That metformin can cause a “lactic acidosis” on occasions suggests
that it may either induce or compound the severity of anaerobic metabolism
(1). This is important for the development of a tissue acidosis may have
an adverse effect upon outcome (2).
The term “lactic acidosis” is misleading for being a base, not an
acid, an elevated blood lactate per se does not establish the presence of
a tissue acidosis or of anaerobic metabolism. Conversely inhibiting the
generation of lactate with iodoacetate in vitro does not prevent the
development of a tissue acidosis in anerobiosis and any lactate present in
blood in vivo may be removed very rapidly and used as a fuel by the heart
or converted into glucose and hence glycogen by the liver. Thus the
finding of a normal blood lactate does not exclude the presence of
anaerobic metabolism which may exist chronically and only become evident
when the demand for energy from ATP hydrolysis exceeds the capacity for
ATP resynthesis by mitochondrial oxidative phosphorylation (2,3).
A fall in gastric intramucosal pH is a very sensitive predictor of
adverse outcome from the translocation of gut toxins, cytokine release,
and hence organ dysfunctions, nosocomial infections, and organ failures
(2,3). Patients with chronic renal failure on haemodialysis have an
abnormally low gastric intramucosal pH but a normal arterial pH (4). This
means that patients with chronic renal failure are more likely to develop
gut mucosal injury and suffer from the adverse consequences of the
translocation of bacterial toxins, notably endotoxin, the release of
cytokines and the increase in permeability of the mitochondrial membrane
they may induce (5).
An increase in permeability of mitochondrial membranes causes a proton
leak which dissipates the proton gradient thus uncoupling oxidative
phosphorylation. This induces or compounds the severity of any impairment
of mitochondrial oxidative phosphorylation present. The presence of a
compensated metabolic acidosis in patients with chronic renal failure
makes them more likely to develop an uncompensated gastric intramucosal
acidosis and even a systemic tissue acidosis. The metabolic acidosis
might even represent an adaptation by enzymes regulating ATP hydrolysis
and resynthesis to an unappreciated presence of an impairment of
mitochondrial oxidative phosphorylation in patients with chronic renal
failure (6).
Given this pathophysiologic scenario it would seem appropriate to
withhold metformin from any patient who has a gastric intramucosal
acidosis or develops a gastric intramucosal acidosis after the
administration of metformin regardles of whether they have renal failure.
A negative exercise stress test whilst on metformin should increase the
confidence in prescribing metformin without precipitating anaerobiosis. A
negative stress test might not, however, avoid compounding the severity
of a gastric intramucosal acidosis and having an adverse effect upon
outcome should it develop for other reasons during the course of a
critical illness (7).
1. "Lactic acidosis": the common denominator? Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7374/1202#28322, 2 Jan 2003
2. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid-
base balance.
Br J Anaesth. 1995 May;74(5):591-606. Review.
3. Fiddian-Green RG. Monitoring of tissue pH: the critical measurement.
Chest. 1999 Dec;116(6):1839-41.
4. Diebel L, Kozol R, Wilson RF, Mahajan S, Abu-Hamdan D, Thomas D.
Gastric intramucosal acidosis in patients with chronic kidney failure.
Surgery. 1993 May;113(5):520-6.
5. Lassus P, Opitz-Araya X, Lazebnik Y. Requirement for caspase-2 in
stress-induced apoptosis before mitochondrial permeabilization. Science.
2002 Aug 23;297(5585):1352-4.
6. Hochachka PA, Somero GW. Biochemical adaptation. Oxford University
Press, New York, NY, 2002
7. Kolkman JJ, Groeneveld AB, van der Berg FG, Rauwerda JA, Meuwissen SG.
Increased gastric PCO2 during exercise is indicative of gastric ischaemia:
a tonometric study.
Gut. 1999 Feb;44(2):163-7.
