acute renal failure. Sodium bicarbonate haemodialysis therapy led to a dramatic improvement. Consciousness and hemodynamic status recovered rapidly.
Intensive Care Med (1987) 13:383-387
Intensive Care M e d i c i n e © Springer-Verlag 1987
Bicarbonate haemodialysis: an adequate treatment for lactic acidosis in diabetics treated by metformin J.D. Lalau 1, P.E Westeel 1, X. Debussche r, H. Dkissi 2, M. Tolani 2, B. Coevoet 2, B. Temperville 1, A. Fournier 2 and J. Quichaud 1 rService de M~dicine Interne-End°crin°l°gie, 2Servicede N6phrologie-Rdanimation,Centre Hospitalier R6gional et Universitaire, Amiens, France
Received: 15 September 1986; accepted: 22 December 1986
Abstract. Lactic acidosis in diabetics on metformin
therapy is rare but still associated with poor prognosis. The authors report here five cases. Three patients were initially with a cardiovascular collapse and all had an acute renal failure. Sodium bicarbonate haemodialysis therapy led to a dramatic improvement. Consciousness and hemodynamic status recovered rapidly. Severe metabolic and blood gases derangements were also rapidly corrected. Plasma metformin removal, appreciated by repeated blood samplings in 3 cases, was satisfactory. All patients survived. However, blood metformin levels remained abnormally high at the end of the dialytic therapy. In conclusion, (1) bicarbonate dialysis is an adequate treatment of lactic acidosis observed in diabetic patients treated with metformin since it rapidly corrects the acid-base disorders and partially removes metformin; (2) the sole accumulation of metformin is not sufficient to explain lactic acidosis since this latter might be corrected in spite of persisting high levels of blood metformin. Bicarbonate haemodialysis - Metformin therapy - Diabetic coma Key words: Lactic acidosis -
Lactic acidosis in diabetics on metformin therapy is rare but still associated with poor prognosis. Highdose intravenous sodium bicarbonate therapy has been recently criticized [4, 111. It worsens rather than improves hepatic lactate metabolism and cardiac output in hypoxic dogs [4]. On the other hand, in experimental conditions, dichloroacetate is effective in that it lowers blood lactate levels and normalizes cardiac index [5]. However, whether dichloroacetate increases survival in diabetic human beings is not known. Haemodialysis may be an alternative to dichloroacetate: its advantages are rapid removal of biguanides
and excess lactate ions and the ability to administer sodium bicarbonate without the hazard of fluid overload. However, experience of dialysis in lactic acidosis in diabetics on biguanides is very limited. If we except a few single case-reports, we found only two works in the literature concerning the effects of dialysis [l, 8]. Therefore, we report here five cases of lactic acidosis that occurred in diabetic on metformin, with dramatic improvement after bicarbonate dialysis and no fatal outcome. To clarify the relationship between metformin accumulation and lactic acidosis, plasma metformin removal was appreciated by repeated samplings of blood and dialysate.
Patients and methods
Patients The clinical history of the cases is as follows: female, diabetic, 70 years, metformin 1700 rag/day. In spite of dehydration by vomiting and diarrhea with progressive rise of serum creatinine up to 600 ~tmol/l, the treatment was continued. Lactic acidosis occurred suddenly with coma and collapse. Case A:
Case B: male, diabetic, 48 years, metformin at the excessive dose of 5100 rag/day and glibornuride. On admission, a scrotal abcess was diagnosed, treated by colimycine and explored by excretory pyelography without stopping metformin. On the next day, a surgical incision of the abcess was performed, followed by a shock. Serum creatinine was 750 ~mol/1. C." female, diabetic, 62 years, metformin 3400 rag/day and glibenclamide. She presented with a gram-negative septicemia and shock. Serum creatinine was 386 ~mol/1. Case
384
J.D. Lalau et al.: Bicarbonate haemodialysis for metformin-lactic acidosis
Case D: female, diabetic, 80 years, metformin 2550 mg/day, gliclazide and furosemide. On admission, renal function was normal. An arteriography of the vessels of the neck was performed for neurologic problems, followed by an anuria. Serum creatinine at this time was 846 Ismol/1. E: male, diabetic, 61 years, metformin 1700 mg/day. He presented with a coma vigil and an acute renal failure by renal and ureteral lithiasis in a single kidney (contro-lateral kidney was atrophic). Serum creatinine was above 2000 ~tmol/1. Case
Methods
Dialysis was performed using a closed recirculating system with 1 needle (cases B, C and D) or 2 needles (case A), with a 75-1 tank of dialysate. In case E, the dialysis was performed with a single pass system, one needle and a double-pump system. Bicarbonate dialysis was performed with a dialysate containing bicarbonate, 34 mEq/1 and acetate, 4 mEq/1. Dialysers had a cuprophan membrane with an area of 1.2 m 2 in cases A, B, C and D and 1.3 m z in case E. Blood flow was 2 0 0 - 2 5 0 ml/min; dialysate flow was 500 ml/min. Levels of blood lactates were determined before and after each dialysis. Plasma metformin removal was measured during the dialysis by repeated samplings of blood and dialysate in patients C, D and E. In patient C, evaluation of the quantity of metformin removed was made by multiplying the concentration of metformin in the dialysate by the volume of the dialysate. Lactates were measured with an enzymatic method using a commercial kit (Boehringer Mannheim). The assay of metformin was performed by gas-liquid chromatography using a nitrogen detector (Laboratoires Aron, Suresnes, France [3]).
