel. However, the relative increase in glucose levels was greater in adipose tissue than in blood. On the other hand, the increase in glycerol concentration in adipose tissue (35%) was markedly less than that in venous plasma (250%). Lactate and pyruvate levels in adipose tissue and blood remained unchanged. After the resumption of intravenous insulin, free insulin in plasma rose to approximately 600 pM. At the same time, the glucose levels in blood and adipose tissue decreased rapidly, and the glycerol concentration in these tissues decreased to 50% of the baseline levels. The lactate and pyruvate levels in subcutaneous tissue increased briefly after insulin replacement, whereas the lactate but not pyruvate levels in blood showed a similar increase. The alpha- or beta-blocking agents phentolamine and propranolol in the ingoing tissue perfusate did not influence tissue glycerol at any time during the experiment. We concluded that insulin-induced changes in circulating metabolites only partly reflect variations in adipose tissue substrate kinetics. During insulin deprivation, glucose is accumulated in the adipose tissue extracellular compartment, probably because of reduced utilization by the adipocytes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical study of arterial ketone body ratio (ACAC/beta-OHCS) during hepatectomy

The changes in arterial ketone body ratio (acetoacetate/beta-hydroxybutyrate) were investigated in 7 patients undergoing hepatectomy under epidural anesthesia with nitrous oxide and oxygen. The plasma levels of glucose, insulin, glucagon, lactate, pyruvate and non-esterified free fatty acid (NEFA) were measured during the operation. The plasma level of insulin activity increased significantly during surgery. The secretory capability of insulin against glucose load was relatively preserved. Arterial ketone body ratio also increased during the operation. The plasma insulin activity was positively correlated significantly with the arterial ketone body ratio (Y = 0.98 + 0.76X; r = 0.76). Both lactate and pyruvate increased significantly during surgery. No remarkable changes of L/P ratio reflecting the redox state in cytoplasma were found in both groups. Our results suggest that the quantity of glucose load and insulin activity should be considered when arterial ketone body ratio is measured during the operation.     

Adrenaline: relationship between infusion rate, plasma concentration, metabolic and haemodynamic effects in volunteers.

The present study investigated the relationship between supraphysiological plasma concentrations of adrenaline and the resulting haemodynamic and metabolic effects. Adrenaline was administered at five infusion rates (0.01-0.2 micrograms kg-1 min-1) in an escalating sequence to eight volunteers. The arterial plasma concentration of adrenaline increased from 53 +/- 44 to 4349 +/- 818 ng litre-1 during the highest infusion rate. Typical haemodynamic responses, such as increase in blood pressure and heart rate, were seen. The plasma concentrations of glucose and lactate increased from 5.2 +/- 0.4 to 13.7 +/- 1.3 mmol litre-1 and from 0.9 +/- 0.3 to 4.7 +/- 2.6 mmol litre-1, respectively, during the highest infusion rate without a significant increase in insulin concentration. Non-esterified fatty acids increased from 379 +/- 97 to 1114 +/- 331 mumol litre-1 during the 0.06 microgram kg-1 min-1 infusion rate. Adrenaline had no selective haemodynamic effect. If similar metabolic effects occur in patients during treatment with adrenaline or other sympathomimetics, they may further increase breakdown of energy stores in a situation of increased catabolism, and impair utilization of parenteral nutrition.     

