One of the misplaced criticisms that have been made about the SUPPORT trial and the consent forms was that we should have known before the trial that there would be a difference in mortality, and that there would be a difference in retinopathy.

Is that true?

What was the actual state of knowledge before the oxygen saturation targeting trials? I wanted to give a brief description of the history, to explain in more detail to those who read this blog but who are not aware how little we knew before SUPPORT and the other O2 trials.

There had indeed been previous trials of different levels of oxygen, but they were from 2 separate, very different, eras in neonatal care. Among the first Randomized Controlled Trials (RCTs) in medical care of the newborn infant, the first group of trials of restricted versus liberal oxygen therapy included a total of just over 400 babies. They compared prolonged use of very high oxygen such as >80% in one trial, or >50% for at least 28 days in another, to an alternate approach of limiting oxygen therapy, usually by means of a maximum FiO2 that could be given. One of those trials for example only allowed any oxygen if the baby was cyanosed, and then the maximum that could be given at any time was 40%. So even if the baby was blue and bradycardic, an increase in oxygen concentration was not allowed.

At this time, assisted ventilation was not available, blood gases were difficult to perform (often giving results the nest day), there was no CPAP, babies were often starved for the first few days of life to avoid regurgitation even though there was no intravenous nutrition, and only infants who survived the first 2 days were entered into the largest of these studies; of course, the large majority of babies with significant lung disease had already died by that time.

The results of these trials were emphatic. Very prolonged, very high concentrations of oxygen caused retinal damage in moderately preterm infants. Such high oxygen treatment had become the standard of care despite a lack of evidence of safety or efficacy. Not only did the liberal oxygen groups have much more severe retinopathy of prematurity (RoP), there were no apparent adverse effects from restricted oxygen, specifically, despite what we would now consider inappropriate restrictions in the low O2 group, there was no increase in mortality. It may be that there was significant O2 toxicity in the high oxygen groups leading to pulmonary and other multi-organ injury to balance the adverse effects of the O2 restriction in the low oxygen groups. Or perhaps the studies were just too small to have the required power.

It was only later, using epidemiologic data, that there were suggestions that mortality may have been increased by restriction of oxygen. If it is indeed true, it may be because physicians began limiting oxygen exposure from the moment of birth, including during the first 2 days even though the strategy had never been tested during that interval. It may also be that the epidemiologic analysis was misleading, the paper by Cross (Cross KW: Cost of preventing retrolental fibroplasia? The Lancet 1973, 302(7835):954-956.) has been widely quoted, but the analysis is rather questionable, being based on projecting what the trends in neonatal mortality might have been if O2 had not been restricted.

I well remember reading, in the 1970’s, a newspaper article (I seem to remember it was in the Sunday Times) about the history of clinical trials which reported the horrific tale of the trial that had blinded 20 babies. I was shocked, as a teenager wanting to go into medicine, that doctors could do such terrible things. Of course the truth was that the blinded babies were in the usual treatment group, and the restricted oxygen group, the newer therapy, had less blindness and the trial saved the eyesight of many thousands of babies as a result. But the newspaper wasn’t about to let a little thing like the facts get in the way of a good story (clearly, this still happens!).

After this, manufacturers of incubators used to make them with holes in the sides, so that when you gave oxygen, usually just by attaching a tube to the oxygen inlet in the incubator and turning on the flow, the O2 concentration would stay below 40%. There was often a large red flag that became visible behind the incubator when you turned the mechanism to occlude those holes and risked exceeding 40%! Air/O2 mixers often required a manual override if you wanted to give more than 40% O2. I presume this was to try and shift the legal liability from the manufacturers to the doctors, if there was a case of RoP.

A few years later, when routine blood gas measurement became available, and other forms of medical supportive therapy were also developing, a second attempt was made to address oxygen therapy. This second wave of trials (more of a ripple) included only 2 studies, with a total of only 170 infants. The low oxygen groups had a PaO2 which was targeted to stay below 50 mmHg in one study or below 40 mmHg in the other (if a capillary blood sample was used the PO2 was kept below 35mHg), while it was kept around 100 mmHg in the comparison groups. Both studies suggested that aiming at a lower PO2 was safe, and seemed to lead to improved resolution of lung disease, in aggregate there was a slightly lower mortality in the babies who had more restricted oxygen therapy, which was not statistically significant. There was no effect on RoP in these trials, indeed by avoiding frank hyperoxia, there was no significant RoP in either group.

Interestingly Dr Usher noted in the report of his trial, only ever described in a book, and sadly never published in a peer-reviewed journal, (which makes it quite hard to get hold of, thanks to Lisa Askie for sending me a copy) that even the low oxygen group often needed more than the arbitrary limit of 40% oxygen.

