Plasma lactate and 3-hydroxybutyrate levels in patients with acute ethanol intoxication

In order to assess the frequency and severity of lactic acidosis and 3-hydroxybutyric acidosis in ethanol abusers, 29 patients who presented to an emergency room with acute intoxication were tested. Most were also chronic ethanol abusers but were not otherwise seriously ill. Their serum ethanol concentrations averaged 226.5 +/- 94.8 mg/dl (range 98 to 426 mg/dl). In 20 patients, the plasma lactate level was elevated only mildly or not at all (1.1 to 3.0 mmol/liter). Seven patients had plasma lactate levels between 3.5 and 4.3 mmol/liter, and only two patients had moderately elevated levels, 5.1 and 8.7 mmol/liter. Thus, severe lactic acidosis was uncommon in these ethanol-intoxicated patients. Only two patients had even trivially elevated plasma levels of 3-hydroxybutyrate, 1.0 and 1.2 mmol/liter. Thus, these patients did not have unrecognized "alcoholic ketosis" manifested mainly as 3-hydroxybutyric acidosis. An unexpected and unexplained finding was the presence of hyperchloremia in 10 of the 29 patients, with serum chloride levels of more than 110 mmol/liter.     

Metformin therapy in patients with chronic kidney disease

Metformin therapy is limited in patients with chronic kidney disease (CKD) due to the potential risk of lactic acidosis. This open‐label observational study investigated metformin and lactate concentrations in patients with CKD (n = 22; creatinine clearances 15–40 ml/min) and in two dialysed patients. Patients were prescribed a range of metformin doses (250–2000 mg daily) and metformin concentrations were compared with data from healthy subjects (scaled to 1500 mg twice daily). A subset of patients (n = 7) was controlled on low doses of metformin (250 or 500 mg daily). No correlation between metformin and lactate concentrations was observed. Three patients had high lactate concentrations (>2.7 mmol/l) and two had high metformin concentrations (3–5 mg/l), but none had any symptoms of lactic acidosis. Reducing metformin dosage and monitoring metformin concentrations will allow the safe use of metformin in CKD, provided that renal function is stable.     

Biguanide-associated lactic acidosis. Case report and review of the literature.

PURPOSE--The biguanides are a class of oral hypoglycemic agents that are commonly used in the treatment of diabetes mellitus. Such agents include metformin, phenformin, and buformin. The use of phenformin was discontinued in the United States in 1976 because of probable association with lactic acidosis. However, metformin is currently in common use in many parts of the world. In this report, we describe a patient with severe lactic acidosis secondary to metformin administration, and review the literature relevant to biguanide-associated lactic acidosis. PATIENT--We describe a diabetic man with end-stage renal failure and diabetes mellitus who was hospitalized with life-threatening lactic acidosis (lactate, 10.9 mmol/L). Unbeknownst to the hospital staff, he was being treated with metformin, which had been prescribed in Indonesia. RESULTS--Arterial blood gas analysis revealed a pH of 6.76 and a bicarbonate level of 1.6 mmol/L prior to treatment. Following therapy, which included oxygen, volume expansion, other supportive therapy, and hemodialysis, the patient completely recovered and was discharged from the hospital. CONCLUSIONS--Lactic acidosis can complicate biguanide therapy in diabetic patients with renal insufficiency. We review the literature relevant to the pathogenesis and therapy of biguanide-associated lactic acidosis. Physicians who have completed their training after 1976 may not be familiar with metformin and other biguanides, but with the increasing numbers of immigrants to the United States, physicians should be aware of the potential complications of these medications.     