Metabolic sensors mediate hypoglycemic detection at the portal vein

The current study sought to ascertain whether portal vein glucose sensing is mediated by a metabolic fuel sensor analogous to other metabolic sensors presumed to mediate hypoglycemic detection (e.g., hypothalamic metabosensors). We examined the impact of selectively elevating portal vein concentrations of lactate, pyruvate, or beta-hydroxybutyrate (BHB) on the sympathoadrenal response to insulin-induced hypoglycemia. Male Wistar rats (n = 36), chronically cannulated in the carotid artery (sampling), jugular vein (infusion), and portal vein (infusion), underwent hyperinsulinemic-hypoglycemic ( approximately 2.5 mmol/l) clamps with either portal or jugular vein infusions of lactate, pyruvate, or BHB. By design, arterial concentrations of glucose and the selected metabolite were matched between portal and jugular (NS). Portal vein concentrations were significantly elevated in portal versus jugular (P < 0.0001) for lactate (5.03 +/- 0.2 vs. 0.84 +/- 0.08 mmol/l), pyruvate (1.81 +/- 0.21 vs. 0.42 +/- 0.03 mmol/l), or BHB (2.02 +/- 0.1 vs. 0.16 +/- 0.03 mmol/l). Elevating portal lactate or pyruvate suppressed both the epinephrine (64% decrease; P < 0.01) and norepinephrine (75% decrease; P < 0.05) responses to hypoglycemia. In contrast, elevating portal BHB levels failed to impact epinephrine (P = 0.51) or norepinephrine (P = 0.47) levels during hypoglycemia. These findings indicate that hypoglycemic detection at the portal vein is mediated by a sensor responding to some metabolic event(s) subsequent to the uptake and oxidation of glucose.     

Evidence for aerobic glycolysis in lambda-carrageenan-wounded skeletal muscle

Classically, increased lactate production in wounded tissue is ascribed to anaerobic glycolysis although its oxygen consumption has been found to be similar to normal tissue. This apparent inconsistency was studied in a standardized isolated perfused wound model. Male Sprague-Dawley rats were wounded (group W) with intramuscular injections of lambda-carrageenan and fed ad lib.; not wounded and pair fed to the decreased food intake of the wounded animals (group PFC); or not wounded and fed ad lib. (group ALC). After 5 days, the hindlimbs of animals from each group were either perfused using a standard perfusate with added [U-14C]glucose or [1-14C]pyruvate or assayed for the tissue content of lactate and pyruvate. In addition, the effect of a 30% hemorrhage on the tissue lactate and pyruvate concentration was examined. Wounding increased glucose uptake and lactate production by 100 and 96%, respectively, above that seen in ALC animals. Oxygen consumption was unchanged by wounding (5.74, 5.14, and 5.83 mumole/min/100 g in W, PFC, and ALC, respectively). Glucose and pyruvate oxidation were also unaltered among the groups. Hemorrhage resulted in a comparable increase in lactate and pyruvate in tissue from wounded and pair-fed control animals (above those concentrations found in tissue harvested without preexisting hemorrhage). As a consequence, the same relationship in L/P ratio was maintained after hemorrhage. Taken together, these results confirm the presence of aerobic glycolysis in wounded tissue (unchanged oxygen consumption, glucose, and pyruvate oxidation). In addition, pyruvate dehydrogenase activity in the wound was apparently the same as that found in muscle from pair-fed control animals.     

Decreases in myocardial glucose and increases in pyruvate but not ischaemia are observed during porcine endotoxaemia

Background: Myocardial dysfunction occurs commonly in septic shock. It is not known whether this is due to local ischaemia and metabolic disturbances. Our hypothesis was that endotoxaemic myocardial dysfunction may be associated with interstitial ischaemic and metabolic changes, measured using interstitial microdialysis (MD).
Methods: Eighteen pigs were randomized to control ( n =6) or endotoxin infusion ( n =12). MD catheters were inserted into the myocardium for measurement of interstitial glucose, pyruvate and lactate concentrations. Plasma glucose and lactate concentrations and systemic haemodynamic parameters were measured simultaneously.
Results: Compared with the control group, the endotoxaemic animals had significantly decreased left ventricular stroke work and venous oxygen saturation (SvO2), and increased mean pulmonary artery pressure and plasma lactate. In the endotoxaemic group, decreases in interstitial glucose were observed, occurring simultaneously with increases in interstitial pruvate. Interstitial lactate : pyruvate ratios decreased with time in all animals.
Conclusions: Despite severe systemic and pulmonary haemodynamic changes, interstitial MD measurements revealed no evidence of anaerobic metabolism in the myocardium of endotoxaemic pigs. There were, however, changes in glucose and pyruvate concentrations, suggesting local energy metabolic disturbances.     

