Authors: Karakosta P., Aslanidis Th., Voudouris A., Agaliadou-Dioritou U.
Intensive Care Unit, St. Paul General Hospital, Thessaloniki, Greece
Metformin – associated lactic acidosis treated with Continuous Renal Replacement Therapy in a critically ill patient: Case report and review of the literature.
Though metformin is considered as first choice drug in type II diabetes, clinicians should be alert both for presence of potential contraindications to its use and to possible adverse reactions. Bad therapy compliance along and/or concomitant comorbidities may lead to serious toxicity. We hereby describe a case of extreme lactic acidosis- associated with metformin therapy- in an elder woman, managed with Continuous Renal Replacement Therapy in Intensive Care Unit environment. Short review of the literature about the place of renal replacement therapy in such cases is also discussed.
Available since 1985, metformin has gained its place in clinical practice as first-line treatment in adults with type II diabetes melitus. It can be used either as monotherapy or combination therapy with glucagon-like peptide-1 receptor agonist (GLP-1 RA), sodium-glucose co-transporter inhibitor (SGLT2i), dipeptidyl peptidase-4 inhibitor (DPP4-I), thiazolidinedione (TZD), sulfonylurea (SU), and insulin1. Moreo ver, today its use is recommended in prediabetes2,3, type I diabetes melitus2,4, gestational diabetes melitus, polycystic ovary syndrome2,5. At the same time, there are a lot of reports about its cardioprotective and neuroprotective effects, its antitumor and antiaging effects; and its positive results as secondary prevention strategy for antipsychotic-related weight gain2.
Metformin adverse reactions include mainly (up to 20%) gastrointestinal intolerance and taste sense change, while hypoglycaemia, allergic reactions and hypothyroidism are rare2. Vitamin B12 deficiency and lactic acidosis are considered as very rare side effects. The later has worse progress when it is associated with presence of infection, dehydration or concomitant use of diuretics. Though rare, mortality approaches 30-50 %6.
We hereby describe a case of extreme type B lactic acidosis associated with metformin therapy in an elder woman, managed with Continuous Renal Replacement Therapy in Intensive Care Unit environment.
A 72-years old female patient was transported to Emergency Department (ED) due to weakness, dizziness, shortness of breath, loss of appetite, nausea and oliguria. Her medical history included obesity (ICD10– E66) with BMI – 37 kg/m2, type II diabetes mellitus (ICD10-E11.8) under metformin 850 mg b.i.d., arterial hypertension (ICD10-I10) under olmesartan medoxomil/hydrochlorothiazide 20 mg/12.5 mg o.d. and dyslipidemia (ICD10– E78.5) under rosuvastatin 20 mg o.d.; yet with bad compliance to drug therapy. Initial clinical examination revealed hypotension (Blood Pressure – 60/25 mmHg), tachycardia (Heart Rate – 105 bpm), tachypnoea (Respiratory rate of 35 bpm) with measured SpO2 in air of 95% and a Glasgow Coma Scale (GCS) of E3/V4/M6. Yet, her initial arterial blood gases (ABG) analysis revealed a serious lactic acidosis. During her ED ealuation, her mental status decreased rapidly to GCS E2/V2/M3, thus Rapid Sequence Intubation (RSI) where performed and the patient was admitted at Intensive Care Unit. Calculated initial severity scores were: APACHE (Acute Physiology and Chronic Health Evaluation) II 39, APACHE IV 156, SAPS II (Simplified Acute Physiology Score) 86 and SOFA (Sequential Organ Failure Assessment) score 15.
Upon admission, aggressive treatment with fluids, bicarbonate administration and inotropic therapy (noradrenaline 1.2 μg/kg/min c.i.v. and adrenaline 0.3 μg/kg/min c.i.v.). However, anuria and severe metabolic acidosis continued and decision for CRRT (continuous renal replacement therapy) was taken. The patient was put on CVVHDF (Continuous Venovenous Hemodiafiltration) which continued for 45 hours with progressive correction of acidosis. Selected laboratory and ABG exams during her ICU hospitalization are displayed in Tables 1 and 2 respectively.
The rest of her drug regiment included empiric antibiotic prophylaxis, gastric ulcer antithrombotic prophylaxis.
