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Metformin toxicity

April 11, 2019 by Josh Farkas

CONTENTS

Physiology of metformin-induced lactic acidosis (#physiology_of_metformin-induced_lactic_acidosis)

Epidemiology & de�nitions (#epidemiology_&_de�nitions)

Clinical presentation (#clinical_presentation)

Differential diagnosis (#differential_diagnosis)

Prognosis (#prognosis)

TreatmentDecontamination after acute ingestion (#decontamination_after_acute_ingestion)

Evaluate for other causes & consider empiric treatment for sepsis (#exclusion_of_other_illness_&_empiric_therapy_for_sepsis)

Glucose management & insulin (?) (#glucose_administration_&_diabetes_management)

Volume resuscitation (#volume_resuscitation)

Respiratory support (#respiratory_support)

Dialysis indications (#dialysis)

Methylene blue?? (#methylene_blue??)

Checklist (#checklist)

Podcast (#podcast)

Questions & discussion (#questions_&_discussion)

Pitfalls (#pitfalls)

physiology of metformin-induced lactic acidosis(back to contents) (#top)

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primary mechanism of toxicity

The main effect of metformin is inhibition of the mitochondrial transport chain complex-I, which essentially poisons the mitochondria.The mitochondrial transport chain is generally the �nal component of metabolism which generates ATP using NADH (above).  If themitochondrial transport chain stops working:

NADH builds upThe Krebs cycle eventually gets backed upPyruvate gets converted into lactate (rather than moving into the Krebs cycle)

(http://theawkwardyeti.com)

epidemiology & de�nitions(back to contents) (#top)

The following de�nition system has emerged within the past couple years. It hasn't been uniformly adopted, but it seems to be emerging as thebest way to understand metformin toxicity:

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The MILA – MALA – MULA spectrum

Lactate due to other acute illness

Lactate due to metformin

MILAmetformin-induced lactic acidosis

MALAmetformin-associated lactic acidosis

MULAmetformin-unrelated lactic acidosis

The Internet Book of Critical Care, by @PulmCrit

(https://emcrit.org/wp-content/uploads/2019/04/milamalamula.svg) metformin-induced lactic acidosis (MILA)

High levels of metformin are the primary cause of illness.(1) Acute metformin overdose

Acute poisoning may lead to MILA in the absence of renal dysfunction.Precise amount of metformin required to do this is unclear, but seems to be high (e.g. >20 grams).Patients with acute ingestion look �ne initially, but deteriorate subsequently (“toxin bomb”).

(2) Subacute accumulation of metformin due to renal failureMetformin is renally cleared.Progressive renal failure (with GFR << 30 ml/min) eventually leads to metformin accumulation and toxicity.These patients may present with marked lactic acidosis, yet have fairly preserved hemodynamics and look OK.

metformin-associated lactic acidosis (MALA)

De�nition:Patient on metformin develops an acute life-threatening illness (e.g. septic shock, cardiogenic shock).Metformin ampli�es the degree of lactic acidosis, but it's not the sole cause of the illness.

Risk factors include renal insu�ciency, higher doses of metformin, and alcoholism.

metformin-unrelated lactic acidosis (MULA)

Metformin levels are low; metformin is an innocent bystander.Clinically it will be impossible to differentiate this from MALA

Differentiation of MULA from MALA requires measurement of metformin levels, which isn't available at most hospitals.

clinical presentation(back to contents) (#top)

signs & symptoms of metformin toxicity

Vitals:  The following abnormalities may be seen:HypothermiaHypotension progressing to vasopressor-refractory shock can occur.

GI symptoms often predominate:  Nausea, vomiting, diarrhea, epigastric pain.Delirium, decreased consciousness

evaluation

Fingerstick glucose (hypoglycemia may occur)ABG or VBGComplete set of chemistries (including Ca/Mg/Phos), CoagsAnion-gap labs:

Lactate level (requisite for diagnosis)beta-hydroxybutyrate level (frequently elevated)

Liver function testsIf infection is possible:  Blood cultures, urinalysis, chest X-ray, procalcitonin.

