Elsevier

The Lancet

Volume 352, Issue 9126, 8 August 1998, Pages 433-440
The Lancet

Articles
International randomised controlled trial of acetazolamide and furosemide in posthaemorrhagic ventricular dilatation in infancy

https://doi.org/10.1016/S0140-6736(97)12390-XGet rights and content

Summary

Background

Furosemide and acetazolamide are widely used in the treatment of posthaemorrhagic ventricular dilatation (PHVD) in the hope of avoiding the need for surgical management, but this approach has not been evaluated in a controlled trial. This multicentre randomised controlled trial tested the hypothesis that these drugs would reduce the rate of shunt placement and increase disability-free survival at 1 year of age.

Methods

Between 1992 and 1996, 177 infants aged less than 3 months past term, and with ventricular width more than 4 mm above 97th centile after intraventricular haemorrhage, were randomly assigned standard therapy alone or standard therapy plus treatment with acetazolamide (100 mg/kg daily) and furosemide (1 mg/kg daily). A minimisation algorithm ensured balance between groups with respect to both referral centre and the presence of a cerebral parenchymal lesion on cerebral ultrasonography at enrolment. The trial was stopped in September, 1996, because the data showed a clear advantage with standard therapy.

Findings

We report outcomes for 151 infants whose expected date of delivery was before the end of 1995, with complete information at 1 year for 129 infants. The median gestational age was 28 weeks, mean birthweight 1299 g, and mean postnatal age at enrolment 25 days. 44% had a parenchymal lesion at randomisation. Death or shunt placement occurred in 49 of 75 infants allocated drugs plus standard therapy, compared with 35 of 76 allocated to standard therapy alone. The relative risk was 1·42 (95% CI 1·06–1·90; p=0·026), which is equivalent to one extra death or shunt placement for every five infants allocated drug therapy. 84% (52/62) of infants assigned drug therapy had died or were disabled or impaired at 1 year, compared with 60% (40/67) of those assigned standard therapy (relative risk 1·40 [1·12–1·76]; p=0·012).

Interpretation

These preliminary results suggest that the use of acetazolamide and furosemide in preterm infants with PHVD is associated with a higher rate of shunt placement and increased neurological morbidity, and so cannot be recommended.

Introduction

Posthaemorrhagic ventricular dilatation (PHVD) affects 17 in 1000 infants born at less than 32 weeks of gestation1 and has a poor neurodevelopmental prognosis.1, 2, 3, 4, 5, 6 Outcome may be affected in two ways—either by the cerebral parenchymal injury that may occur in association with the haemorrhage, or by secondary damage caused by hydrocephalus and its treatment. Mild PHVD resolves with conservative management in most cases.7 In the UK, moderate to severe PHVD is usually managed at first by intermittent removal of cerebrospinal fluid (by ventricular taps with or without a reservoir, or by lumbar puncture). Controlled trials, however, have been unable to demonstrate any benefit of this treatment.6, 8, 9 In particular a large multicentre randomised study showed that early removal of cerebrospinal fluid in PHVD did not reduce the need for subsequent shunt placement, and was associated with a higher incidence of infections of the central nervous system.6 At the follow-up examinations at 1 year and 2·5 years, 85% of survivors had abnormal neuromotor signs and 73% were disabled, irrespective of treatment allocation.6, 10

Ventriculoperitoneal shunting is an effective treatment if conservative management fails to halt the progression of PHVD. It is, however, fraught with complications, particularly in small infants with disorders affecting many systems, reduced immunity, and high concentrations of protein in cerebrospinal fluid, and carries lifelong risks associated with late infection or shunt failure.11 Third ventriculostomy has lately become available; however, it is not effective in many cases of communicating hydrocephalus arising at the level of the arachnoid villi, which commonly occurs in PHVD.12

Non-surgical methods for reducing cerebrospinal fluid pressure have obvious advantages in avoiding the risks of invasive procedures. Drug therapy with diuretics has been used for many years.13, 14, 15, 16 Osmotic diuretics such as isosorbide and glycerol have limited efficacy and may cause dehydration,14, 17, 18 whereas diuretics that reduce the formation of cerebrospinal fluid, such as acetazolamide and furosemide, are less dehydrating, have been used for over 30 years,13, 15, 16, 17 and are a widely accepted treatment.11, 12 One uncontrolled study of a group of infants with hydrocephalus of various causes suggested that treatment with acetazolamide and furosemide in combination led to a near 50% reduction in the need for shunt insertion.16 Side-effects of treatment with these drugs include acidosis, carbon dioxide retention, poor feeding, electrolyte disturbance, osteopenia, nephrocalcinosis, diarrhoea, and vomiting. In view of these side-effects and uncertain effectiveness, we report here the results of an international multicentre randomised controlled trial to examine the effect of treatment with acetazolamide and furosemide on survival, shunt placement, and neurodevelopmental outcome.

Section snippets

Trial organisation

The trial was overseen by a multidisciplinary steering group. The coordinating centre was in Southampton, UK, and additional data management and analysis were undertaken at the National Perinatal Epidemiology Unit in Oxford. An independent data-monitoring committee was established to review accumulating data. The terms of reference of the committee stated that interim results should not be revealed to the steering group, except where there was a strong reason to stop the trial, such as a

Participating infants

177 infants from 55 centres worldwide were enrolled in the trial (89 allocated standard and 88 allocated drug plus standard treatment; figure 1). This report describes the characteristics at trial entry of all 177 infants and the outcome between trial entry and the age of 1 year, corrected for prematurity, of the 151 infants whose expected date of delivery was earlier than Dec 31, 1995. Status at first hospital discharge is known in 147 (97%), the primary outcome of death or shunt placement at

Discussion

Shunt placement might seem the most direct measure of effectiveness of treatment of ventricular dilatation but an excess of deaths before shunt placement in one treatment group would conceal an adverse effect of allocation to that group if outcome was defined in this way. We therefore chose shunt placement, death, or both, as the primary outcome measure. Allocation to acetazolamide and furosemide therapy of PHVD in this trial was associated with an increased risk of death or shunt placement,

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