How much oxygen?

Posted on 9 May 2013 by Keith Barrington

At the PAS meeting in Washington DC, that has just finished, the COT trial results were presented, as well as the short term outcomes of the BOOST trials.

These are a series of clinical trials which have compared higher saturations 91 to 95% to lower saturations 85 to 89%. As I mentioned before when discussing the SUPPORT trial, which had the same target ranges, and the same technique of using masked pulse oximeters, these target ranges are within the ranges that were being used routinely in NICUs around the world, but we did not know if one target range was better or worse than the other, overall. There has been a remarkable international collaboration to get several similar trials performed at around the same time, so that we can then get even more power by putting the results together.

The COT trial showed no significant difference between the high and low sat target ranges. The BOOST trials (BOOST UK (and Ireland) BOOST Australia and BOOST NZ) showed the increased mortality, in the low saturation group, that we have already heard about, and the increased retinopathy in the high saturation group similar to the SUPPORT trial. Both of these studies have also just been published, COT here and the BOOSTs here

Now what?

Closer examination of the COT results shows that there were more deaths in the low saturation group, 16.6% vs 15.3%. Although this is not significant (at usual levels of statistical significance) it is not very different in magnitude to the increased mortality in the other trials results. Even more concerning, the difference in mortality between the groups occurred entirely after introducing the new software in the Masimo oximeters. After changing the software, the mortality in the 2 groups was 16.8% in the low saturation group, and 14.1% in the high saturation group.

Also, in COT, retinopathy of prematurity (RoP) was not different between the groups, this is harder for me to understand, there was really no difference at all between the saturation groups. If COT had been published first, then I would have thought that maybe the increase in RoP with oxygen mostly occurs with higher sats, and is not different between the high 80s and the low 90s, but the other trials now all show more RoP between these target ranges.

So probably, and this question was asked by Richard Martin in the meeting, a meta-analysis will show that the confidence limits of the COT mortality difference have a wide overlap with the other oxygen trials, and most likely the overall analysis will still show a significant increase in mortality with lower saturations, and, I would guess, with very little heterogeneity.

One of the strengths of these oxygen trials, as I mentioned above, was that even from before they started there was a plan to perform a prospective meta-analysis, whereby the individual patient data are entered into a database, but with variables defined a priori, and the data to be collected agreed from the start. All of the oxygen trials (SUPPORT, COT, the BOOSTs) agreed to participate in this NeoProm collaboration, one of the reasons that many of us were very happy to participate in COT , was the participation in NeoProm (I actually initiated COT in two hospitals, the Royal Victoria Hospital in Montreal, where it was ably taken over by Nabeel Ali when I left, and then at Sainte Justine).

I think it is vitally important that we all continue this collaboration, to be able to answer the important questions, that were raised several years ago, with the greatest confidence.

Lisa Askie, the expert in this kind of analysis in the perinatal field, has written a review of the current situation (already a bit out of date with these new presentations, and publications). She notes the preliminary data regarding increased mortality, and describes the NeoProm collaboration in some detail. As she notes, the BOOST trials were stopped early as a combined preliminary analysis showed the increase in mortality that I am describing, COT did not contribute to this preliminary analysis, and an article published in Trials (open access) recently by the BOOST steering committee describes the history of what happened as the steering committees were struggling to decide what to do with the data showing increased mortality with lower saturations.

I think the time has come for complete openness with trial data. Iain Chalmers notes that the enrollment in the BOOSTs was stopped after the interim analysis, a process which would have been easier and done with more confidence if the COT data had been available, such a decision has major consequences whichever way it goes, reducing sample size and reducing power, exposing subjects to risks, or truncating a trial which did not truly have differential risks. These are all potentially of great importance. The only way to make a good decision is to have all the available relevant information.

NeoProm will help us to finally answer the question posed in the title of this post: each of the 2 new publications is accompanied by an editorial, (here and here) both of them state that we should now target 90 to 95% saturation, which should avoid the increased risk of death with the lower saturations, and although there will probably be some more retinopathy, the risk of serious visual problems in the long term is not increased because of the high quality ophthalmological screening and treatment we currently have.

The data from clinical trials do not belong to the PIs and the steering committees of the trials. They should be considered to be the property of the whole community: the babies and families who participated, the funding agencies and the societies that support them, and the investigators and health care workers who facilitate the trials.