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If intentional ingestion:  Additional toxicologic evaluation (e.g. acetaminophen, salicylate levels, toxic alcohols, carboxyhemoglobin).

di�erential diagnosis(back to contents) (#top)

Lactate due to other acute illness

Approach to the patient with hyperlactatemia on metformin

Acute, large metformin intoxication?

Yes

Is patient actually taking metformin? Not metformin-relatedNo

Elevated lactate level plus metformin prescription

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Probably metformin-induced lactic acidosis (MILA)(especially no alternative explanation i.e. coingestion)

Yes

Lactate due to metformin

MILA(metformin-induced lactic acidosis)

MALA(metformin-associated lactic acidosis)

MULA(metformin-unrelated lactic acidosis)

Features favoring MILA end of spectrum Features favoring MULA end of spectrum

Higher metformin dose Lower metformin dose

Chronic or subacute renal failureMarkedly reduced GFR

No renal failure (or very acute renal failure)Fairly preserved GFR

No other obvious causes of elevated lactate Other causes of elevated lactate (e.g. sepsis)

No response to basic supportive/resuscitative measures Lactate rapidly decreases following initial resuscitation

No

(https://emcrit.org/ibcc/metformin/)

Note that many patients may be ill due to a combination of metformin plus an acute illness.  Therefore, a thorough search must always be madefor any additional causes of physiologic stress.  

metformin-induced lactic acidosis vs. DKA

Compared to isolated DKA, patients with metformin-induced lactic acidosis have greater degree of hyperlactatemia, with less extensiveketoacidosis.It can be very di�cult to sort this out in some situations.  When in doubt, treat both conditions (the treatment for DKA may actually improveMILA/MALA).  More on treatment of this below.

other causes of lactic acidosis, for example:

Shock of any etiology (septic shock, adrenal insu�ciency, cardiogenic shock, etc.)Acute mesenteric ischemiaSeizureLiver failureThiamine de�ciencyMedications

HIV antiretroviralsLinezolidPropylene glycolPropofol infusion syndromeBeta-adrenergic medications (e.g. albuterol, epinephrine)Massive acetaminophen overdose

prognosis(back to contents) (#top)

acute metformin intoxication

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Poor prognostic signs:More severe acidemia (pH < 6.9)Higher lactate levels (>15 mM)Prolongation of prothrombin time (INR)

chronic metformin use

Lactate level and pH seem to lack prognostic signi�cance in these patients.  The reason for this is that historically patient cohorts havecontained a mixture of MILA, MALA, and MULA.  With such a heterogeneous group of patients, prognostic relationships get muddied.

decontamination after acute ingestion(back to contents) (#top)

Activated charcoal may be considered for patients who present very shortly following acute ingestion, without contraindications (e.g. normalmental status without risk of aspiration).

exclusion of other illness & empiric therapy for sepsis(back to contents) (#top)

Evaluate for alternative causes of illness, especially septic shock.If sepsis is possible, consider empiric antibiotic therapy (along with further diagnostics, including blood cultures and possibly procalcitoninlevels).

Antibiotics may be discontinued within 24-48 hours if additional evidence of sepsis doesn't emerge over time.

glucose administration & diabetes management(back to contents) (#top)

1) basic glucose management (all patients)

Follow �ngerstick glucose frequently.Provide IV dextrose as needed.

2) treatment of diabetic ketoacidosis?

Diabetic ketoacidosis may be tricky to diagnose in the context of metformin:Metformin itself may promote the catabolism of fats and production of ketoacid.Metformin may cause hypoglycemia (so the patient may not have features of classic diabetic ketoacidosis).In some cases, it may be hard to sort out whether the patient has euglycemic DKA versus metformin poisoning (and to some extentthis may be a linguistic issue).