Continuous Assessment of Local Metabolism by Microdialysis inCritical Limb Ischaemia

OBJECTIVE: to investigate the feasibility of using microdialysate glucose, lactate and pyruvate concentrations for grading the severity of blood flow reduction in patients with critical limb ischaemia. PATIENTS AND METHODS: microdialysis catheters were inserted (two subcutaneously and one intramuscularly) in the symptomatic limb of ten patients. To further reduce limb perfusion, the lower leg was elevated during part of the experiment. RESULTS: elevation reduced ankle and toe blood pressure and transcutaneous oxygen tension. Microdialysate glucose concentration decreased at all three catheter sites, while lactate increased in the intramuscular catheter. Two patients interrupted the elevated position prematurely due to severe pain in the foot. They had among the highest lactate levels in the horizontal position and the most marked increases following provocation. Neither initial metabolite concentrations nor concentration changes during elevation were shown to correlate to conventional methods used to assess limb perfusion. CONCLUSIONS: in patients with critical limb ischaemia microdialysis can be used without complications. A significant decrease in glucose concentration may reflect lowered blood flow in the elevated position. Metabolic response, i.e. increase in lactate concentration during profoundly reduced limb perfusion was heterogeneous, indicating an overestimation of the presence of ischaemia in some patients using current diagnostic methods.     

The disposal of intravenous glucose studied using glucose and insulin clamp techniques in sepsis and trauma in man

Whole body glucose uptake and oxidation during a hyperglycemic clamp have been shown to be depressed in hypermetabolic septic patients compared to control subjects despite similar plasma insulin concentrations. Forearm glucose uptake was similarly impaired. Metabolic rate was not increased further by the glucose infusion in the patients although a 20% rise was elicited in the controls. This resistance to the effects of insulin was also clearly demonstrated in trauma patients using the euglycemic clamp technique. The maximal rate of glucose disposal after injury was half that found in controls and the pattern of response was consistent with the insulin resistance being a post-receptor defect.     

Metabolic effects of l-alanyl-glutamine in burned rats

Burn injury elicits a sustained hypermetabolic state characterized by accelerated hepatic synthesis of amino acids and proteolysis leading to negative nitrogen balance. This paper was aimed at studying the effects l-alanyl-glutamine (Ala-Gln) exogenous offer to rats submitted to thermal burn. Twenty-four anesthetized male Wistar rats were submitted to scald burn of dorsal skin (30% body surface). Eighteen and 42-h later rats were randomized to receive (by gavage) 2ml of water (G-1) or equal volume (0.5g/kg weight/day) of Ala-Gln solution (G-2). Tissue and blood samples were collected at the end of 24 and 48-h post-burn trauma (PBT). Blood concentrations of metabolites (glucose, pyruvate, lactate and ketone bodies) were similar in all groups. There were significant differences in tissue metabolites concentrations in Ala-Gln treated rats (G-2) compared to control (G-1) following scald injury. The administration of Ala-Gln to burned rats induces a fall ATP (muscle, healthy skin), pyruvate and ketone bodies (liver) concentrations 24-h PBT. It also induces significant increase of lactate (burned skin) 24-h and glucose (liver) 28/48-h PBT. Rise of tissue lactate concentrations may be due to enhanced anaerobic glycolysis resulting from increased availability of glutamate, derived from glutamine, with possible activation of the malate-aspartate shuttle.     