duration of dialysis was 10 h. On discharge, serum creatinin was 100 ~tmol/1 and the prescribed treatment was metformin, 840 mg/day, and glibenclamide. Case C: after administration of plasma-volume expanders and dobutamine infusion, hemodynamic status was restored and dialysis was performed during 5 h. On discharge, serum creatinin was 100 Ixmol/1. The prescribed treatment was metformin, 1700rag/ day. Case D: renal function recovered slowly, only after 6 dialyses. The first, which corrected the acidosis, was performed during 4 h. The patient was discharged with a serum creatinin at 210 ~tmol/1, without antidiabetic treatment.
50 OO O
@@@
0 0 @ @
30-
•
E~
:&
[]
o
E
Results
During and after the dialysis therapy, clinical state dramatically improved. Consciousness and hemodynamic status recovered rapidly and all individual patients were discharged for home in good condition. No complication of dialysis was observed. Clinical course was as follows: Case A: consciousness and hemodynamic status dramatically improved soon after starting the 4-h dialysis. The patient was discharged on insulin. Serum creatinin at this time was 210 ~tmol/1. Case B: satisfactory hemodynamic status was only obtained after the third dialysis; the two first were shortened because of coagulation problems. Total
cose D
0
0
[]
QJ
[]
0 case E
[] [] []
[] []
[] [] [] caseC
10-
I i
0
~ I I
1
i
[
t
I
I
2
3
&
5
6
Durotion of dialysis (h] Fig. 1. Time-course of blood metformin changes during bicarbonate dialysis. Normal fasting values of blood metformin in patients taking 1700 nag/day are inferior to I ~tg/ml * indicates dialysate metformin concentration in case C
J.D. Lalan et al.: Bicarbonate haemodialysis for metformin-lactic acidosis
385
this view since (a) in different animal models of type B lactic acidosis (without clinical evidence of hypoxemia), therapy with NaHCO3 leads to decreased cardiac output, a decline in blood pressure, increased concentrations of lactates in blood, decreased lactate metabolism and increased subject mortality; (b) in dogs with hypoxic lactic acidosis induced by inhalation of CO 2 (type A lactic acidosis), N a H C O 3 elevates blood lactates, decreases arterial pH, bicarbonate concentration and cardiac output. Even if the relevance of these experimental observations to the clinical disorder is uncertain [9], the search for alternative treatment modalities is warranted. Dichloroacetate (DCA) is a promising substance, that lowers blood lactate levels in a variety of
Case E." consciousness recovered soon after starting a 6-h dialysis. On discharge, serum creatinin was 110 gmol/1. Antidiabetic treatment was discontinued. Effects of bicarbonate dialysis on metabolic parameters and blood metformin levels are reported in Table 1 and in Fig. i respectively.
