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Outcome of severe lactic acidosis associated with metformin accumulation
Critical Care 2010, 14:R226
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Outcome of severe lactic acidosis associated with
metformin accumulation
Sigrun Friesecke1, Peter Abel1, Markus Roser2, Stephan B Felix1, Soeren Runge3 1Department of Cardiology, Pneumology and Intensive Care Medicine, Ernst Moritz Arndt University, 2Department of Clinical Chemistry and Laboratory Medicine, Ernst Moritz Arndt University, 17475 3Department of Gastroenterology, Nephrology, Endocrinology, Nutrition, Ernst Moritz Arndt University, Address for correspondence:
E-mail: [email protected] Abstract
Introduction: Metformin associated lactic acidosis (MALA) may complicate metformin therapy,
particularly if metformin accumulates due to renal dysfunction. Profound lactic acidosis (LA) generally predicts poor outcome. We aimed to determine if MALA differs in outcome from LA of other origin Methods: Retrospective analysis of all patients admitted with LA to our medical ICU of a tertiary
referral center during a 5 year period. MALA patients and LAOO patients were compared with respect to parameters of acid-base balance, serum creatinine, hospital outcome, Simplified Acute Physiology Score II (SAPS II) and Sequential Organ Failure Assessment (SOFA) score, using Pearson’s Chi- Results: Of 197 patients admitted with LA, 10 had been diagnosed with MALA. With MALA, median
arterial blood pH was significantly lower (6.78 [range 6.5 to 6.94]) and serum lactate significantly higher (18.7 ± 5.3 mmol/L) than with LAOO (pH 7.20 [range 6.46 to 7.35], mean serum lactate 11.2 ± 6.1 mmol/L). Overall mortality, however, was comparable (MALA 50%, LAOO 74%). Furthermore, survival of patients with arterial blood pH < 7.00 (N=41) was significantly better (50% vs. 0%) if MALA (N=10) was the underlying condition compared to LAOO (N=31). Conclusions: Compared to similarly severe lactic acidosis of other origin, the prognosis of MALA is
significantly better. MALA should be considered in metformin-treated patients presenting with lactic Introduction
Metformin is recommended as the treatment of choice in patients with type 2 diabetes mellitus as it decreases cardiovascular morbidity and mortality [1, 2] . Nevertheless, metformin-associated lactic acidosis (MALA) is a rare but potentially life threatening complication with a mortality rate of 30-50% [3, 4]. The biochemical mechanism of MALA is still not fully understood. Presumably, accumulated metformin suppresses biological oxidation and the enzymes of citric acid cycle [3, 5-7]. Moreover, recent studies have reported that metformin action may also be mediated by regulation of gene expression [8-10]. Pathogenesis of MALA is debated controversely. MALA is assumed to be triggered by an acute primary tissue hypoxia as in septic shock or cardiovascular failure in most cases [1, 3, 11, 12]. Some authors dispute whether metformin may contribute to lactic acidosis (LA) at all [12, 13]. However, cases of MALA solely following drug accumulation have been reported [5, 14-16]. Furthermore, data of a U.S. poison centre give some evidence that a large single ingestion can lead to Remarkable is the fact that severe MALA may have an unexpectedly favourable outcome [4, 14, 15]. Therefore, the aim of this study was to compare the outcomes of MALA and LA of other origin (LAOO). Materials and methods
This retrospective analysis was approved by the institutional Ethics Committee at Ernst Moritz Arndt University of Greifswald. The necessity of patients’ consent was waived. All patients admitted to the Medical Intensive Care Unit of our tertiary referral centre during a 5-year period (2004 – 2008) were screened for LA (i. e., lactate > 5 mmol/L and pH ≤ 7.35 [11]) on admission Clinical characteristics, admission laboratory results, metformin plasma levels and hospital survival of all LA patients were extracted from patient files. To compare severity of disease, Simplified Acute Physiology Score II (SAPS II) [18, 19], and Sequential Organ Failure Assessment (SOFA) score [20, 21] were extracted from ward database. According to discharge diagnoses, patients were assigned the following entities of LA: MALA, post-cardiopulmonary resuscitation (CPR), septic shock, cardiogenic shock, acute mesenteric ischaemia, haemorrhagic shock, other. The diagnosis of