An Experimental model of phenformin-induced lactic acidosis in rats

Summary An experimental model of phenformininduced lactic acidosis was established in rats. Following a subtotal nephrectomy, renal failure developed (serum creatinine 4.5±0.1mg/100ml and 2.8±0.1 mg/100 ml on the 1st and 8th postoperative days respectively). Immediately after nephrectomy intra-peritoneal phenformin treatment, 16 mg/day, was commenced. Lactic acidosis developed progressively within 8 days, or earlier in the rats with the most severe renal insufficiency. The metabolic pattern was very similar to that observed in diabetic patients with a biguanide-induced lactic acidosis: on the 8th day, 2 h after the last phenformin injection, blood lactate was 10.8±1.0 mmol/1 (controls: 1.50±0.03); pyruvate was 0.56±0.06 mmol/1 (controls: 0.10±0.01) and blood pH: 7.00 ± 0.02 (vs 7.34±0.02); 3-hydroxybutyrate was 1.41±0.37 mmol/1 (vs 0.32 ±0.03); acetoacetate: 0.51±0.15 mmol/1 (vs 0.17 ±0.01), and free glycerol: 0.63 ±0.07 mmol/1 (vs 0.14 ±0.02). Increased concentrations of alanine (1.66±0.26 mmol/1, vs 0.48 ± 0.04 in controls) and low blood glucose levels (23± 8 mg/ 100 ml vs 70 ± 2, after a 12 hours fast) accompanied the lactic acidosis in spite of high glucagon levels (2030±170 pg/ml vs 108±10 in controls) and low insulin/glucagon molar ratio (0.19 vs 6.9 in controls). Normal rats, treated with phenformin at same doses, and nephrectomized rats injected with saline served as controls and remained free of lactic acidosis. Hydroxyphenformin (16 mg/day) injected in nephrectomized rats, was biologically inactive. Glucose production from¹⁴C-lactate was 425 ±85 mol/100 g body wt/h, vs 1050 ± 90 in control animals. Blood lactate specific activity declined more slowly in the lactic acidotic rats than in controls, suggesting that a decrease in lactate utilization contributed to hyperlactataemia more than an increased lactate production.     

Experiences of a poison center with metformin-associated lactic acidosis.

Metformin is widely used in the treatment of type 2 diabetes, though it is recognized to be associated with the risk of lactic acidosis. A case of pronounced lactic acidosis with cardiac arrest (pH 6.60, lactate 17.5 mmol/l, base excess - 30, standard bicarbonate 2.5 mmol/l, core body temperature 27.8 degrees C) is presented in a 61-year-old woman under metformin therapy. The key laboratory abnormalities observed during the intensive care treatment including repeated hemodialysis are described. The patient showed a complete recovery with residually reduced mental capabilities. Furthermore, an explorative data analysis of our poison center database from 1995 until 2003 concerning metformin was performed. In 109 inquiries for metformin a lactic acidosis (mean pH 6.87 +/- 0.11, mean lactate 20.9 +/- 8.1 mmol/l) was present in 14 cases (9 female, 5 male, average age 57.7 years) with 8 patients under regular metformin therapy and 6 patients who ingested large amounts of metformin to attempt suicide. 4 patients did not survive the severe metabolic disturbance. The present report demonstrates that metformin-associated lactic acidosis is a rare but critical complication of metformin therapy of type 2 diabetes as well as in acute suicidal ingestion of metformin. Early diagnosis and rapid correction of the metabolic acidosis using hemodialysis provides the possibility of a positive outcome even in severe cases. If metformin-associated lactic acidosis is suspected we recommend early involvement of a poison center.     

Reality of severe metformin-induced lactic acidosis in the absence of chronic renal impairment

BACKGROUND: Lactic acidosis in metformin use is a widely recognised but rare side effect. Case reports usually describe elderly patients with conditions which in themselves can cause lactic acidosis or with known contraindications to metformin. We present cases of an elderly woman, a younger woman and a man who developed serious metformin-induced lactic acidosis in the absence of chronic renal impairment. RESULTS: Laboratory results showed acute renal failure in all patients. The pH was 6.77, 6.98 and 6.7, respectively, and lactate levels were 18.2, 18.4 and 11.7 mmol/l, respectively. Metformin plasma levels were 58, 57 and 39 mg/l. All patients received continuous veno-venous haemofiltration (CVVH), using bicarbonate as a buffer solution shortly after arrival on our ICU. In the subsequent hours, a steep decline in the plasma levels was observed, with a concomitant increase in pH. No other diagnoses were made, so we concluded that all patients were suffering from metformin-induced lactic acidosis. Despite the severity of the metabolic acidosis, both female patients survived. Our male patient died after a prolonged stay in the ICU, but this was not related to metformin. CONCLUSION: Metformin-induced lactic acidosis does exist. Metformin-induced lactic acidosis may occur in patients with previously normal renal function, even in young patients. Patients with extreme (lactic) metabolic acidosis caused by metformin can survive when CVVH treatment is initiated rapidly. Intercurrent symptoms or diseases that affect renal perfusion can precipitate lactic acidosis.     

