PANCURONIUM AND PNEUMOTHORAX

286 agree that well over 100 babies would be needed to evaluate the possibility of a preventiveI effect on PVH considerably smaller than that found by Donn et al. Dr Kuban and Dr Leviton go on to claim that we did not consider whether the phenobarbitone groups was more ill and therefore more susceptible to PVH. Although 12 of the phenobarbitone group had 1 min Apgar scores of less than 3 (as against 9 in the placebo group) 5 of the placebo group had an Apgar score of below 7 at 5 min (as against 3 in the phenobarbitone group). When the 1 min and 5 min Apgar scores are considered together there is no overall difference between the two groups, nor is there for gestational age, birthweight, sex, respiratory failure before the injection, pneumothorax, hypercapnia, acidosis, and vaginal delivery. Thus the randomization produced very even matching. We cannot conclude that the increase in ventilator dependency after phenobarbitone injection was explained by differences in Apgar scores or pulmonary disease. We affirm that 20 mg/kg of phenobarbitone may have an adverse effect on spontaneously breathing, very-low-birthweight infants, and we await with interest the results of further studies of phenobarbitone in ventilated

truly

National Perinatal Epidemiology Unit, Radcliffe Infirmary, Oxford OX2 6HE

infants. Department of

Paediatrics and Neonatal Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London W12 0HS

ANDREW WHITELAW LILLY DUBOWITZ MALCOLM LEVENE

SiR.—Dr Whitelaw and colleagues’ is the latest of four trials2-5

to

the role of phenobarbitone in preventing intraventricular and cases are being recruited for at least two other trials. In view of the small size of the published trials, it is not surprising that investigators have come to different conclusions about the value of phenobarbitone. There are two important consequences of small trials. Firstly, real and clinically significant differences between treatments may be incorrectly dismissed because they fail to achieve statistical significance. Secondly, if statistically significant differences are observed, these will tend to overestimate the true differences. Whitelaw et al make the important observation that in all four trials there have been fewer parenchymal haemorrhages among phenobarbitone-treated infants than among controls (table). The summary relative risk (0 - 36) of parenchymal haemorrhage in babies 6 given phenobarbitone, calculated by the Mantel-Haenszel method on data from all four trials, suggests that the incidence of this most serious form of periventricular haemorrhage may be substantially reduced by prophylactic phenobarbitone. As Whitelaw and his colleagues have observed, however, this difference does not achieve conventional levels of significance (p 0 - 07; 95% confidence limits relative risk x 0-12 -1 - 09). We hope that this analysis may serve as a reminder of the dangers of false inference from both non-randomised comparisonsand small randomised trials. Many trials in the perinatal period require sample sizes larger than any single unit can generate within a reasonable length of time. A recognition of this reality, combined with the impact of Whitelaw’s diplomacy, has resulted in more than assess

haemorrhage,

=

1. Donn

dozen neonatal units joining together to enter cases into the first collaborative trial of neonatal practice ever to have been mounted in Britain. The objective of this is to assess alternative ways of managing post-haemorrhagic ventricular dilatation-but there is no reason why it could not provide a framework for collaboration to address other clinically important questions. A high priority among these must surely be to assess whether phenobarbitone or other drugs9,10 can reduce the incidence of parenchymal haemorrhage in very low birthweight infants. a

S, Roloff D, Goldstein G. Prevention of intraventricular haemorrhage in preterm infants by phenobarbitone. Lancet 1981; ii: 215-17. 2. Goldstein G, Donn S, Roloff D. Further observations on the use of phenobarbital to prevent neonatal intracranial hemorrhage. In: 2nd Special Ross Conference in Perinatal Intracranial Hemorrhage (Washington, DC). Columbus, Ohio: Ross Laboratories, 1982: 810-15. 3. Cooke RWI, Morgan MEM, Massey RF. Phenobarbitone to prevent intraventricular haemorrhage. Lancet 1981; ii: 414-15. 4. Bedard M, Shankaran S, Slovis T, Pantoja A, Dayal B, Poland R. Decreased severity of periventricular haemorrhage following phenobarbital treatment. In: 2nd Special Ross Conference in Perinatal Intracranial Hemorrhage (Washington, DC). Columbus, Ohio: Ross Laboratories, 1982: 1051-64 5 Whitelaw A, Placzek M, Dubowitz L, Lary S, Levene M Phenobarbitone for prevention of periventricular haemorrhage in very low birth weight infants: A randomised double-blind trial. Lancet 1983; ii: 1168-70. 6. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 710-48. 7. Miettinen O. Estimability and estimation in case-referent studies. Am J Epidemiol 1976; 103: 226-35. 8 Hope PL, Stewart AL, Thornburn RJ, Whitehead MD, Reynolds EOR, Lowe D. Failure of phenobarbitone to prevent intraventricular haemorrhage in small preterm infants. Lancet 1982; i. 444-45.