MALA was confirmed retrospectively by critical review of patient charts including medical history, clinical presentation, highly elevated plasma levels of metformin, and absence of other common causes of lactic acidosis. None of the patients had evidence of hepatic failure. All MALA patients had ECG and bedside echocardiography to rule out myocardial infarction and relevant cardiac dysfunction. None had evidence of a septic focus in chest X-ray, abdominal and thoracic ultrasound, blood cultures, urinary dipstick – if not anuric –, and computed tomography – if indicated. MALA patients were compared to all LAOO patients and to the severely acidotic subgroup (pH<7.0) of LAOO patients with respect to parameters of acid-base balance, serum creatinine, SAPS II and hospital outcome, using Pearson’s Chi-square or the Mann-Whitney U-test. During the study period, 197 patients were admitted with LA. MALA was diagnosed in 10 patients, none had deliberately overdosed (daily metformin dose 1900 ± 356 mg), but all had severe renal failure (median admission serum creatinine 776 µmol/L [range 347 – 1502]) that had not been noticed before. In 6 patients, previous diarrhea and/or vomiting were reported; in the other 4 no cause for acute renal failure could be identified, but 3 of them had pre-existing chronic renal insufficiency. Metformin plasma levels were highly toxic in all MALA patients (median 55 mg/L, range 31 – 85, therapeutic range 0.2-1.3). All MALA patients were in circulatory shock and treated with vasopressors. Nevertheless, in eight of them, circulatory failure deteriorated up to cardiocirculatory arrest, reversible with cardiopulmonary resuscitation. All MALA patients were mechanically ventilated, and immediately treated with continuous veno-venous haemodialysis or haemofiltration. In MALA, lactic acidosis and renal dysfunction were significantly more severe, other organ dysfunctions were similar, but mortality was not significantly higher compared to all LAOO and to each of the causal entities of LAOO (Table 1). All MALA patients and 31 of the LAOO patients had very severe acidosis (pH < 7.0). In this subgroup, acid-base imbalance was still slightly more profound in MALA than in LAOO, severity of disease and non-renal organ dysfunction (SAPS II, SOFA - score) were comparable, but outcome was significantly better (50% survivors in MALA vs. 0% in LAOO, Table 2). There was no difference within the MALA group between survivors and non-survivors regarding serum metformin level, the degree of lactic acidosis, or organ dysfunction (Table 3). MALA patients who did not survive, died from refractory circulatory failure after a median of 27 hours (range: 3 - 41 hours) Discussion
In 10 out of 197 patients in our study, LA on admission was found to be associated with metformin accumulation. MALA patients had the most severe acid-base imbalance, but no worse outcome. Mortality rates in our study are in accordance with those published by other authors. For MALA, a mortality of 30 - 50% is reported [3, 4, 22], for LA in general up to 83% [23, 24]. Mortality is generally correlated with lactate levels [24, 25]. For MALA, data are less clear. Lalau and Race, after a retrospective analysis in 1999, reasoned that neither lactate nor metformin levels were of prognostic value in MALA because, in their study, survivors had similar lactate and higher metformin levels than patients who died [25, 26]. They suppose that the underlying condition and not metformin accumulation determined outcome. In contrast, DellAglio [27] reported a correlation between pH nadir, Recently, observations in two series of MALA were published [4, 22]. Peters reported 30 patients generally less sick than ours – less acidotic, less frequently in shock, lower SAPS II, less frequently ventilated – in whom mortality was 30% compared to our 50% [22]. Seidowsky reported 42 patients, 29 of them with incidental metformin accumulation. In these, severity of acidosis (mean pH 6.9) and mortality (48.3%) were comparable to our MALA patients [4]. In both series, decreased prothrombin activity on admission was associated with mortality [4, 22]. In our small number of cases, we could not Compared to our LAOO subgroup with similarly severe acid-base imbalance (pH < 7.0), the outcome of MALA patients was significantly better. In line with our results Lalau, reported decreased mortality for patients with pH < 7 if they had