Fludrocortisone for Cerebral Salt Wasting in Tuberculosis Meningitis Results in Earlier Serum Sodium Normalization

Usha K. Misra, DM, from the Department of Neurology at the Sanjay Gandhi Post Graduate Institute of Medical Sciences

Usha Misra, DM

The use of fludrocortisone in patients with tuberculosis meningitis to treat cerebral salt wasting may result in earlier serum sodium normalization compared to only saline.

New trial results from Usha K. Misra, DM, from the Department of Neurology at the Sanjay Gandhi Post Graduate Institute of Medical Sciences, in Lucknow, Uttar Pradesh, and colleagues, revealed that patients treated with fludrocortisone normalized their serum sodium levels in only 4 days—significantly quicker than saline alone, which took 15 days (P = .004).

Misra and colleagues noted that the administration of fludrocortisone in daily doses of 0.2 mg to 0.6 mg “has been attempted in the treatment of [cerebral salt wasting] in 6 studies of patients with stage II or III [tuberculosis meningitis] who were aged 6 months to 70 years. Overall, serum sodium levels improved in 0.5 to 10 days.”

Of the 36 patients included in the single-center, open-label trial, half (n = 18) were randomized to receive fludrocortisone with saline and oral salt supplementation and half were administered saline and oral salt supplementation alone. The median age of the patients included was 30 years (range, 20 to 46 years), and the median duration of illness was 61 days (range, 24 to 165). All patients received RHZE (rifampicin, isoniazid, pyrazinamide, and ethambutol), aspirin, and prednisolone.

The findings showed that serum sodium was normalized within 14 days in 83% (n = 15) of the patients in the fludrocortisone arm, compared to 39% (n = 7) of the patients in the control arm (P = .006). The median treatment duration of fludrocortisone was 7 days (range, 4 to 14). A single patient in the control arm received saline at a 3% concentration for the correction of severe hyponatremia (109 mEq/L) with convulsions.

Misra and peers also noted that the time to correction of hyponatremia “was longer in the control arm, with a hazard ratio of 4.18 (95% CI, 1.58 to 11.11; P = .004) on Cox proportional hazards regression analysis after adjusting age, stage of TBM, and severity of hyponatremia”

The secondary endpoints of in-hospital mortality and mortality at 3 months were also assessed, found to be not statistically different between the 2 treatment arms. In total, there were 4 (22%) in-hospital deaths in the fludrocortisone group and 3 (17%) in the control group (P >.99), while at 3-month follow-up, there were 6 (33%) and 4 (22%) deaths, respectively. Additionally, disability at both 3 months and 6 months were similar between groups.

Five (28%) patients developed stroke after fludrocortisone administration compared to 8 (44%) in the control group (P = .30). The number of infarctions in the internal border zone—all of which occurred in the polyuric phase—were lower in the fludrocortisone arm (1 patient; 6%) than the control arm (6 patients; 33%; P = .04).

In terms of adverse events, severe hypokalemia (<2.5 mEq/L) occurred in 2 patients in the fludrocortisone arm, which resulted in dose reduction in 1 patient and discontinuation in another. Overall, the incidence of hypokalemia (<3.5 mEq/L) was similar in both arms. Pulmonary edema occurred in a single patient in the fludrocortisone arm, and 2 patients experienced hypertension in the treatment group, though antihypertensive therapies were not required. The frequency of recurrent hyponatremia after the primary endpoint was lower in patients administered fludrocortisone (4 patients; 22%) compared to the control arm (7 patients; 39%; P = .28).

“In the present study, oral fludrocortisone resulted in earlier normalization of serum sodium compared with saline alone, but it neither ameliorated polyuria nor affected mortality or the development of disability,” Misra and colleagues wrote. “There was no difference in the frequency of stroke, but there were fewer deep border zone infarcts in the fludrocortisone arm. These results are in agreement with a randomized clinical trial in aneurysmal [subarachnoid hemorrhage].”

REFERENCE

Misra UK, Kalita J, Kumar M. Safety and Efficacy of Fludrocortisone in the Treatment of Cerebral Salt Wasting in Patients With Tuberculous Meningitis: A Randomized Clinical Trial. JAMA Neurol. epub August 13, 2018. doi:10.1001/jamaneurol.2018.2178