Metformin Associated Lactic Acidosis

Follow-Up Rounds

7/25/2015
Presenter: Dr. Mayuri Patel, PGY-3
Metformin Associated Lactic Acidosis
Synopsis: Great case and discussion on a rare complication of a commonly prescribed medication that touches on some important toxicologic topics.

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The Case

CC: 66 female presents with abdominal pain, nausea, diarrhea x 3d

HPI

• Generalized abdominal pain
  • ↓PO intake x 1w
  • a/w N/D
• Denies f/c/recent travel/recent hospitalization/sick contacts/recent changes in medication/CP/SOB/cough/urinary complaints
• Reports increase in chronic LBP for which she takes ibuprofen

PMH: DM, HTN, HLD, Chronic LBP
PSH: Hysterectomy
Medications: Statin, metformin, glipizide, HCTZ, ASA, ibuprofen
Allergies: NKMA
Social: Denies EtOH, tobacco, illicit substance use

PHYSICAL EXAM
Vitals: BP 105/70, HR 70, RR 20, O2 sat 95% on RA, FS 110
General: AAOx1 (not baseline), uncomfortable, following commands
HEENT: Dry MM
CVS: RRR, S1, S2, no murmurs
Pull: CTAB
Abd: +BS, soft, NT, ND
Ext: No cyanosis or edema

STUDIES
CBC: 20 > 13.3/34 < 310
BMP: 137/5.7   100/7   90/7.3   < 168; AG 30
LFTs: WNL
Lactate: >20
VBG: pH 6.7, pCO2 20, pO2 75

ED COURSE
Within 30 minutes of evaluation, patient noted to be tachypneic, altered, dropping O2 saturation, and hypotense to SBP 80-90s.

DIAGNOSIS: Metformin-associated lactic acidosis

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Teaching points

Two types of lactic acidosis 

• Type A
  • Due to impaired tissue perfusion
  • Commonly in the following
    • Hypovolemia
    • Heart failure
    • Sepsis
• Type B
  • Due to decreased utilization of lactate
  • May be due to:
    • Alcoholism
    • ↓ Lactate utilization secondary to hepatic dysfunction
    • ↓ NAD+/NADH ratio leads to ↑ conversion of pyruvate to lactate
    •  Metformin
    • DKA (D-lactate production)
    • Liver Disease
    • Malignancy
    • CO poisoning
    • Cyanide poisoning

Metformin-associated Lactic Acidosis

Background

• Acute and chronic use of metformin can lead to rare complication of Metformin-associate lactic acidosis (MALA)
• Excreted (unmetabolized) in proximal tubules
• Lactate accumulation due to:
  • Increased anaerobic glucose metabolism in splanchnic bed
  • Decreased glucosegenesis from lactate
• Associated with overdose, renal failure, liver disease, and septicemia
• Acidosis onset several hours after acute ingestion
• Mortality rate 45%
  • Lactate only predictive of mortality in overdose patients, not in incidental metformin accumulation
    • pH >6.9, lactate >25 portends a poor prognosis
  • Elevated PT associated with increased mortality

Clinical Features

• Nausea
• Vomiting
• Diarrhea
• Altered mental status
• Dyspnea
• Hypotension
• Tachycardia
• Tachypnea

Diagnosis

• FS
• [ASA]
• [APAP]
• EKG
• bHCG
• ABG
• Chem
• Lactate

Management

• If intubated, maintain minute ventilation so as to not remove respiratory compensation for acidosis
• Activated charcoal if peri-ingestion/AMS appropriate
• Metformin should not cause hypoglycemia and, if present, should lead to work up of cause
• Sodium Bicarbonate
  • No evidence to support its use in MALA patients
• Renal Replacement Therapy
  • Metformin can be cleared with hemodialysis and CVVH (continuous venovenous hemofiltration)
    • Former preferred
    • CVVH should be used in unstable patient
  • Reduction in metformin levels following acute ingestion reported to require prolonged HD
  • Consider if:
    • pH <7.1
    • Renal insufficiency
  • Mortality benefits mainly from improving acidosis rather than removing Metformin

References

1. Goldfrank, Lewis R. Goldfrank’s Toxicologic Emergencies. 9th Ed. New York: McGraw-Hill, 2011
2. Seidowsky, A., Nseir, S., Houdret, N., & Fourrier, F. Metformin-associated lactic acidosis: a prognostic and therapeutic study. Critical Care Medicine 2009;7:2191–2196.
3. Dell’Aglio, D. M., Perino, L. J., Kazzi, Z., Abramson, J., Schwartz, M. D., & Morgan, B. W. Acute metformin overdose: examining serum pH, lactate level, and metformin concentrations in survivors versus nonsurvivors: a systematic review of the literature. Annals of Emergency Medicine 2009;6:818–823.
4. Kruse, J. A. Metformin-associated lactic acidosis. The Journal of Emergency Medicine 2001;3:267–272.
5. Barrueto, F., Meggs, W. J., & Barchman, M. J. Clearance of metformin by hemofiltration in overdose. Journal of Clinical Toxicology 2002;2:177–180.
6. Rifkin, S. I., McFarren, C., Juvvadi, R., & Weinstein, S. S. Prolonged hemodialysis for severe metformin intoxication. Renal Failure 2011;4:459–461.

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FOAM RESOURCES

1. http://lifeinthefastlane.com/ccc/metformin-related-lactic-acidosis/