Friesecke et al. Critical Care 2010, 14:R226 http://ccforum.com/content/14/6/R226 RESEARCH Open Access Outcome of severe lactic acidosis associated with metformin accumulation Sigrun Friesecke1*, Peter Abel1, Markus Roser2, Stephan B Felix1, Soeren Runge3 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 (LAOO). Methods: We conducted a 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-square or the Mann-Whitney U-test. 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 acidosis. Introduction of MALA solely following drug accumulation have been Metformin is recommended as the treatment of choice reported [5,14-16]. Furthermore, data from a US poison in patients with type 2 diabetes mellitus because it center give some evidence that a large single ingestion decreases cardiovascular morbidity and mortality [1,2]. can lead to LA [17]. Remarkably, severe MALA may Nevertheless, metformin-associated lactic acidosis have an unexpectedly favorable outcome [4,14,15]. (MALA) is a rare but potentially life-threatening compli- Therefore, the aim of this study was to compare the cation with a mortality rate of 30% to 50% [3,4]. The outcomes of MALA and LA of other origin (LAOO). biochemical mechanism of MALA is still not fully understood. Presumably, accumulated metformin sup- Materials and methods presses biological oxidation and the enzymes of the This retrospective analysis was approved by the institu- citric acid cycle [3,5-7]. Moreover, recent studies have tional ethics committee at Ernst Moritz Arndt University reported that metformin action may be mediated by the of Greifswald. The necessity of patient consent was regulation of gene expression [8-10]. The pathogenesis waived. All patients admitted to the medical intensive of MALA is controversial. MALA is assumed to be trig- care unit of our tertiary referral center during a 5-year gered by an acute primary tissue hypoxia as in septic period (2004 to 2008) were screened for LA (that is, lac- shock or cardiovascular failure in most cases [1,3,11,12]. tate of greater than 5 mmol/L and pH of not more than Some authors dispute whether metformin may contri- 7.35 [11]) on admission by using the laboratory database. bute to lactic acidosis (LA) at all [12,13]. However, cases Clinical characteristics, admission laboratory results, metformin plasma levels, and hospital survival of all LA * Correspondence: [email protected] patients were extracted from patient files. To compare 1Department of Cardiology, Pneumology and Intensive Care Medicine, Ernst severity of disease, Simplified Acute Physiology Score II Moritz Arndt University, 17475 Greifswald, Germany Full list of author information is available at the end of the article (SAPS II) [18,19] and Sequential Organ Failure © 2010 Friesecke et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Friesecke et al. Critical Care 2010, 14:R226 Page 2 of 5 http://ccforum.com/content/14/6/R226 Assessment (SOFA) score [20,21] were extracted from creatinine of 776 μmol/L, range of 347 to 1,502) that had the ward database. According to discharge diagnoses, not been noticed before. In 6 patients, previous diarrhea or patients were categorized under the following entities of vomiting or both were reported; in the other 4, no cause LA: MALA, post-cardiopulmonary resuscitation, septic for acute renal failure could be identified, but 3 of them shock, cardiogenic shock, acute mesenteric ischemia, had pre-existing chronic renal insufficiency. Metformin hemorrhagic shock, or other. The diagnosis of MALA plasma levels were highly toxic in all MALA patients (med- was confirmed retrospectively by critical review of ian of 55 mg/L, range of 31 to 85, therapeutic range of 0.2 patient charts, which included data on medical history, to 1.3). All MALA patients were in circulatory shock and clinical presentation, highly elevated plasma levels of were treated with vasopressors. Nevertheless, in 