Dobutamine-induced myoclonia in severe renal failure

Sir,

Dobutamine is a catecholamine with ß1-, ß2- and {alpha}1-adrenergic properties. This drug is marketed as a racemic mixture containing two stereoisomers having different distribution and elimination properties. Pharmacological activity also differs: the L-enantiomer is a potent {alpha}1-agonist whereas the D-enantiomer is a potent ß1-agonist [1]. Dobutamine is widely used in the treatment of severe heart failure. Tachycardia is the most common effect. To our knowledge, no neuromuscular disturbances with dobutamine administration have been reported.

We observed six cases of dobutamine-induced myoclonia in four women and two men (68.6±6.35 years old) hospitalized for congestive cardiac failure responsible for severe renal insufficiency (creatinine clearance: 15.5±2.5 ml/min/1.73 m2). Mean arterial pressure was 62±5 mmHg. Serum ASAT and ALAT were increased by 25% above normal range and total bilirubin and alkaline phosphatases were normal. The patients had moderate hyponatraemia (127±3 mmol/l). Plasma potassium was normal, mean plasma total calcium was decreased (2.17± 0.05 mmol/l) and serum magnesium was slightly increased (1.3±0.1 mmol/l). All patients had metabolic acidosis, with a mean arterial pH at 7.31±0.02 and plasma bicarbonate at 20.5±1.0 mmol/l.

Patients received dobutamine (10–20 µg/kg/min) in order to correct their haemodynamic disorders without changing other simultaneously given treatments, namely trinitrin and furosemide received at mean doses of, respectively, 3±1 mg/h and 250±125 mg/day. Myoclonia appeared on the second or third day after starting dobutamine treatment, persisted throughout treatment and disappeared 2 days after treatment arrest. This neurological sign has been attributed to dobutamine after having excluded all other potential causes of myoclonia. The close relationship between the occurrence of myoclonia and its disappearance in association with dobutamine treatment was a strong clinical argument in favour of a causal link, in the absence of other clinical or biological changes.

To explain this side effect, we propose a more marked dobutamine uptake by the central nervous system, induced by two cumulative mechanisms secondary to renal failure: a decrease of dobutamine biotransformation and an increase of blood–brain barrier (BBB) permeability caused by P-glycoprotein (Pgp) inhibition. The principal dobutamine metabolic pathway is O-methylation by catechol-O-methyltransferase (COMT). An association between renal failure and impaired hepatic drug metabolism has been reported [2]. In uraemic patients, O-methylation could be altered by non-competitive erythrocyte COMT inhibition due to larger amounts of endogenous methyl acceptors in uraemic plasma than in normal plasma [3]. This mechanism could prolong dobutamine half-life.

Pgp activity has been shown to be reduced in rats with acute renal failure [4], together with a suppression of its brain function [5]. Pgp inhibition could be enhanced by furosemide [6], which was part of patients’ treatment. It is admitted at present that Pgp, which is expressed at the site of the blood–brain barrier, limits the entry of xenobiotics and prevents them from reaching toxicological concentrations. Therefore, Pgp inhibition could increase brain delivery of dobutamine.

Our hypothesis would explain a longer dobutamine half-life and a more marked penetration of the drug into the nervous system, ultimately responsible for myoclonia. As for other {alpha}1 adrenergic drug-like tricyclic antidepressants, stimulation of {alpha}1 post-synaptic adrenergic receptors leads in turn to an activation of serotoninergic neurons. This could induce myoclonia, when occurring at the cortical level. To our knowledge, dobutamine-induced myoclonia has not been reported before, despite the wide utilization of this drug, considering the well-known prevalence of congestive heart failure. Severe renal failure appears to be an obligatory associated condition to induce myoclonia. It is possible that in such patients the described side effect of dobutamine is likely to be underestimated or neglected because of other major signs and symptoms caused by severe cardiac failure.

Conflict of interest statement. None declared.

Laurence Wierre1, Bertrand Decaudin1, Joseph Barsumau2, Marie X. Vairon2, Sandrine Horrent1, Pascal Odou1,3 and Raymond Azar2

1Pharmacy Department 2Nephrology Department C.H. Dunkerque 3Biopharmacy and Clinical Pharmacy Department Faculty of Pharmaceutical and Biological Sciences Lille, France Email: RaymondAzar{at}netinfo.fr

References

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