IAIN CHALMERS DIANA ELBOURNE ADRIAN GRANT

PANCURONIUM AND PNEUMOTHORAX and colleagues (Jan 7, p 1) report a highly in the incidence of pneumothorax in ventilated babies treated with pancuronium and in whom a specific respiratory pattern had been identified. Encouraged by a preliminary report of their work, but unable to do the respiratory function tests Greenough et al employed, we used early pancuronium paralysis selectively in ventilated infants of less than 32 weeks’ gestation who struggled against the ventilator or who required peak airway pressures of more than 20 cm water or ventilation rates above 30/min. On these criteria, 50% of our series of infants were paralysed, compared with 40% in the Cambridge study. We compared the results of the first 6 months (July to December, 1983) of this new "policy" with those of the two preceding 6 month periods when pancuronium was used only when other methods had failed to produce adequate gas exchange. Infants of 26 weeks’ gestation and less are considered separately from those of 27-32 weeks’ gestation (table). In the smallest infants no significant change was seen in frequency of pneumothorax, survival, or intraventricular haemorrhage (IVH) after the introduction of the new policy. In the larger infants the frequency of pneumothorax fell significantly, and there was a reduction (not significant) in mortality. Disappointingly, there was no change in the incidence of IVH. There seems to be an association between IVH and previous pneumothorax, and mechanisms linking the two directly have been suggested. 1-3 Prevention of pneumothorax would seem a practical way of reducing perinatal brain damage and death. Perhaps these studies are too small to show such an effect. IVH is multifactorial in origin, and pneumothorax may be the preceding factor in only 16% of cases in very-low-birthweight infants.4Alternatively, factors such as hypercapnia and acidosis rather than the pneumothorax itself may be more important in the with IVH than aetiology of IVH. Both are more strongly associated 4 pneumothorax when treated as single variables.4

SIR,-Dr Greenough significant reduction

9

Morgan MEI, Benson JWI, Cooke RWI. Ethamsylate reduces the incidence of periventricular haemorrhage in very low birth weight babies. Lancet 1981; ii 830-31. .

10. Chiswick ML, Johnson M, Woodhall C, Gowland M, Davies J, Toner N, Sims D. Protective effect of vitamin E (DL-alpha-tocopherol) against intraventricular haemorrhage in premature babies. Br Med J 1983; 287: 81-84. 1. Lipscomb AP, Thorburn RJ, Reynolds EOR, et al Pneumothorax and cerebral haemorrhage in preterm infants. Lancet 1981; i: 414-16. 2 Dykes FD, Layara A, Ahmann P, Blumenstein B, Schwartz J, Brann AW. Intraventricular hemorrhage: a prospective evaluation of etiopathogenesis. Pediatrics 1980; 66: 42-49 3. Hill A, Perlmann JM, Volpe JJ. Relationship of pneumothorax to occurrence of intraventricular hemorrhage in the premature newborn. Pediatrics 1982; 69: 144-49. 4. Cooke RWI, Morgan MEI. Precipitants of neonatal periventricular hemorrhage. Variability with postnatal age In: Proceedings of 2nd Perinatal Intracranial Hemorrhage Conference, 1982. Columbus, Ohio: Ross Laboratories (in press).

287 OUTCOME OF SELECTIVE PANCURONIUM POLICY

(JULY TO DECEMBER, 1983) AND LAST-RESORT USE

*=5’3(p<0’05

when

compared with either preceding 6 month period).

Even if pancuronium does not prevent IVH secondary to pneumothorax, the prevention of pneumothorax in the sick preterm baby is invaluable. The technique for indentifying expiration against the ventilator described by Greenough et al may not be easy in a busy neonatal unit without a trained technician or research fellow to practise it. We have noted that the transthoracic impedance respirogram that is displayed on most monitors can give objective information about asynchrony of respiration. Perhaps such information could be used to identify the at-risk subgroup to be treated with pancuronium. Regional Neonatal Intensive Care Unit, Department of Child Health, Liverpool Maternity Hospital, Liverpool L77BN

. Placebo it

p <

0

0.05

L 0 05% Bromocriptine 0 025% b.-omocriptine ** p < 0 01 compared with placebo

Percentage change Values

are

means

comparison with

in IOP.

