Severe Metformin Associated Lactic Acidosis : a Case Series of an Intensive Care Unit

Results: Twenty one patients were admitted in ICU due to severe MALA (less than 1% of all admissions) with an ICU mortality rate of 23.8% (N=5). The baseline clinical characteristics were similar in survivors and nonsurvivors, both with a high prevalence of cardiovascular comorbidities as well as frequent concomitant therapy with angiotensin-converting-enzyme inhibitors and diuretics. All patients were treated with continuous renal replacement therapy (CRRT) and other organ failure support. Normal acid-base balance was achieved in all survivors in the first 24 hours. At baseline, the clinical and laboratory features of nonsurvivors were undistinguishable from survivors.


Introduction
In 1995, metformin was approved by Food and Drug Administration (FDA) to treat type 2 diabetes mellitus, with established results concerning mortality and morbidity, especially in overweight patients [1].Metformin is a 165 kDa dimethylbiguanide, eliminated unchanged by renal tubular secretion, with no protein binding and a volume of distribution greater than 3 L/kg [2].The hypoglycemic effect is due to the reduction of insulin resistance and to the inhibition of gluconeogenesis from alanine, pyruvate and lactate [3][4].As a direct consequence of the accumulation of these carboxylic precursors, previously reported in some in vitro studies, lactic acidosis is the most serious side effect of metformin [5].Metabolic acidosis with hyperlactatemia is a classic feature of biguanides toxicity, namely phenformin [6].
The exact mechanism for lactic acid accumulation in diabetic patients taking metformin is not clear.Some authors advocate that metformin associated lactic acidosis (MALA) results from the inhibition of complex I in mitochondrial respiratory chain through the decrease of pyruvate dehydrogenase activity [7].As a result, the consumption of oxygen (VO 2 ) and the production of carbon dioxide are depressed.Other consequence of pyruvate dehydrogenase inhibition is the shift towards anaerobic metabolism of carboxylic precursors, thus increasing the conversion of pyruvate to lactate [8].
Estimated prevalence of MALA is rare, 2-9 cases per 100,000 patients treated with metformin each year [9] with a mortality rate reaching 50% [2].Previous case reports have pointed out that MALA normally develops in patients with an underlying disease that predisposes to acidosis such as congestive heart failure, respiratory and renal failure as well as other conditions like dehydration, infection, alcohol consumption and fasting [2,9].
We aimed to assess the prevalence of MALA in our Intensive Care Unit (ICU), describe the main de-mographic and clinical characteristics and identify factors associated with poor outcome.

Materials and methods
We conducted a 13-year retrospective analysis of patients admitted in an ICU with the diagnosis of MALA, between January 2000 and January 2013.The local Ethics Committee waived the need of informed consent due to the retrospective study design.Data from MALA patients was extracted from the ICU database, namely clinical, laboratory and demographic characteristics.Metformin induced lactic acidosis was defined as lactate level > 4 mmol/L, bicarbonate level < 22 mEq/L and pH < 7.35.Other causes of lactic acidosis were excluded based on clinical history, physical examination, laboratory data and additional investigations whenever needed.For each patient we evaluated: demographic and clinical variables, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, time to recovery and continuous renal replacement therapy (CRRT), vasopressor requirements, mechanical ventilation, ICU complications and mortality, creatinine and prothrombin time and arterial blood gases parameters.We compared survivors with nonsurvivors.For the purpose of mortality analysis, nonsurvivors were divided in early deaths, that is, those occurring within the first 24 hours of admission without normalization of blood gases parameters and late deaths, those occurring after the initial normalization of metabolic imbalance.
Collected data was presented as means and standard deviation (SD) for the entire population variables, or as medians, interquartile range (IQR) and extreme values according to data distribution.The comparison between survivors and nonsurvivors was made using the Mann-Whitney U test.Statistical analyses were performed using SPSS (version 18.0, SPSS Inc., Chicago IL, USA)

