Decrease In Lactate Levels Research Articles

The effects of dobutamine on microcirculatory alterations in patients with septic shock are independent of its systemic effects*

To evaluate the effects of dobutamine on microcirculatory blood flow alterations in patients with septic shock. Prospective, open-label study. A 31-bed, medico-surgical intensive care unit of a university hospital. Twenty-two patients with septic shock. Intravenous administration of dobutamine (5 mug/kg.min) for 2 hrs (n = 22) followed by the addition of 10 M acetylcholine (topically applied, n = 10). Complete hemodynamic measurements were obtained before and after dobutamine administration. In addition, the sublingual microcirculation was investigated with an orthogonal polarization spectral imaging technique before and after dobutamine administration and after topical application of acetylcholine. Dobutamine significantly improved capillary perfusion (from 48 +/- 15 to 67 +/- 11%, p = .001), but with large individual variation, whereas capillary density remained stable. The addition of topical acetylcholine completely restored capillary perfusion (98 +/- 1%, p = .001) and capillary density. The changes in capillary perfusion during dobutamine administration were not related to changes in cardiac index (p = .45) or arterial pressure (p = .29). Interestingly, the decrease in lactate levels was proportional to the improvement in capillary perfusion (y = 0.07 - 0.02x, r = .46, p = .005) but not to changes in cardiac index (p = .55). The administration of 5 mug/kg.min dobutamine can improve but not restore capillary perfusion in patients with septic shock. These changes are independent of changes in systemic hemodynamic variables.

Interactive effects of high stocking density and food deprivation on carbohydrate metabolism in several tissues of gilthead sea breamSparus auratus

The influence of high stocking density (HSD) and food deprivation was assessed on carbohydrate metabolism of several tissues of gilthead sea bream Sparus auratus for 14 days. Fish were randomly assigned to one of four treatments: (1) fed fish under normal stocking density (NSD) (4 kg m(-3)); (2) fed fish under HSD (70 kg m(-3)); (3) food-deprived fish under NSD; and (4) food-deprived fish under HSD. After 14 days, samples were taken from the plasma, liver, gills, kidney and brain for the assessment of plasma cortisol, levels of metabolites and the activity of several enzymes involved in carbohydrate metabolism. HSD conditions alone elicited important changes in energy metabolism of several tissues that in some cases were confirmatory (5-fold increase in plama cortisol, 20% increase in plasma glucose, 60% decrease in liver glycogen and 20% increase in gluconeogenic potential in the liver) whereas in others provided new information regarding metabolic adjustments to cope with HSD in the liver (100% increase in glucose phosphorylating capacity), gills (30% decrease in capacity for phosphorylating glucose), kidney (80% increase in the capacity of phosphorylating glucose) and brain (2.5-fold increase in ATP levels). On the other hand, food deprivation alone resulted in increased plasma cortisol, and metabolic changes in the liver (enhanced gluconeogenic and glycogenolytic potential of 13% and 18%, respectively) and brain (10% increase in glycolytic capacity), confirmatory of previous studies, whereas new information regarding metabolic adjustments during food deprivation was obtained in the gills and kidney (decreased lactate levels in both tissues of 45% and 55%, respectively). Furthermore, the results obtained provided, for the first time in fish, information indicating that food deprivation increased the sensitivity of gilthead sea bream to the stress induced by HSD compared with the fed controls, as demonstrated by increased plasma cortisol levels (50% increase vs. fed fish) and a further increase in the capacity to export glucose mobilized from liver glycogen stores (70% decrease vs. fed fish). These results lend support for a cumulative effect of both stressors on plasma cortisol and parameters assessed on carbohydrate metabolism in the present experiments, and provide information regarding reallocation of metabolic energy to cope with simultaneous stressors in fish.

