American Journal of Respiratory and Critical Care Medicine

Awareness of the relevance of early life events to lung health in adults, and the need to identify and treat lung disease before changes become irreversible in children with chronic respiratory conditions such as cystic fibrosis (CF), has led to a resurgence of interest in infant respiratory physiology. Following recommendations from the ATS/ERS Task Force on infant pulmonary function testing (IPFT) (1), commercially available equipment has been developed. While potentially facilitating the use of IPFTs as outcome measures in studies such as that described in the current issue of the Journal (2) (pp. 1387–1397), this increased availability presents challenges as to how and when such tests should be used.

The study by Davis and coworkers addresses several significant issues relating to the future use of IPFT as objective outcome measures in multicenter clinical trials of young children with CF, including feasibility, repeatability and required sample size (2). One hundred infants with CF, recruited from 10 centers across the United States, were studied on up to four occasions, with repeated measures after 1 month in a subset. Significant decrements in pulmonary function were observed in infants with CF when compared with historical control subjects. Changes were most marked for plethysmographic lung volumes, whereas, in contrast to previous reports (3, 4), forced expiratory flow-volume (FEFV) outcomes from the Raised Volume Technique discriminated poorly. Based on acceptability rates, variability, and the potentially large sample sizes required to detect reasonable treatment effects, the authors concluded that IPFT do not yet appear ready to be used as primary efficacy endpoints for multicenter clinical trials, particularly at inexperienced sites.

This was a large and important study that was generally well conceived and executed by a group of leaders in CF care and IPFT. The authors are to be congratulated on the rigorous training and quality control applied across centers. However, interpretation of their findings is hampered by one major flaw in the study design: the lack of a prospective control group. The inability to recruit control subjects was attributed to failure by the relevant Institutional Research Boards (IRB) to give permission to sedate healthy infants, on the grounds that sedation represents “more than minimal risk and that the research would be of no benefit to a healthy child.”

Opinion on the ethics of children participating in clinical research continues to evolve (511). The former view that only research that is of therapeutic benefit to the infant is acceptable has been replaced by an acknowledgment of the importance of noninterventional studies and the benefits they bring to infant health and well being, a position that shifts the debate to considerations around “benefit” and “harm,” and the quantification of “negligible” and “minimal” risk. Clinical trials are held to be the gold-standard approach to defining the therapeutic evidence base, yet in a randomized trial, where the aim is to demonstrate one treatment to be superior to another, one randomized group will de facto receive less or even no therapeutic benefit.

Should healthy children be sedated for research reasons? The minimal risk of occasional oral sedation in healthy infants in the doses administered for IPFT is evidenced by the thousands of healthy babies that have participated in such studies without adverse effect, apart from occasional emesis or short-lived disturbance of sleep (12). Indeed, during the past 5 years, at least 36 publications from three continents, including two centers in the USA, have reported IPFT results from healthy sedated infants.

The risk of adverse effects from sedation rises in those born preterm (13) or with respiratory problems, in whom special precautions have always been advocated (14). Before infants with respiratory disease are recruited into clinical research studies, it is imperative that the study design is sound, conclusions will be robust, and the benefits, whether on a population or individual basis, will be tangible. Unfortunately, this has not always been the case where IPFTs are involved. Lack of prospective control subjects or appropriate reference data with which to distinguish the effects of growth and development from those of disease (15) have limited interpretation of at least 50% of studies published in this field over the past 5 years. Poor study design, inappropriate methods, equipment and quality control, insufficient sample size and lack of knowledge about within-subject repeatability, within- and between-tests (without which it is impossible to interpret the effects of any intervention), have also limited the usefulness of many studies.

When faced with the decision of the IRB, Davis and colleagues may have decided that they could rely on the reference equations they selected (16, 17), since they had personally been instrumental in developing these. However, the equations used to interpret plethysmographic lung volumes were only based on 22 children studied on 35 occasions, whereas at least 300 subjects may be required to avoid bias and estimate between-subject variability reliably (18). Reference equations for FEFV parameters were based on a much bigger sample size (17), but, as for plethysmography, were derived from children studied using equipment developed “in-house” rather than the commercially available device used in the actual study. Using a different commercial device can lead to serious misinterpretations (19).

By providing an honest and critical appraisal of the limitations of their study, Davis and coworkers have made an important contribution to the field of IPFT. Their data will hopefully help fuel discussions as to how best to address these issues. It is reassuring that the Canadian Healthy Infant Longitudinal Development Study will undertake serial PFTs using the same device in around 750 normal infants over the next few years, though difficult to understand why such a study is considered ethical in Canada, but not across the border. Once available, these normative data may facilitate more meaningful interpretation of the current multicenter study, but will not be able to address issues of inter-center differences, nor substitute for the current need to study healthy infants in all centers that intend undertaking IPFT for research or clinical purposes. As demonstrated in this study by Davis and colleagues, the complexities and subtleties of IPFT are such that, even with thorough training and ongoing supervision, equipment cannot simply be placed in inexperienced laboratories with the expectation that reliable results will be forthcoming.

Anyone who has recruited to infant studies knows that considerable time is required to explain the study. Nevertheless, in our experience, parents that consent generally find the experience interesting and rewarding and frequently return to participate in longitudinal studies that stretch well beyond infancy (19, 20). The wealth of knowledge that now exists regarding the early determinants of lung function, origins of adult lung disease, and impact of CF, prematurity, and wheezing disorders on the developing lung would not have been possible without studies in healthy infants. Unless such studies continue, both the research and clinical utility of IPFT will be severely curtailed. We suggest that IRBs ask the following questions when considering the sedation of healthy infants for IPFT research. Have alternative approaches been considered? Is the study design sound? Will the study improve clinical care? Are the investigators competent? Are the facilities suitable for infants? Have parents been fully informed? If the answers are all in the affirmative, surely the opportunity to improve the care of infants with lung disease should be welcomed?

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