8 of them, metformin, and absence of other common causes of LA. circulatory failure deteriorated up to cardiocirculatory None of the patients had evidence of hepatic failure. All arrest, which was reversible with cardiopulmonary resusci- MALA patients had an electrocardiogram and a bedside tation. All MALA patients were mechanically ventilated echocardiogram to rule out myocardial infarction and and immediately treated with continuous veno-venous relevant cardiac dysfunction. None had evidence of a hemodialysis or hemofiltration. In MALA, LA and renal septic focus in chest x-ray, abdominal or thoracic ultra- dysfunction were significantly more severe, other organ sound, blood cultures, urinary dipstick (if not anuric), or dysfunctions were similar, but mortality was not signifi- computed tomography (if indicated). MALA patients cantly higher compared with all LAOO patients and with were compared with all LAOO patients and with the each of the causal entities of LAOO (Table 1). severely acidotic subgroup (pH < 7.0) of LAOO patients All MALA patients and 31 of the LAOO patients had with respect to parameters of acid-base balance, serum very severe acidosis (pH < 7.0). In this subgroup, acid- creatinine, SAPS II, and hospital outcome by using the base imbalance in MALA was still slightly more profound Pearson chi-square test or the Mann-Whitney U test. than in LAOO, severity of disease and non-renal organ dysfunction (SAPS II and SOFA score) were comparable, Results but outcome was significantly better (50% survivors in During the study period, 197 patients were admitted with MALA versus 0% in LAOO) (Table 2). LA. MALA was diagnosed in 10 patients, none had deliber- There was no difference within the MALA group ately overdosed (daily metformin dose of 1,900 ± 356 mg), between survivors and non-survivors in regard to serum but all had severe renal failure (median admission serum metformin level, the degree of LA, or organ dysfunction Table 1 Comparison of patients with metformin-associated lactic acidosis with patients with lactic acidosis of other origin All MALA LAOO Post- Septic Cardiogenic Mesenteric Hemorrhagic Other patients (n = 10) (n = 187) cardiac shock shock ischemia shock causes (n = 197) arrest (n = 42) (n = 39) (n =8) (n = 13) (n = 13) (n = 72) Age, years 67 ± 13 66 ± 9 67 ± 13 65 ± 13 68 ± 12 73 ± 11 72 ± 9 64 ± 15 56 ± 14 Male gender 121 (61%) 4 (40%) 117 (63%) 45 (62%) 24 (57%) 26 (67%) 6 (75%) 7 (54%) 9 (69%) SAPS II 74 ± 20 88 ± 23 73 ± 19a 81 ± 16 71 ± 19a 75 ± 18 73 ± 25 54 ± 15b 54 ± 14b SOFA score 12.5 ± 3.6 14.3 ± 1.4 12.4 ± 3.7 12.9 ± 2.9 12.1 ± 4.5 11.8 ± 2.8b 14.4 ± 4.4 13.4 ± 4.6 9.6 ± 4.2b Respiratory 2.5 ± 1.0 2.7 ± 0.9 2.5 ± 1.0 2.7 ± 0.9 2.1 ± 1.3 2.4 ± 0.6 2.6 ± 1.1 2.3 ± 1.5 2.2 ± 1.4 Renal 2.4 ± 1.2 4.0 ± 0.0 2.3 ± 1.2b 2.1 ± 1.2b 2.5 ± 1.2b 2.5 ± 1.1b 2.8 ± 0.8a 2.1 ± 1.5b 1.9 ± 1.3b Hepatic 0.7 ± 1.0 0.3 ± 0.7 0.7 ± 1.0 0.3 ± 0.6 1.3 ± 1.2a 0.6 ± 0.8 0.6 ± 0.9 1.8 ± 1.7 0.9 ± 0.9 Cardiovascular 3.3 ± 1.4 4.0 ± 0.0 3.3 ± 1.5 3.5 ± 1.3 3.2 ± 1.5 3.4 ± 1.5 4.0 ± 0.0 2.9 ± 1.8 2.1 ± 2.0a Hematologic 0.9 ± 1.2 0.5 ± 0.8 0.9 ± 1.2 0.6 ± 0.9 1.3 ± 1.4 0.3 ± 0.7 2.2 ± 1.6 2.6 ± 1.1 0.9 ± 1.2 Neurologic 2.7 ± 1.4 2.8 ± 1.5 2.7 ± 1.4 3.7 ± 0.6a 1.7 ± 1.3a 2.8 ± 1.2 2.2 ± 1.3 1.8 ± 1.4b 1.6 ± 1.2 Lactate, mmol/L 11.6 ± 6.2 18.7 ± 5.3 11.2 ± 6.1b 12.8 ± 6.1b 8.7 ± 4.5b 10.9 ± 5.2b 8.6 ± 3.3b 13.5 ± 9.5b 10.8 ± 7.1b pH 7.13 ± 0.19 6.75 ± 7.15 ± 7.07 ± 0.19b 7.23 ± 0.09b 7.18 ± 0.14b 7.27 ± 0.04b 7.26 ± 0.07b 7.14 ± 0.18b 0.13 0.17b Bicarbonate, 14.6 ± 5.9 4.4 ± 2.4 15.2 ± 5.6b 14.5 ± 5.6b 16.6 ± 5.8b 14.9 ± 4.0b 16.2 ± 1.8b 15.8 ± 5.7b 14.1 ± 8.8b mmol/L Creatinine, μmol/L 307 ± 265 796 ± 324 227 ± 141b 169 ± 128b 318 ± 181b 182 ± 48b 299 ± 125a 303 ± 122a 214 ± 57b Survival 52 (26%) 5 (50%) 48 (26%) 19 (26%) 9 (21%) 9 (23%) 0 5 (38%) 6 (46%) Values are presented as mean ± standard deviation or as number (percentage).