Metformin lactic acidosis with

In patients taking metformin, lactic acidosis is rare (3 per 100 000 patient-years) and is most often seen when contraindications to metformin (impaired kidney or liver function, alcoholism, circulatory problems, old age) are neglected or not detected (64). Although the relative risk of lactic acidosis with metformin is significantly lower than with phenformin or buformin (65), it has been repeatedly reported (SEDA-6, 371) (66), even in the absence of known contraindications (67). 

In reaction to a report of lactic acidosis at a therapeutic metformin concentration (SEDA-22, 476), in which a mitochondrial defect was supposed to have increased susceptibility to metformin, it has been observed that diabetes itself may dispose to hyperlactatemia (71). Others (72) have taken issue with the opinion (SEDA-22, 476) that the association of lactic acidosis with metformin may be coincidental, as lactic acidosis can also emerge during critical illnesses (type A lactic acidosis, caused by circulatory insufficiency). However, patients with type B lactic acidosis, with high biguanide concentrations, will also develop circulatory insufficiency after some hours. 

In a review of reports to the Australian Adverse Drugs Reactions Advisory Committee between 1985 and 2001 there were 48 cases of lactic acidosis with metformin (86). In 35 of the 48 cases known susceptibility factors were identified. The estimated frequency was one case of lactic acidosis in 30 000 patients taking metformin. The authors... 

Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev 2003 (2) CD002967. 

Drug Interactions. Cimetidine competes for renal tubular secretion of metformin and concomitant administration leads to higher metformin serum concentrations. At least one case report of lactic acidosis with metformin therapy implicates cimetidine. Other cationic... 

Iodine contrast agents interact with metformin, an oral hypoglycaemic drug used to treat type 2 diabetes (see Chapter 6). Iodine contrast agents increase the risk of a patient developing lactic acidosis with metformin, particularly if their kidney function is impaired. Metformin has to be stopped prior to radiological examination and should not be restarted until normal renal function has resumed. 

There is a risk of acute renal failure when iodi-nated contrast material that is used for radiological studies is administered with metformin. Metformin therapy is stopped for 48 hours before and after radiological studies using iodinated material. Alcohol, amiloride, digoxin, morphine, procainamide, quini-dine, quinine ranitidine, triamterene, trimethoprim, vancomycin, cimetidine, and furosemide all increase the risk of hypoglycemia. There is an increased risk of lactic acidosis when metformin is administered with the glucocorticoids. 

Hepatic function impairment Because impaired hepatic function has been associated with cases of lactic acidosis, avoid metformin in patients with clinical or laboratory evidence of hepatic disease. 

In another review it was suggested that the risk of lactic acidosis when metformin is used as recommended is close to zero (84). The author discussed the COSMIC study, which compared metformin treatment for 1 year (n = 7227) with usual care with other antidiabetic agents (n = 1505). There were no cases of lactic acidosis. The findings in controlled trials contrast with case reports of lactic acidosis. About one million patients have received metformin in the USA and the FDA has received 47 reports of lactic acidosis (20 fatal). Of these, 43 patients had renal insufficiency or susceptibility factors for lactic acidosis, such as congestive cardiac failure. Only four cases appeared to have no other susceptibility factors, one of which may have been precipitated by urinary sepsis none of these four died. 

The authors reported that two other cases of metformin-associated lactic acidosis with concurrent NSAID therapy have been reported to the Committee on Safety of Medicines in the UK. Indometacin can impair kidney function and may have done so in this case. Phenformin can cause tubular damage and oliguria in animals (145) and so it is conceivable that metformin-induced renal damage may also have contributed. 

Nucleoside analogue reverse transcriptase inhibitors can rarely cause lactic acidosis with hepatic steatosis and might potentiate the effect of metformin. 

Berner B, Hummel KM, Strutz F, Ritzel U, Ramadori G, Hagenlocher S, Kleine P, Muller GA. Metformin-asso-ziierte Lactatazidose mit akutem Nierenversagen bei Diabetes mellitus Typ 2. [Metformin-associated lactic acidosis with acute renal failure in type 2 diabetes mellitus.] Med Klin (Munich) 2002 97(2) 99-103. 

Chan NN, Darko D, O Shea D. Lactic acidosis with therapeutic metformin blood level in a low-risk diabetic patient. Diabetes Care 1999 22(1) 178. 

Lalau JD, Race JM. Lactic acidosis in metformin therapy searching for a link with metformin in reports of metformin-associated lactic acidosis . Diabetes Obes Metab 2001 3(3) 195-201. 

Harvey B, Hickman C, Hinson G, Ralph T, Mayer A. Severe lactic acidosis complicating metformin overdose successfully treated with high-volume venovenous hemofiltration and aggressive alkalization. Pediatr Crit Care Med 2005 6 598-601. 