Vacuum-Assisted Fascial Closure for Patients With Abdominal Trauma

Massive fluid resuscitation often is required for patients with intraabdominal trauma. Subsequently, fascial closure is not always possible in this subset of patients. Under these circumstances, an initial step can be the use of a temporary abdominal closure method. The authors currently use a vacuum-assisted closure to manage the open abdomen for some of their trauma patients. They present their experience over the past 3 years. From January 2000 to December 2002, 48 trauma patients were treated with temporary abdominal closure using a vacuum-assisted dressing. The ultimate management of the abdominal defect, the serum lactate levels measured in the emergency department, and the fluid balance at the last attempt to accomplish fascial closure were reviewed. Delayed fascial closure was achieved in 23 (71.9%) of 32 patients who survived to discharge (26 of 48, 54.2%). Of the 32 patients who survived to discharge, 9 (28.1%) required an alternative closure, most often a split-thickness skin graft. Of the 16 patients who died before discharge, 8 died within 24 hours after admission. Whereas 5 of the 16 deaths occurred after delayed abdominal closure, 11 patients died without abdominal closure. Emergency department serum lactate levels above 8 mg/dL show a positive correlation with in-hospital mortality (6 of 16 patients; 38%; p = 0.001) and mortality within 24 hours of admission (6 of 8 patients; 75%; p = 0.003). Admission lactate levels were not associated with the type of closure achieved. However, primary closure was associated with a significant decrease in lactate levels during the first 12 hours. Complications included five abdominal abscesses, two enterocutaneous fistulas, and one split-thickness skin graft failure. Patients requiring temporary abdominal closure have a significant in-hospital mortality rate of 33%. Delayed primary closure with vacuum assistance was achieved for 71.9% of the surviving patients. Maintaining a negative or total positive fluid balance of less than 20 L before the last attempted fascial closure improves successful closure rates, as seen in 19 of 22 patients (86.4%). The vacuum-assisted closure technique also enabled successful primary closure for two patients with extreme delay (>8 days). Elevated serum lactate levels are significantly correlated with early and in-hospital mortality. A significant decrease in lactate level during the first 12 hours is associated with achievement of primary closure.

Nutritional and exercise-based therapies in the treatment of mitochondrial disease.

This review will critically summarize the nutritional and exercise-based interventions that have been used to treat mitochondrial disease, with a focus on the biochemical or molecular rationale for their use as well as recent advances in the field. Many nutritional-based treatment strategies have been used in an attempt to target energy impairment and its sequelae. Recently, coenzyme Q10, idebenone and triacylglycerol have been shown to bypass defective respiratory enzymes or scavenge free radicals, whereas creatine monohydrate has provided an alternative energy source. Thiamine has been used to decrease lactate levels and increase flux through aerobic metabolism, and riboflavin has been used as a precursor to complexes I and II. Several therapies employing various antioxidants in combination with other supplements have been effective at targeting several of the final common pathways of mitochondrial disease. Miscellaneous supplements, such as L-arginine and uridine, have also had recent success. However, although positive responses have been reported with these agents, many reports have shown no benefit, and there is widespread disparity in the literature. An alternative approach to treatment is exercise training. Both resistance and endurance exercise training have had positive outcomes in patients with mitochondrial disease, although several questions remain to be answered. There is no currently recognized treatment for mitochondrial disease. Future clinical trials are needed, as well as research into the potential for in-vitro screening of various compounds within affected cells from patients. Until this time, an accurate diagnosis will facilitate treatment on a case-by-case basis.

Effect of endogenous β-hydroxybutyrate on brain glucose metabolism in fetuses of diabetic rabbits, studied by 13C magnetic resonance spectroscopy