Results
During the study period, 3479 patients were admitted in the ICU and 21 had the diagnosis of MALA, representing 0.6% of total admissions.Table 1 summarizes the baseline characteristics of the study population.
Most of the patients were male with mean age of 75 years and an APACHE II of 29.5.Almost a quarter of patients were taking an unknown dose of metformin.We found a high prevalence of comorbidities and vascular risk factors such as hypertension and chronic renal failure (CRF).All 5 patients with CRF had glomerular renal filtration rate > 30 mL/m before acute illness.Besides metformin, the majority of patients were also treated with angiotensin converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) and diuretics.The main clinical presentations were diarrhea and vomits.
Our patients with MALA had extremely low pH (minimum 6.7 and mean 7.0) and bicarbonate (minimum 1.5 mEq/L and mean 6.1 mEq/L) reflecting the severity of this condition.
All patients had acute oliguric renal failure on ICU admission presenting in acute kidney injury network (AKIN) stage 3. Continuous veno-venous hemodiafiltration (CVVHDF) was initiated immediately after admission to achieve a 35ml/kg/h of dialysis dose, using a high-flux dialyzer membrane.Figure 1 represents lactate levels during the first 24 hours of continuous renal replacement therapy (CRRT).The great majority of patients corrected the hyperlactatemia in the first 24 hours of CRRT.In Figure 2 is represented the pH variation during the same time period.
We were unable to find significant differences between survivors and nonsurvivors concerning

InternatIonal archIves of MedIcIne
Section: Pulmonary and critical care medicine Issn: 1755-7682 baseline clinical characteristics and clinical course (Table 2).Gastrointestinal signs and symptoms were more frequent in survivors.The number of patients with shock and on invasive mechanical ventilation was similar in both groups.The bicarbonate and pH levels were lower and arterial lactate and creatinine were higher in nonsurvivors, but these differences were non-significant.
The ICU mortality was 23.8% (N=5).We registered two early deaths: one in a 59-years old man with initial pH of 6.8 and the other in an 84-years old female with previous CRF and pH of 7.2 at admission.Both patients had persistent elevation of lactate levels and died in the first 8 and 12 hours, respectively, due to refractory shock.The other three patients were late deaths.An 85-year old female developed ventilation-associated pneumonia and died one week after being admitted.The other patients, both female with 73 and 70 years old, presented sudden unexplained cardiorespiratory arrest on second and third day of admission, respectively.Despite rapid correction of the initial metabolic disturbance, the 70 years old woman presented an extremely low initial pH value of 6.7 while the other had shock at admission with severe acute hepatic failure.

