Metformin Associated Lactic Acidosis and of glucose (increased production of lactate) in the Iodinated Contrast Media
intestinal wall and decreased conversion of lactate
Usage of metformin in NIDDM patients does not
Metformin associated lactic acidosis is referred to
cause MALA. However, if these patients have
the development of lactic acidosis due to the use of
concomitant illness such as acute cardiorespiratory
metformin in patients with type II diabetes mellitus1,2.
dysfunction, sepsis, renal dysfunction, or liver
failure, these will increase the risk of developing
Metformin associated lactic acidosis (MALA) is
rare but once it has developed, it could result in
Contrast Medium Nephrotoxicity
severe consequences. Research was conducted in
Contrast medium nephrotoxicity (CMN) is
Saskatchewan, Canada, on the incidence of MALA.
defined as an acute decline in renal function after
Data between 1980 and 1995 was collected and
administration of ICM11. Reduction in renal function
analyzed. The results indicated the incidence of
usually occurs within 72 hours post ICM injection12.
MALA is approximate 9 cases per 100,000 person-
Iodinated contrast media has demonstrated
years (adding number of days of each prescription)
several mechanisms that cause renal tubular
epithelial cell toxicity and renal medullary ischemia
that result in decreasing renal function11. ICM
Metformin associated lactic acidosis can occur in
vasoconstrictors such as endothelin and adenosine
patients with normal renal function. It can also result
and reduces the release of vasodilators such as
after diagnostic examinations or procedures with
nitric oxide and prostacyclin12. The imbalance of
parenteral injection of radiographic iodinated contrast
vasoconstrictors and vasodilators causes decreases
in renal blood flow, which leads to a decrease in
renal function. ICM also activates the oxygen free
radicals and damages the renal tubules. Most CMN
The two major groups of oral hypoglycemic
are self-limiting and resolve within 1 – 2 weeks,
agents are sulphonylureas such as glyburide and
however, permanent renal damages have also been
biguanides such as metformin and buformin4.
Metformin is the first line oral antihyperglycemic
agent for patients with non-insulin dependent
Metformin associated Lactic Acidosis Resulted
diabetes mellitus (NIDDM or type II DM)1,3. It is called
from the use of Iodinated Contrast Media
an antihyperglycemic agent as it does not stimulate
Metformin is not nephrotoxic and does not
the production of insulin and will not cause
interact with iodinate contrast media5. However, if
hypoglycemia5. Metformin is hydrophilic and not
CMN occurs, metformin excretion will be decreased.
bound with plasma protein; it is mainly absorbed in
Excessive accumulation of metformin may result in
the small intestine. Metformin is not metabolized in
metformin associated lactate acidosis13. The risk of
the body and is excreted unchanged via the renal
MALA is very low (0.005%), however, mortality rate
Prevention measures of MALA post ICM injection
gluconeogenesis in liver, decreasing intestinal
include intravascular volume expansion. Some
glucose absorption, increasing insulin sensitivity,
researchers suggest intravenous infusion of NaCl
promoting peripheral cellular glucose uptake, and
0.9% 100mL/h starting 4 hours before the procedure
increasing glucose oxidation1,7. Plasma half-life of
with ICM and continuing with the infusion for 24
metformin is about 2-5 hours for patients with normal
hours post procedure12 if not contraindicated. Avoid
renal function8. Metformin blocks the conversion of
concomitant uses of nephrotoxic medications14.
lactate in liver, which can result in lactate
Acetylcysteine is an antioxidant that inhibits
production of hydrogen peroxide in renal epithelial
Metformin associated lactic acidosis could be the
cells11. Use of acetylcysteine as prophylaxis for
combined result of increased anaerobic metabolism
patient with decreased renal function is also suggested12.
Diagnostic test Reference
Metformin associated lactic acidosis is a high
Tonolini, M. (2012). Iodine-based radiographic contrast medium
anion gap metabolic acidosis15. Arterial blood gas
may precipitate metformin-associated lactate acidosis in diabetic patients. A case report, literature review and practice approach.
results with pH < 7.35 and serum lactate >
Clinical Therapeutics, 163, 59-62.
5.0mmol/L with no other causes can be diagnosed
Vecchio, S., & Protti, A. (2011). Metformin-induced lactic
acidosis: No one left behind. Critical Care, 15, 107.
Stang, M.R., Wysowski, D.K., & Butler-Jones, D. (1999).
Incidence of lactic acidosis in metformin users. Diabetes Care, 22, 925-927.
The goals of treatments for MALA include earlier
recognition of the problem, supportive care, correct
antihyperglycaemic agents in patients with renal insufficiency.
acid-base imbalance, volume expansion, and
Clinical Pharmacokinetics, 31, 111-119.
