Usual Care and Informed Consent in Clinical Trials of Oxygen Management in Extremely Premature Infants

<div><p>Objective</p><p>The adequacy of informed consent in the Surfactant, Positive Pressure, and Pulse Oximetry Randomized Trial (SUPPORT) has been questioned. SUPPORT investigators and publishing editors, heads of government study funding agencies, and many ethicists have argued that informed consent was adequate because the two oxygen saturation target ranges studied fell within a range commonly recommended in guidelines. We sought to determine whether each oxygen target as studied in SUPPORT and four similar randomized controlled trials (RCTs) was consistent with usual care.</p><p>Design/Participants/Setting</p><p>PubMed, EMBASE, Web of Science, and Scopus were searched for English articles back to 1990 providing information on usual care oxygen management in extremely premature infants. Data were extracted on intended and achieved oxygen saturation levels as determined by pulse oximetry. Twenty-two SUPPORT consent forms were examined for statements about oxygen interventions.</p><p>Results</p><p>While the high oxygen saturation target range (91 to 95%) was consistent with usual care, the low range (85 to 89%) was not used outside of the SUPPORT trial according to surveys and clinical studies of usual care. During usual care, similar lower limits (< 88%) were universally paired with higher upper limits (≥ 92%) and providers skewed achieved oxygen saturations toward the upper-end of these intended ranges. Blinded targeting of a low narrow range resulted in significantly lower achieved oxygen saturations and a doubling of time spent below the lower limit of the intended range compared to usual care practices. The SUPPORT consent forms suggested that the low oxygen saturation arm was a widely practiced subset of usual care.</p><p>Conclusions</p><p>SUPPORT does not exemplify comparative effectiveness research studying practices or therapies in common use. Descriptions of major differences between the interventions studied and commonly practiced usual care, as well as potential risks associated with these differences, are essential elements of adequate informed consent.</p></div

Usual care oxygen supplementation practices in preterm infants obtained from surveys, randomized controlled trials and observational studies.

<p>Data on usual care SpO₂ target ranges used and patient or subject characteristics are displayed when available from surveys, randomized controlled trials and observational trials.</p

Excerpts from SUPPORT informed consent forms.

<p>^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0155005#t002fn001" target="_blank">*</a>} A selection of statements extracted from the 22 institutional review board-approved SUPPORT consent forms that characterized the oxygen management interventions are displayed in a tabular format. Institutions are blinded in this table.</p

Usual care median achieved SpO₂ values in 14 care centers for preterm infants receiving oxygen therapy compared to low and high SpO₂ arms in COT and BOOST II.

<p>Panel A compares the median achieved SpO₂ values, and interquartile range, of each of these 14 usual care NICUs with the intended SpO₂ range established in the same NICUs (represented by dark grey vertical bars). Panel B compares median achieved SpO₂ values, and interquartile range, from these 14 NICUs to the target ranges of the low (lower grey-shaded area) and high (upper grey-shaded area) SpO₂ arms of the SUPPORT, BOOST II and COT trials. In panel C median achieved SpO₂ values are plotted in 7 low and 7 high SpO₂ arms during the BOOST II and COT trials, as well as in the 14 NICUs included in the AVIOx study; the latter are separated into 9 centers using a lower limit of the intended SpO₂ target range at or below 88% and 5 centers using a lower limit of the intended target SpO₂ range ≥90%. This separation was done to compare usual care to the clinical trial arms with comparable lower limits of the intended target SpO₂ ranges. For each of four compared groups, the median (thick horizontal line) and the mean (thin horizontal line) of the achieved SpO₂ values are plotted. The number of study arms is 7 for each target range because in three trials (BOOST II Australia and U.K. and COT) the data were provided separately from before and after recalibration of the Masimo pulse oximeters.</p

Usual care oxygen saturation (SpO₂) target ranges in 14 centers for preterm infants (24 to 27 weeks) compared to low and high SpO₂ target ranges in SUPPORT, COT and BOOST II.

<p>In panel A, the usual care SpO₂ intended target ranges from 14 neonatal intensive care units (NICUs) in the AVIOx study are plotted (dark grey vertical bars). On the X-axis, letters randomly assigned to each of the 14 NICUs in the AVIOx study are provided. NICUs are ordered on the x-axis from the lowest to the highest lower limit of the target range employed. The bar for all centers/patients combined delineates the medians of the upper limits and lower limits of the 14 ranges. The light grey-shaded area represents the low target range studied in the five clinical trials. Panel B shows the relationship of the lower limit of the target ranges (X-axis) to their total width or size (Y-axis) for the individual usual care neonatal intensive care units (NICUs) of the AVIOx study (open circles) and for the low (light grey triangle) and high (dark grey square) SpO2 target range arms of the clinical trials. Panel C shows the relationship of the lower limit (X-axis) to the upper limit (Y-axis) of the same target ranges. The ellipse represents the 95% prediction region for this relationship in the 14 usual care NICUs (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0155005#sec006" target="_blank">METHODS</a>).</p

Percentage of time spent below an oxygen saturation (SpO₂) value of 85%, and below the intended SpO₂ range.

<p>The mean ± SE of the percentage of time spent below a true SpO₂ value of 85% for 7 low SpO₂ arms from the BOOST II and COT trials (light grey bar) is plotted <i>versus</i> the time spent below 85% for 7 high SpO₂ arms from the same trials (dark grey bar) <i>versus</i> the time spent below the lower limit of the intended range for the nine usual care neonatal intensive care units from the AVIOx study that had with comparable lower limits of the intended range (median lower limit of 88%; white bar). The number of low and high SpO₂ arms is 7 because in three trials (BOOST II Australia and U.K. and COT), the data were provided separately for before and after recalibration of the Masimo pulse oximeters.</p