And those were the only reliable controlled data available pre-SUPPORT. There never was an O2 targeting trial using continuous monitoring, even when transcutaneous PO2 monitoring was introduced the limits to be aimed for were selected arbitrarily. In the early 1980’s pulse oximetry was introduced for continuous monitoring. The direct continuous non-invasive measurement of hemoglobin oxygen saturation was a great advance. The main disadvantage of pulse oximetry is the difficulty in avoiding hyperoxia; as the devices are accurate to plus or minus 5%, a measured saturation of 94% could actually be a saturation of 99% and a very high PaO2, in the range shown to be associated with RoP. This was considered to be less important than the advantages of truly continuous monitoring. Several workers suggested keeping the saturation below 95% or below 94% to reduce the risk. However, the failure to perform early trials examining different goals of oxygen therapy with continuous monitoring meant that there was no clear understanding of what level of oxygen saturation to aim for, and whether any particular saturation range was better than another.

One center in the UK decided that, because preterm babies ‘should’ still be in the uterus, where their saturation might be as low as 70%, there was no need to give oxygen unless the saturation was below 70%. Others were worried that a saturation too low might affect pulmonary vascular relaxation and they therefore kept saturations much higher, some with no maximum limit at all.

After the provocative publication from the UK, which showed very little RoP and no apparent harms, in particular no higher mortality, there were a large number of observational studies, mostly showing advantages to the development of RoP of lower saturation targets, and none showing increased adverse effects, in particular none showed any increase in mortality with their lowered saturation targets, nor any augmentation in adverse neurological consequences in the long term. However, the saturation targets examined in those observational studies all varied, and in most the lower saturation limits were in the low 90’s. The reduction in retinopathy was thought to be due to a reduction in frank hyperoxia. Further reductions to the high 80’s were suggested as a way of reducing oxidative damage (then being more widely investigated as a causal factor in other conditions such as bronchopulmonary dysplasia and even intracranial bleeding), and perhaps further reducing the incidence of RoP, but it was not known if this would be effective or safe, nevertheless, based on the observational data and the very old studies some centers did take up even lower saturation ranges.

I must be clear, keeping the saturations below 95% was considered adequate to prevent hyperoxia, and seemed to probably reduce RoP. It was thought by some that oxygen was no longer a major culprit in the causation of RoP as long as hyperoxia was avoided, so there were many studies looking at other potential risk factors, hypocarbia, hypercarbia, blood transfusions, and inadequate nutrition were all considered to be possibly important (and may indeed be important). It was not at all clear whether or not dropping the saturation ranges even lower, to below 90%, would actually have any additional benefit in reducing RoP.

And retinopathy had become a problem again. Since the introduction of continuous monitoring much more immature babies were surviving, the kinds of babies tested in the 2 early groups of trials almost never developed retinopathy, it was mostly babies of 26 weeks gestation and below who were developing the condition, also universal retinal screening was refined, and was picking up many more cases.

This is the situation that led to the enormous variations in O2 saturation targeting. Some centers felt that a saturation of 90 to 95% was the best idea, largely avoiding hyperoxia, and not wanting to risk hypoxia. So they would have a unit routine. The alarm limits for all preterm babies in the NICU would be set to, say, 89 and 96. Then the nurse would adjust the oxygen delivered, sometimes every couple of minutes, to stay within the target range, and the alarms would frequently sound, when the baby passed beyond those limits. Every preterm baby in the NICU would have the same limits, until they no longer needed oxygen. As the babies’ lungs improve, they will often have saturations above 95% even without supplemental O2, sometimes up to 100%. So if the oxygen requirements drop to 21% O2, and the saturation is above the target limit, the high saturation alarm is switched off. Some babies in the NICU never need oxygen, they may right from the start have high saturations even in 21% oxygen. We accept this because the PaO2 of a baby in room air, 21%, cannot easily exceed about 105 mmHg. Which was considered safe. It is very rare for a baby who has never had supplemental oxygen to develop RoP, even though their saturations may be above 95% for their whole life.

Another center examining the same data would set their oximeter alarm limits to a lower range. With that approach fewer babies ever get supplemental oxygen, they will tend to come out of oxygen earlier, but they will continue to have the same saturation target whenever they need oxygen until they are nearly ready to go home.

Unfortunately, some families who participated in SUPPORT have been misled by pressure groups, consisting of doctors who have never worked in an NICU, and PhD ethicists who have never even set foot in an NICU or taken the trivial effort of talking to someone who has. One such family who spoke on the day of the recent OHRP meeting noted (I paraphrase) ‘I didn’t realize that if my baby was in the trial that they would not receive the usual care of adjusting the saturation range according to his needs’. Unfortunately, whoever told them that lied to them.

As part of the preparation for the conference in Sydney where I just presented, I pulled out the PowerPoint presentation that I gave several years ago, when we were planning the O2 trials, and I was asked to present the rationale for the COT, Canadian Oxygen Trial (I think it was at the annual Canadian Paediatric Society meeting). In that presentation were two slides, one was the claims of the doctors who were happy using higher saturations, the other included the claims and rationale of those of us who were advocating lower saturations. Both groups claimed that their favorite range would reduce death, reduce BPD, and reduce morbidity in the long term. The low saturation proponents were in addition claiming that retinopathy might be reduced, the high saturation groups were claiming that retinopathy would not be further affected by going lower!

Yes we really were completely unsure what ranges were the best.