Discussion
In our critically ill patient population, severe MALA had an incidence less than 1% but an ICU mortality rate of 23.8%, although this was not greater than the global mortality in our ICU (35%).Our patients had extremely low values of pH and bicarbonate as well as high levels of lactate, consistent with severe acid-base imbalance.
The real prevalence of MALA is probably uncertain because it requires a high level of suspicion and the clinical presentation may be undistinguishable from other severe diseases [7].It is consensual among authors that metformin toxicity may be enhanced by other conditions that predispose to tissue hypoxia and lactate accumulation such as chronic heart and respiratory failure, hepatic and renal dysfunction, severe dehydration and sepsis [11][12][13].Our patients present no medical condition that could explain such degree of acidosis, other than MALA, although we have to recognize that the level of metformin was not measured, since the test is not available in our institution.In any case, the utility of metformin measurement is limited, since it is mainly an intracellular toxin with a high volume of distribution [2].The presence of cardiovascular risk factors such as hypertension, CRF or heart failure was frequent in our population.We may admit that these patients have a higher risk of developing MALA.In our population, more than 50% of patients were on ACEIs or ARBs (38% and 24%, respectively).It is possible that the inhibition of renal auto-regulation mechanism by ACEIs and ARBs may precipitate lactate and metformin accumulation, thereby predisposing to acidosis but this direct relation is still unclear [15].We also found a significant number of patients previously treated with diuretics (43%).In this case, the associated volume depletion could interfere with renal perfusion and precipitate acute renal failure [16].
All 21 patients were treated with high-volume CVVHDF at admission to the ICU.As a non-plasma protein bound molecule, metformin may be removed, at least partially, as soon as CVVHDF is performed.Even in severe cases of lactic acidosis, dialysis techniques may quickly restore acid-base status and correct lactatemia [3,10].Some authors advocated the use of bicarbonate prior to dialysis for treatment of lactic acidosis [17,18].Others have reported the use of tris-hydroxymethyl aminomethane with CRRT [19].Our therapeutic approach was immediate high-volume CVVHDF with bicarbonate buffered solution from Fresenius HF BIC ® , in order to remove the offending drug and correct high anion gap metabolic acidosis.Intravenous bicarbonate administration is controversial and could be associated with a higher mortality [20].In case of MALA, not only may bicarbonate worsen myocardial contractility and intracellular pH through the production of carbon dioxide buffer but also delay CRRT [17,20].In our study, 19 out of 21 patients achieved a normal acid-base balance, with normalization of pH and bicarbonate level in the first 24 hours without prior intravenous administration of bicarbonate.At discharge, excluding patients who died, all the others had recovered renal function probably due to the early initiation of CVVHDF that prevented further renal cell damage.
In our study, the ICU mortality rate (23.8%) was lower than previously reported by other authors [2,9].We may hypothesize that the rapid recognition of MALA and prompt initiation of high volume renal replacement technique contributed to this lower mortality rate.The two early deaths were directly related to worsening of metabolic acidosis and refractory shock whereby the CRRT was unable to correct the acid base disturbances.We think that this was probably a consequence of established cell damage.The three late deaths occurred after initial correction in pH, lactate and bicarbonate.One death was directly related to septic shock and ventilation-associated pneumonia.The other two patients presented sudden cardiac arrest, without an obvious explanation.We could speculate that the rapid correction of acidosis was not associated with total clearance of metformin from intracellular compartment and toxicity still exerts its effect in endomembrane system and proteins, resulting in late cell death.[21][22][23].It is still unclear why some patients recover from severe MALA while others invariably die.In both early and late deaths, patient performance status, comorbidities and the total time of exposition to severe acidemia (data not collected), surely contributed to the different outcomes.This could be the case in one of the early death patients with known CRF (glomerular renal filtration of 30 ml/min) and 84 years old.It is important to notice that, as a result of the logarithmic nature of pH equation, small differences in pH represent a significant variation in total body acid load and may have a non-despicable contribution to patient outcome.[23] To the best of our knowledge, our 21 case series, however small, is one of the largest series reported in literature.An important aspect of this study is our overall good result with early implementation of high volume CRRT.This approach may have been determinant in the achievement of stated mortality rate as a result of the rapid clearance of the offending drug.
There are some important limitations in our study, namely the sample size that precluded the execution of a multivariate analysis and the retrospective analysis of data that may be associated with several uncontrolled bias.Also, it was not possible to measure serum metformin concentration, as this test is not available in our institution.

Conclusions
Severe MALA is an uncommon but life threatening condition without a specific antidote.The authors advocate that early institution of highvolume CVVHDF may efficiently remove metformin, restore the normal acid-base balance and directly contribute to a better outcome.The authors emphasize the need for continuous reassessment of contra-indications for the use of metformin, as patients may develop an acute infection, dehydration or acute renal failure.In these cases, the use of metformin should be carefully discussed or even discontinued.Patients should be instructed to suspend metformin in case of diarrhea, vomits and acute infections.
Larger and prospective studies are needed to draw firm recommendations on the treatment of MALA.Where Doctors exchange clinical experiences, review their cases and share clinical knowledge.You can also access lots of medical publications for free.Join Now! http://medicalia.org/

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Figure 1 :
Figure 1: Lactate levels during the first 24 hours of continuous renal replacement therapy; increase in lactate levels in the two early deaths after 8 hours and 12 hours of CRRT.

Figure 2 :
Figure 2: pH value during the first 24 hours of continuous renal replacement therapy.

Table 2 .
Clinical and laboratorial characteristics according to patient outcome.