Chalmers paper mentioned above includes the following sentence ‘If the academic community wishes to be seen to be putting the interests of patients and science above individual agendas, concerns and benefits, the issue of sharing interim analyses needs to be given more attention’ they give examples of 2 situations in which similar on-going trials have agreed to share data during the performance of those trials. Only by doing this will we be able to avoid situations where continuing trials, or stopping them too early, causes unnecessary harm.

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Smaller plates please

Posted on 2 May 2013 by Keith Barrington

In this study, first grade children were randomly given either adult sized plates or smaller kiddie plates. (DiSantis KI, Birch LL, Davey A, Serrano EL, Zhang J, Bruton Y, Fisher JO: Plate Size and Children’s Appetite: Effects of Larger Dishware on Self-Served Portions and Intake. Pediatrics 2013, 131(5):e1451-e1458). The kids took more food when given the bigger plates, and ate most of the extra food that they took. The answer to the obesity epidemic!

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Neonatal Updates #31

Posted on 2 May 2013 by Keith Barrington

Yoder BA, Stoddard RA, Li M, King J, Dirnberger DR, Abbasi S: Heated, Humidified High-Flow Nasal Cannula Versus Nasal CPAP for Respiratory Support in Neonates. Pediatrics 2013. A multi-center RCT among just over 400 infants who were at least 1 kg and at least 28 weeks gestation. Infants who would otherwise receive CPAP were randomized to either CPAP (at 5 or 6 cm H2O) or high flow cannulae at between 3 and 5 liters per minute depending on their body weight. Babies were eligible either in the first 24 hours or after extubation. The outcomes were very similar in the two groups, with some minor evidence of benefit with CPAP (fewer days of positive pressure in total).

Azzopardi D, Robertson NJ, Kapetanakis A, Griffiths J, Rennie JM, Mathieson SR, Edwards AD: Anticonvulsant effect of xenon on neonatal asphyxial seizures. Archives of Disease in Childhood – Fetal and Neonatal Edition 2013. Of 14 infants receiving xenon gas in addition to cooling, 5 had seizure. The seizures stopped during xenon therapy, started again when xenon was withdrawn, and stopped again when xenon was restarted.

Bohnhorst B: Usefulness of abdominal ultrasound in diagnosing necrotising enterocolitis. Archives of Disease in Childhood – Fetal and Neonatal Edition 2013. A good quality review, appropriately cautious about the place of ultrasound. I have certainly had radiologists tell me that a baby had penumatosis on an abdominal ultrasound performed for other reasons entirely, I do think that portal venous gas is probably a reliable sign of NEC, and ultrasound is probably much more sensitive than x-ray for this finding.

Bremer DL, Rogers DL, Good WV, Tung B, Hardy RJ, Fellows R: Glaucoma in the Early Treatment for Retinopathy of Prematurity (ETROP) study. Journal of American Association for Pediatric Ophthalmology and Strabismus 2012, 16(5):449-452. It is not common, but I was unaware that babies with high risk prethreshold RoP are at risk of glaucoma, about 2% before 6 years of age, regardless of whether they had early laser treatment or not.

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Music has charms to soothe a savage breast

Posted on 1 May 2013 by Keith Barrington

William Congreve, The Mourning Bride, 1697: (from Act 1 Scene 1)

Musick has Charms to sooth a savage Breast,
To soften Rocks, or bend a knotted Oak.
I’ve read, that things inanimate have mov’d,
And, as with living Souls, have been inform’d,
By Magick Numbers and persuasive Sound.
What then am I? Am I more senseless grown
Than Trees, or Flint? O force of constant Woe!
‘Tis not in Harmony to calm my Griefs.
Anselmo sleeps, and is at Peace; last Night
The silent Tomb receiv’d the good Old King;
He and his Sorrows now are safely lodg’d
Within its cold, but hospitable Bosom.
Why am not I at Peace?

Our preterm babies in general do not have savage breasts, they are cool, and rarely savage at all.  But it may be anyway that music helps them to be soothed. (Loewy J, Stewart K, Dassler A-M, Telsey A, Homel P: The Effects of Music Therapy on Vital Signs, Feeding, and Sleep in Premature Infants. Pediatrics 2013.)