Patients with renal impairment should not receive metformin. Other contraindications include hepatic disease, a past history of lactic acidosis, cardiac failure requiring pharmacological therapy, or chronic hypoxic lung disease. The drug also should be discontinued temporarily prior to the administration of intravenous contrast media and prior to any surgical procedure. The drug should not be readministered any sooner than 48 hours after such procedures, and should be withheld until renal function is determined to be normal. These conditions all predispose to increased lactate production and hence to the potentially fatal complication of lactic acidosis. The reported incidence of lactic acidosis during metformin treatment is less than 0.1 cases per 1000 patient-years, and the mortality risk is even lower. 

Biguanides, especially the older drug phenformin, have been associated with lactic acidosis. Thus metformin should be avoided in patients with conditions that increase the risk of lactic acidosis, including alcoholism. The answer is (D). 

B. Lactic acidosis from metformin or phenformin may begin with nonspecific symptoms such as malaise, vomiting, myalgias, and respiratory distress. The mortality rate for severe lactic acidosis is reportedly as high as 50%. 

Teutonico A, Libutti P, Lomonte C, Antonelli M, Casucci F, Basile C. Treatment of metformin-associated lactic acidosis with sustained low-efficiency daily dialysis. NDT Plus 2008 1(5) 380-1. 

The role of concomitant medication is not clear due to the lack of good clinical studies [9]. It is recommended to stop nonsteroidal anti-inflammatory drugs, metformin for the risk of lactic acidosis with decreasing renal function, and diuretics. Usually, diuretics used for long-term treatment of hypertension and inhibitors of the renin-angiotensin system should not be discontinued. 

A class of drug derived from guanidine, including metformin and phenformin. Metformin is currently widely used in humans for the treatment of type 2 diabetes. Phenformin was formerly also widely used but was withdrawn because of problems with lactic acidosis. 

Lactic acidosis (buildup of lactic acid in the blood) may also occur with die administration of metformin. Although lactic acidosis is a rare adverse reaction, its occurrence is serious and can be fatal. Lactic acidosis occurs mainly in patients with kidney dysfunction. Symptoms of lactic acidosis include malaise (vague feeling of bodily discomfort), abdominal pain, rapid respirations, shortness of breath, and muscular pain. In some patients vitamin B12 levels are decreased. This can be reversed with vitamin B12 supplements or with discontinuation of the drug therapy. Because... 

MANAGING LACTIC ACIDOSIS. When taking metformin, the patient is at risk for lactic acidosis. The nurse monitors die patient for symptoms of lactic acidosis, which include unexplained hyperventilation, myalgia, malaise, gastrointestinal symptoms, or unusual somnolence If the patient experiences these symptoms, the nurse should contact the primary care provider at once. Elevated blood lactate levels of greater than 5 mmol/L are associated with lactic acidosis and should be reported immediately. Once a patient s diabetes is stabilized on metformin therapy, the adverse GI reactions that often occur at the beginning of such therapy are unlikely to be related to the drug therapy. A later occurrence of GI symptoms is more likely to be related to lactic acidosis or other serious disease. 

Biguanides such as metformin are thought to inhibit mitochondrial oxidation of lactic acid, thereby increasing the chance of lactic acidosis occurring. Fortunately, the incidence of lactic acidosis in clinical practice is rare. Patients at greatest risk for developing lactic acidosis include those with liver disease or heavy alcohol use, severe infection, heart failure, and shock. Thus, it is common practice to evaluate liver function prior to initiation of metformin. 

Metformin is a biguanide used to treat diabetes mellitus. It is contraindicated in patients undergoing general anaesthesia since anaesthesia can interfere with renal function. The risk of lactic acidosis associated with metformin increases in patients with renal impairment. Metformin should be stopped before and during surgery where anaesthesia is indicated. Metformin should only be restarted after the renal function has returned to normal. 

Lactic acidosis Lactic acidosis is a rare, but serious, metabolic complication that can occur because of metformin accumulation during treatment when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis also may occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever... 

The onset of lactic acidosis often is subtle and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient s physician must be aware of the possible importance of such symptoms. Instruct the patient to notify the physician immediately if these symptoms occur. Withdraw metformin until the situation is clarified. Serum electrolytes, ketones, blood glucose, and, if indicated, blood pH, lactate levels, and blood... 

Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking metformin, immediately discontinue the drug and promptly institute general supportive measures. Because metformin is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. 

Renal function impairment Metformin is known to be excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Do not give metformin to patients with serum creatinine levels above the upper limit of normal for their age. 

Hypoxic states Cardiovascular collapse (shock), acute CHF, acute Ml, and other conditions characterized by hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. If such events occur, discontinue metformin. Surgicai procedures Temporarily suspend metformin for surgical procedures (unless minor and not associated with restricted intake of food and fluids). Do not restart until the patient s oral intake has resumed and renal function is normal. 

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