Prolonged Hemodialysis for Severe Metformin Intoxication

Abstract

Lactic acidosis is a rare and often lethal complication of metformin therapy. We describe a patient who ingested at least 52 g, and possibly more, of metformin and presented with severe lactic acidosis and acute renal failure. He was treated with prolonged hemodialysis: a 3.5 h treatment that did not result in significant clinical improvement, followed by an additional 31 h treatment. With this treatment regimen, his lactate levels gradually decreased and his clinical status improved. A metformin level drawn approximately 25 h after the initiation of the second hemodialysis treatment was still elevated at about five times the upper therapeutic limit. It is suggested that prolonged dialysis is indicated in patients with severe metformin overdose, particularly those with renal failure. In patients whose cardiovascular status permits, prolonged hemodialysis should be strongly considered.

• Metformin
• hemodialysis
• diabetes mellitus
• intoxication
• renal failure

INTRODUCTION

Metformin is a biguanide oral antihyperglycemic agent that has been used for over three decades worldwide and the United States since 1995 for the treatment of type 2 diabetes mellitus. Its primary mechanisms of action appear to be suppression of gluconeogenesis and enhancement of peripheral glucose utilization. It was the most prescribed antidiabetic medication in the United States in the year 2000.¹ It has been recommended as the drug of first choice in patients diagnosed with type 2 diabetes in a consensus document issued by the American Diabetic Association and the European Association for the Study of Diabetes.² As it is so effective, it has recently been proposed that guidelines for its use might be liberalized to include more patients with renal insufficiency.³ Its predecessor, phenformin, was withdrawn from the market in 1977 because of its association with spontaneous lactic acidosis. However, except in overdose situations, the association of metformin with lactic acidosis is quite rare with an estimated incidence of 3 per 100,000 patient-years ⁴ and a recent large review did not find an increased risk for lactic acidosis for metformin versus other antihyperglycemic treatments.⁵ When it does occur, metformin-associated lactic acidosis is most often associated with an intercurrent disease and renal insufficiency.⁶ Fully reported cases of metformin overdose are not common and a 2009 review article⁷ could identify only 22 cases of metformin overdose with documented mortality data and values of serum pH, lactate level, and metformin concentrations. Management of metformin overdose includes conservative measures, bicarbonate therapy, and several types of dialysis. We describe a patient with a substantial metformin overdose who was successfully treated with prolonged hemodialysis and discuss treatment options.

CASE SUMMARY

The patient is a 50-year-old male with a past medical history of diabetes mellitus type 2, depression, and polysubstance abuse. His history is also significant for a prior intentional drug overdose. He was taking metformin 500 mg twice daily.

The patient was brought to the Tampa General Hospital emergency department after the patient's roommate noted he was acting strangely. Questioning of the roommate suggested that the patient had ingested at least 52 g of metformin in a suicide attempt. The patient's mental status deteriorated in the emergency department and he was electively intubated. He became hypotensive and was started on vasopressors.

Laboratory evaluation showed blood urea nitrogen (BUN) 15 mg/dL, serum creatinine 4.2 mg/dL, carbon dioxide 3 mEq/L, anion gap 33, pH 6.84 with a lactic acid level greater than 20 mmol/L through the blood gas analyzer. Initial creatine phosphokinase (CPK) was 56 U/L and after 12 h it was 15,700 with phosphorus of 16.9 mg/dL. Urine output progressively decreased. The patient was diagnosed with metformin-associated lactic acidosis (MALA). The patient received hemodialysis for 3.5 h on a bicarbonate bath of 40 mEq/L. Laboratory values 1 h after completion of hemodialysis revealed that the serum bicarbonate had only increased to 5 mEq/L and the lactic acid level was 21.2 mmol/L. The patient was then placed back on hemodialysis for an additional 31 h. Laboratory tests were done periodically (Table 1). After 12 h of hemodialysis, the serum bicarbonate and pH substantially improved and better patient response to vasopressor agents was noted. Hemodialysis was continued until the serum bicarbonate, lactic acid level, and anion gap were deemed corrected and stable. At that time, the patient was converted to continuous veno-venous hemodiafiltration (CVVHDF) to continue treatment of his anuric acute kidney injury. The results of a metformin blood level drawn after about 28.5 h of hemodialysis and received about a week later showed a level of 10.2 µg/mL, which is about five times the upper limit of the therapeutic range. After 48 h of CVVHDF, the patient was successfully transitioned to intermittent hemodialysis. His renal function was significantly improved by hospital day 19 and dialysis was stopped. The patient was discharged home with a serum creatinine of 1.9 mg/ dL (baseline serum creatinine 0.9 mg/dL).

Table 1.  Arterial blood gas results, lactate levels, metformin level, and time of hemodialysis

Date	Time	pH	HCO3 (mEq/L)	Dialysis	Lactic acid (mmol/L)	pCO2 (mmHg)
7/1	0054	6.84	3	Dialysis started 0615, stopped 0935	>20	16
	1140	7.11	5		>20	16
	1644	7.23	9	Dialysis restarted 1320	>20	20
	2204	7.28	10		21.2	20
7/2	0200	7.32	12		14.9	24
	0522	7.35	14		12.8	25
	1000	7.38	15		8.8	26
	1400	7.38	20	Metformin level = 10 µg/mL at 1435	7.0	34
	1800	7.50	23	Dialysis stopped 2015	3.5	29
	2200	7.49	22		3.2	28

DISCUSSION

Severe metformin overdose usually presents with a compatible history and profound lactic acidosis. Cardiovascular collapse follows shortly thereafter. Treatment should be twofold: (a) to treat the acidosis and (b) to decrease metformin blood levels. Treatment of acidosis generally means use of sodium bicarbonate. However, this treatment has been called into question as bicarbonate therapy may increase intracellular acidosis and thus exacerbate the patient's metabolic derangements. Large amounts of sodium bicarbonate may also lead to hypernatremia.⁸ Addressing the elevated metformin blood levels entails treatments such as activated charcoal to prevent further gastrointestinal absorption and dialytic procedures to remove metformin. Dialysis therapy has the added benefit of correcting the acidosis while removing the toxin.

