in the previous issue of critical care , friesecke and colleagues demonstrate that the survival rate of patients with severe lactic acidosis due to metformin accumulation can be strikingly higher than expected based on the initial clinical evaluation .
metformin is nowadays the first - line drug of choice for the treatment of adults with type 2 diabetes .
this drug is the sixth most frequently prescribed in the usa ( > 50 million prescriptions in 2009 ) and is taken by almost 1.5% of the italian population .
metformin is a safe drug when correctly used in properly selected patients . in particular , no cases of lactic acidosis ( a relatively common side effect of other biguanide compounds ) were reported in 347 trials with 70,490 patient - years of metformin use .
real life can differ from research settings , however , and lactic acidosis has been repeatedly , although rarely , observed in patients treated with metformin .
the number of inquiries to the swedish poison information centre for metformin intoxication has increased 10 times during the past decade , with 25 cases of severe lactic acidosis reported in 2007 and 2008 . according to the american association of poison control centers
forty - nine cases of lactic acidosis and accidental metformin accumulation were reported to the poison control centre of pavia ( italy ) from january 2005 to august 2010 , resulting in 11 deaths .
since metformin use is constantly increasing - there has been a 10 to 15% rise in prescriptions per year in the usa and italy   - related cases of lactic acidosis may become less rare .
the term metformin - associated lactic acidosis refers to any case of lactic acidosis that develops in a patient treated with metformin , with no further mechanistic insight . in most of the cases ,
however , lactic acidosis can not be directly attributed to metformin use but rather depends on concomitant low cardiac output , anemia , hypoxemia or liver failure .
the term metformin - induced lactic acidosis specifically refers to cases that can not be explained by any major risk factor other than metformin overdose .
the distinction between these two entities is sometimes very subtle and metformin accumulation may coexist with other risk factors , all contributing to the pathogenesis of lactic acidosis .
the present case series includes 10 patients admitted to intensive care with lactic acidosis and metformin accumulation due to renal failure . at admission ,
arterial ph was 6.75  0.13 and lactatemia was 19  5 mmol / l .
the simplified acute physiology score ii was 88  23 and the predicted mortality was 96% .
eight ( 80% ) patients had a cardiac arrest during their stay in intensive care .
treatment consisted of vital function support and renal replacement therapy . despite the dramatic severity of clinical presentation , hospital survival was 50% .
conversely , there were no survivors out of 31 patients with similarly severe lactic acidosis from other causes ( mainly cardiogenic , septic or hemorrhagic shock ) who were admitted to the same institution during the same period of time .
this finding is in line with previous observations . in 49 patients treated with metformin who developed severe lactic acidosis , survival was 17% among those with no drug accumulation ( that is , lactic acidosis was actually due to another precipitating event ) and was 71% in those with metformin accumulation , despite a similar severity of hyperlactatemia
. in another series , one out of 10 ( 10% ) patients with lactic acidosis probably due to metformin accumulation actually died despite an initially predicted mortality of around 55% .
we have recently reviewed the data for 24 critically ill patients with lactic acidosis and proven or probable metformin intoxication . despite an expected mortality of 70% , observed mortality was 21% .
even patients with initial arterial ph down to 6.62 , lactatemia up to 33 mmol / l or simplified acute physiology score ii as high as 87 managed to survive to hospital discharge . that lactic acidosis carries
lactic acid per se , however , is unlikely to be the explanation for this association .
this response provides some energy and a chance for cells to survive , even when oxygen availability or utilization are defective .
cancer cells in a way provide the best evidence for lactate overproduction being an efficient response to hypoxia . by mainly relying on anaerobic metabolism , malignant cells
can not only survive but even proliferate in a hypoxic environment , so that tumor growth can exceed angiogenesis . according to the theory of lactate shuttles proposed by brooks
acidosis itself may arise as an adaptive response to inadequate energy provision and may extend cellular viability .
the prognosis of lactic acidosis primarily depends on the underlying mechanism and on its reversibility . when lactic acidosis is due to metformin accumulation ,
then renal replacement therapy can efficiently remove the toxic substance ( that is , metformin and not lactate ! ) and prognosis can be surprisingly good
. the situation can be much more complex and less easily reversible when lactic acidosis is primarily due to severe hypoxia or tissue hypoperfusion .
based on present and past observations , one may conclude that the decision to treat ( or not to treat ) a patient with suspected metformin - induced lactic acidosis can not be based only on the severity of clinical presentation .
we personally believe that treatment of the critically ill patient should always include drug removal , as long as metformin accumulation is thought to be responsible for severe lactic acidosis .
since a plasma metformin dosage is rarely available in most centers , intoxication should be considered highly probable whenever lactic acidosis and renal failure are uncommonly severe , other primary explanations are not evident and chronic metformin use is reported .
 metformin is a safe drug when correctly used in properly selected patients . in real life , however , associated lactic acidosis has been repeatedly , although rarely , reported . 
 the term metformin - induced lactic acidosis refers to cases that can not be explained by any major risk factor other than drug accumulation , usually due to renal failure . 
 treatment consists of vital function support and drug removal , mainly achieved by renal replacement therapy . despite dramatic clinical presentation , 
 the prognosis of metformin - induced lactic acidosis is usually surprisingly good . 
None
Competing interests