Biguanides

• Buformin
• Metformin
• Phenformin

Biguanide overdose has a significant mortality and is associated with an induced lactic acidosis which may be severe. Lactic acidosis associated with phenformin therapy has been reported to have a mortality rate of up to 50% in published cases and requires intensive supportive care with very careful and gradual correction of the acidosis. It is likely that a large part of the mortality relates to the underlying causes of the lactic acidosis (made worse by the phenformin) and the pre-existing state of the patients. Based on very limited evidence, the use of glucose/insulin infusions, dichloroacetate and haemodialysis are all probably beneficial. Metformin seems much less likely to be associated with lactic acidosis during routine therapy. In overdose, metformin induced lactic acidosis can be extremely severe but is often surprisingly well tolerated.

There are two forms of lactic acidosis with biguanides. One is a biguanide associated acidosis (MALA) where there is a pre-existing cause of lactic acidosis in an unwell patient which is exacerbated by the biguanide. The mortality and morbidity is related mainly to the underlying issues in the patient and may be very high. The second is a biguanide induced lactic acidosis (MILA) where the sole cause of the acidosis is high concentrations of the biguanide such as accumulation in renal insufficiency or overdose. The mechanism of the development of the lactic acidosis is not well understood. It is believed to result from the inhibition of microsomal enzymes involved in glucose metabolism including those involved in gluconeogenesis from lactate and pyruvate and also inhibit the enzyme pyruvate dehydrogenase which converts pyruvate into acetyl-coenzyme-A. They have numerous other actions that are believed to be important in their glucose lowering action (McGuinness & Talbot, 1993). Dichloroacetate, which has been proposed as an antidote, has directly opposing actions to biguanides as it stimulates pyruvate dehydrogenase, decreases glycolysis (thus decreasing lactate formation) and increases lactate oxidation to pyruvate (Stacpoole et al, 1992). It appears that the metabolic acidosis is the primary event in biguanide poisoning (rather than it occurring secondary to decreased perfusion or tissue hypoxia as in most cases of lactic acidosis). Thus a specific antidote, if given early enough, may be effective. This has been observed in some animal models of biguanide poisoning (Ryder, 1987).

Biguanides reduce elevated blood glucose concentrations in patients with diabetes, but it do not increase insulin secretion. There is no blood-glucose-lowering effect in non-diabetic subjects. Augmentation of muscular glucose uptake and utilisation, and reduction of increased hepatic glucose production through an antigluconeogenic action explain the blood-glucose-lowering effect, but the contribution of each of these processes to the overall effect has not been defined. The intestinal glucose absorption may be slightly delayed. Increased glucose utilisation by the intestines and erythrocytes results in increased lactate formation. The formation of glucose from lactate and the lack of an insulinotropic (release of insulin) effect explain the absence of clinical hypoglycaemia during biguanide treatment. In healthy subjects, counter-regulatory mechanisms, such as increased gluconeogenesis from lactate, mask the effect of the drugs, and blood glucose remains unchanged. In diabetic subjects, however, the blood glucose elevation is variably reduced.

Metformin is poorly and slowly absorbed. Peak concentrations in therapeutic use occur between 2 and 3.5 hours after ingestion. Bioavailability is low and falls with increasing doses (Scheen, 1996)

Metformin is widely distributed into intracellular compartments where it binds to microsomes. The volume of distribution is 1-5 L/kg. There is no plasma protein binding. As a basic drug, its movement into cells (intracellular pH being lower than systemic pH) may be enhanced by systemic alkalinisation (Ryder 1984).

Buformin and metformin are renally cleared by glomerular filtration and the various cation transport systems (OCT1–3, MATE1 and MATE2K) affect its pharmacokinetics and pharmacodynamics thus there are interactions with cimetidine and other basic cations and genetic variability. Phenformin is both metabolised by CYP2D6 and renally cleared. The half-life of all of these drugs is greatly prolonged with renal impairment and the half-life of phenformin is also prolonged in those without CYP2D6 (8 to 9% of Caucasians) and in severe liver disease.