The aim of our research was to uncover perturbations in in-utero fetal cerebral metabolism resulting from hyperglycemia and hyperketonemia, which occur during maternal diabetes. Therefore, we examined the effects of glucose overload and hyperketonemia on glucose metabolism in the diabetic fetal brain; more specifically, the effect of diabetes on the glucose flux via pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) and subsequent metabolism in the fetal cerebral tricarboxylic acid (TCA) cycle were examined, as well as the effect of diabetes on energy fuel utilization in the neurons and glia. Diabetes was induced in pregnant rabbits, and towards term, [U- 13C 6]glucose was infused into maternal circulation, and [ 13C]glucose metabolites were subsequently studied in fetal brain extracts by 13C MRS isotopomer analysis. Significantly elevated maternal and fetal plasma glucose levels (three- and up to fivefold, respectively) and fetal brain glucose levels (up to eightfold) accompanied by an increase of β-hydroxybutyrate (β-HBA) levels (∼20-fold) were found in the hyperketonemic diabetic animals, whereas fetal cerebral lactate levels were decreased. Alterations in the 13C labeling patterns, mainly of glutamine, led us to suggest that the entry of β-HBA-derived acetyl-CoA inhibits formation and entry of labeled glucose-derived acetyl-CoA into the TCA cycle, mainly in glia. Accumulation of glucose and the decrease in lactate levels in the fetal brain are most likely the result of an inhibitory effect of β-HBA on glycolysis. In addition, loss of 13C enrichment of TCA cycle intermediates and products, glutamate and glutamine, in the hyperketonemic diabetic fetal brain may be attributed to the effect of β-HBA fuel utilization by the fetal brain.

A multicentre study of the efficacy and safety of topiramate in mania

The aim of the current study was to evaluate the relationship between quetiapine's effect on the improvement of mood symptoms in bipolar patients and brain metabolite level changes as measured by proton magnetic resonance spectroscopy (1H-MRS). Rapid cycling bipolar patients in the manic state were recruited and treated with quetiapine for 12 weeks. Clinical assessment was performed using the Young Mania Rating Scale (YMRS), the 17-item Hamilton Depression Rating Scale (HDRS) and the Clinical Global Impression-Severity scale (CGI-S) at baseline and weekly intervals during the 12-week period. In order to evaluate metabolite level changes over time, 1H-MRS scans were acquired at baseline and week 12. There were significant reductions in YMRS scores (by 43.0%), HDRS scores (by 27.5%) and CGI-S score (by 44.6%) over the 12 week-period. Lactate levels significantly decreased over the 12-week study period (22.4%). This change in lactate levels was more prominent in quetiapine responders than in non-responders. Additionally, there was a positive correlation between changes in lactate levels and those in YMRS scores (r = 0.52, p = 0.003). Our findings suggest that quetiapine's antimanic and antidepressant efficacy in patients with rapid cycling bipolar disorder may potentially be related to decreased lactate levels in frontal regions of the brain.

Evaluation of Lactate as a 1 H Nuclear Magnetic Resonance Spectroscopy Index for Noninvasive Prediction and Early Detection of Tumor Response to Radiation Therapy in EMT6 Tumors

In a recent study (Int. J. Radiat. Oncol. Biol. Phys. 36, 635-639, 1996), 1H nuclear magnetic resonance (NMR) spectroscopy was used to demonstrate significant decreases in lactate levels after gamma irradiation of radiosensitive RIF-1 tumors in vitro. For comparison, we have examined the effects of gamma radiation on lactate levels in the more radioresistant EMT6 tumor. Single-slice (5-6 mm thick) localized 1H spectra of subcutaneous RIF-1 (untreated) and EMT6 tumors (pretreatment, 24 and 48 h postirradiation with 4, 10 or 20 Gy of gamma radiation) were measured by the selective multiple quantum coherence transfer method (Sel-MQC, approximately 4 min acquisition time). Both pretreatment lactate levels and pretreatment lactate dehydrogenase (LDH) activities were found to be similar in RIF-1 and EMT6 tumors, suggesting that steady-state lactate levels are unlikely to be reliable indices for predicting response to radiation therapy. After 10 Gy gamma irradiation, EMT6 tumors showed a 21% decrease relative to pretreatment lactate levels at 48 h (1.04 +/- 0.22 to 0.82 +/- 0.16; P = 0.06); after 20 Gy a 40% decrease was observed at 48 h (1.34 +/- 0.27 to 0.81 +/- 0.10; P = 0.07). No significant changes in lactate levels were observed in control EMT6 tumors or in tumors treated with 4 Gy of gamma radiation, in contrast to changes detected previously in RIF-1 tumors, which showed a significant decrease in lactate by 48 h for both 2 and 4 Gy. The decreased effect of radiation on lactate levels in EMT6 compared to RIF-1 tumors may be attributed to the higher hypoxic fraction and lower radiosensitivity of EMT6 tumors (Int. J. Radiat. Oncol. Biol. Phys. 10, 695-712, 1984). The decrease in lactate levels did not, however, strictly reflect the extent of the response to therapy for the high dose of 20 Gy. This study together with our earlier study (Int. J. Radiat. Oncol. Biol. Phys. 36, 635-639, 1996) provides evidence to support the hypothesis that changes in steady-state tumor lactate levels may serve as sensitive early indices of tumor response to gamma radiation at doses of the order of 2 to 4 Gy.