been treated with metformin (81% vs. 99%) [28]. We suppose, the different outcome of MALA and LAOO may have been because LA in MALA is primarily not due to shock or ischemia as in most cases of LAOO, and our patients had no underlying condition serious enough to cause severe lactic acidosis in the absence of metformin accumulation. Furthermore, it has been hypothesised that metformin might even be protective in shock, possibly through its beneficial effects on vasomotility [26, 29]. MALA may develop without an underlying disease, it may aggravate LAOO, or metformin may accumulate just coincidentally with LA [3, 12]. In any given patient, it will be difficult to establish the causative role of metformin accumulation in the development of LA [4]. Furthermore, the role of metformin in the development of LA is debated controversly, some authors denying any causal involvement [12, 13] altogether, others believing metformin to actually induce lactic acidosis in certain cases [30]. Clinical data in general and our retrospective observation in particular are not suitable to decide this issue definitely, but our results and those of other authors point to the latter position [4, 5, 14-17, 22, 27]. In our MALA patients, no other cause for LA was identified and highly elevated metformin plasma levels were measured. In these patients previously unnoticed deterioration of renal function explained why metformin had accumulated although taken in usual doses. The much greater extent of renal dysfunction in MALA compared to similarly severe LAOO suggests that renal failure indeed contributed to the pathogenesis rather than only complicating MALA. Progressive renal impairment has been recognised as a risk factor for MALA [14, 15, 30] and can not be held responsible for LA as a single condition in the absence of metformin [31]. MALA may be more common in severely acidotic patients – 24% of our patients with pH < 7 were diagnosed with MALA. Therefore, given the unexpectedly favourable prognosis, it appears important to consider MALA and to enquire possible metformin therapy when a patient is admitted with very severe lactic acidosis. It may safely be assumed that, in such severely ill patients, only prompt and rigorous therapy allows this favourable prognosis [14]. Anecdotal evidence suggests that high-volume renal replacement therapy may be beneficial in severe MALA [5, 32, 33]. Our study included a limited number of patients. The incidence of MALA is low, therefore recruitment of patients is demanding. In this study, we included 10 patients seen in one institution during a 5-year period. A second limitation is the retrospective design. A bias in patient selection can not be excluded. As metformin levels were usually not determined in cases where alternative causes of LA had been identified, coincident metformin accumulation may have been missed. To our knowledge, though, this is the first direct comparison between MALA and LAOO. Conclusions
The outcome of very severe metformin-associated lactic acidosis (pH < 7) is much better than might be expected from the comparison to similarly severe lactic acidosis of other origin. To ensure adequate therapy, it appears important to consider association with metformin and enquire a possible metformin medication in all cases of very severe lactic acidosis. Key messages
• Given the same profound level of acidosis, prognosis of MALA is significantly better than for • It is important to consider MALA in any metformin treated patient and to start therapy promptly. Abbreviations
MALA: metformin associated lactic acidosis; LA: lactic acidosis; LAOO: lactic acidosis of other origin; SAPS II: Simplified Acute Physiology Score II; CPR: cardiopulmonary resuscitation; DIC: disseminated intravascular coagulation; SOFA: Sequential Organ Failure Assessment. Competing interests
The authors declare that they have no competing interests. Authors’ contributions
SFriesecke conceived of the study and helped to draft the manuscript, PA participated in the design of the study and performed the statistical analysis. MR carried out data collection and data analysis, SFelix participated in the design and coordination of the study. SR participated in the design of the study and drafted the manuscript. All authors read and approved the final manuscript. References
Jones GC, Macklin JP, Alexander WD: Contraindications to the use of metformin. Bmj
2003, 326:4-5.
