Thiazide-induced hyponatremia associated with death or neurologic damage in outpatients

Seven elderly patients were encountered who had been taking thiazides or thiazide-like diuretics (hydrochlorothiazide, polythiazide or metolazone) for less than 16 days and who presented with severe symptomatic hyponatremia (serum SODIUM = 105 ± 6 meq/liter). In five patients, urine sodium + potassium was 156 meq/liter whereas that in serum was 108 meq/liter (P < 0.01). All patients had central nervous manifestations of hyponatremia (seizures, stupor, coma, extensor plantar response) and all but one were treated with 3 percent sodium chloride to raise the serum sodium level above 130 meq/liter within 44 hours. Three patients died, two had permanent paralysis, and two recovered. Other causes of the neurologic dysfunction were ruled out by negative lumbar punctures, brain scan and computerized axial tomography (CAT) scan. In all, serum creatinine was below 1.1 mg/dl.

The patients who recovered were studied. In two patients, the administration of oral metolazone (10 mg/day for two days) or hydrochlorothiazide (100 mg/day for two days) with ad libitum water intake resulted in decrements in serum sodium of 13 to 18 meq/liter in 36 hours. In both, serum sodium levels fell below 125 meq/liter with resultant symptoms. In one patient, the response to a standard oral water loading test was studied before and after 10 mg of metolazone administration. After metolazone therapy, the percent excretion of a standard oral water load in 4 hours fell from 65 percent to 15 percent, minimal urine osmolality, which had been 130 to 371 mosmol/kg, increased to 371 mosmol/kg, free water clearance fell from 2.25 to −0.25 ml/min and urine sodium excretion increased from 62 to 159 μeq/min. Plasma antidiuretic hormone (ADH) levels were undetectable before and after the administration of metolazone but rose after overnight dehydration. Thus, metolazone resulted in impaired ability to dilute the urine and excrete a water load, with 256 percent increase in urine sodium loss. Therefore, in a susceptible subgroup of outpatients, thiazides may rapidly induce severe hyponatremia with permanent neurologic damage or death.