Randomized, controlled trial of acetazolamide and furosemide in posthemorrhagic ventricular dilation in infancy: follow-up at 1 year.
OBJECTIVE
Posthemorrhagic ventricular dilation (PHVD) is a complication of intraventricular hemorrhage in preterm infants and is associated with a high risk of long-term disability. Furosemide and acetazolamide are used widely in the treatment of PHVD in the hope of avoiding the need for placement of a ventriculoperitoneal shunt, but these drugs have not been evaluated in a controlled trial. This article reports a multicenter, randomized, controlled trial designed to test the hypothesis that these drugs would reduce the rate of shunt placement (or death) and increase survival to 1 year of age without disability.


METHODS
Between 1992 and 1996, 177 infants who were less than 3 months past term and had ventricular width >4 mm above the 97th centile following intraventricular hemorrhage were assigned randomly to either standard therapy or standard therapy plus drug therapy with acetazolamide (100 mg/kg/d) plus furosemide (1 mg/kg/d). Infants who were enrolled in the trial had a median gestational age of 28.6 weeks and were enrolled at a mean postnatal age of 3.6 weeks. Forty-four percent were reported to have a cerebral parenchymal lesion on ultrasound scan at randomization. The primary outcome measure of death or shunt placement (known in all but 1 infant) occurred in 56 of 88 infants who were allocated to drug plus standard therapy compared with 46 of 88 who were allocated to standard therapy. The risk ratio was 1.23 (95% confidence interval: 0.95-1.59). Neurodevelopmental outcome information at a corrected age of 1 year (known in all but 3 of 149 surviving infants) included disability or neuromotor impairment in 54 of 67 infants (81%) who were allocated to drug plus standard therapy and 52 of 69 infants (66%) who were allocated to standard therapy. Seventy-two of 85 infants (85%) who were allocated to drug therapy either died or were disabled or impaired at 1 year compared with 62 of 89 infants (70%) who were treated with standard therapy (risk ratio: 1.22; 95% confidence interval: 1.03-1.4376). The excess risk of these adverse outcomes was greater among infants who did not have a cerebral parenchymal lesion seen on ultrasound examination at trial entry.


CONCLUSIONS
These results suggest that the use of acetazolamide and furosemide in preterm infants with PHVD is ineffective in decreasing the rate of shunt placement and is associated with increased neurologic morbidity. This treatment therefore cannot be recommended.
Kennedy
C R
CR
Department of Pediatric Neurology, Southampton General Hospital, Southampton, England. crk1@soton.ac.uk
Ayers
S
S
Campbell
M J
MJ
Elbourne
D
D
Hope
P
P
Johnson
A
A
D000086:Acetazolamide / Q000009:adverse effects / Q000627:therapeutic use*; D002508:Cephalometry; D002543:Cerebral Hemorrhage / Q000150:complications*; D002557:Cerebrospinal Fluid Shunts; D004232:Diuretics / Q000009:adverse effects / Q000627:therapeutic use; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D005665:Furosemide / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D006849:Hydrocephalus / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000601:surgery; D007223:Infant; D016015:Logistic Models; D018570:Risk Assessment; D015996:Survival Rate; D016896:Treatment Outcome; D014463:Ultrasonography
D004232:Diuretics; D005665:Furosemide; D000086:Acetazolamide