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A profound lactic acidosis is the most consistent reported finding in overdose. The pH is often less than 7.0 and high concentrations of lactate are observed. In some cases ketones are also high and account for some of the acidosis. The serum bicarbonate is low and there is usually a large anion gap. Hyperkalaemia is often associated with the lactic acidosis and is presumably secondary to cellular shifts resulting from the acidosis. Hypoglycaemia (Bingle et al, 1970) has occasionally been reported but is very uncommon. Biguanides impair gluconeogenesis and this case presented quite late after a prolonged period of fasting. The metabolic acidosis initially increases the respiratory rate (Kussmaul's respiration) leading to a compensatory respiratory alkalosis. If this cannot be maintained due to respiratory disease or increasing sedation then the pH will fall rapidly.

Hypotension and tachycardia are common, as is reduced cardiac output. These may progress to cardiogenic shock. Patients may be dehydrated secondary to impaired consciousness and/or vomiting. All of these may contribute to the lactic acidosis (by reducing tissue perfusion) and should be corrected if possible. Myocardial infarction has occurred secondary to profound acidosis.

Nausea and vomiting are common in the early stages; delirium, sedation, coma, and seizures may all occur secondary to the acidosis.

Hypothermia, acute renal failure, pulmonary oedema, pneumonia may all complicate the episode, particularly in delayed presentations.

These are unhelpful in management. There is not a good correlation between blood concentrations of biguanides and outcome. In many of the series of acidosis occurring in chronic therapeutic use, the majority of patients have had undetectable concentrations at the time of presentation.

Electrolytes, glucose, renal function, anion gap and lactate should all be measured at regular intervals (say 2-4 hourly) and more frequently if there are particular concerns (e.g., hyperkalaemia).

A baseline ECG should be performed. Continuous ECG monitoring is advisable in patients with severe acidosis as complications secondary to either acidosis or hyperkalaemia may occur.

The differential diagnosis is of any agent that causes profound acidosis and CNS effects and would include ethylene glycol, salicylate, methanol, isoniazid, alcoholic and diabetic ketoacidosis. Lactic acidosis secondary to decreased tissue perfusion from toxicological (e.g. carbon monoxide, cyanide) or non-toxicological (sepsis or cardiogenic shock) causes also must be considered.

Lactic acidosis in therapeutic use is far more common with phenformin than metformin and phenformin has been removed from the market in most countries. There are insufficient data to determine if such differences are also true in overdose.

The following are associated with a less favourable outcome (mortality and morbidity):

• Elderly (age >60)
• Complicating medical conditions (e.g. ischaemic heart disease, respiratory disease)
• Renal failure
• Hypotension (shock)
• Diabetes
• Low pH on presentation (pH<7.0)
• Low bicarbonate on presentation (HCO3 < 6.0 mmol/L)
• High lactate ( > 17 mmol/L)

However, none of these is a particularly good predictor of outcome.

All patients with significant acidosis should be admitted to intensive care. Intravenous fluids should be given and it may be useful to closely monitor fluid balance with a central line as either over or under hydration may worsen the acidosis or cardiac function. Ventilation must be maintained and if the respiratory rate is falling then the patient should be ventilated.

Oral activated charcoal should be given to all patients who present within 1 hour of ingestion as these drugs are quite slowly absorbed. There is unlikely to be any benefit from repeated doses of activated charcoal. Generous fluid replacement to counteract the volume depletion associated with gastrointestinal decontamination is particularly important in overdose with drugs that lead to hypotension.

Acidosis

Maintaining adequate tissue perfusion, oxygenation and glucose delivery and maximising compensatory hyperventilation are all important factors in the treatment of significant acidosis. The use of specific antidotes (including bicarbonate) to correct acidosis is controversial and may provide no additional benefit. We would recommend routine use of glucose and insulin, very slow and low doses of sodium bicarbonate if the pH is less than 6.9 - 7.0, and dichloroacetate if it is available.