Although a life-threatening condition, survival from severe metformin overdose is not unusual. Dell'Aglio et al. reported⁹ survival in a patient with a nadir pH of 6.59, peak serum lactate level of 40 mmol/L, and admission serum metformin concentration of 160 µg/mL. This patient underwent 3 h of hemodialysis followed by a second round several hours later and a third hemodialysis treatment on hospital day 3. Giuliani et al.¹⁰ reported survival (although he did suffer a cardiac arrest) in a patient with a nadir pH of 6.68 treated with continuous veno-venous hemofiltration (CVVH) and then continuous veno-venous hemodialysis (CVVHD).

Analysis of survival factors has produced conflicting results. In a group of patients with documented mortality data and values for serum pH, lactate level, and metformin concentrations, no patient died who had a nadir serum pH greater than 6.9, peak serum lactate concentration less than 25 mmol/L, or peak serum metformin concentration less than 50 µg/mL.⁷ Contrarily, Lalau and Race¹¹ were not able to demonstrate a correlation between metformin blood levels, lactate levels, and survival, but rather suggested that survival depended upon the severity of underlying diseases. Seidowsky et al.,⁶ in a study of 42 patients, found a correlation between metformin levels and pH, but no difference in mean metformin levels and survival or nonsurvival. Stades et al.¹² did a literature search and found that neither lactate concentration nor mortality correlated with serum metformin concentrations.

Metformin is a relatively small molecule with a molecular weight of 165 Da. It is not protein bound and is readily cleared by the kidney with about 90% of the drug eliminated by glomerular filtration and tubular secretion in 12 h.⁴ Renal clearance may exceed 450 mL/min in healthy subjects.¹³ Thus, renal insufficiency is a risk factor for drug accumulation.

After absorption, metformin rapidly moves into the tissue compartment and has a high volume of distribution (range 63–276 L). Lalau et al.¹⁴ also demonstrated a biphasic pattern of metformin elimination according to a two-compartment model. They found a metformin dialysance of 68 mL/min in the case of relatively low blood flow, which reached 170 mL/min under good hemodynamic conditions. This two-compartment model suggests that an initial brief hemodialysis will be only partially effective in eliminating metformin. Thus it has been suggested that prolonged¹⁵ hemodialysis is indicated in patients with severe overdose who are able to tolerate hemodialysis. Seidowsky et al.⁶ demonstrated a bicompartmental elimination pattern of metformin by hemodialysis and found that cumulative hemodialysis duration of 15 h was associated with the return of metformin levels to the therapeutic range. The mean duration of hemodialysis in their group was 13 ± 9 h. Guo et al.¹⁵ successfully hemodialyzed two patients with severe MALA (pHs of 6.85 and 6.81) for 21 and 25 h (combined with charcoal hemoperfusion for 12 of the 25 h), respectively. Interestingly, both patients had significantly elevated lactate levels at the end of their treatments and both required further dialysis for acute renal failure. Unfortunately, no metformin levels are reported.

Continuous renal replacement therapy has also been shown to be effective in the treatment of metformin overdose, primarily in patients whose cardiovascular status precludes the use of hemodialysis. Clearance of 50.4 mL/min was found by Barrueto et al.¹ using CVVHD. Harvey et al.¹⁶ successfully treated a patient using high-volume veno-venous hemofiltration over approximately 30 h. Bruijstens et al.¹⁷ successfully treated three patients with metformin intoxication and acute renal failure with prolonged CVVH, although one patient later died of an unrelated cause. Panzer et al.¹⁸ reported a patient whom they initially treated with hemodialysis for 11 h (with a 1 h interruption), followed, because of progressive hemodynamic instability and persistently very high lactate levels, with CVVH for an additional 16 h using one and then two machines to obtain higher volumes for clearance.

Our patient's initial 3.5 h hemodialysis was not effective in treating his acidosis. As he was critically ill and had tolerated the first dialysis, he was then placed back on hemodialysis and the dialysis was run continuously for an additional 31 h. As the dialysis progressed, his acidosis improved and we also noted improvement in his cardiovascular status. The finding of an elevated metformin level in our patient over 25 h after initiation of the second dialysis treatment emphasizes the need for prolonged hemodialysis to clear tissue-bound drug in patients with severe metformin overdose, particularly in those with acute renal failure. As metformin levels are not available on an emergent basis, timing and duration of dialysis will need to be based on a careful clinical evaluation and, in any event, duration should be considerably longer than a standard hemodialysis treatment.

We would suggest that, in patients with severe metformin overdose, particularly those with renal failure and whose cardiovascular status permits, prolonged hemodialysis be strongly considered.

Declaration of interest:

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.