Clinical and laboratory improvement continued slowly after the cessation of CRRT, inotropic drug infusions were stopped the following 4 days and at 11th day of hospitalization mechanical ventilation discontinued, and the patient was extubated.
Table 1. Selected Laboratory exams during ICU hospitalization. The rest of the examined parameters (lactate dehydrogenase, amylase, alkaline phosphatase, γ-glutamyl transferase, liver transaminases) were within normal values.
Hct- haematocrit (%), Hb- haemoglobin (g/dl), PLT-platelets (k/μl), WBC- white cells (k/μl), CRP- c reactive protein (mg/dl), PCT-procalcitonin (ng/ml), Glu- glucose (mg/dl), Cr – creatinine (mg/dl), Ur -urea (mg/dl), BUN- blood urea nitrogen (mg/dl), Prtot- Protein total (g/dl), Alb-albumin (g/dl), CPK- creatine phosphatase (mg/dl).
Table 2. Time course of Arterial Blood Gases exams during ICU hospitalization.
PaO2– arterial Partial Oxygen pressure (mmHg), PaCO2– arterial partial carbon dioxide pressure (mmHg), FiO2 -fraction of inspired oxygen (%), HCO3—bicarbonates (mEq/l), Lac- Lactate (mmol/l), BE – base excess, AGc – anion gap corrected, ΔGc -delta gap corrected, Δ/Δ –delta delta ratio, SIDa- Strong Ion Difference actual, SIDe – strong ion difference estimated, SIG – strong Ion Gap. Bold values represent ABG during CVVHDF.
Two days later she was discharged from ICU without any sequels.
Metformin-associated lactic acidosis (MALA) refers to blood lactate concentrations greater than 5 mmol/L and arterial pH less than 7.35 in association with metformin exposure7. A newer definition system recognises three conditions: a. MALA, where metformin amplifies the degree of lactic acidosis, but it is not the sole cause of illness; usually there are other contributing co-morbidities. b. MULA metformin unrelated lactic acidosis, where metformin is just an innocent bystander; yet, metformin blood levels are necessary to distinguish from MALA and c. MILA – metformin induced lactic acidosis, where high levels of metformin are the primary cause of acidosis. MILA can be either acute poisoning in absence of renal dysfunction or subacute accumulation due to renal failure8.
The latter is what we suggest that was the toxicity mechanism in our case: we presume that diabetic nephropathy was already in progress; and that along with bad compliance to therapy, metformin resulted a high anion gap type B lactic acidosis.
The mechanism of MALA is complex. Metformin promotes the conversion of glucose to lactate in the splanchic bed of the small intestine. It also inhibits mitochondrial respiratory chain complex 1, leading to decreased hepatic gluconeogenesis from lactate, pyruvate and alanine. This results in additional lactate and substrate for lactate production7-8.
Initial therapy is resuscitation and supportive care. Gastrointestinal decontamination (use of active charcoal) is only an early option. Bicarbonate has been used but concerns are raised about the possibility of worsening intracellular acidosis. Thus, it is considered as an option only in extremely low bicarbonate levels (<5mEq/l); as in our case7. Glucose management and volume resuscitation included Actrapid® 8 ui i.v. bolus once and mainly NaCl 0.9% infusion (along with bicarbonate). Literature present various approaches: A case series of three patients with metformin-associated lactic acidosis and concurrent euglycemic DKA reported clinical improvement when treated with glucose infusion and dialysis alone (without an insulin infusion)9. Volume resuscitation options include either D5W with 1/2 NaCl 0.9%, plus 50 mEq of bicarbonate added per liter or simultaneous infusions of normal saline and isotonic bicarbonate. Insulin therapy may be beneficial; yet Glucose, Insulin, Potassium (“GIK”) therapy is generally not recommended10.
Though often reported, there is lack of solid guidelines regarding the use CRRT for MALA. EXTRIP11 guidelines suggest several indications for starting and ending CRRT in those cases (Table 3).