Lactic acidosis after concomitant treatment with metformin and tenofovir in a patient with HIV infection

We present an uncommon case of lactic acidosis after concomitant administration of Metformin and Tenofovir. This is a 74-year-old man with a history of diabetes mellitus receiving treatment with metformin. He had coronary artery disease and HIV infection treated with emtricitabine, tenofovir and recently started on efavirenz. He presented with zoster-like abdominal pain, tachypnoea, nausea and vomiting. On clinical examination, the patient was afebrile, hypotensive and tachycardic, he was markedly dehydrated and oliguric. The abdomen was soft, tender on palpation, not distended without rebound tenderness. The arterial blood gases revealed marked lactic acidosis and the laboratory tests on admission showed acute renal failure. The patient received nine treatments of slow continuous veno-venous hemofiltration (CVVHF). Despite the prolonged period of anuria, urine output progressively improved after 25 days and serum biochemical parameters of renal function returned to normal within 40 days. Health professionals must be aware of this uncommon effect in patients on antiretroviral treatment. Prompt initiation of CVVHF resulted in resolution of both lactic acidosis and renal failure.     

Lactic acidosis associated with stavudine administration: a report of five cases.

Type "B" lactic acidosis has been described in patients receiving the nucleoside analogs zidovudine, didanosine, and fialuridine. Lactic acidosis has also been described in 4 patients receiving combination therapy with stavudine and lamivudine. We describe the development of chronic type "B" lactic acidosis in 3 patients receiving stavudine as a single agent and in 2 patients receiving combination therapy with stavudine and either lamivudine or delavirdine, a nonnucleoside analog. All patients presented with abdominal pain, vomiting, and hepatic steatosis. Other signs of mitochondrial toxicity included pancreatitis and myopathy (2 cases). The mean duration of stavudine therapy was 9.4 months, and the mean observed peak lactate level+/-SD was 10.3+/-5 mmol/L. After discontinuation of stavudine treatment, lactic acidosis improved in 4 patients after 4-60 weeks, and 1 patient died. Evaluations for other causes of lactic acidosis, including hypoxemia, malignancy, sepsis, and cardiogenic shock, were negative.     

Lactate levels as predictors of the relationship between oxygen delivery and consumption in ARDS

We reviewed the changes in Do2 and Vo2 in 58 patients with ARDS after interventions which included fluid loading, blood transfusion, and PEEP. After a significant change in Do2, patients with lactic acidosis (lactate level greater than 2.4 mmol/L) exhibited significant corresponding changes in Vo2 (p less than 0.001); however, no change in Vo2 was observed in patients without lactic acidosis (1-beta greater than 0.8). We conclude that a biphasic pattern of oxygen utilization in patients with ARDS emerges when subsets of patients with and without lactic acidosis are compared. Lactic acidosis, a marker of anaerobic metabolism, may be a characteristic of patients with ARDS who exhibit changes in Vo2 that are dependent on changes in Do2.     

A case report of acute lymphoblastic leukemia complicated by lactic acidosis

Type B lactic acidosis (LA) is a distinct form of metabolic acidosis characterized by low blood pH (≤7.35) accompanied by accumulation of lactate (blood concentration ≥ 5 mmol/L) (Luft et al. in Am J Clin Pathol 80:484–489, 1983). There are two types of LA that are caused by different mechanisms. Type A is more common, and is caused by the lack of oxygen (tissue hypoxia or hypoperfusion). In this case, impaired cellular respiration leads to lower pH level and at the same time the cells are forced to metabolize glucose anaerobically, which leads to increased production of lactate. The other type, Type B, is relatively rare, and is occasionally found in patients with hematological malignancies, such as leukemia or lymphoma. The molecular mechanism of Type B LA is not fully understood. Here, we report a case of precursor B cell acute lymphoblastic leukemia who initially shows manifestations of Type B LA and bilateral renal enlargement.     