and SEM. Paired two-tailed

t

tests were

used for

placebo. PROLACTIN LEVELS

R. W. I. COOKE

J. M. RENNIE

SIR,-Dr Greenough and her colleagues correctly ascribe pneumothorax to the baby’s fighting the ventilator, but they are wrong about the mechanism. Any sac will rupture when distended beyond its elastic limit. The transpulmonary pressure (the difference between ventilator and oesophageal pressure) determines the volume of the lungs, depending on their compliance. When the maximum safe volume (or elastic limit) is exceeded, something must rupture. This may happen when the baby’s spontaneous inspiratory effort coincides with ventilator inflation, as indicated on Greenough’s graph by a positive ventilator pressure and a negative oesophageal pressure, resulting in a high inspiratory flow rate, followed immediately by a peak lung volume. Four such peaks occur in their graph; fortunately, in none do peak inflation neonatal

pressure and peak negative oesophageal pressure perfectly coincide. Instead of paralysing inspiratory muscles with curare, one may restrict movement with a tight binder or with weights over the chest and abdomen1 as a method of circulatory assistance. Paralysis with curare lowers the intra-abdominal pressure that is largely responsible for maintaining the flow of portal blood through the liver-more precisely, it is the transdiaphragmatic pressure differential that aids portal blood flow. Thus curare may cause pooling of venous blood in the abdominal viscera, by paralysing the diaphragm muscle. 8552 Canton Center

Road,

Canton, Michigan 48187, USA

SAM I. LERMAN

balanced design. In the second study, six volunteers received either 0 -025% or 0 -05% bromocriptine or placebo eyedrops. The placebo was vehicle only (thiomersal, polyvinylpyrrolidone, methanesulphonic acid 10%, and sodium chloride). In both studies, pupil diameter, IOP, and plasma prolactin concentrations were measured before and 1, 2, 3, and 4 h after instillation of one eyedrop into the left eye only. IOP was measured by non-contact tonometry,3pupil diameter by a pupil gauge4and prolactin by radioimmunoassay. Data were analysed by analysis of covariance with the pretreatment value as the covariate, and by pairedt tests at each time point. Bromocriptine 0 - 0 1 07o drops caused a small reduction in IOP in the left eye, but this was not significant. Bromocriptine 0 -025% and 005% drops reduced IOP in the left eye (p<0 - 01) without affecting pupil diameter or prolactin concentrations (see figure and table). The drops were well tolerated, except in one man who had moderate conjunctival injection lasting 2 days after the 0 025% drops and 4 days after placebo eyedrops; this man did not receive 005% drops and was excluded from further study. In the other subjects the investigator noted conjunctival injection up to 2 h after all treatments, but this caused no discomfort. The reduction in IOP by bromocriptine eyedrops was similar to that seen after oral administration.2 The effect cannot be caused by systemic absorption of the drug since IOP in the contralateral eye in this was not significantly reduced, although there was a direction after the 0 . 02501o drops. Potter and Burke showed that bromocriptine 0. 1% eyedrops lower IOP in the contralateral eye after topical administration in rabbits. We do not know how bromocriptine reduces IOP. This drug may have alpha-adrenoceptor antagonist actionsand may inhibit

trend

BROMOCRIPTINE EYEDROPS LOWER INTRAOCULAR PRESSURE WITHOUT AFFECTING PROLACTIN LEVELS

SIR,-Bromocriptine 1. 25 morally lowers intraocular pressure (IOP) in healthy volunteers. We now report the effect of bromocriptine eyedrops on IOP, pupil diameter, and prolactin concentrations in healthy volunteers. Nine healthy men aged 20-32 consented to participate in one or both studies. In the first study, six volunteers attended at the same time of day on two occasions at least one week apart; they received either 0’ 01% bromocriptine or placebo eyedrops in a double-blind, 1.

Summer W Cardiac augmentation by phasic high intrathoracic pressure. Chest 1983; 84: 371-75 2. Mekki QA, Hassan SM, Turner P. Bromocriptine lowers intraocular pressure without affecting blood pressure in man Lancet 1983; i: 1250-51.

Pinsky M,

3. Grolman B. A new tonometer system. Am J Optometry 1972; 49: 646-50. 4. Cogan DG. Simplified entopic pupillometer. Am J Ophthalmol 1941; 24: 1431-33. 5. Potter DE, Burke JA. Effects of ergoline derivatives on intraocular pressure and iris function in rabbits and monkeys. Curr Eye Res 1983; 2: 281-88. 6. Montastruc JL, Montastruc P. Alpha-adrenolytic properties of bromocriptine in dogs. 7.

Arch Int Pharmacodyn 1982; 260: 83-90. Ziegler MG, Lake CR, Williams AC, Teychenne PF, Shoulson I, Steinsland O. Bromocriptine inhibits norepinephrine release. Clin Pharmacol Ther 1979; 25:

137-42. 8. Potter DE. Adrenergic pharmacology of aqueous humour dynamics. Pharmacol Rev 1981; 33: 133-53. 9 Niederer W, Richardson BP, Donatsch P. Hormonal control of aqueous humour production. Exp Eye Res 1975; 20: 329-40.