PRE-OPERATIVE CARBAMAZEPINE-INDUCED HYPONATRAEMIA: SHOULD WE ACCEPT A RESET HYPO-OSMOLAR BASELINE AND PROCEED WITH SURGERY?

Abstract

Editor, Hyponatraemia is an increasingly ubiquitous abnormality that whilst often reversible, is becoming a recognised pre-operative prognostic indicator. A known caveat of subclinical disease, hyponatraemia has been associated with perioperative coronary events, pneumonias and prolonged in-hospital stays, but has not yet been proven to be a causal determinant of mortality 1 . We present a 31-year-old Caucasian woman with community-acquired hyponatraemia, whose elective thymectomy for myasthenia gravis has been deferred in light of the perceived hazards of serum sodium less than 130mmol/L. Further analysis revealed an inability to dilute urine (Ur-Osmolality 561mOsm/kg) despite a serum hypo-osmolality (Sr-Osmolality 265mOsm/kg) and high urine sodium content (160mmol/L), classically in keeping with the syndrome of inappropriate secretion of anti-diuretic hormone. Physical examination was unremarkable, and the patient was clinically euvolaemic and asymptomatic throughout. She did however have a complex medical background that included a trans-osseous cerebral arterio-venous-malformation, epilepsy, gastro-oesophageal reflux and depression, as well as myasthenia gravis. Four Endocrinologists independently concluded on a diagnosis of drug-induced chronic hyponatraemia. Contributory medications included: Carbamazepine (Tegretol-PR 400mg BD), Omeprazole and Fluoxetine; and being seizure-free for many years, there was strong reluctance to stop Tegretol but Omeprazole and Fluoxetine were stopped. In-spite of this and diligent fluid restriction, her serum sodium remained static between 122-128mmol/L. At this point Demeclocycline (300mg BD) was tried, but was futile and served only to exacerbate symptoms of her myasthenia, a recognised side effect of Demeclocycline. Treatment was escalated to Tolvaptan (15mg twice-weekly). Although it had marginal impact on zenith sodium (129mmol/L) she noted excessive thirstiness and nausea as side effects. Tolvaptan was nonetheless persevered with. Biochemistry results and treatment timeline are listed in Table 1. Table 1 Biochemistry Results and Treatment Timeline. 2014 2015 2016 9-Dec* 9-Nov** 15-Apr*** 4-Jul Sr Na 131 127 122 129 Sr Osmo 275 265 Ur Na 188 160 Ur Osmu 601 561 * May 2015 Fluoxetine/Omeprazole Stopped ** Mar 2015 Demeclocycline Commenced *** Apr 2016 Tolvaptan Commenced The chronicity and refractory nature of her hyponatraemia led to the consensus of a reset hypothalamic osmostat to a lowered hypo-osmolar threshold, a recognised phenomenon, most likely due to prolonged use of Tegretol, and to ever achieve pre-operative serum sodium close to 135mmol/L would require significant volume losses. Carbamazepine was initially thought to only potentiate antidiuretic hormone (vasopressin) secretion from the posterior pituitary, but it has been shown to increase the sensitivity of the renal tubule to vasopressin as well, suggesting a duality in cause-effect 2 . To this effect, Carbamazepine has been used to treat polyuric patients with cranial diabetes insipidus specifically for its anti-diuretic properties 3 . However, a study by De Bragança et al revealed that Carbamazepine could itself exert an effect on the nephron, independent of vasopressin. Carbamazepine was found to directly stimulate the V2-vasopressin receptor and thus increase aquaporin-2 expression on the membrane of the collecting-ducts, allowing increased osmotic permeability and water absorption leading to a dilutional hyponatraemia 4 . Furthermore, they realised Carbamazepine could partially recover aquaporin-2 expression in Lithium-induced nephrogenic diabetes insipidus 4 (NDI), suggesting a possible novel treatment modality for Carbamazepine in NDI. Thymectomy can potentially benefit this patient. Whilst unable to forego Carbamazepine, her consequent hyponatraemia, and gradual resetting to a hypo-osmolar state, has become her baseline. Her hyponatraemia will necessitate closer perioperative surveillance, but acknowledging the mechanism for her hypo-osmolar reset should provide the confidence to proceed with surgery.