Discussion
Therapy for lactic acidosis has been disputed. Traditional view is that patients should receive high doses of intravenous sodium bicarbonate in order to compensate for the low blood bicarbonate. Recent data from Graf, Park and Arieff [4, 5, 10] have challenged
Table 1. Metabolic data in patients treated by metformin with lactic acidosis: effects of bicarbonate dialysis (BD) treatment Case
A
Timea IV bicarbonate, m E q BD, duration (h) pH Lactates, mmol/1 Bicarbonates, mmol/1 pCO 2
B
Time 1V bicarbonate BD, duration pH Lactates Bicarbonates pCO z
t2h ~-
Time IV bicarbonate BD, duration pH Lactates Bicarbonates pCO 2
t2h30
~
~
t60h 170
IBD:4h ] 6.88 1.8 8
7.15 18.4 3.1 8
7.39 9.13 12 19
to t2h45 750-* I BD: 2h30b [ 7.11 7.22 20.2 17.9 8 10.3 23 23
Time IV bicarbonate BD, duration pH Lactates Bicarbonates pCO 2 Time IV bicarbonate BD, duration pH Lactates Bicarbonates pCO 2
to 250
t9h ~-
8
to 125
t6h I BD: 3h30 b ] 7.43 13 18.5
7.51 2.3 29.1 35.5 t 12h
7.37 11.2 13.2 22
tl9h
t25h
7.47 7.3 19.4 26.5
t5h
5hi
7.14 12.7 14.6 42.8
7.43 5.7 24.6 35.5
to ~
t4h
7.48 2.4 30.6 39
7.39 6.7 22 30
5.9 14 25 to
t6h 5
. 7.85 3 17.2
7.39 14.6 23.4
a Time: to is the time of beginning of the first dialysis. Data occurring before to are reported under a negative time. Quantities of sodium bicarbonate infused are indicated between arrows b Dialyses shortened because of coagulation problems
386
J.D. Lalau et al.: Bicarbonate haemodialysis for metformin-lactic acidosis
experimental and clinical situations. In dogs with lactic acidosis, D C A therapy results in normalization of cardiac index and improvement in arterial pH, bicarbonate, lactate and liver intracellular p H [5, 14]. In h u m a n beings, D C A lowers blood lactate levels in some patients who had lactic acidosis due to tissue hypoxia [2, 12]. However, in the report of Stacpoole et al. [12], all patients but one died of their underlying disease. Moreover, except for one patient of Irsigler et al. [6], who died, effects of D C A in diabetics with lactic acidosis is not known. In lactic acidosis occurring in patients treated by metformin, dialysis should be a therapy of choice, since it removes lactate ions and metformin and corrects acid-base status. Some evidences indicate that lactate ion is harmful p e r s e on myocardial function [7, 15], but this has been disputed by Park and Arieff since infusion of lactic acid has no effect on cardiac output in the dog [10]. Experience of haemodialysis in biguanidelactic acidosis is limited: (a) Althoff et al. [1] reported severe lactic acidosis in 9 diabetic patients on buformin or phenformin treated with acetate-buffered haemodialysis; 7 survived; (b) Larcan et al. [81 reported nine cases also of severe hyperlactatemia in diabetics on phenformin (three cases) or metformin (six cases) treated by bicarbonate-buffered haemodialysis of w h o m only 2 survived (those with massive intoxication with metformin). We report here five cases of lactic acidosis in diabetics on metformin therapy, of whom 3 were initially with a cardiovascular collapse. Renal failure was the prominent causal factor in the precipitation of the lactic acidosis in 5 patients (cases A, B, D and E). In patient 4 (case C), lactic acidosis was due to a septic shock. The dialytic therapy was associated with infusion of moderated quantities of sodium bicarbonate in all cases, prior the admission in our care unit in three cases. This additional treatment could be justified to allow the return of systemic p H to hemodynamically safe levels before the obtention of the metabolic effects of dialysis. Furthermore, as discussed above, the deterious effects of infusion of bicarbonate concern only administration of massive amounts. The modalities for an optimal dialysis therapy are not defined. Two questions arise: (a) the first is whether bicarbonate-buffered dialysis should preferred to acetate. Advantages of bicarbonate include provision of bicarbonate as such, rather than alkali precursors, avoidance of the risk of further hypobicarbonatemia due to an imbalance between the diffusive losses of bicarbonate into the dialysate and alkali generation from the acetate, the prevention of acetate dialysis-induced hypoxemia [in 9]. In fact, the better metabolic tolerance of bicarbonate is not well
