Pancreatitis and severe metabolic abnormalities due to phenformin therapy

Two elderly diabetic patients with abdominal pain were demonstrated to have complications of phenformin hydrochloride therapy. The first developed severe lactic acidosis treated with sodium bicarbonate given intravenously and followed by rebound alkalosis. The second showed severe acidosis (specimens for lactate determination were unfortunately unsatisfactory for analysis) and similar alkalotic rebound after therapy. She then developed severe pancreatitis, proved at operation, no cause for which other than phenformin was apparent. Poor renal and hepatic function predispose to these conditions by increasing serum phenformin levels and by decreasing urinary excretion of its metabolites. The acidosis should be treated judiciously with sodium bicarbonate administered intravenously. A rebound alkalosis, ensuring as the accumulated lactate is metabolized, is best treated by potassium chloride and ammonium chloride given intravenously. The mechanism by which phenformin causes pancreatitis is unknown, but termination of therapy causes cessation of the pancreatitis.     

Lactate metabolism and lactic acidosis

Lactate can be viewed as a metabolic dead end in that it can only be produced or utilized via pyruvate. Lactate production is determined primarily by pyruvate concentration and to a lesser extend by the redox state. Increased lactate production may result from tissue hypoxia, alkalosis, catecholamine and alanine transamination to pyruvate. Hyperlactatemia is observed in many pathological conditions. Current diagnostic criteria for lactic acidosis are a pH less than 7.35 and lactate concentration greater than 5 to 6 mmol/l. In our study series, malignancy was the most common underlying disease accompanied by lactic acidosis. Organ failure, cardiovascular disease and diabetes mellitus were also common. The prognosis of patients with these diseases were grave. In cases of lactic acidosis associated with diabetes mellitus, alcoholic liver disease, rhabdomyolysis and diabetic comas were noticeable as complications. Alcohol abuse was the most common cause of lactic acidosis associated with diabetes mellitus. In these cases, laboratory data showed prominent hyperlactatemia, hyperglycemia and acidemia and elevated anion gap. The mortality rate in these cases was 36% and higher in cases with organ failure. Treatment of lactic acidosis consists of alkalization by sodium bicarbonate with carbicarb, insulin-glucose-infusion, dichloroacetate therapy, tham administration, bicarbonate-buffered peritoneal dialysis and high bicarbonate-containing dialysis.     

Epinephrine-induced lactic acidosis following cardiopulmonary bypass

OBJECTIVE: To determine if lactic acidosis occurring after cardiopulmonary bypass could be attributed to the metabolic or other effects of epinephrine administration. DESIGN: Prospective, randomized study. SETTING: Postsurgical cardiothoracic intensive therapy unit. PATIENTS: Thirty-six adult patients, without acidosis, requiring vasoconstrictors for the management of hypotension after cardiopulmonary bypass. INTERVENTIONS: Randomized administration of either epinephrine or norepinephrine by infusion. MEASUREMENTS AND MAIN RESULTS: Hemodynamic and metabolic data were collected before commencement of vasoconstrictor therapy (time 0) and then 1 hr (time 1), 6 to 10 hrs (time 2), and 22 to 30 hrs (time 3) later. Six of the 19 patients who received epinephrine developed lactic acidosis. None of the 17 patients receiving norepinephrine developed lactic acidosis. In the epinephrine group, but not in the norepinephrine group, lactate concentration increased significantly at times 1 and 2 (p = .01), while pH and base excess decreased (p < or = .01). Blood glucose concentration was higher in the epinephrine group at time 2 (p = .02), while the cardiac index (p < .03) and the mixed venous Po2 (p = .04) were higher at time 1. compared with the norepinephrine group, the patients receiving epinephrine had higher femoral venous lactate concentrations (p = .03), increased lower limb blood flow (p = .05), and increased femoral venous oxygen saturations (p = .04). CONCLUSIONS: The use of epinephrine after cardiopulmonary bypass precipitates the development of lactic acidosis in some patients. This phenomenon is presumably a beta-mediated effect, and is associated with an increase in whole-body and lower limb blood flow and a decrease in whole-body and transfemoral oxygen extraction. The phenomenon does not appear to be related to reduced tissue perfusion and does not have the poor outlook of lactic acidosis associated with shock.     

Phenformin and hyperamylasemia in lactic acidosis

All cases of lactic acidosis occurring during a 23-month period in a metropolitan teaching hospital were reviewed to ascertain the frequency of hyperamylasemia. Serum amylase activity had been measured in 12 of 26 patients and was elevated in eight (67%). Hyperamylasemia was not significantly more frequent in patients with phenformin-associated lactic acidosis than in patients with lactic acidosis who had not received phenformin. Serum amylase activity did not correlate with the severity of acidosis (arterial pH) or with renal function (serum creatinine).     