UKPDS: Effect of intensive blood-glucose control with metformin on complications in
overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study
(UKPDS) Group. Lancet 1998, 352:854-865.
Kirpichnikov D, McFarlane SI, Sowers JR: Metformin: an update. Ann Intern Med 2002,
137:25-33.
Seidowsky A, Nseir S, Houdret N, Fourrier F: Metformin-associated lactic acidosis: a
prognostic and therapeutic study. Crit Care Med 2009, 37:2191-2196.
Chang CT, Chen YC, Fang JT, Huang CC: Metformin-associated lactic acidosis: case
reports and literature review. J Nephrol 2002, 15:398-402.
Leverve XM, Guigas B, Detaille D, Batandier C, Koceir EA, Chauvin C, Fontaine E,
Wiernsperger NF: Mitochondrial metabolism and type-2 diabetes: a specific target of
metformin. Diabetes Metab 2003, 29:6S88-94.
Dykens JA, Jamieson J, Marroquin L, Nadanaciva S, Billis PA, Will Y: Biguanide-induced
mitochondrial dysfunction yields increased lactate production and cytotoxicity of
aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol Appl Pharmacol
2008, 233:203-210.
Caton PW, Nayuni NK, Kieswich J, Khan NQ, Yaqoob MM, Corder R: Metformin suppresses
hepatic gluconeogenesis through induction of SIRT1 and GCN5. J Endocrinol 2010,
205:97-106.
Fujita Y, Hosokawa M, Fujimoto S, Mukai E, Abudukadier A, Obara A, Ogura M, Nakamura Y,
Toyoda K, Nagashima K, Seino Y, Inagaki N: Metformin suppresses hepatic
gluconeogenesis and lowers fasting blood glucose levels through reactive nitrogen
species in mice. Diabetologia 2010, 53:1472-1481.
Kim YD, Park KG, Lee YS, Park YY, Kim DK, Nedumaran B, Jang WG, Cho WJ, Ha J, Lee IK,
Lee CH, Choi HS: Metformin inhibits hepatic gluconeogenesis through AMP-activated
protein kinase-dependent regulation of the orphan nuclear receptor SHP. Diabetes 2008,
57:306-314.
Salpeter SR, Greyber E, Pasternak GA, Salpeter EE: Risk of fatal and nonfatal lactic
acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-
analysis. Arch Intern Med 2003, 163:2594-2602.
Misbin RI: The phantom of lactic acidosis due to metformin in patients with diabetes.
Diabetes Care 2004, 27:1791-1793.
Holstein A, Stumvoll M: Contraindications can damage your health--is metformin a case
in point? Diabetologia 2005, 48:2454-2459.
Fitzgerald E, Mathieu S, Ball A: Metformin associated lactic acidosis. Bmj 2009,
339:b3660.
Runge S, Mayerle J, Warnke C, Robinson D, Roser M, Felix SB, Friesecke S: Metformin-
associated lactic acidosis in patients with renal impairment solely due to drug
accumulation? Diabetes Obes Metab 2008, 10:91-93.
Velzen A, Riel A, Vries I, Meulenbelt J: The dangers of metformin: Fatal lactic acidosis
with therapeutic use due to renal failure Toxicology letters 2008, 180S:S142.
Wills BK, Bryant SM, Buckley P, Seo B: Can acute overdose of metformin lead to lactic
acidosis? Am J Emerg Med 2009, in press.
Le Gall JR, Lemeshow S, Saulnier F: A new Simplified Acute Physiology Score (SAPS II)
based on a European/North American multicenter study. JAMA 1993, 270:2957-2963.
Le Gall JR, Neumann A, Hemery F, Bleriot JP, Fulgencio JP, Garrigues B, Gouzes C, Lepage
E, Moine P, Villers D: Mortality prediction using SAPS II: an update for French intensive
care units. Crit Care 2005, 9:R645-652.
Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, Sprung CL,
Colardyn F, Blecher S: Use of the SOFA score to assess the incidence of organ
dysfunction/failure in intensive care units: results of a multicenter, prospective study.