Table 3. Extra corporeal therapy recommendations (ECTR) for MALA11.
|General ECTR is recommended in severe metformin poisoning (1D)
Indications ECTR is recommended if
Lactate concentration > 20 mmol/L (180 mg/dL) (1D)
Blood pH ≤ 7.0 (1D)
Standard therapy (supportive measures, bicarbonate, etc.) fails (1D)
ECTR is suggested if
Lactate concentration is 15–20 mmol/L (135–180mg/dL) (2D)
Blood pH 7.0–7.1 (2D)
Comorbid conditions that lower the threshold for initiating ECTR
Impaired kidney function (1D)
Decreased level of consciousness (2D)
Liver failure (2D)
Cessation of ECTR is indicated when Lactate concentration is < 3 mmol/L (27mg/dL) and pH > 7.35 (1D)
Choice of ECTR
As an initial ECTR, intermittent HD with bicarbonate buffer is preferred (1D), but CRRT is an acceptable alternative if HD is not available (2D) After the initial ECTR session, either HD(1D) or CRRT (1D) is appropriate if necessary.
Mode of CRRT chosen varies from haemodialysis, sustained low efficiency dialysis (SLED), continuous hemofiltration (CVVH) to CVVHD; with survival rates from ICU patients with MALA undergoing CRRT reaching in some reports to 80%12. Adopted dialysis policy of early, extended, continuous, and high efficiency CRRT could have contributed to the reported positive results. On the other hand, there are also reports of cases refractory even to haemodialysis therapy in the setting of concomitant alcohol13.
Finally, other suggested rescue therapy options as methylene blue, are still controversial7.
Since patients under metformin therapy are a large part of diabetic population, clinicians should be alert about the possibility of MALA. Early diagnosis, resuscitation measures and an early dialysis (HD of CRRT) therapy could contribute to successful outcome. Furthermore, increasing report rate could help improve existing therapy guidelines for such cases.
- American Diabetes Association et al. Diabetes Care. 2019; 42(Suppl. 1): S90S102.
- Stoica RA, Ștefan DS, Rizzo M, et al Metformin Indications, Dosage, Adverse Reactions, and Contraindications. http://dx.doi.org/10.5772/intechopen.88675
- Cefalu WT, Riddle M. More evidence for a prevention-related indication for metformin: Let the arguments resume! Diabetes Care. 2019;42:499-501.
- Petrie JR, Chaturvedi N, Ford I, REMOVAL Study Group, et al. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): A double-blind, randomised, placebo-controlled trial. The Lancet Diabetes and Endocrinology. 2017; 5:597-609.
- Morley LC, Tang T, Yasmin E, et al. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database of Systematic Reviews. 2017;11(11):CD003053.
- Aharaz A, Pottegård A, Henriksen DP, et al. Risk of lactic acidosis in type 2 diabetes patients using metformin: A case control study. PLoS One. 2018;13(5):e0196122.
- Wang G, Hoyte C. Review of Biguanide (Metformin) Toxicity. J Intensive Care Med. Aug 2018:885066618793385.
- Lalau J, Kajbaf F, Protti A, et al. Metformin-associated lactic acidosis (MALA): Moving towards a new paradigm. Diabetes Obes Metab. 2017;19(11):1502-1512.
- 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.
- Farkas J. Metformin toxicity. The internet book of critical care 2019. Available from: https://emcrit.org/ibcc/metformin/ (accessed 10/11/2019).
- Calello D, Liu K, Wiegand T, et al. Extracorporeal Treatment for Metformin Poisoning: Systematic Review and Recommendations From the Extracorporeal Treatments in Poisoning Workgroup. Crit Care Med. 2015;43(8):1716-1730.
- Mariano F, Pozzato M, Inguaggiato P, et al. Metformin-associated lactic acidosis undergoing renal replacement therapy in intensive care units: a five-million population-based study in the North-West of Italy. Blood Purif. 2017;44:198–205.
- Benmoussa JA, Chaucer B, Chevenon M, et al. Metformin-associated lactic acidosis refractory to hemodialysis in the setting of concomitant alcohol intoxication. J Diabetes Metab Disord Control. 2018;5(6):204-206.
Authors Karakosta P, Aslanidis Th, Voudouris A, Agaliadou-Dioritou U have no conflicts of interest or financial ties to disclose.
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