Studies on associations of glycolytic and glutaminolytic enzymes in MCF-7 cells: role of P36.

Isoelectric focusing of MCF-7 cell extracts revealed an association of the glycolytic enzymes glyceraldehyde 3-phosphate-dehydrogenase, phosphoglycerate kinase, enolase, and pyruvate kinase. This complex between the glycolytic enzymes is sensitive to RNase. p36 could not be detected within this association of glycolytic enzymes; however an association of p36 with a specific form of malate dehydrogenase was found. In MCF-7 cells three forms of malate dehydrogenase can be detected by isoelectric focusing: the mitochondrial form with an isoelectric point between 8.9 and 9.5, the cytosolic form with pl 5.0, and a p36-associated form with pl 7.8. The mitochondrial form comprises the mature mitochondrial isoenzyme (pl 9.5) and its precursor form (pl 8.9). Refocusing of the pl 7.8 form of malate dehydrogenase also gave rise to the mitochondrial isoenzyme. Thus, the pl 7.8 form of malate dehydrogenase is actually the mitochondrial isoenzyme retained in the cytosol by the association with p36. Addition of fructose 1,6-bisphosphate to the initial focusing column induced a quantitative shift of the pl 7.8 form of malate dehydrogenase to the mitochondrial forms (pl 8.9 and 9.5). In MCF-7 cells p36 is not phosphorylated in tyrosine. Kinetic measurements revealed that the pl 7.8 form of malate dehydrogenase has the lowest affinity for NADH. Compared to both mitochondrial forms the cytosolic isoenzyme has a high capacity when measured in the NAD --> NADH direction (malate --> oxaloacetate direction). The association of p36 with the mitochondrial isoenzyme may favor the flow of hydrogen from the cytosol into the mitochondria. Inhibition of cell proliferation by AMP which leads to an inhibition of glycolysis has no effect on complex formation by glycolytic and glutaminolytic enzymes in MCF-7 cells. AMP treatment leads to an activation of malate dehydrogenase, which correlates with the increase of pyruvate and the decrease of lactate levels, but has no effect on the distribution of the various malate dehydrogenase forms.

Effect of 1,3-butanediol on cerebral energy metabolism. Comparison with β-hydroxybutyrate

Previous studies have shown that 1,3-butanediol (BD) has beneficial effects in experimental models of hypoxia or ischemia but the mechanism by which it exerts its protective effects remains unknown. BD is converted in the body to beta-hydroxybutyrate (BHB) and it has been proposed that its effects were linked to its ketogenic effect. The effects of BD (25 and 50 mmol/kg) on cerebral energy metabolism of rats were studied by measuring the cerebral level of energy metabolites and by evaluating the cerebral metabolic rate according to the Lowry's method. BD induced an increase in [cortical glucose]/[plasma glucose] ratio which was associated with a decrease in lactate level and an increase in glucose and glycogen stores. In contrast, BHB treatment which mimicked hyperketonemia equivalent to BD did not modify cerebral glycolysis metabolites. Calculation of the energy reserve flux after decapitation showed that BD did not reduce the cerebral metabolic rate excluding a protective effect due to a depressant, barbiturate-like, action. These results suggest that BD induces a reduction of cerebral glycolytic rate. However, the effect is not linked to hyperketonemia but might be due to intracerebral conversion of BD to BHB.

