Discussion
We conducted a multicentre pragmatic cross-over study to evaluate the performance of the PRICO A-FiO2 system. We found that this A-FiO2 system markedly increased time in normoxaemia which was mainly driven by a reduction in time spent in hyperoxaemia.
The difference in the mean time in the target range (23% (95% CI 16% to 30%)) is slightly higher than reported in two systematic reviews which included 14 studies investigating eight different A-FiO2 systems.9 10 The subgroup meta-analysis in one review, including only those studies using a target range of 90%–95% as we used, showed a difference of 18% (95% CI 5% to 32%).9 Our finding is within these confidence limits. In addition to differences in the A-FiO2 algorithms, the larger treatment effect might be related to manual oxygen titration practices, staffing levels and inclusion of bigger infants.
To date, three other studies have investigated the efficacy of the PRICO system in infants. These studies12 13 17 reported a median improvement of the time within the target range between 6% and 16%, again considerably lower than this study. This larger difference between A-FiO2 and M-FiO2 seems to be mediated on the one hand by a higher percentage of time within the target range during A-FiO2 with a lower percentage of time within the target range in the M-FiO2. While all studies, including ours, tended to reduce time above and below the target range, there was considerable variation in the reduction at SpO2 extremes in the different studies. Two suggested a more prominent effect in reducing the time in severe hypoxaemia13 17 while our study showed better performance of A-FiO2 in avoiding severe hyperoxaemia. One study reported a decrease in severe hypoxaemia but did not report exposure to severe hyperoxaemia.12 Although it is unclear what caused these differences in performance, it is important to emphasise, that there were important differences between the studies which may have impacted the efficacy of both automated and manual FiO2 control. One study by Dijkman et al, only included infants on HFNC, which allows for a large leak at the nasal interface.13 Two of the previous studies used a broader SpO2 target range (88%–95%)13 17 and a shorter measurement period (8 hours),17 which may also have impacted performance. Finally, there were differences in the patient characteristics, such as gestational age, respiratory support modalities and the postnatal age at inclusion. Overall, these findings suggest that the relative effectiveness of an A-FiO2 system is not fixed but will vary between different patients, target ranges and modes of respiratory support. As an example, two recent reports suggest the relative effectiveness of A-FiO2 compared with M-FiO2 is most marked in unstable infants.17 18
Although most of the focus when evaluating the performance of an A-FiO2 system has been on the time in the intended SpO2 target range, what happens with oxygenation during those episodes outside the target range is also of clinical importance. Especially, prolonged periods in extreme hyperoxaemia and hypoxaemia have been associated with neonatal morbidity in the short term and long term.5 8 We found that the differences between A-FiO2 and M-FiO2 in per cent time at SpO2 extremes were consistent with the number of prolonged episodes. This finding is consistent with other reports,5 19 further supporting the premise that reducing prolonged episodes outside target range is associated with improved time in the target range and leads to potential long-term benefits of A-FiO2.
Besides, the benefit of improved SpO2 control, A-FiO2 also promises to reduce nursing stress and labour. Only one of the previous studies of PRICO reported on the reduction in manual FiO2 adjustments.12 They reported a modest decrease of nine adjustments per day. In contrast we found a decrease of 22 per day (30–8). Clearly, the need for manual adjustments is dependent on the stability of the infant, which probably also explains the large IQR during manual control (upper quartile 106 adjustments/day) compared with automated control (upper quartile 12 adjustments/day).
We found no difference in the response to SpO2 dropouts between A-FiO2 and M-FiO2, suggesting PRICO’s fall-back to a clinician’s set FiO2 level is as effective as nursing response. Others have suggested the importance of the response to drop-outs,20 but we are unaware of published evaluations of the effectiveness of other A-FiO2 fall-back strategies for periods without reliable SpO2 readings.
Our report has some strengths and limitations. First of all, it enrolled more subjects than most evaluations of A-FiO2 systems. Also, the enrolment was not restricted to extremely preterm infants. In addition, it reflects a multicentre experience. While its cross-over design is the typical approach for evaluating the performance of an A-FiO2 system, the differences identified in this type study might not be projectable to routine care. This was a pragmatic study which generally provides a better basis for projection to the impact in routine use, however, the impact of different approaches to respiratory care and settings are confounding. While another strength of the study was the use of A-FiO2 in different respiratory support modes, the study was only powered to detect an overall difference in performance. Therefore, it was inadequate to evaluate the relative effect of different respiratory support modes. Particularly, additional studies during high-frequency oscillatory ventilation are warranted. Eight of the subjects were being managed by A-FiO2 when randomised, but a previous study suggests that this probably does not affect our findings.21 Finally, the study centres were all experienced with both the ventilator and the use of A-FiO2, and the finding should be projected to naïve centres cautiously.