Working group on "sepsis-related problems" of the European Society of Intensive Care
Medicine. Crit Care Med 1998, 26:1793-1800.
Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H, Reinhart CK, Suter
PM, Thijs LG: The SOFA (Sepsis-related Organ Failure Assessment) score to describe
organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems
of the European Society of Intensive Care Medicine. Intensive Care Med 1996, 22:707-
710.
Peters N, Jay N, Barraud D, Cravoisy A, Nace L, Bollaert PE, Gibot S: Metformin-associated
lactic acidosis in an intensive care unit. Crit Care 2008, 12:R149.
Stacpoole PW, Wright EC, Baumgartner TG, Bersin RM, Buchalter S, Curry SH, Duncan C,
Harman EM, Henderson GN, Jenkinson S, et al.: Natural history and course of acquired
lactic acidosis in adults. DCA-Lactic Acidosis Study Group. Am J Med 1994, 97:47-54.
Smith I, Kumar P, Molloy S, Rhodes A, Newman PJ, Grounds RM, Bennett ED: Base excess
and lactate as prognostic indicators for patients admitted to intensive care. Intensive
Care Med 2001, 27:74-83.
Lalau JD, Race JM: Lactic acidosis in metformin-treated patients. Prognostic value of
arterial lactate levels and plasma metformin concentrations. Drug Saf 1999, 20:377-384.
Lalau JD, Race JM: Lactic acidosis in metformin therapy. Drugs 1999, 58 Suppl 1:55-60;
discussion 75-82.
Dell'Aglio DM, Perino LJ, Kazzi Z, Abramson J, Schwartz MD, Morgan BW: Acute metformin
overdose: examining serum pH, lactate level, and metformin concentrations in
survivors versus nonsurvivors: a systematic review of the literature. Ann Emerg Med
2009, 54:818-823.
Lalau JD, Race JM: Metformin and lactic acidosis in diabetic humans. Diabetes Obes
Metab 2000, 2:131-137.
Gras V, Bouffandeau B, Montravers PH, Lalau JD: Effect of metformin on survival rate in
experimental sepsis. Diabetes Metab 2006, 32:147-150.
Fantus IG: Metformin's contraindications: needed for now. Cmaj 2005, 173:505-507.
De Backer D: Lactic acidosis. Intensive Care Med 2003, 29:699-702.
Panzer U, Kluge S, Kreymann G, Wolf G: Combination of intermittent haemodialysis and
high-volume continuous haemofiltration for the treatment of severe metformin-induced
lactic acidosis. Nephrol Dial Transplant 2004, 19:2157-2158.
Friesecke S, Abel P, Kraft M, Gerner A, Runge S: Combined renal replacement therapy for
severe metformin-induced lactic acidosis. Nephrol Dial Transplant 2006, 21:2038-2039.
Table 1: Comparison of MALA and all LAOO patients Values are mean ± standard deviation, or number (percentage). MALA metformin associated lactic acidosis; LAOO lactic acidosis of other origin; SAPS II Simplified Acute Physiology Score II; SOFA Sequential Organ Failure Assessment score. Comparison with MALA: * p<0.05, ** p<0.01 Other causes of LA: respiratory exhaustion (3), alcoholic LA (3), acute liver failure (2), status epilepticus (2), anaphylactic shock, hypovolaemic shock, DIC in acute myeloic leucaemia. Table 2: Comparison of MALA and very severe LAOO (pH<7.0) Values are mean ± standard deviation, or number (percentage). MALA metformin associated lactic acidosis; LAOO lactic acidosis of other origin; SAPS II Simplified Acute Physiology Score II; SOFA Sequential Organ Failure Assessment score. Table 3: Comparison of survived vs. deceased MALA patients MALA metformin associated lactic acidosis; LAOO lactic acidosis of other origin; SAPS II Simplified Acute Physiology Score II; SOFA Sequential Organ Failure Assessment score. (#) 1 patient omitted with prothrombin activity 11% due to cumarin therapy.

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