Pathogenic mechanism, prophylaxis, and therapy of symptomatic acidosis induced by acetazolamide.
BACKGROUND
Acetazolamide, a noncompetitive carbonic anhydrase inhibitor, can produce symptomatic acidosis and bone marrow suppression by a mechanism that is still unknown. This presentation occurs in the elderly, patients with renal or liver failure, people with diabetes, and newborns. The objective of this study was to understand the pathogenic mechanism of these adverse effects and to propose a possible prophylaxis and therapy.


METHODS
Four human clinical cases were studied, and one animal experiment was performed. Four preterm newborns with posthemorrhagic ventricular dilation developed severe metabolic acidosis after treatment with acetazolamide. The acidosis suddenly disappeared after a packed red blood cell transfusion. Metabolic studies were performed in one patient and in newborn guinea pigs treated with 200 mg/kg acetazolamide.


RESULTS
Acetazolamide can produce severe lactic acidosis with an increased lactate-to-pyruvate ratio, ketosis with a low beta-hydroxybutyrate-to-acetoacetate ratio, and a urinary organic acid profile typical of pyruvate carboxylase deficiency. The acquired enzymatic injury resulting from the inhibition of mitochondrial carbonic anhydrase V that provides bicarbonate to pyruvate carboxylase can produce tricarboxylic acid cycle damage. We demonstrate that the dramatic disappearance of metabolic acidosis and normalizing metabolism after blood transfusion were due to the citrate contained in the packed red blood cell bag. This hypothesis was confirmed by animal experimentation. We argue that the metabolic disorder and bone marrow suppression may be related.


CONCLUSIONS
We demonstrate how acetazolamide can lead to symptomatic metabolic acidosis and probably to bone marrow suppression. We suggest citrate as a possible prophylaxis and treatment for these adverse reactions.
Filippi
Luca
L
Department of Critical Care Medicine, University of Florence, Careggi Hospital, Italy. filippi.luca@virgilio.it
Bagnoli
Franco
F
Margollicci
Maria
M
Zammarchi
Enrico
E
Tronchin
Michele
M
Rubaltelli
Firmino F
FF
D000086:Acetazolamide / Q000009:adverse effects*; D000140:Acidosis, Lactic / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D000831:Animals, Newborn; D002257:Carbonic Anhydrase Inhibitors / Q000009:adverse effects*; D019343:Citric Acid / Q000627:therapeutic use; D004195:Disease Models, Animal; D017707:Erythrocyte Transfusion; D005260:Female; D005865:Gestational Age; D006168:Guinea Pigs; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D016896:Treatment Outcome
D002257:Carbonic Anhydrase Inhibitors; D019343:Citric Acid; D000086:Acetazolamide