The infants in this multicenter trial were randomly put in one of 4 experimental conditions, control, parents favourite lullaby, a noise maker that sounds a bit like breathing (Remo ocean disk) and a gato box which produces two gentle tones that can be timed to the babies rhythms.

I think this is a reasonable thing to think about, lullabies are known in all cultures, they seem to have similar characteristics in different cultures, and they do calm down babies.

Unfortunately there are some flaws in the paper, the authors list 4 different primary outcomes, which they say were ‘included’ in the primary outcomes. So how many they analyzed isn’t clear; it looks like they did a repeated measures test for each individual intervention, with each outcome variable, making about 20 tests for the short term physiologic responses. They also say in the methods ‘The study was powered to detect any outcome that was measured along a continuum that had a small ES’ (Effect Size). I have no idea what that means, I don’t think it means anything. They also present data about sleep without giving any indication how different sleep stages were diagnosed, and then talk about ‘good sleep’ while the graph they show is ‘for % active sleep’

This is a randomized controlled trial but the report does not follow CONSORT guidelines. as the journal website says that it must.

One neat feature of the study was that when the parents did not identify a particular lullaby, they all got ‘twinkle twinkle’. They were then able to show that the specific lullaby of the family was more effective than the generic ‘twinkle’. The lullabies where mostly sung by the parents, after some hints from the music therapists, but sometimes it was other caregivers.

Despite the limitations of this report, I think it looks like it is safe to have parents sing to their preterm babies (!) and indeed lullabies may well soothe the babies breasts.

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What the… #2

Posted on 1 May 2013 by Keith Barrington

Some of you may remember my rant about the article that was supposedly about in-hospital developmental care recently published in Early Human Development. Well I sent a note to the editor through the web page telling him about my concerns. I received a reply, not from the editor, but from someone at Elsevier asking me to submit a letter to the editor. I found this a little strange, as I did not write to Elsevier and it is the editors responsibility what is published in the journal, but nevertheless I went to the website to submit the letter. The journal website now has instructions for authors available on the appropriate page, which was blank when I visited previously, maybe it was just a glitch, but the instructions to authors clearly state that all RCT reports should comply with CONSORT. Which this one did not.

The text of my letter is reproduced below. I will keep you posted.

To the editor:

Re: Chen L-C, Wu Y-C, Hsieh W-S, Hsu C-H, Leng C-H, Chen WJ, Chiu N-C, Lee W-T, Yang MC, Fang L-J et al: The effect of in-hospital developmental care on neonatal morbidity, growth and development of preterm Taiwanese infants: A randomized controlled trial. Early Human Development 2013, 89(5):301-306.

This recent publication is an embarrassment to the medical community. The authors have been allowed to publish an article in which the infants were enrolled before they were eligible, where some of the outcome variables are used as exclusion criteria, where other outcome variables could not possibly have been affected by the intervention, where the number of outcome variables and statistical analyses is so great that one can have no confidence whatsoever in the results. In addition the interventions are so poorly described that it is impossible to know what they were investigating.

Unfortunately the investigators have used substantial resources, enrolled large numbers of infants, and I am sure had the best of intentions.

Even the title of the article is profoundly misleading, as the intervention started at 34.7 weeks, and continued after discharge (apparently, even though even this is not clear), and we are informed that all groups received ‘in-hospital developmental care’ including the controls. The different interventions, which started on enrollment into the study, commenced at 34.7 weeks PMA as noted in table 2.

Eligibility criteria: the authors state in the eligibility criteria that these include being ‘physiologically stable, i.e., no ventilator use, absence of apnea, bradycardia, or desaturation with or without oxygen use at post-menstrual age (PMA) of 36 weeks; [6] hospital discharge prior to PMA of 44 weeks’ so the infants were not eligible until 44 weeks PMA, but they were enrolled and had intervention started by 34 .7 weeks, i.e. 10 weeks before they were eligible, if the authors did not have access to a time machine this is clearly impossible.

Outcome variables: the outcome variables used include BPD, as infants were not eligible until after 36 weeks the authors would already know if they had BPD when enrolled. RoP is also used as an outcome variable, when it is also an exclusion criterion, and again would have been diagnosed by the time the infants were eligible. Feeding desaturation; as noted above infants were ineligible for the study if they had desaturation, so to include feeding desaturation as an outcome variable is incomprehensible.