A case series of three patients with metformin-associated lactic acidosis and concurrent euglycemic DKA reported clinical improvementwhen treated with glucose infusion and dialysis alone (without an insulin infusion).   This suggests that the presence of ketoacidosis alonedoesn't mandate insulin therapy.  However, persistent euglycemic DKA which doesn't improve may be an indication for insulin therapy (moreon euglycemic DKA (https://emcrit.org/ibcc/dka/#euglycemic_DKA) here).

3) glucose, insulin, and potassium (GIK therapy) ???

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Insulin therapy may be bene�cial for metformin poisoning (aside from any question of DKA).  Bene�ts of insulin may include the following:Reduced generation of lactate because of:

Reduced catabolism of protein into pyruvateReduced NADH/NAD ratioStimulation of pyruvate dehydrogenase activity (PDH), which tends to push pyruvate into the Krebs cycle

Reduced catabolism of fat will tend to decrease ketoacid production (thereby improving pH)If given to patients with normal glucose and potassium levels, then insulin must be accompanied by the administration of glucose andpotassium (hence the name “GIK therapy”).There is only very weak evidence to support this therapy:

Seems to reduce lactate levels in dogs poisoned by phenformin.Retrospective case series of phenformin poisoning suggest that insulin was helpful.

GIK therapy cannot be recommended for routine therapy.  However, if nothing else is working and the patient is actively dying, this might beworth a try?

(Of course, talk to your toxicologist if possible before doing this)

volume resuscitation(back to contents) (#top)

Assess volume status in the usual fashion and replete as necessary to target euvolemia.  Patients won't necessarily be hypovolemic, but they mayoften be.

bicarbonate?

Undesirable for a few reasons:Might increase cellular permeability to metformin.Bicarbonate has never been shown to be a useful therapy for lactic acidosis.Raising the pH with bicarbonate may actually stimulate glycolysis and thereby increase lactate generation.

Often quoted as being a component of “standard therapy.”  However, bicarbonate is supported by no evidence here and seems undesirable(unless the bicarbonate level is extremely low, for example <5 mEq/L).

other options aren't great either

Normal saline is an acidotic �uid that will exacerbate the acidosis.Lactated Ringers isn't a good choice, as these patients cannot metabolize lactate.Plasmalyte or normosol aren't good either (they contain acetate which is normally metabolized into bicarbonate via the Krebs cycle – butmay not be metabolized properly in this situation).

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compromise options?

No matter what you do here, folks will �nd fault with it.  The following are two compromise options which might represent a reasonablemiddle-ground:(1) D5W with 1/2 normal saline, plus one ampule (50 mEq) of bicarbonate added per liter.(2) Simultaneous infusions of normal saline and isotonic bicarbonate

If the saline is infused about six times faster than the bicarbonate, the combination will produce an isotonic �uid with an effectivebicarbonate concentration of 25 mEq/L (Strong Ion Difference of 25 mEq/L).This allows you to resuscitate mostly with normal saline, but at the same time not exacerbate the acidosis.

respiratory support(back to contents) (#top)

Intubation usually isn't necessary (if it is, increase minute ventilation to compensate for acidosis).High-�ow nasal cannula may be used to improve ventilatory e�ciency and reduce the work of breathing, for a patient with substantialacidosis and Kussmaul respiration, who is at risk of tiring out.

In this application, the �ow rate should be increased as high as tolerated, with a low FiO2 (e.g. 50-60 liters/minute �ow with 30% FiO2).

dialysis(back to contents) (#top)

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EXTRIP indications for dialysis

Main indicationsLactate >15-20 mMpH <7.0-7.1Failure to improve despite standard supportive measures

Comorbid conditions which may lower the threshold for dialysisShock

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Impaired kidney functionLiver failureDecreased level of consciousness

Full text of the EXTRIP guidelines on metformin here (PDF of Calello DP et al 2015 (https://emcrit.org/wp-content/uploads/2019/04/calello2015-2.pdf) ).

Who benefits most from dialysis?

