Use of urea containing dialysate to avoid disequilibrium syndrome, enabling intensive dialysis treatment of a diabetic patient with renal failure and severe metformin induced lactic acidosis

Cornelius J. Doorenbos1,2, Renate J. Bosma1 and Paul J. N. Lamberts3

1 Department of Internal Medicine 2 Department of Nephrology 3 Department of Hospital Pharmacy, Deventer Hospital, Deventer, The Netherlands

Sir,

Metformin decreases insulin resistance in non-insulin-dependent diabetes mellitus. It is eliminated unchanged by glomerular filtration and tubular excretion. Metformin may induce conversion of glucose to lactate in the intestinal mucosa and it also inhibits the respiratory chain in liver mitochondria, causing impaired gluconeogenesis from lactate [1]. Severe lactic acidosis develops rarely, predominantly when contraindications like renal insufficiency are overlooked [2]. Bicarbonate haemodialysis has been used successfully to correct metabolic acidosis and to remove lactate and metformin [3].

Dialysis disequilibrium syndrome is a central nervous system disorder developing in uraemic patients, when treatment is started with rapid intensive haemodialysis and when there is a concomittant severe metabolic acidosis. The symptoms are attributed to cerebral oedema, due to a brain-to-plasma urea gradient, caused by delayed urea diffusion from the brain to the blood [4]. Addition of urea to the dialysate was shown to prevent the development of cerebral oedema in rats, despite rapid dialysis [5].

Case.

A 66-year-old woman had hypertension and non-insulin-dependent diabetes mellitus, complicated by retinopathy and nephropathy. Large doses of insulin failed to control her diabetes and metformin was added in increasing doses, up to three times daily 850 mg from February 2000. Her creatinine level rose to 161 µmol/l in May and to 236 µmol/l in August 2000. In September, she was admitted to the department of internal medicine because of severe vomiting. She could not take food or drink, but she continued taking her medication, including metformin and an ACE inhibitor. On examination, she was soporous, her blood pressure was 105–80 mmHg, her heart rate 100 bpm. Her abdomen was painful, but no other abnormalities were noted. Relevant laboratory results were: potassium 5.7 mmol/l, urea 22.1 mmol/l, creatinine 498 µmol/l, glucose 4.9 mmol/l, pH 7.36, PCO2 4.3 kPa, PO2 11.9 kPa, bicarbonate 18 mmol/l, base excess -6.3 mmol/l. The urinalysis showed albumin +++, glucose +, and traces of ketone bodies. A CT-scan of the abdomen showed no abnormalities. In the evening, a plasma lactate level of 10.3 mmol/l was found. The next morning, the patient was anuric and tachypnoic. Laboratory evaluation showed urea 28.8 mmol/l, creatinine 640 µmol/l, with severe hyperkalaemia 7.8 mmol/l and lactic acidosis: 13.5 mmol/l, pH 7.12, PCO2 2.9, PO2 13.8, bicarbonate 7 mmol/l, base excess -21.2 mmol/l.

A nephrology consultation was requested. A presumptive diagnosis was made of lactic acidosis due to metformin intoxication. Haemodialysis was started through a single lumen femoral vein catheter, using an F60-S polysulfon dialyser, a blood flow of 400/400 ml/min and bicarbonate dialysate. The metformin level was 19.4 mg/l (therapeutic level 1 mg/l). During 7 h of dialysis, the metformin level decreased to 8.4 mg/l, the lactic acid to 2.0 mmol/l, the bicarbonate rose to 25 mmol/l and the urea fell to 10.4 mmol/l (Figure 1Go). Dialysis was stopped to prevent the provocation of disequilibrium syndrome.



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Fig. 1. Rapid decrease of blood urea level during first conventional dialysis treatment (circles) with no change during second (squares) and third (triangles) treatment using urea containing dialysate (upper panel) and progressive decline of metformin level during these treatments (lower panel).

 
Nevertheless, 6 h after dialysis she became restless and developed bradycardia, hypotension and hypoxia. Her right pupil was dilated, with conserved pupillary reflexes. She was treated with atropin and oxygen. There was a relapse of acidosis, partly due to respiratory factors and partly to lactic acidosis: pH 7.15, PCO2 6.1, PO2 16.4, bicarbonate 15 mmol/l, base excess -12.4 mmol/l and lactate 3.2 mmol/l, which later increased to 4.6 mmol/l despite a satisfactory circulatory status with a blood pressure of 170–100 mmHg. Dialysis disequilibrium syndrome was suspected, due to the prolonged dialysis treatment with a rapid, marked decline of plasma urea and a considerable rise of plasma bicarbonate.

To enable the removal of metformin and the correction of the lactic acidosis without further urea reduction, a modified dialysate was prepared. A solution of 4.42 mol/l urea was made in the hospital pharmacy and 500 ml were added to 10 l of the acid concentrate. The Hospal Integra dialysis monitor was set to bicarbonate 2.7 and sodium 14.2. This resulted in a dialysate containing: sodium 137 mmol/l, potassium 2.1 mmol/l, chloride 111 mmol/l, urea 10.1 mmol/l and bicarbonate 26 mmol/l according to laboratory analysis. The patient was dialysed for 6 h without further adverse reactions and the plasma metformin level decreased from 9.7 to 4.3 mg/l, while the urea level remained constant (Figure 1Go). The next day her clinical condition improved, and another similar dialysis session was performed, resulting in a further decrease of plasma metformin from 5.0 to 1.9 mg/l, without a change of plasma urea (Figure 1Go). Renal function improved to the level before admission and no further dialysis treatment was required.

Comment.

This patient developed a severe metformin intoxication with lactic acidosis due to pre-existent renal failure, which was further aggravated by vomiting and the continued use of an ACE inhibitor. Her abdominal symptoms were probably also due to metformin intake. The anuria, which initially did not respond to volume expansion, prevented renal excretion of the drug. Prolonged dialysis treatment resulted in significant removal of metformin, with a half life of around 6 h. However, the patient developed symptoms consistent with the disequilibrium syndrome.

A repeated dialysis treatment was indicated to eliminate the metformin still present and to correct the recurrent lactic acidosis. Addition of urea to the dialysate and lowering the dialysate bicarbonate concentration resulted in the ability to repeat dialysis treatment and to remove metformin and correct the lactic acidosis without further neurological problems.

In patients with renal failure with elevated blood urea levels and severe lactic acidosis due to metformin accumulation, repeated prolonged bicarbonate dialysis is needed to remove significant amounts of metformin. Addition of urea to the dialysate permits this intensive treatment while avoiding the provocation of the disequilibrium syndrome.

References

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  4. Arieff AI. Dialysis disequilibrium syndrome: current concepts on pathogenesis and prevention. Kidney Int1994; 45: 629–635[ISI][Medline]
  5. Silver SM, DeSimone JA, Smith DA, Sterns RH. Dialysis disequilibrium syndrome (DDS) in the rat: Role of the ‘reverse urea effect’. Kidney Int1992; 42: 161–166[ISI][Medline]