Significance of statistics. The authors never state which outcomes were primary or secondary, they have therefor performed 18 t tests (having decided to ignore the fact that there were 2 different intervention protocols). There is no adjustment for multiple testing which means that there was over a 60% chance of a type 1 error. The 2 outcomes which are supposed to be different between groups are outcomes which could not have been different between groups, as RoP occurred before the children were eligible and feeding desaturation made the infants ineligible.

It is inconceivable that an intervention which commences at 34.7 weeks could have any effect on BPD or on RoP.

Your instructions to authors page clearly states in detail that all RCT reports should comply with CONSORT. This publication did not. There is no flow sheet, it does not specify primary and secondary outcomes, and there are many other failings.

The publication of this trial in your journal makes clear that the editorial standards and refereeing of ‘Early Human Development’ are inadequate. It makes it impossible to have any confidence in any of the articles published in your journal. This article should be retracted.

Sincerely

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‘Creating’ impairment?

Posted on 1 May 2013 by Keith Barrington

A new publication by Annie Janvier and Marc Mercurio, which tries to explain why newborn infants, and especially preterm infants, are treated differently to older children and adults. (Janvier A, Mercurio MR: Saving vs creating: perceptions of intensive care at different ages and the potential for injustice. Journal of Perinatology 2013, 33(5):333-335.) They compare 2 cases of a very preterm infant, just born, and a critically ill older child who has developed a serious infection. Although the older child has a lower predicted survival and similar long term outcomes, the initial approach to therapy, just about everywhere in the developed world, is routine institution of intensive care for the older child, but a selective approach for the very preterm baby whose life is considered optional.  This is very much what Annie and I found in our questionnaire study (Janvier A, Leblanc I, Barrington KJ: Nobody likes premies: the relative value of patients’ lives. J Perinatol 2008, 28(12):821-826). which Annie has since replicated around the world.

In this new publication the authors try to explain why this might be, one of their suggestions, and I think they are on to something here, is that the older child has been home with a family at least for a while, and his/her illness is blamed on the germ causing the infection. The preterm baby in contrast is newly minted, has never known anything but being in the hospital and when there are complications or long term impairments the caregivers feel guilty, as if they ‘created’ the problems, rather than saving the older child.

As they rightly point out this is not  necessarily rational, in both cases the infant would be dead if it were not for the intensive care unit, in both cases the therapies have risks and benefits, and in both cases the teams are trying to get the best outcome they can. But nevertheless it does appear to be one of the reasons for differential treatment, indeed one that has been expressed by some of the respondents of another study that Annie has been doing with Amélie Dupont-Thibodeau, a neonatologist and PhD student. Presented as an abstract at a previous PAS meeting, the theme of feeling responsible for the impairments that some preterm infants experience came through.

Its hard to keep up with all of Annie’s publications, but another article that she has just published with Steve Leuthner addresses what is almost the opposite problem, why is it sometimes so difficult to withdraw active interventions?  (Janvier A, Leuthner SR: Chronic Patients, Burdensome Interventions and the Vietnam Analogy. Acta Paediatrica 2013). They refer to the situation that many of us have dealt with, the newborn infant who has already had multiple complications during their stay in the NICU, who has always been technology dependent, and who now develops another very serious complication that might well lead to their death. After so much emotional investment in a baby, so many interventions, much discomfort, surgery, ventilation, TPN etc etc, to pull out seems to be more difficult than not starting at all. The analogy is to the Vietnam war, where after so many years of battle, so many young men killed, so many enemy combatants and innocent civilians destroyed, the idea of pulling out was delayed and delayed, maybe just one more battle, one more intensification, would finally prove successful.

This is another normal human response I think, how to counter it? (If we should?) I think this will always be the case, I can’t imagine it will ever be easy to limit curative interventions in such a case, but sometimes there is unintended suffering (of everyone involved) prior to a delayed death in such cases; Annie and Steve talk about the need to talk openly about death, which is fine as far as it goes, but does that imply that we talk about death even when things are going well, or when a baby has just recovered from a complication? I don’t suppose that is what they mean, as we also need to be able to talk positively and support the reasonable and rational hopes of parents. I think that already caregivers often temper their interactions with parents, with provisos and ‘things are going well today, but you never know about tomorrow there could be..’ ‘ we aren’t out of the woods yet you know’. Finding the right balance, to be hopeful yet realistic, to be positive but not Panglossian, to be ready to reassess the situation without always crushing the spirits of the parents, is the real challenge of our daily interactions with our families.