Lactate due to other acute illness

Lactate due to metformin

MILAmetformin-induced lactic acidosis

MALAmetformin-associated lactic acidosis

MULAmetformin-unrelated lactic acidosis

Benefit from dialysis

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additional thoughts regarding dialysis

In addition to the above criteria, the overall clinical context and diagnosis needs to be considered.  For example, in a patient with a pH of 6.95due mostly to a non-anion gap metabolic acidosis (with a lactate level of 3 mM), dialysis might not be needed.The bene�t of dialysis is probably greatest in MILA patients, with extremely elevated metformin levels.

if dialysis is performed:

It should ideally be continued until the lactate <3 mM and pH >7.35.Hemodialysis is preferable to continuous renal replacement therapy (to achieve adequate clearance of metformin).

methylene blue??(back to contents) (#top)

potential mechanism of action

(1) Metabolic rescueThe main problem in metformin-associated lactic acidosis is blockade of electron transport at Complex I on the mitochondria.Methylene blue is capable of accepting electrons from NADH and transferring them to cytochrome c in the mitochondria (bypassingComplex I).   This should function as a bridge to re-establish the �ow of electrons through the mitochondria.  Theoretically this couldbe a silver bullet which re-starts the stalled Krebs cycle and re-establishes normal metabolism.However, some evidence suggests that this may not work due to poor cellular penetration by methylene blue.

(2) Vasoconstriction:  Methylene blue can also function as a vasoconstrictor (by scavenging nitric oxide).  It's possible that its e�cacy insome cases of refractory shock with metformin toxicity is due purely to its e�cacy as a vasoconstrictor.

evidence & recommendations?

Limited to case studies.G6PD de�ciency is a contraindication, as methylene blue may increase the risk of hemolytic anemia.May be considered in cases refractory to conventional therapy.A reasonable dose might be 2 mg/kg loading dose over 15-30 minutes, followed by ~0.25 mg/kg/hour infusion.

checklist(back to contents) (#top)

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Metformin associated lactic acidosisEvaluation

Basic labs including glucose, electrolytesLactate & beta-hydroxybutyrate levels, liver function testsABG or VBGAcute ingestion: Additional toxicology labs (e.g. acetaminophen & salicylate levels)Possible sepsis: Infectious workup (e.g. blood cultures, urinalysis, CXR, procalcitonin)

Glucose managementFollow glucose & administer IV dextrose PRNPersistently & markedly elevated beta-hydroxybutyrate: consider tx for euglycemic DKA?

Volume resuscitationEvaluate volume status and resuscitate if needed to target euvolemiaIdeal resuscitative fluid debatable (possibly some combination of a lot of normal saline &some isotonic bicarbonate)

Respiratory supportConsider HFNC at high flow rate to reduce work of breathing in marked acidosis

HemodialysisIndications:

Lactate > 15-20 mMpH < 7.0-7.1Failure of standard supportive therapy

Lower threshold for dialysis in patients with renal failure, shock, delirium, or hepatic failureSalvage therapy: r efractory to avoid measures

Methylene blueGIK therapy (Glucose infusion, Insulin infusion, and potassium)

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podcast(back to contents) (#top)

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Follow us on iTunes (https://itunes.apple.com/ca/podcast/the-internet-book-of-critical-care-podcast/id1435679111)

The Podcast Episode

Want to Download the Episode?Right Click Here and Choose Save-As (http://tra�c.libsyn.com/ibccpodcast/IBCC_EP_32_-_Metformin_Toxicity_Final.mp3)

questions & discussion(back to contents) (#top)

To keep this page small and fast, questions & discussion about this post can be found on another page here (https://emcrit.org/pulmcrit/metformin/) .

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Under-diagnosis:  Failure to consider metformin as a cause of lactic acidosis.Over-diagnosis:  The assumption that all patients with metformin and lactic acidosis have MILA (without any other problems going on).  Thisassumption could lead to overlooking simultaneous problems, such as septic shock plus MALA.Trying to �x metformin-induced lactic acidosis with large-volume �uid resuscitation.  Unless the patient is hypovolemic, �uid isn't the answer.