Magnetic resonance imaging in lactic acidosis

Mitochondrial defects, defects in gluconeogenesis, and biotin-responsive multiple carboxylase deficiency are disorders characterized by primary lactic acidosis. In this review, characteristic findings in magnetic resonance imaging (MRI) of the brain, as related to histopathological abnormalities, are described for the different disorders and the diagnostic value of the MRI findings is discussed. Inborn errors of metabolism with primary lactic acidosis should be considered in particular when MRI shows lesions similar to or reminiscent of effects of focal or generalized hypoxia-ischaemia, or when MRI shows signs of chronic neurodegeneration, but rarely in cases with predominantly white-matter changes.     

Can phenformin-induced lactic acidosis be prevented?

Although patients taking phenformin are more likely to develop lactic acidosis in the presence of renal, cardiovascular, or hepatic disease, criteria for safe use of the drug are not well established. Eight diabetics died of lactic acidosis in Nottingham in 1972-5 and all were taking phenformin in therapeutic doses. Six had attended the diabetic clinic within a month of their terminal illness. Two patients had appreciable renal impairment and should not have been given phenformin. Four had hypertension and minimal evidence of renal disease, while in two no predisposing factor was identified. There are so many contraindications to the use of phenformin that it is doubtful whether patients on the drug can be monitored adequately. We suggest that phenformin should be withdrawn from general use.     

Severe transient neonatal lactic acidosis during prophylactic zidovudine treatment

BACKGROUND: Psychic symptoms and depression have been reported in coeliac disease (CD). The aim of this study was to explore depression in a large cohort of adult CD patients. METHODS: Depressive symptoms were evaluated in 92 adult coeliacs, 100 normal controls (NC), and 48 chronic persistent hepatitis (CPH) patients by means of a modified version of the Zung Self-Rating Depression Scale (M-SDS). CD patients were evaluated for the level of knowledge about CD and the compliance with diet. RESULTS: The M-SDS score differentiated CD patients from NC. Age at diagnosis and duration of and compliance with diet did not correlate with depression. Three main factors could be identified with the M-SDS: 'reactiveness', 'pessimism', and 'anhedonic-asthenic'. CONCLUSION: Depressive symptoms are a feature of CD; they are present to a similar extent in patients with childhood- and adulthood-diagnosed CD. The results underline the relevance of personal psychologic resources, which play a fundamental role in determining and sustaining depression.     

Epinephrine-induced lactic acidosis in the setting of status asthmaticus

A relationship between intravenous epinephrine infusion and the development of lactic acidosis has been well described. We report a temporal association between the administration of subcutaneous epinephrine and the development of lactic acidosis in the setting of status asthmaticus. A 20-year-old woman with a history of asthma came to the emergency service in acute respiratory distress and was treated with subcutaneous epinephrine. Six hours later, serial arterial blood gas studies revealed the onset of a primary metabolic acidosis. Additional diagnostic studies revealed a serum lactate level of 9.5 mumol/L. The lactic acidosis resolved within 15 hours. The patient never exhibited signs of hypotension, hypoxemia, or sepsis, and other potential etiologies for lactic acidosis were excluded. We believe the events of this case constitute a new observation and theorize a mechanism of peripheral vasoconstriction and transient tissue hypoperfusion mediated by the subcutaneous epinephrine.     

Pyridoxine for severe metabolic acidosis and seizures due to isoniazid overdose

A 15-year-old girl took 3 g of isoniazid (15 tablets) in a suicide attempt and was brought unconscious to the emergency room. She was in respiratory failure, with seizures that could not be stopped with diazepam. Severe metabolic acidosis with normal serum lactate developed (pH 6.85), but did not improve after infusion of bicarbonate. Intravenous administration of pyridoxine led to prompt cessation of the seizures and to gradual improvement of acid-base status. She recovered consciousness after several hours and was discharged a week later.     

Severe lactic acidosis associated with intravenous alcohol for premature labor

A patient receiving intravenous alcohol for premature labor developed mild aspiration pneumonia. In the course of her evaluation it was noted that she also had severe lactic acidosis. The patient responded well to hydration and intravenous sodium bicarbonate. Lactic acidosis represents a previously unrecognized danger of intravenous alcohol therapy.     

Severe perioperative lactic acidosis: how clinically significant is it?