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More support for SUPPORT

Posted on 25 April 2013 by Keith Barrington

A new editorial in the PNEJM from 2 PhD ethicists. I specify that as they are not neonatologists, nor pediatricians nor yet medical researchers, and have no conflict of interest of any kind as far as I can see. Yet their criticism of the OHRP ruling is as severe as mine and as Dr Lantos’s (but in more measured language than mine!)

Their final statement is as follows:

‘…the OHRP is asking that research be described as riskier than it really is and is suggesting that the parents were duped into enrolling their frail infants in dangerous research. Not only is that not true, but it also poses substantial risk to the conduct of valuable comparative effectiveness research both for premature infants and for the general public’.

I sent an Op-Ed piece to the NY Times, as an attempt to balance what they had published; they appear not to have accepted it, so I will reproduce what I wrote below.

The editorial printed in the April 16 issue of the New York Times reports the findings of an OHRP investigation into a recent clinical research study. The editorial quotes the OHRP report, which noted that they determined ‘that the informed consent document for this trial failed to adequately inform parents of the reasonably foreseeable risks and discomforts of research participation.’

Neonatal Intensive Care has come a long way in the past 50 years. From the early days, the USA has been the world leader in pursuing improvements in care of sick preterm infants, and has been the country which has performed the most important research studies that have led to those improvements, here and around the world.

Unfortunately there remain many unknowns in how we should care for the infants who are born very prematurely. As a result there are great variations in practice around the country, and across the world. One of these variations, until recently, was the target ranges of oxygen saturation which, as noted in the editorial are usually between 85% and 95%, although they may even be higher or lower than these limits.

Until this study was performed there was no good reason for choosing one range over another; the study actually compared what happened if you used the upper part of this range which was already in use, to the lower part of the range.

In other words, no baby in the study was exposed to anything which was outside of usual clinical practice.

It is mistaken to think that there was a ‘standard of care’ prior to this study. Even now there is discussion about the best saturation target range, and there is no standard of care. This is one major failing of this report from the OHRP which mentions frequently ‘standard care’ and ‘standard of care’ without understanding that there was (and is) no such thing.

Your editorial supposes that an infant who needed a different oxygen range might have been given a different oxygen range, and could have been harmed as a result. This is untrue. Firstly there was no reason before this study to use one target range rather than another for an infant. Oxygen target ranges are not individualized in the NICU according to patient needs, they are standardized according to whether the baby is premature or not. Secondly if there were some unusual circumstances which made a doctor think that an individual baby did need a specific range of oxygen, then it is usual practice to take the baby out of the study, and give them the therapy (in this case a specific oxygen target range) that you think they need.

This report was developed after the study was completed and published, but at the time of the planning and performance of the study there was no reason to prefer one particular range of oxygen saturation over another. If it had already been known which oxygen saturation target level was preferable, the study would not have been done. The importance of this issue is demonstrated by the fact that a never before seen collaboration across the world, with, in addition to this trial, studies in Canada, the UK, Australia and New Zealand, a collaboration called ‘NeoProm’ was created to study the issue of oxygen saturation targeting, with very similar studies being done in all of those countries.

Research such as this study are essential for the future of care of the premature baby, and rulings such as this misguided opinion of the OHRP puts such research at risk.

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Adrenal function in critical illness

Posted on 22 April 2013 by Keith Barrington

A very interesting article in the PNEJM that made me question a lot of my ideas; I always like that when it happens. Boonen E, Vervenne H, Meersseman P,  et al: Reduced Cortisol Metabolism during Critical Illness. Prestigious New England Journal of Medicine 2013, 368(16):1477-1488. The authors have performed a sequence of elegant tests in critically ill adults, which show 1. as we already knew cortisol levels are much higher when you are critically ill. 2. as I certainly didn’t know, this is not mostly due to the adrenal glands making more cortisol, it is actually mostly due to decreased metabolism of cortisol. They produce several lines of evidence for this, but it looks robust to me. In fact ACTH was reduced during serious illness, probably secondary to the increase in cortisol concentrations.