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Failing to initiate dialysis in a patient who is extremely ill and meets guideline criteria for dialysis.  It's hard to know precisely which patientswill bene�t from dialysis, but there are probably some who need dialysis to recover.  When in doubt, consult your toxicologist and consider atrial of dialysis.

Going further: 

Metformin-associated lactic acidosis (https://lit�.com/metformin-associated-lactic-acidosis/) (Chris Nickson, LITFL)Metformin-associated lactic acidosis (https://coreem.net/podcast/episode-124-0/) (CoreEM, Anand Swaminathan)

References

1. Mason R. Time out for asthma. Ann Allergy. 1989;63(5):366-368. [PubMed (https://www.ncbi.nlm.nih.gov/pubmed/2817525) ]

2. Lalau J, Kajbaf F, Protti A, Christensen M, De B, Wiernsperger N. Metformin-associated lactic acidosis (MALA): Moving towards a newparadigm. Diabetes Obes Metab. 2017;19(11):1502-1512. [PubMed (https://www.ncbi.nlm.nih.gov/pubmed/28417525) ]

3. Wang G, Hoyte C. Review of Biguanide (Metformin) Toxicity. J Intensive Care Med. August 2018:885066618793385. [PubMed (https://www.ncbi.nlm.nih.gov/pubmed/30126348) ]

4. Schwetz V, Eisner F, Schilcher G, et al. Combined metformin-associated lactic acidosis and euglycemic ketoacidosis. Wien Klin Wochenschr.2017;129(17-18):646-649. [PubMed (https://www.ncbi.nlm.nih.gov/pubmed/28865058) ]

5. Kwong S, Brubacher J. Phenformin and lactic acidosis: a case report and review. J Emerg Med. 1998;16(6):881-886. [PubMed (https://www.ncbi.nlm.nih.gov/pubmed/9848705) ]

6. Loubatières A, Ribes G, Valette G, Lignon F, Rondot A. [Actions of sodium dichloroacetate in combination with insulin on hyperlactatemiaand hyperpyruvicemia induced in dogs by phenformin]. C R Seances Soc Biol Fil. 1977;171(1):150-155. [PubMed (https://www.ncbi.nlm.nih.gov/pubmed/20198) ]

7. Moioli A, Maresca B, Manzione A, et al. Metformin associated lactic acidosis (MALA): clinical pro�ling and management. J Nephrol.2016;29(6):783-789. [PubMed (https://www.ncbi.nlm.nih.gov/pubmed/26800971) ]

8. Goldfrank’s Toxicologic Emergencies, 10th Edition, 2015, Chapter 53 by George Bosse, Page 729.

9. Calello D, Liu K, Wiegand T, et al. Extracorporeal Treatment for Metformin Poisoning: Systematic Review and Recommendations From theExtracorporeal Treatments in Poisoning Workgroup. Crit Care Med. 2015;43(8):1716-1730. [PubMed (https://www.ncbi.nlm.nih.gov/pubmed/25860205) ]

10. Wen Y, Li W, Poteet E, et al. Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem.2011;286(18):16504-16515. [PubMed (https://www.ncbi.nlm.nih.gov/pubmed/21454572) ]

11. Piel S, Ehinger J, Chamkha I, et al. Bioenergetic bypass using cell-permeable succinate, but not methylene blue, attenuates metformin-induced lactate production. Intensive Care Med Exp. 2018;6(1):22. [PubMed (https://www.ncbi.nlm.nih.gov/pubmed/30069806) ]

12. Graham R, Cartner M, Winearls J. A severe case of vasoplegic shock following metformin overdose successfully treated with methyleneblue as a last line therapy. BMJ Case Rep. 2015;2015. [PubMed (https://www.ncbi.nlm.nih.gov/pubmed/26150642) ]

The Internet Book of Critical Care is an online textbook written by Josh Farkas (@PulmCrit), an associate professor ofPulmonary and Critical Care Medicine at the University of Vermont.

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