Follow-up shows no adverse outcomes of CNEP in neonatesBMJ 2006; 332 doi: https://doi.org/10.1136/bmj.332.7544.745 (Published 30 March 2006) Cite this as: BMJ 2006;332:745
Long term follow-up shows no adverse outcomes of CNEP in neonates London Susan Mayor
Long term follow-up of a controversial trial of continuous negative extrathoracic pressure (CNEP) in newborn babies has shown no adverse outcomes, results published in the Lancet this week show (2006;367:1080-5). The trial had resulted in an inquiry and prolonged suspension of the lead investigators.
The original study, carried out in the early 1990s, randomised newborn infants with respiratory distress syndrome to continuous negative extrathoracic pressure (pressure applied to the child’s chest to help breathing) or standard treatment with supplemental oxygen or positive pressure ventilation, delivering pressurised air to the lungs. At the time, there was concern that positive pressure ventilation via an intratracheal tube might contribute to the high prevalence of chronic lung disease occurring in these children.
Initial results showed that babies given CNEP improved in overall composite illness score, which was the primary outcome of the study. They needed to be given oxygen for fewer days and developed less chronic lung disease than babies given conventional oxygen treatment. Mortality and the prevalence of abnormal brain scans increased non-significantly, however (Pediatrics 1996;98:1154-60).
When the results were published, some of the parents whose children had taken part in the study raised concerns, leading to severe criticism of the study by the media and a series of inquiries into the trial. Members of the research team, including David Southall, who was a consultant paediatrician at the North Staffordshire Hospital Centre, Stoke-on-Trent, were suspended after allegations about consent procedures—which were found to be without foundation in 2001 (BMJ 2001;323:885).
In an inquiry commissioned by the Department of Health and published in 2000, Rod Griffiths, who was regional director of public health at the University of Birmingham at the time, called for a review of research governance and long term follow-up of the neonates included in the study (BMJ 2000;320:1291).
Results from the recommended long term follow-up, which assessed 133 of the 205 survivors from the original trial assessed at 9-15 years of age, have shown no evidence of poorer outcome after neonatal CNEP. The primary outcome of death or severe disability was equally distributed between the two treatment options (odds ratio for the CNEP group 1.0; 95% confidence interval 0.4 to 2.4). Full IQ did not differ between the two groups, but mean performance IQ was 6.8 (1.5 to 12.1) points higher in the CNEP group than in the conventionally treated group. Results of neuropsychological testing were similar, with scores on language production and visuospatial skills were significantly higher in the CNEP group (Lancet 2006;367:1080-5).
In a commentary in the Lancet, David Southall and Martin Samuels, two of the researchers from the original trial—who both still work in the academic department of paediatrics at the University of Keele, North Staffordshire Hospital Centre, Stoke-on-Trent—welcomed the absence of harm in the long term neurodevelopment of the preterm infants treated with CNEP. They noted, however, "CNEP was discontinued in our hospital in November, 1999, just before we were suspended. As a result we fear that over the past six years many infants with bronchiolitis presenting to our children’s unit have received unnecessarily intensive care."
They added that the failure to develop CNEP equipment had meant that infants in developing countries, where intubation and intensive care is unavailable, might also have suffered.
Also commenting on the long term follow-up results, Professor Griffiths, now the president of the Faculty of Public Health, London, said, "We now know that despite what seemed to be an increase in issues related to brain damage when the original trial reported, the longer term study shows that CNEP might, if anything, be kinder on the brain. The paediatric community now has to decide whether CNEP has a place in the care of these babies or whether everything has moved on."
Professor Griffiths said that his inquiry had "tried to blame the system rather than individuals." In his commentary, he said that he considered that implementation of research governance could have avoided the suspensions and disciplinary hearings that took place at the time.
He added, "David Southall and his team have to be congratulated on having done a randomised trial when they did. Material became available after our report, which suggested that the design of the trial was better than we had been led to believe, and had it been made available to us we would have written some paragraphs differently, making less of some of the criticisms. The important thing, which we acknowledged in the report, was that the randomised design gave a good possibility of effective longer term follow-up, which has proved to be the case."
The case also impeded wider neonatal research, according to Professor Sir Alan Craft, who is president of science and research of the UK Royal College of Paediatrics and Child Health. In a further commentary in the Lancet, he and vice president Neil McIntosh, said that the public must be protected from maverick researchers.
"The inquiries into this case have shown . . . Southall and colleagues were not mavericks but careful and dedicated researchers. The development of the bureaucracy that surrounds research was underway at the time of, and accelerated by, the highly critical Griffith’s report.
"Several multicentre neonatal trials in progress around that time were delayed or unable to recruit enough patients to confirm or refute well designed research hypotheses. Public condemnation of Southall probably contributed to the failure of these studies."
Professors Craft and McIntosh continued, "Southall and his colleague Martin Samuels, were suspended for long periods, the former for more than two years. The pressure on them personally and on their families has been incalculable. We must protect patients, but we must also find better ways to protect professionals. If we do not, medical progress will cease, particularly in controversial and distressing areas." (See Personal View on bmj.com.)
Report of a Review of the Research Framework in North Staffordshire Hospital NHS Trust is available at www.dh.gov.uk.
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