Effects of dichloroacetate on exercise performance in healthy volunteers.

Dichloroacetate (DCA), a stimulator of the pyruvate dehydrogenase complex, decreases lactate levels and peripheral resistance and increases cardiac output. This study was performed to examine the effects of DCA on exercise performance in humans. Eight healthy male volunteers (age 20-28 years) were tested by bicycle spiro-ergometry using a microprocessor-controlled gas analysis system after infusion of DCA (50 mg/kg body weight) or saline. Prior infusion of DCA significantly reduced the increase of lactate levels during exercise when compared with infusion of saline (1.40 +/- 0.21 vs 2.10 +/- 0.09 mmol.l-1 at 50% of the expected maximal working capacity, P < 0.05; 8.53 +/- 0.45 vs 9.92 +/- 0.59 mmol.l-1 at maximal working capacity, P < 0.05). Oxygen uptake increased significantly after DCA when compared with saline from 7.5 +/- 0.4 vs 7.4 +/- 0.5 to 27.2 +/- 1.5 vs 23.7 +/- 1.7 (P < 0.05) at anaerobic threshold and to 35.6 +/- 1.7 vs 30.5 +/- 1.0 ml.kg-1 min-1 (P < 0.05) at maximal exercise capacity. Following DCA infusion the workload at which the anaerobic threshold was reached was significantly higher (160 +/- 7 vs 120 +/- 5 W, P < 0.05) and the maximal working capacity was significantly increased (230 +/- 9 vs 209 +/- 8 W, P < 0.05). In summary, DCA reduced the increase of lactate levels during exercise and increased oxygen uptake at the anaerobic threshold and at maximal working capacity, which was significantly increased. These results warrant further studies on a potential therapeutic application of DCA in patients with reduced exercise capacity.

Lack of a Relationship between Induced Changes in Oxygen Consumption and Changes in Lactate Levels

To determine whether the levels of oxygen consumption (VO2) required to relieve an existing oxygen debt are variable, increases in VO2 produced by increases in oxygen delivery (DO2) were evaluated longitudinally in septic patients with lactic acidosis and related to changes in lactate levels. Interventions were performed in 17 patients and consisted of fluid administration (n = 11), packed red blood cell transfusion (n = 19), or dobutamine infusion (n = 14). Interventions associated with a decreased lactate level or an unchanged/increased lactate level demonstrated similar increases from baseline VO2 (49 +/- 9 and 47 +/- 6 ml/min.m2, respectively) and similar postintervention absolute VO2 values (187 +/- 13 and 189 +/- 10 ml/min.m2, respectively) (both p greater than 0.6). When all interventions were considered, correlations were not observed between changes in lactate levels and changes in VO2 (r = 0.21, p greater than 0.60) or between changes in lactate levels and the postintervention VO2 values (r = 0.08, p greater than 0.45). These observations demonstrate that optimal levels of VO2 are variable and suggest that therapeutic interventions should be tailored to a patient's individual tissue needs and guided by an assessment of an oxygen debt (eg, lactate levels) rather than absolute VO2 measurements.

Cardiac arrhythmias are ameliorated by local inhibition of angiotensin formation and bradykinin degradation with the converting-enzyme inhibitor ramipril