Gas exchange responses to constant work-rate exercise in patients with glycogenosis type V and VII

During constant work-rate exercise above the lactic acidosis threshold, oxygen consumption fails to plateau by 3 minutes, but continues to rise slowly. This slow component correlates closely with the rise in lactate in normal subjects. We investigated if oxygen consumption during constant work-rate exercise could rise after 3 minutes in the absence of a rise in lactate. We studied five patients with McArdle's disease, one patient with phosphofructokinase deficiency and six normal subjects. Subjects performed two 6-minute duration constant work-rate exercise tests at 40 and 70% of peak oxygen consumption. During low-intensity exercise, oxygen consumption reached steady state by 3 minutes in both groups. Lactate rose slightly in control subjects but not in patients. During high-intensity exercise, oxygen consumption rose from the third to the sixth minute by 144 (21-607) ml/minute (median and range) in control subjects and by 142 (73-306) ml/minute in patients (p = not significant, Mann-Whitney U test). Over the same period, lactate (geometric mean and range) rose from 2.68 (1.10-5.00) to 5.39 (2.70-10.00) mmol/L in control subjects, but did not rise in patients (1.20 [0.64-1.60] to 0.70 [0.57-1.20] mmol/L). We conclude that the slow component of oxygen consumption during heavy exercise is not dependent on lactic acidosis.     

Fatal hyperphosphatemia from a phosphosoda bowel preparation

Oral phosphosoda is increasingly being used as a bowel preparation for colonoscopy, as it requires that a much smaller volume be ingested and is equally effective and less costly than polyethylene glycol-based electrolyte solutions. Oral phosphosoda has a good safety record, but complications of its use may occur. We describe a patient who died as a result of severe hyperphosphatemia after an oral phosphosoda bowel preparation. A 55-year-old man was admitted with rectal bleeding, abdominal pain, and vomiting. He had a history of diabetes, hypertension, and end-stage renal disease and had successful renal transplant 3 years prior. His initial serum creatinine, calcium, phosphate, and electrolyte levels were normal. He vomited after polyethylene glycol-based electrolyte solution, and an alternate bowel preparation with oral phosphosoda was recommended. He received 90 mL of oral phosphosoda as a single dose. Six hours later, he had cardiorespiratory arrest and was found to have hyperphosphatemia (serum phosphate, 17.8 mg/dL), a high anion gap acidosis, hypoxia, and oliguric renal failure. Resuscitation was unsuccessful. Autopsy showed ischemic colitis. We conclude that bowel preparation with phosphosoda may be associated with severe complications and should be avoided if there is any suggestion of impaired renal function or poor gut motility.     

Glucose and lactate kinetics in children with severe malaria

Children with severe malaria often present with lactic acidosis and hypoglycemia. Although both complications independently predict mortality, mechanisms underlying their development are poorly understood. To study these metabolic derangements we sequentially allocated 21 children with falciparum malaria and capillary lactate concentrations of 5 mmol/L or more to receive either quinine or artesunate as antimalarial therapy, and dichloroacetate or saline placebo for lactic acidosis. We then administered a primed infusion (90 min) of L-[3-13C1]sodium lactate and D-[6,6-D2]glucose to determine the kinetics of these substrates. The mean (SD) glucose disposal rate in all patients was 56 (16) micromol/kg x min, and the geometric mean (range) lactate disposal rate was 100 (66-177) micromol/kg x min. Glucose and lactate disposal rates were positively correlated (r = 0.62; P = 0.005). Artesunate was associated with faster parasite clearance, lower insulin/glucose ratios, and higher glucose disposal rates than quinine. Lactate disposal was positively correlated with plasma lactate concentrations (r = 0.66; P = 0.002) and time to recovery from coma (r = 0.82; P < 0.001; n = 15). Basal lactate disposal rates increased with dichloroacetate treatment. Elevated glucose turnover in severe malaria mainly results from enhanced anaerobic glycolysis. Quinine differs from artesunate in its effects on glucose kinetics. Increased lactate production is the most important determinant of lactic acidosis.     

Salsalate exacerbation of chronic renal insufficiency. Relation to inhibition of prostaglandin synthesis

Nonacetylated salicylates have not been reported to cause the hemodynamically mediated acute renal failure associated with nonsteroidal anti-inflammatory drug therapy. A 73-year-old woman with a creatinine clearance of 0.33 mL/s (20 mL/min), hypertension, and arteriosclerotic cardiovascular disease developed reversible renal insufficiency when her dose of salsalate was increased to 4.5 g/d (serum salicylate concentration, 2.22 mmol/L [30.7 mg/dL]). Under close observation the patient was re-treated with lower doses of salsalate while renal function and the urinary excretions of prostaglandins were monitored. The excretion of prostaglandin E2 decreased abruptly while the excretion of 6-keto-prostaglandin F1 alpha decreased more gradually as the dose of salsalate was increased. Renal function appeared to decline in parallel with the decrease in 6-keto-prostaglandin F1 alpha and recovered rapidly after discontinuation of salsalate therapy. Nonacetylated salicylates can cause a hemodynamically mediated acute renal failure in patients at risk for this nephropathy.     

