Neonatal Research

Public Citizen are at it again, repeating and expanding their idiotic criticisms of the SUPPORT trial. And stating that the trial was ‘even worse than originally thought’. They are now focusing on the ‘problem’ that the NICUs used ‘intentionally inaccurate’ pulse oximeters.

The most disturbing finding from our review of the newly available information was the failure of half of the IRB-approved consent forms to disclose to the parents of the subjects the experimental procedure, under which the entire medical team caring for each premature baby in the study was intentionally given inaccurate information about the baby’s blood oxygen saturation levels by using pulse oximeters miscalibrated across the wide range of oxygen saturations between 85% and 95%. Of note, oxygen saturation measured by a pulse oximeter is a clinical parameter of such importance in monitoring critically ill patients that it is sometimes referred to as the “fifth vital sign.

Because of the inaccurately high oxygenation saturation values provided to the medical team by the pulse oximeters for babies in the low-oxygen experimental group, it is plausible that the medical team may have treated some critically ill babies with too little oxygen, potentially resulting in brain injury and death secondary to hypoxemia (deficient oxygen). In contrast, because of the inaccurately low oxygenation saturation values provided to the medical team by the pulse oximeters for babies in the high-oxygen experimental group, it is also plausible that the medical team may have treated those babies with more oxygen than they needed, resulting in severe retinopathy of prematurity, requiring surgery and possibly causing blindness. What we do not know because the study lacked a usual standard of care control group, but suspect, is that if the medical teams had been given the correct information about oxygen saturation levels and these babies had been treated based on their individual needs as per current routine standard of practice, some deaths might have been prevented in the low-oxygen group, and some cases of severe retinopathy might have been prevented in the high-oxygen group.

This is the core of the new ‘concerns’ raised by Public Citizen, and all they really show is the ignorance of the authors about how neonatology works.

For any readers who are also unaware, we choose saturation limits based on NICU protocols not on individual prescribed values. We have no data from which to prescribe individual limits, that is why we did these studies. Yes the saturations were offset by 3%, the only way to make this a masked study. And no this did not make being in the study more dangerous, in fact being in the study was less dangerous than being in the NICU and not in the trial. So in contrast to what they state, that there was no ‘usual standard of care control group’, there were many babies in the NICUs who were not enrolled in the trial, and were treated according to usual NICU practice, who had a higher mortality than the babies in SUPPORT. Let me also explain that in our unit at the time we allowed saturations to be between 84 and 95%. That is including both of the ranges of saturation that were tested in SUPPORT, we thought that that entire range was safe, and that being in the lower part was probably safer, we now know, only as a result of SUPPORT, BOOST2 AusNZ, BOOST2 UK, and COT, that we were wrong. That babies who were not in the trial were at higher risk, that the lower part of that range, which is where most NICUs were heading before these trials, is associated with increased mortality.

Later in the public citizen document they state

Understanding the clinical importance of oxygen saturation levels in the routine management of premature babies is essential for recognizing the serious risks of providing protocol-specified misinformation to the NICU medical teams that cared for the infants in the SUPPORT study

This is almost humorously ironic, as the authors of this document clearly don’t understand the importance of saturation monitoring, and how we had no idea which saturations to target prior to the trial.

The  authors of this report, one of which appears to be an adult nephrologist who does some lab research, another a Bioethicist, the 3rd another MD but I am unsure what he does, go on to pontificate about how we look after extremely preterm infants. A subject on which they are unqualified, and misinformed. They don’t even seem to know how pulse oximeters work!

Given the complexities of routine medical management of extremely premature infants and the interaction between the different complex experimental interventions of the SUPPORT study, the minimization of the risks to babies enrolled in the study would have required a detailed plan for unblinding the NICU medical teams when the masking procedure using intentionally miscalibrated pulse oximeters posed a threat to the health of the babies.

If, in the course of any study, the physician feels that the study procedures are putting a patient at risk, or course the patient needs to be taken out of the study. In some circumstances it is important to know what treatment the patient has been receiving, and to unmask the study. In this particular study all you needed to do was to use an ordinary pulse oximeter. Indeed, that was done a few times, a doctor thought that a baby with pulmonary hypertension, for example, and treated the baby with higher saturation targets, using an unadulterated oximeter, unmasking would not be necessary.

The reason that happened very rarely is that we do not fix individual saturation targets in the NICU. They are set by protocol.

Protocols which were arbitrary, based on guesses, and many of those guesses were wrong.

I guess the authors of this document think that all of the investigators in SUPPORT, all of the investigators in the other trials around the world are unethical, and don’t really care about preterm babies. Maybe if they stopped to consider that they are maligning hundreds of people who have dedicated their lives to looking after small newborn babies it would make them reconsider their ill-conceived and slanderous attacks.