We investigated the influence of the angiotensin-converting enzyme (ACE) inhibitor ramipril on cardiac arrhythmias in guinea pigs and rats. Ramiprilat, the active moiety of ramipril, did not influence action potentials of isolated guinea-pig papillary muscle or rabbit sinus node, thereby excluding cellular electrophysiological evidence of anti-arrhythmic properties. Ramipril protected against cardiac arrhythmias induced by digoxin infusion in guinea pigs. This effect was comparable with that of lidocaine. In isolated perfused ischemic working rat hearts, angiotensin (ANG) I (3 x 10(-9) M/l) and ANG II (1 x 10(-9) M/l) aggravated reperfusion arrhythmias, accompanied by deterioration of cardiodynamic and metabolic events. Bradykinin (BK) (1 x 10(-10)-1 x 10(-8) M/l), in contrast, protected against reperfusion arrhythmias, which corresponded to an increase in energy-rich phosphates and glycogen stores and a decrease in lactate levels in myocardial tissue. Identical changes were seen in hearts from rats pretreated with ramipril (1 mg/kg PO) or perfused with ramiprilat (2.58 x 10(-7)-2.58 x 10(-5) M/l). Local ACE inhibition in these ischemic hearts antagonized ANG I but not ANG II effects and enhanced BK effects. The BK antagonist D-Arg-(Hyp2, Thi5,8, D-Phe7)BK abolished the beneficial effects of BK, ramipril, and ramiprilat. Increased concentrations of BK or ramiprilat were able to reverse the antagonism. The antiarrhythmic agent nicainoprol, a fast-sodium-channel blocking drug (class Ib), also protected isolated rat hearts against reperfusion arrhythmias, but was without beneficial effects on cardiac hemodynamics and biochemical parameters, in contrast to the ACE inhibitor. These results suggest that the beneficial effects of the ACE inhibitor ramipril on digoxin and reperfusion arrhythmias are not mediated by their direct actions on ionic channels in the cell membrane. It seems that other factors are responsible for its beneficial effects on reperfusion arrhythmias, cardiac function, and metabolism, which are associated with a reduction in ANG II generation and BK degradation by local ACE inhibition in the heart.

Effect of dichloroacetate in the treatment of anoxic lactic acidosis in dogs.

Lactic acidosis is seen frequently after severe anoxia and circulatory failure. Because dichloroacetate (DCA) has been shown to be effective in the treatment of lactic acidosis, we studied its effect on lactate levels and pH in arterial and sagittal sinus blood specimens in a pediatric canine model of anoxic cardiac arrest followed by CPR. Lactate levels rose steadily in all puppies receiving DCA alone (group 1), DCA plus bicarbonate (group 2), bicarbonate alone (group 3), or neither drug (group 4). Arterial and sagittal-sinus lactate levels were in the range of 2 mmol/L during the baseline period, 6 mmol/L after anoxic arrest, and 10 mmol/L after 20 min of CPR. Bicarbonate, but not DCA, significantly raised arterial pH. Neither drug reversed the progression of acidosis in the sagittal sinus; mean pH ranged from 6.85 to 6.92 among the four groups after 20 min of CPR. We speculate that DCA did not decrease lactate levels or raise the pH in either the peripheral circulation or the CNS (sagittal sinus) because of poor perfusion achieved during closed-chest cardiac compression.

On the mechanism of action of the antianginal drug nonachlazine on ischemic myocardium.

The activity of a new antianginal drug, nonachlazine, synthetized in the Institute of Pharmacology, Academy of Medical Sciences of the USSR, has been demonstrated using model myocardial ischemias on anesthetized dogs and conscious cats. Antianginal activity was evaluated by ECG, epicardial electrogram, lactate level, and lactate/pyruvate ratio in the venous blood flowing from the ischemic myocardial area. The study of the cardiotropic effect of nonachlazine provided the following findings: (1) nonachlazine enhances ino- and chronotropic functions of the heart via stimulation of its beta-adrenergic receptors; (2) nonachlazine's positive chronotropic effect is substantially less marked than the inotropic one; (3) nonachlazine decreases the intensity of chronotropic reactions of the heart induced by isopreterenol. Biochemical analysis showed that in addition to its activation of oxidative phosphorylation, the ability of nonachlazine to stimulate glycogenolysis is also of importance in the development of its antianginal effect. This conclusion has been suggested by the following: (1) in acute myocardial ischemia, nonachlazine decreased lactate level and increased ATP level up to the norm; (2) at day 3 after ligation of the coronary artery, nonachlazine did not change lactate content, increased ATP and NAD, and decreased NADH2; (3) in experiments on rabbit myocardial mitochondria in vivo and in vitro nonachlazine was found to stimulate oxidative phosphorylation; (4) nonachlazine was found capable of increasing the norepinephrine level and of increasing phosphorylase a activity and the rate of glycogenolysis.

