Lactic Acidosis with Phenformin Therapy

Nine cases of severe acidosis occurring in patients with maturity onset diabetes who were receiving phenformin therapy were reviewed. All had evidence of renal disease. Lactic acidosis was diagnosed by elevated blood lactate levels in seven patients, and by the clinical manifestations and laboratory information in the other two. Contributing factors are discussed, as well as means of treatment and prevention. Although the specific etiology of renal disease is not emphasized in this paper, unrecognized progressive deterioration of renal function is implicated in the etiology of lactic acidosis.     

Significance of Perfusate Lactic Acidosis in Cadaveric Renal Transplantation

Thirty-two human cadaver kidneys were assessed by continuous perfusion before transplantation. Altogether, 26 were transplanted. Ten kidneys functioned immediately, of which nine had excellent renal function at three months. Sixteen had delayed onset of function, of these only five had excellent function at three months. There was no difference in warm ischaemic interval between the two groups or in ice storage time. The immediate function group, however, were perfused for twice as long as the delayed function group. The two groups could not be separated on donor history, but they could be precisely separated during perfusion by measuring lactic acidosis and lactic acid dehydrogenase (LDH). The biggest single difference between the groups was in terms of donor preparation.     

Involvement of Lactic Acidosis in Anoxia-Induced Perturbations of Synaptosomal Function

L-Lactate (4-32 mM) added exogenously to resting or depolarised rat forebrain synaptosomes led to a significant decrease in intrasynaptosomal pH. Similarly depolarisation-induced increases in intrasynaptosomal calcium, calcium uptake, and acetylcholine release were all inhibited. These effects mimicked those previously observed in synaptosomes under anoxic conditions and suggest that lactate may be involved in limiting the damage due to calcium accumulation occurring during ischaemia. D-Lactate (added exogenously up to 32 mM) did not produce similar effects on these parameters even though the concentrations of intrasynaptosomal D-lactate reached levels comparable to those obtained with L-lactate (at 8-16 mM exogenous concentration). The results suggest that the mechanism of action of lactate on these parameters is stereospecific for the L-enantiomer. The effect of glucose availability on lactate production was assessed to explore the role of substrate availability on ischaemia/anoxic events. When exogenous glucose was increased (10-60 mM), there was no further increase in lactate production in normoxic synaptosomes, which suggests that glucose is not limiting under these conditions. When glucose was removed, as may occur in complete ischaemia, there was a significant decrease in lactate production after 60 min under anoxic or normoxic conditions. It would seem likely therefore that the mechanism underlying the changes observed in synaptosomes incubated under conditions reflecting complete ischaemia does not involve lactate.     

A Case of Hypoglycemia,Lactic Acidosis,and Hematologic Malignancy

ObjectiveTo report a case of chronic and persistent hypoglycemia and lactic acidosis in a 74-year-old military veteran.MethodsThe clinical, laboratory, radiologic, and cytogenetic details of the case are presented, followed by a discussion of the related literature.ResultsThe patient was treated for septicemia without evidence of infection. Mitochondrial dysfunction was explored because of the possibility of environmental exposures during military service. On bone marrow biopsy, he was found to have immature B-cell lymphoma and myelodysplasia. There have been 28 previously reported cases of non-Hodgkin lymphoma-induced lactic acidosis in adult patients (11 with hypoglycemia), which has been associated with a high mortality rate.ConclusionOur case is unique because, to our knowledge, it is the first reported case of immature B-cell lymphoma/leukemia and myelodysplasia with a complex karyotype based on extensive cytogenetic studies in a patient presenting with hypoglycemia, lactic acidosis, and central nervous system involvement by lymphoma. (Endocr Pract. 2010;16:241-243)     

Effects of Lactic Acidosis on the Function of Cerebral Cortical Synaptosomes

Synaptosomes exposed to anoxic insult produce lactate at a slow rate (measured over 60 min). No measurable damaging effects were produced by prolonged depolarisation, anoxic insult, or exogenous lactate (2-32 mM) either on the synaptic plasma membrane (as judged by release of lactate dehydrogenase and soluble proteins), or on synaptosomal phospholipases (as judged by choline release from membrane phospholipids). Potassium-stimulated acetylcholine release was decreased by incubation in the presence of lactate (2-32 mM), as was potassium- and veratrine-stimulated calcium uptake and the calcium content of depolarised synaptosomes. The intrasynaptosomal pH was also reduced but there was no stimulation of oxygen radical production (as judged by H2O2 generation) by exogenous lactate. The role that lactic acidosis may play in giving rise to the altered calcium homeostasis and decreased acetylcholine release from synaptosomes exposed to anoxic insult is discussed.     

Effect of Sodium Bicarbonate Administration on Mortality in Patients with Lactic Acidosis: A Retrospective Analysis

Background

Lactic acidosis is a common cause of high anion gap metabolic acidosis. Sodium bicarbonate may be considered for an arterial pH <7.15 but paradoxically depresses cardiac performance and exacerbates acidosis by enhancing lactate production. This study aimed to evaluate the cause and mortality rate of lactic acidosis and to investigate the effect of factors, including sodium bicarbonate use, on death.