BACKGROUND: Lactic acidosis, generally defined as a plasma lactate concentration in excess of 5 mmol/L with a concomitant blood pH less than 7.25, is reported to have a direct association with mortality. OBJECTIVE: To report a case of unexplained perioperative lactic acidosis and to discuss the etiology, recognition, treatment, and importance of a transient rise in plasma lactate concentration. SUMMARY: Severe lactic acidosis developed in a 40-year-old man with Crohn's disease during major abdominal surgery. The plasma lactate concentration reached 16.9 mmol/L (normal range 1.5 to 2.2 mmol/L). This condition resolved within 14 hours without harm to the patient. CONCLUSIONS: When lactate accumulates in the perioperative period, the responsible condition is most often self-limiting. Reversible, subacute, marked lactic acidosis should not be assumed to predict mortality as it does in patients whose plasma lactate concentrations remain chronically elevated during severe systemic diseases such as sepsis.     

Sj?gren's syndrome presenting as hypokalemic paralysis due to distal renal tubular acidosis

A 57-year-old woman presented with a flaccid paralysis, muscle tenderness, and respiratory depression. Laboratory results demonstrated severe hypokalemia with hyperchloremic metabolic acidosis and abnormally acidified urine. The urinary anion gap was positive in the presence of acidemia, thus establishing the diagnosis of distal renal tubular acidosis (DRTA). The patient fully recovered after potassium and alkali replacement. Further investigation revealed Sj?gren's syndrome as the underlying cause of DRTA.     

The importance of cerebrospinal fluid lactate in the evaluation of congenital lactic acidosis

Bilioma is a rare complication of traumatic liver injury, and the precise site of bile leak is often difficult to demonstrate with a non-invasive technique. We report a case of post-traumatic bile leak in a 15-year-old girl in whom spiral CT after intravenous cholangiography allowed excellent preoperative demonstration of the extent of the liver rupture and an exact location of the bile leak. We think that spiral-CT cholangiography could be an accurate, non-invasive technique to investigate the biliary system in cases of paediatric liver trauma.     

Cerebral blood flow in mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes

BACKGROUND AND PURPOSE: The precise mechanism of neurological symptoms with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) is still controversial. We investigated the correlation between strokelike episodes and cerebral blood flow in two patients with MELAS and discuss the pathogenesis of strokelike episodes with MELAS. SUMMARY OF REPORT: Cerebral dynamic computed tomography and cerebral angiography were used to measure cerebral circulation in the first case, that of a 20-year-old woman with MELAS. The second subject was a 13-year-old female who was studied with xenon-enhanced computed tomography. The cerebral blood flow studies were performed 3-72 hours after the onset of strokelike episodes. Serial cerebral angiography, dynamic computed tomography, and xenon-enhanced computed tomography showed vasodilation localized in the affected cerebral cortexes during strokelike episodes, without any reduction in regional cerebral blood flow. CONCLUSIONS: Our study suggests that the strokelike episodes associated with MELAS are different in origin from ischemic stroke.     

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes with deterioration during pregnancy

We report a 31-year-old woman who developed myopathy and neuropathy during pregnancy. She was diagnosed as having mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). A T-to-C transition mutation at nucleotide position 3271 was detected in the mitochondrial gene. Her symptoms subsided spontaneously and she delivered a male infant at 38 weeks of gestation. Prior reports on mitochondrial diseases with pregnancy are very rare, probably because of the early onset of the disease. The metabolic changes during pregnancy increase the stress on the mitochondrial function, particularly in patients with impaired mitochondrial function. Therefore pregnancy can aggravate mitochondrial diseases.     

Delayed posthypoxic demyelination. Association with arylsulfatase A deficiency and lactic acidosis on proton MR spectroscopy

Delayed demyelination is a rare and poorly understood complication of hypoxic brain injury. A previous case report has suggested an association with mild-to-moderate deficiency of arylsulfatase A. We describe a 36-year-old man who recovered completely from an episode of hypoxia related to drug overdose, and 2 weeks later progressed from a confusional state to deep coma. MRI showed diffuse white matter signal changes, and brain biopsy demonstrated a noninflammatory demyelinating process. Proton magnetic resonance spectroscopy revealed elevated choline and lactate and reduced N-acetyl aspartate signal in the affected white matter, consistent with demyelination and a shift to anaerobic metabolism. Arylsulfatase A activity from peripheral leukocytes was approximately 50% of normal, consistent with a "pseudodeficiency" phenotype. These findings confirm the hypothesis that relative arylsulfatase A deficiency predisposes susceptible individuals to delayed posthypoxic leukoencephalopathy and implicates lactic acidosis in the pathogenesis of this disorder.