The effect of 5-hydroxytryptamine and histamine on glycolysis in the mouse brain.

Following the intraventricular injection of 5-hydroxytryptamine into the lateral ventricles of conscious mice, the concentration of brain lactate rose immediately but then decreased significantly compared with the saline injected controls. The concentration of brain glucose increased 20 min after the injection of 5-hydroxytryptamine. These effects of 5-hydroxytryptamine on lactate and glucose were qualitatively similar to those found following the administration of methysergide. After the parenteral administration of 5-hydroxytryptophan, the lactate levels showed a bephasic change but brain glucose was significantly decreased for up to 90 min following the injection. p-Chlorophenylalanine potentiated the effect of 5-hydroxytryptamine by further increasing glucose and decreasing lactate levels. After histamine had been injected into the ventricles, the concentrations of bound glycogen and lactate were decreased whereas free glycogen and glucose were raised. It is suggested that 5-hydroxytryptamine, and possibly histamine, are involved with control of glycolysis in the mouse brain.

Serial determinations of blood lactate in respiratory distress syndrome.

Blood lactate was measured 4-hourly in 21 newborn babies with respiratory distress syndrome, of whom 13 survived and 8 died. In general, lactate levels were higher in babies who died than in survivors, but there were inconsistencies which were uninterpretable if only a single estimation were made in a baby. Analysis of serial determinations showed that all patients in whom the lactate level never exceeded 35 mg/100 ml survived, and babies with high but falling values also did well. Only those who had rising lactate values, even if initially normal, died. In most cases a high or normal P a o 2 was associated with normal or decreasing lactate level; but babies with P a o 2 below 60 mmHg had often also normal or decreasing lactate levels. Some babies had high and increasing lactate levels despite having normal P a o 2 . In order to use lactate levels for prognosis in respiratory distress syndrome (RDS) serial determinations are required. It is concluded that there may be a wide range of hypoxaemia without oxygen deficit in body tissues, so that it is not possible to define a `lower acceptable P a o 2 9 which will define adequate tissue oxygenation.

Studies in liver glycogen disease: Effects of glucagon and other agents on metabolic pattern and clinical status

Clinical and biochemical studies in nine children with liver glycogen disease are reported. Major discrepancies were observed between in vitro determinations of hepatic enzyme activity and clinical findings in the subjects under study. In particular, there was no correlation between the levels of glucose-6-phosphatase measured in biopsy specimens of liver and the degree of fasting hypoglycemia. It is concluded that none of the enzymatic defects so far described account satisfactorily for the manifestations of liver glycogen disease. In most of the patients studied, hyperlacticemia was a prominent feature of the fasting state. Feeding or glucose infusion resulted in decrease of the blood lactate levels. Injection of glucagon appeared to induce hepatic glycogenolysis, but with lactate as the principal end product instead of glucose. Decrease in liver size was observed in these patients during glucagon infusion. Two patients behaved differently, however; lactate levels in their blood were normal during fasting, and administration of glucagon did not result in release of either glucose or lactate by the liver. In five of six patients so studied, the administration of glucagon after feedings resulted in sustained elevation of blood glucose levels, with an initial increase, then a sharp decrease in lactate levels in blood. After this, concentrations of lactate were maintained near normal levels for several hours. When long-acting glucagon was administered, the effects appeared to persist up to eight hours. Explanations are suggested for the fasting hyperlacticemia, acidosis and ketosis of liver glycogen disease and for the characteristic hyperlipemia and fat accumulation in the liver. Postprandial injections of glucagon may be useful in the management of some children with liver glycogen disease.