Methods

We conducted a single center analysis from May 2011 through April 2012. We retrospectively analyzed 103 patients with lactic acidosis among 207 patients with metabolic acidosis. We used SOFA and APACHE II as severity scores to estimate illness severity. Multivariate logistic regression analysis and Cox regression analysis models were used to identify factors that affect mortality.

Results

Of the 103 patients with a mean age of 66.1±11.4 years, eighty-three patients (80.6%) died from sepsis (61.4%), hepatic failure, cardiogenic shock and other causes. The percentage of sodium bicarbonate administration (p = 0.006), catecholamine use, ventilator care and male gender were higher in the non-survival group than the survival group. The non-survival group had significantly higher initial and follow-up lactic acid levels, lower initial albumin, higher SOFA scores and APACHE II scores than the survival group. The mortality rate was significantly higher in patients who received sodium bicarbonate. Sodium bicarbonate administration (p = 0.016) was associated with higher mortality. Independent factors that affected mortality were SOFA score (Exp (B) = 1.72, 95% CI = 1.12–2.63, p = 0.013) and sodium bicarbonate administration (Exp (B) = 6.27, 95% CI = 1.10–35.78, p = 0.039).

Conclusions

Lactic acidosis, which has a high mortality rate, should be evaluated in patients with metabolic acidosis. In addition, sodium bicarbonate should be prescribed with caution in the case of lactic acidosis because sodium bicarbonate administration may affect mortality.     

L-Arginine Affects Aerobic Capacity and Muscle Metabolism in MELAS (Mitochondrial Encephalomyopathy,Lactic Acidosis and Stroke-Like Episodes) Syndrome

ObjectiveTo study the effects of L-arginine (L-Arg) on total body aerobic capacity and muscle metabolism as assessed by ³¹Phosphorus Magnetic Resonance Spectroscopy (³¹P-MRS) in patients with MELAS (Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like episodes) syndrome.MethodsWe performed a case control study in 3 MELAS siblings (m.3243A>G tRNA^leu(UUR) in MTTL1 gene) with different % blood mutant mtDNA to evaluate total body maximal aerobic capacity (VO_2peak) using graded cycle ergometry and muscle metabolism using ³¹P-MRS. We then ran a clinical trial pilot study in MELAS sibs to assess response of these parameters to single dose and a 6-week steady-state trial of oral L-Arginine.ResultsAt baseline (no L-Arg), MELAS had lower serum Arg (p = 0.001). On ³¹P-MRS muscle at rest, MELAS subjects had increased phosphocreatine (PCr) (p = 0.05), decreased ATP (p = 0.018), and decreased intracellular Mg²⁺ (p = 0.0002) when compared to matched controls. With L-arginine therapy, the following trends were noted in MELAS siblings on cycle ergometry: (1) increase in mean % maximum work at anaerobic threshold (AT) (2) increase in % maximum heart rate at AT (3) small increase in VO_2peak. On ³¹P-MRS the following mean trends were noted: (1) A blunted decrease in pH after exercise (less acidosis) (2) increase in Pi/PCr ratio (ADP) suggesting increased work capacity (3) a faster half time of PCr recovery (marker of mitochondrial activity) following 5 minutes of moderate intensity exercise (4) increase in torque.SignificanceThese results suggest an improvement in aerobic capacity and muscle metabolism in MELAS subjects in response to supplementation with L-Arg. Intramyocellular hypomagnesemia is a novel finding that warrants further study.

Classification of Evidence

Class III evidence that L-arginine improves aerobic capacity and muscle metabolism in MELAS subjects.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01603446","term_id":"NCT01603446"}}NCT01603446.     

Effects of Methylprednisolone on Extracellular Lactic Acidosis and Amino Acids After Severe Compression Injury of Rat Spinal Cord

Abstract: We evaluated in rats with severe spinal cord compression at T8–9 the influence of methylprednisolone (MP) on lactic acidosis and extracellular amino acids, which may cause secondary, perifocal injuries of the cord. MP (30 mg/kg) was given intravenously 30 min before compression and hourly thereafter (15 mg/kg). Other rats with compression, given saline, served as controls. Samples from the extracellular fluid of one dorsal horn were collected by microdialysis and analyzed by HPLC. Microdialysis was performed for 1.5 h to establish basal levels. Samples were collected for 3 h after compression. MP-treated rats showed a reduction of dialysate lactic acid and arginine levels during the first 1–2 h after trauma. The mean dialysate levels of glutamate in MP-treated rats were lower than those of the controls, but the difference was not statistically significant. MP treatment did not influence dialysate levels of aspartate, glutamine, histidine, glycine, threonine, taurine, alanine, GABA, and tyrosine. Our study shows that MP has several effects, including reduced lactic acid formation, reduced levels of arginine (the substrate for nitric oxide production), and a trend toward decreased extracellular accumulation of the excitotoxic amino acid glutamate. We conclude that MP has the capacity to change the composition of the extracellular edema fluid after trauma to the spinal cord. These changes may counteract free radical formation and may be important mechanisms by which MP exerts its beneficial actions.