Rapid Response:
Metformin, "lactic acidosis" and renal failure
That metformin can cause a “lactic acidosis” on occasions suggests
that it may either induce or compound the severity of anaerobic metabolism
(1). This is important for the development of a tissue acidosis may have
an adverse effect upon outcome (2).
The term “lactic acidosis” is misleading for being a base, not an
acid, an elevated blood lactate per se does not establish the presence of
a tissue acidosis or of anaerobic metabolism. Conversely inhibiting the
generation of lactate with iodoacetate in vitro does not prevent the
development of a tissue acidosis in anerobiosis and any lactate present in
blood in vivo may be removed very rapidly and used as a fuel by the heart
or converted into glucose and hence glycogen by the liver. Thus the
finding of a normal blood lactate does not exclude the presence of
anaerobic metabolism which may exist chronically and only become evident
when the demand for energy from ATP hydrolysis exceeds the capacity for
ATP resynthesis by mitochondrial oxidative phosphorylation (2,3).
A fall in gastric intramucosal pH is a very sensitive predictor of
adverse outcome from the translocation of gut toxins, cytokine release,
and hence organ dysfunctions, nosocomial infections, and organ failures
(2,3). Patients with chronic renal failure on haemodialysis have an
abnormally low gastric intramucosal pH but a normal arterial pH (4). This
means that patients with chronic renal failure are more likely to develop
gut mucosal injury and suffer from the adverse consequences of the
translocation of bacterial toxins, notably endotoxin, the release of
cytokines and the increase in permeability of the mitochondrial membrane
they may induce (5).
An increase in permeability of mitochondrial membranes causes a proton
leak which dissipates the proton gradient thus uncoupling oxidative
phosphorylation. This induces or compounds the severity of any impairment
of mitochondrial oxidative phosphorylation present. The presence of a
compensated metabolic acidosis in patients with chronic renal failure
makes them more likely to develop an uncompensated gastric intramucosal
acidosis and even a systemic tissue acidosis. The metabolic acidosis
might even represent an adaptation by enzymes regulating ATP hydrolysis
and resynthesis to an unappreciated presence of an impairment of
mitochondrial oxidative phosphorylation in patients with chronic renal
failure (6).
Given this pathophysiologic scenario it would seem appropriate to
withhold metformin from any patient who has a gastric intramucosal
acidosis or develops a gastric intramucosal acidosis after the
administration of metformin regardles of whether they have renal failure.
A negative exercise stress test whilst on metformin should increase the
confidence in prescribing metformin without precipitating anaerobiosis. A
negative stress test might not, however, avoid compounding the severity
of a gastric intramucosal acidosis and having an adverse effect upon
outcome should it develop for other reasons during the course of a
critical illness (7).
1. "Lactic acidosis": the common denominator? Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7374/1202#28322, 2 Jan 2003
2. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid-
base balance.
Br J Anaesth. 1995 May;74(5):591-606. Review.
3. Fiddian-Green RG. Monitoring of tissue pH: the critical measurement.
Chest. 1999 Dec;116(6):1839-41.
4. Diebel L, Kozol R, Wilson RF, Mahajan S, Abu-Hamdan D, Thomas D.
Gastric intramucosal acidosis in patients with chronic kidney failure.
Surgery. 1993 May;113(5):520-6.
5. Lassus P, Opitz-Araya X, Lazebnik Y. Requirement for caspase-2 in
stress-induced apoptosis before mitochondrial permeabilization. Science.
2002 Aug 23;297(5585):1352-4.
6. Hochachka PA, Somero GW. Biochemical adaptation. Oxford University
Press, New York, NY, 2002
7. Kolkman JJ, Groeneveld AB, van der Berg FG, Rauwerda JA, Meuwissen SG.
Increased gastric PCO2 during exercise is indicative of gastric ischaemia:
a tonometric study.
Gut. 1999 Feb;44(2):163-7.
Competing interests:
None declared
Competing interests: No competing interests