DIGOXIN-INDUCED ARREST OF THE CEREBROSPINAL-FLUID CIRCULATION IN THE INFANT RAT - IMPLICATIONS FOR MEDICAL-TREATMENT OF HYDROCEPHALUS DURING EARLY POSTNATAL LIFE

Three human infants with hypertensive obstructive hydrocephalus were treated with oral doses of digoxin beginning on the 2nd, 7th, and 13th week of postnatal life, respectively. One infant received 0.015 mg/kg/day and two infants were given 0.010 mg/kg/day of digoxin. The drug failed to alleviate any clinical signs of elevated intracranial pressure. Groups of 10-day-old infant rats were acutely digitalized by sc administration of three successive doses of digoxin (3 mg/kg body wt) at 20-min intervals. In the first group electrocardiograms and electroencephalograms were monitored. Additionally, arterial blood pressure was monitored by means of an aortic catheter. The electroencephalographic and cardiovascular response differed from controls only by minor changes in the ECG wave-form (increased amplitude of the QRS and T-waves). In the second group the rate of bulk flow or cerebrospinal fluid (CSF) formation] was assessed by 5-min intrathecal infusion of14C-inulin, performed 20 min after the last injection of digoxin. Comparative values for inulin clearance from the CSF system (μl/min) of experimental and control animals were calculated from inulin concentrations in CSF at stated intervals of 15-22, 22-30, 30-45, and 45-60 min after the last dose of digoxin. Rates of CSF formation were depressed to about 50% of control levels at 15 min, reaching a state of complete arrest between 22 and 45 min, and followed by rapid recovery to resting levels at 60 min. In the third experimental group of digitalized infant rats, concentrations of 5- hydroxyindoleacetic acid (5-HIAA) in CSF and brain were assessed 80 min after the last injection of digoxin. Although no significant change in the amounts of 5-HIAA was found in brain tissue, the 5-HIAA concentrations in the CSF of digoxin-treated rats rose to values that were 140% greater than found in controls. An additional group of 10-day-old rats was killed 60 min after sc injection of probenecid, 250 mg/kg body wt. Probenecid, a drug which competitively inhibits carrier-mediated transport of 5-HIAA from both the brain and CSF system, increased both brain and CSF concentrations of 5-HIAA by 55 and 432%, respectively. Speculation: We speculate that, although digoxin, in doses not toxic to the cardiovascular system, can completely arrest fluid secretion by the choroid plexus of the rat, its duration of action is too brief, rendering it useless for the treatment of chronic hydrocephalus in man. We also speculate that, despite the presence of efficient transport mechanisms localized to the brain parenchyma as well as the choroid plexus, the circulation of CSF is necessary for efficient elimination of acid metabolites from the central nervous system. © 1979 International Pediatric Research Foundation, Inc.