Bicarbonate
Bicarbonate rapidly corrects acidaemia. Unfortunately, it is likely that it temporarily worsens intracellular and CNS acidosis by liberating carbon dioxide which crosses lipid membranes much more efficiently than bicarbonate where it is converted to carbonic acid. Also, rapid alkalinisation decreases oxygen delivery due to inhibition of oxygen dissociation from haemoglobin and reduces ionised calcium. All these factors mean that cardiac output and tissue perfusion may fall which may paradoxically increase lactate production and worsen the acidosis (McGuinness & Talbert, 1993). Neither animal studies nor case series support the use of rapid high doses of sodium bicarbonate, although this is the most common treatment administered. (Ryder, 1987)

Dichloroacetate
Dichloroacetate stimulates pyruvate dehydrogenase, decreases glycolysis (thus decreasing lactate formation) and increases lactate oxidation to pyruvate (Stacpoole et al, 1992). Some, but not all, animal models of biguanide poisoning have shown benefit from the use of dichloroacetate (Ryder, 1987). A large randomised trial of dichloroacetate in lactic acidosis, mostly due to shock and/or sepsis, demonstrated that dichloroacetate was effective in reducing the degree of acidosis but in these patients had no effect on outcome (Stacpoole et al, 1992). However, in biguanide poisoning the lactic acidosis is probably the primary event, rather than secondary to severe organ failure or sepsis, and reversal of the acidosis may provide more benefit.

Dose: 50 mg/kg as a 10% solution infused over 30 minutes repeated 2 hours later. The drug is unlikely to be available except as part of a study protocol.

Glucose & Insulin
It has been postulated that administration of glucose and insulin stimulates pyruvate dehydrogenase. Glucose and insulin will also be useful treatment for patients that have some contributory ketoacidosis. Many patients with lactic acidosis have a larger anion gap than can be accounted for by lactic acid. Two authors have reviewed the outcomes of patients reported in the literature to have been treated with glucose and insulin (Misbin, 1977; Luft et al, 1979). Surprisingly, while Misbin's conclusion was that the patients treated with glucose and insulin had much better reported survival, Luft et al found that all treatments reported had similar survival rates. While these were much better than those reported with no treatment their conclusion was that this probably indicated publication bias for positive treatment outcomes. However, it is unlikely to cause any harm and may provide benefit.

Typical doses have been 2 to 5 units of insulin per hour. Sufficient glucose should be given to maintain blood glucose; often this has required quite low doses (1 to 3 grams of glucose/hour - 10 to 30 mL of 10% glucose/hour).

Tromethamine (THAM, Trometamol)
This proton acceptor has been used to correct biguanide induced lactic acidosis in a few case reports but there is little reason to favour it over either low doses of bicarbonate or dichloroacetate (Ryder, 1987).

As these drugs are renally excreted, it is important to maintain a good urine output to facilitate renal clearance. Clearance is enhanced in acidic urine. So any effort to further increase renal clearance is likely to contribute to the metabolic acidosis and is thus contraindicated.

Haemodialysis
The clearance of metformin may be enhanced by haemodialysis, the other biguanides have larger volumes of distribution and will be less effectively cleared. Haemodialysis against a bicarbonate buffer may also partially correct acid-base and electrolyte abnormalities (Chalopin et al, 1984). There are no clear-cut indications for haemodialysis in this situation but clearly it would be favoured by the presence of renal failure and/or significant electrolyte disturbances. CVVH may be considered though may not be as effective (Arroyo et al, 2010).

Mortality in reported series of phenformin induced lactic acidosis is up to 50%. Long term sequelae do not appear to have been reported but it would be surprising if the hypotension, severe acidosis, and cerebral oedema that may occur with this poisoning did not sometimes result in long term neuropsychiatric deficits. Patients should be followed up at least once after the acute illness has resolved. Other issues that may be dealt with are whether the patient has contraindications to the further use of biguanides.

See PowerPoint presentation by Dr Rama Rao, New York Poisons Information Centre on hypoglycaemics .

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6- Dec- 2014