established and the major advantage of bicarbonate dialysis is to allow a better hemodynamic stability which is particularly precious in patients with cardiovascular shock [13], as it was the case in 3 of our patients; (b) the second question is how long the dialysis should be performed. The answer is difficult because, with a recirculating system, even after reaching an equilibrium between blood and dialysate levels of metformin, the removal of metformin may continue. Effectively, as shown in case C by the metformin dialysate levels, metformin is eliminated at the end of the dialysis as well as at the beginning; this suggests that, in case of accumulation of metformin by renal failure, there is a stockage of metformin in a deep compartment in which the concentration is superior to that of the blood compartment. Thus, the gradient of concentration between the blood and the deep compartments allows a continued removal. The most striking feature is that severe metabolic abnormalities may rapidly be repaired and that the final outcome may be satisfactory after a single dialysis, even when blood metformin levels remain abnormally high after the dialysis. It is also interesting to note that the blood metformin level at the end of dialysis in case D is clearly above to the initial one in case C. This indicates that, in acute renal failure, the accumulation of metformin is a prerequisite in the genesis of lactic acidosis but is not sufficient to trigger it. A certain degree of tissular hypoxia is probably required simultaneously. In conclusion, bicarbonate dialysis is an adequate treatment for lactic acidosis on metformin therapy, in particular in lactic acidosis with shock, since it rapidly corrects acid-base changes and hemodynamic status and it adequately dialyses lactate ions and metformin. All our 5 patients survived. Because this efficiency, prognosis of lactic acidosis in patients on metformin is not so bad than usually considered, in particular in case of metformin accumulation by renal failure.
References 1. Althoff PH, Fassbinder W, Neubauer M, Koch KM, SchOffling K (1978) H~modialysebei der Behandlung unter biguanid-induzierter Lactacidose. Dtsch Med Wochenschr 103:61 2. Blackshear PJ, Fang LST, Axelrod L (1982) Treatment of severe lactic acidosis with dichloroacetate. Diabetes Care 5:39I 3. Brohon J, Noel M (1978) Determination of rnetformin in plasma at therapeutic levelsby gas-liquid chromatographyusing a nitrogen detector. J Chromatogr 146:148 4. Graf H, Leach W, Arieff AI (1985) Evidence for a detrimental effect of bicarbonate therapy in hypoxic lactic acidosis. Science 227:754 5. Graf H, Leach W, Arieff AI (1985) Effects of dichloroacetate in the treatment of hypoxiclactic acidosis in dogs. J Clin Invest 76:919 6. Irsigler K, Kaspar L, Kritz H (1977) Dichloroacetate in biguanide-induced lactic acidosis. Lancet 2:1026
J.D. Lalau et al.: Bicarbonate haemodialysis for metformin-lactic acidosis 7. Jurkowitz M, Scott KM, Altschuld RA, Merola A J, Briefly GP (1974) Ion transport by heart mitochondria. Retention and loss of energy coupling in aged heart mitochondria. Arch Biochem Biophys 165:98 8. Larcan A, Lambert H, Laprevotte-Heully MC, Claude D, Delorme N (198/) Le traitement des acidoses lactiques par h6modialyse sur membrane de polyacrylonitrile. Ann Med Nancy 20:989 9. Madias NE (i986) Lactic acidosis. Kidney Int 29:752 10. Park R, Arieff AI (1983) Lactic acidosis: current concepts. Clin Endocrinol Metab 12:339 l 1. Ryder RE (1984) Lactic acidosis: high-dose or low-dose bicarbonate therapy. Diabetes Care 7:99 12. Stacpoole PW, Harman EP, Curry SH, Baumgartner TG, Misbin RI (1983) Treatment of lactic acidosis with dichloroacetate. N Engl J Med 2:390
387
13. Vanherweghem JL, Vincent JL (1986) Acetate versus bicarbonate for haemodialysis in critically ill patients. Intensive Care World 3:84 14. Ward RA, Wathen RL, Harding GB, Thompson LC (1985) Comparative metabolic effects of acetate and dichloroacetate infusion in the anesthetized dog. Metabolism 34:680 15. Yatani A, Fujino T, Kinoshita K, Goto M (1981) Excess lactate modulates ionic currents and tension components in frog atrial muscle. J Mol Cell Cardiol 13:147 Dr. J. D. Lalau Centre Hospitalier Rdgional et Universitaire B.R 3009 F-80030 Amiens Cedex France