Rasuli, P., & Hammond, I. (1998). Metformin and contrast
elimination of metformin by hemodialysis or
media: Where is the conflict? Canadian Association of
continuous hemofiltration1,9. Using bicarbonate to
Radiologists Journal, 49, 161-166.
correct acidosis should be used with caution
Graham, G.G., Punt, J., Arora, M., Day, R.O., Doogue, M.P., Duong, J.K., Furlong, T.J., Greenfield!, J.R., Greenup, L.C.,
because of its side effects such as excessive sodium
Kirkpatrick, C.M., Ray, J.E., Timmins, P., & and Williams, K.M.
(2011). Clinical Pharmacokinetics of Metformin. Clinical
Hemodialysis or continuous hemofiltration has
demonstrated good effects in metformin and lactic
Di Grande, A., Vancheri, F., Gisustolisi, V., Giuffrida, C., Narbone, G., Licata, M., Le Moli, C., Riccobene, S., Burgio, A.,
Bartolotta, S., Nigro, F., & Cannone, V. (2008). Metformin-
induced lactic acidosis in a type 2 diabetic patient with acute
renal failure. Clinical Therapeutics, 159, 87-89.
It is important to assess the patients’ renal
Laforest, C., Saint-Marcoux, F., Amiel, J-B., Pichon, N., &
function before any diagnostic tests that involve
Merle, L. (2013). Monitoring of metformin-induced lactic acidosis in a diabetic patient with acute kidney failure and effect
injection of ICM. If the patient’s renal function is
of hemodialysis. International Journal of Clinical Pharmacology
compromised, the physician should be notified before
the procedure. Many health care institutions have
Lalau, J.D. (2010). Lactic acidosis induced by metformin: Incidence, management and prevention. Drug Safety, 33, 727-
developed policies for pre-diagnostic test screening,
which include assessing the patient’s renal function.
10) Safadi, R., Dranitzki-Ethalel, M., Popovtzer, M., & Ben-Yehuda,
Monitor for any signs of lactic acidosis such as
A. (1996). Metformin-induced lactic acidosis associated with
tachycardia, hypotension, stupor, and coma5 post
acute renal failure. American Journal of Nephrology, 16, 520-522.
11) Tepel, M., & Zidek, W. (2001). Acetylcysteine for radiocontrast
Monitor for any signs of allergic reaction from the
nephropathy. Current Opinion in Critical Care, 7, 390-392.
ICM such as flushing, nausea and vomiting, pruritus,
12) Morcos, S.K., & Thomsen, H.S. (2001). Adverse reactions to
iodinated contrasr media. European Radiology, 11, 1267-1275.
headache, and urticaria. In severe cases, patients
13) Goergen, S.K., Rumbold, G., Compton, G., & Harris, C. (2010).
may develop hypotension and bronchospasm12.
Systemic review of current guidelines, and their evidence base,
on risk of lactic acidosis after administration of contrast medium for patients receiving metformin. Radiology, 254, 261-269.
suggested metformin should be held 48 hours before
14) Jain, V., Sharma, D., Prabbaker, H., & Dash, H.H. (2007).
and 48 hours after a patient’s angiogram or any tests
Metformin associated lactic acidosis following contrast media-
required ICM. However, in emergency situations, if
induced nephrotoxicity. European Journal of Anaesthesiology,
the diagnostic test with ICM is required, metformin
15) Silvestre, J., Carvalho, S., Mendes, V., Coelho, L., Tapadinhas,
should be held 48 hours after the test1. The patient
C., Ferrerira, P., Povoa, P., & Ceia, F. (2007). Metformin-
should receive alternate medication such as insulin to
induced lactic acidosis: A case series. Journal of Medical Case
control their blood sugar during the time metformin is
on hold. If renal function is normal at 48 hours,
Currently, there is no consensus from the international guidelines about withholding metformin
before and/or after the administration of ICM13.
However, diabetes patients who take metformin can
develop MALA even if they have normal renal
function post administration of ICM14. Individual
institutions should develop their own policy and
guideline carefully to avoid the occurrence of CMN
Disclaimer: The author of this article neither represents nor guarantees that the practices described herein, if followed, ensure safe and effective patient
care. The author further assumes no responsibility or liability in connection with
any information or recommendations contained in this article. The
recommendations and instructions in this article are based on the knowledge and practice in neuroscience as of the date of publication. These
Pharmacy Clinical Practice Leader, Critical Care, South
recommendation and instructions are subject to change based on the
availability of new scientific information.
Iodinated Contrast Medium Intra-renal Vasoconstriction Intra-renal vasodilation Metformin Renal Blood Flow Decrease Metformin Renal Hypoxia excretion Oxygen Free Radicals Lactic Acidosis
Contrast Medium Nephrotoxicity Diagram Showing the Interaction of Iodinated Contrast Medium and Metformin
Guideline No… pÉííáåÖ=ëí~åÇ~êÇë=íç=áãéêçîÉ=ïçãÉåÛë=ÜÉ~äíÜ DELIVERY AFTER PREVIOUS CAESAREAN BIRTH 1. Aim To provide evidence-based information on the management of women undergoing either trial of vaginal birth after previous caesarean section (trial of VBAC) or elective repeat caesarean section (ERCS). This guideline is primarily aimed at the