Epidural analgesia and postoperative lipid metabolism: stable isotope studies during a fasted/fed state

BACKGROUND AND OBJECTIVES: Although previous studies have reported an inhibitory effect of epidural block and glucose feeding on plasma concentrations of glycerol and free fatty acids (FFA), it remains unclear how epidural analgesia modifies the postoperative production and uptake of lipid metabolites. This can be achieved by determining the rate of lipolysis during a feeding state with dextrose. METHODS: Twelve patients with or without postoperative epidural analgesia were studied 48 hours after surgery. They underwent a 6-hour stable isotope infusion study using [1,1,2,3,3,-(2)H(5)] glycerol; 3 hours of fasting, and 3 hours of dextrose infusion (4 mg/kg/min). The rate of glycerol appearance (R(a) glycerol) i.e., rate of lipolysis, and plasma concentrations of glycerol, FFA, glucose, lactate, insulin, glucagon, and cortisol were measured during the fasted and the fed states. RESULTS: The rates of lipolysis were similar in both groups during the fasted state and were not modified by dextrose infusion. In contrast, plasma concentrations of glycerol and FFA were decreased significantly during the fed state (P <.01). Glycerol clearance (ratio between R(a) glycerol and plasma glycerol concentration) increased significantly in both groups (P <.05) with feeding. Similarly, plasma concentrations of glucose and insulin increased significantly following feeding with dextrose in both groups. CONCLUSIONS: The elevated rates of lipolysis associated with surgery cannot be suppressed by either epidural analgesia or dextrose feeding implying that the sustained stress response continues in the postoperative period and is the most important factor responsible for the increased release of glycerol.     

Propranolol diminishes extremity blood flow in burned patients.

Beta adrenergic blockade diminishes the catecholamine-mediated elevations in heart rate and myocardial contractility that characterize postburn hypermetabolism. To examine how these alterations in cardiac performance affect peripheral perfusion, indirect calorimetry and leg blood flow were measured before and then after a 2-hour intravenous propranolol infusion. Five severely burned patients (55% + 7% total burn surface area), given propranolol at 8 micrograms/kg/minute, had a significant reduction in cardiac index and heart rate with an increased leg vascular resistance resulting in a decrease in extremity perfusion. Four healthy volunteers were given propranolol at 5 micrograms/kg/minute, resulting in a comparable decrease in heart rate, yet there was no change in leg vascular resistance or extremity perfusion. In both patient groups, propranolol decreased the plasma lactate concentration. This suggests that in hypermetabolic patients, beta adrenergic blockade reduces peripheral perfusion and that peripheral perfusion is not a principal determinate of plasma lactate levels. Rather adrenergic blockade appears to decrease lactate concentration as a consequence of the inhibition of lipolysis.     

Effect of valproate on renal metabolism in the intact dog

Valproate is an antiepileptic drug known to induce hyperammonemia in humans. This hyperammonemia might result from a reduced detoxification of ammonium in the liver and/or from an accelerated renal ammoniagenesis. Six dogs with normal acid-base equilibrium and eight dogs with chronic metabolic acidosis were infused with valproate directly into their left renal artery in order to obtain arterial concentrations around 3 to 4 mM. The arterial ammonium concentration rose only in chronically acidotic dogs, whereas the lactate concentration and the lactate/pyruvate ratio increased in both groups. The urinary excretion of lactate and pyruvate increased markedly but the urinary excretion of other relevant metabolites remained minimal. Renal glutamine utilization and ammonium production were not changed by valproate administration in normal dogs but increased modestly in acidotic dogs. However, renal lactate utilization was drastically reduced and in fact, changed into a net production of lactate. Valproate strikingly reduced the renal cortical concentrations of glutamine, glutamate, alphaketoglutarate and citrate, and more modestly those of malate, oxaloacetate, aspartate, alanine and ATP. By contrast, the tissue lactate concentration and the lactate/pyruvate ratio were markedly increased. In experiments with brush border membrane vesicles, valproate inhibited the lactate transporter. These results suggest that high concentrations of valproate drastically inhibited the proximal reabsorption and the proximal and distal oxidation of lactate and pyruvate. Valproate probably became itself a significant energetic substrate for the kidney.