A preliminary study of thiamine status in northeastern Thai children with acute diarrhea

This study is a preliminary determination of thiamine status in children with diarrhea and metabolic acidosis admitted to hospital. Children with diarrhea (N = 14; age 2 m-6 yr) were divided into 2 groups according to anion gap type; group 1 (21.4%) with a normal anion gap (5.5 +/- 5.2 mmol/l) and group 2 (78.6%) with a wide anion gap (21.2 +/- 5.2 mmol/l). Blood was taken on the day of admission to determine thiamine and lactate levels. Sixty-six point seven percent of patients in group 1 had a normal lactate level (1.5 +/- 0.8 mmol/l) and 33.3% had a high lactate level (2.2 mmol/l); none had thiamine deficiency (TPPE < 20%). High lactate (3.5 +/- 1.4 mmol/l) was found in 54.5% of group 2 and thiamine deficiency was observed in 18.2% of this group. In conclusion, no thiamine deficiency was noted in patients with normal anion gap, but thiamine deficiency was not uncommon in patients with a wide anion gap, regardless of lactic acidosis.     

肾功能正常的2型糖尿病患者血肌酐与乳酸水平相关

目的 探讨肾功能正常的2型糖尿病患者的血肌酐与血乳酸水平的关系以及应用二甲双胍后对血乳酸的影响.方法 选择肾功能正常的住院2型糖尿病患者723例,其中应用二甲双胍者(用药组)275例,未用双胍类者(对照组)448例.用酶电极法测定血乳酸水平,同时榆测空腹血糖、胰岛素、HbA1C尿素氮、肌酐和丙氨酸转氨酶(ALT)等水平.结果 (1)用药组的平均血乳酸水平高于对照组[(1.33±0.57 vs 1.17±0.47)mmol/L,P<0.01];高乳酸血症的发生率显著高于对照组(9.45% vs 4.91%,P<0.01),但均末达到酸中毒的水平.(2)相关性分析结果显示,血乳酸水平与血肌酐、尿素氮、ALT、体重指数(BMI)呈明显正相关.在校正ALT和BMI后,肌酐仍与血乳酸呈正相关(r=0.345,P<0.01).(3)按肌酐水平进行分层后,血乳酸水平随着血肌酐水平升高而增加,肌酐>90 μmol/L后显著增高;受试者工作特征(ROC)曲线分析表明预测血乳酸水平增高的肌酐截点是95.35 μmol/L.结论 肾功能正常的2型糖尿病患者应用二甲双胍虽具有较好的安全性,但仍有极少数患者可出现乳酸水平的轻度升高.血肌酐>95.35μmol/L者发生高乳酸血症的风险增加.     

Metformin and lactic acidosis: cause or coincidence? A review of case reports

OBJECTIVE: Metformin has been associated with the serious side-effect lactic acidosis. However, it remains unclear whether the use of metformin was a cause or a coincidence in lactic acidosis. DESIGN: A literature search of the Index Medicus (1959-66) and of the databases Embase, Medline, Medline Express (1966-99) was performed using the keywords metformin, biguanides and lactic acidosis. All articles of cases with metformin-induced lactic acidosis (MILA) were cross-referenced. SUBJECTS: Cases were included for analysis if they met the following criteria: serum pH < or =7.35, lactate concentration > or =5 mmol L(-1). INTERVENTION: A forum of six experts in intensive care medicine independently categorized the cases in MILA unlikely (score 0), possible MILA (score 1) or probable MILA (score 2). MAIN OUTCOME MEASURES: Statistical analysis included the paired interobserver agreement (kappa) and multivariate regression analysis. RESULTS: Of 80 reported cases, 33 were excluded because of insufficient quality. The forum scores of the remaining 47 cases were distributed normally with a mean score of 7 (range 2-10). The kappa-value was 0.041 (SD = 0.24, range -0.514, 0.427). Neither lactate concentration nor mortality correlated with serum metformin concentrations. CONCLUSIONS: Given the low interobserver agreement and the lack of any relationship between metformin levels and outcome parameters, the concept that there is a simple, causal relationship between metformin use and lactic acidosis in diabetic patients has to be reconsidered.