I think this is potentially very important for our (or maybe it is just my) understanding of what to do with steroids in the critically ill.

As the authors note, if you give a ‘physiologic replacement dose’ of hydrocortisone to someone who has markedly reduced metabolism, you are probably giving much too much (3 times too much they calculate).

So the authors seem to think that what happens is this, in critical illness there is a transient increase in ACTH, followed by an increase in cortisol, which inhibits further ACTH release, and then other mediators which are being released, such as cytokines, inhibit the breakdown of cortisol. So the cortisol stays high.

We have long known that patients, including preterm infants, who have lower cortisol responses have worse outcomes than those with brisk responses. We have responded to that by studying replacement of cortisol, which has had very mixed success. The latest large adult studies showed no real overall benefit of low dose steroid replacement in the adult (or indeed in the ventilated preterm).

It now looks to me that we don’t understand all these factors well enough, we certainly don’t understand them in the preterm, so we need to rethink our approach.

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Even more SUPPORTive

Posted on 20 April 2013 by Keith Barrington

Another devastating critique of the OHRP ruling regarding the SUPPORT trial is now available. John Lantos, a world leader in pediatric bioethics (and a good friend) has an article  which seems to be open access: ‘OHRP and Public Citizen Are Wrong about Neonatal Research on Oxygen Therapy‘. It is worth reading in its entirety; he refers to criticism of the trial from a group known as ‘Public Citizen’. This group has misunderstood the trial even more than did the OHRP.

John Lantos explains the implications of the OHRP ruling in this way:

Their position is apparently that informed consent forms need to inform parents not only of known risks and of possible risks, but also of risks that the investigators did not think were possible – even after those risks have been shown not to exist. Essentially, there is no risk that does not fall into this category. By these criteria, consent forms should state something like, “ANY risk that you can imagine, and ALL risks that you cannot even imagine, and EVEN RISKS THAT HAVE BEEN SHOWN NOT TO EXIST, are possible as a result of participation in this study.”

Dr Lantos does have some critique of the consent forms, a critique much more subtle and measured than the OHRP. The OHRP state that the consent form did not adequately explain the risks, which claim Dr Lantos destroys with the paragraph reproduced above. On the other hand Dr Lantos does think that the consent form should explain the goals of the study, rather than just the risks. I think he has a point, for the future, to include parents as partners in research projects, rather than as subjects of those projects, we should focus on educating them, and informing them more clearly and completely about why we need to do these projects. I think his criticism of the consent form here goes a little far, if you read the form in its entirety I do think you get a picture of the goals of the study.

For the future we should involve parents in drafting consent forms; forms which describe why the study needs to be done, as well as any reasonably foreseeable risks of the trial.  But criticisms of this trial, and claims that it did not meet OHRP standards are clearly misplaced.

John is always very eloquent, in person and in print, I will reproduce his eloquent last paragraph here

It is shocking that OHRP and Public Citizen did not see fit to understand the study or, apparently, to analyze the results before claiming that it was risky to babies. The real risk to babies comes from reckless and ill-informed opinion about highly ethical scientific studies. To minimize this risk, OHRP and Public Citizen should apologize to the investigators and to the parents of the babies in these studies for their sensationalistic misinterpretations of the SUPPORT study. If they do not, and if fewer babies are enrolled in such studies, then more rather than fewer babies will die, more rather than fewer babies will go blind, and OHRP and Public Citizen will have been responsible for those harms to innocent babies.

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What the….

Posted on 19 April 2013 by Keith Barrington

Unfortunately studies like the new publication in Early Human Development don’t help anyone.

Chen L-C, Wu Y-C, Hsieh W-S,  et al: The effect of in-hospital developmental care on neonatal morbidity, growth and development of preterm taiwanese infants: A randomized controlled trial. Early Human Development 2013, 89(5):301-306. This is a real pity. The authors have put a lot of time and resources into this trial, but there are so many problems with the publication that you can’t tell if they found anything. They randomized 178 VLBW infants into 3 groups.

That it is about all I can tell you for sure about this study. If we ask the simple questions that need to be reported in any publication regarding an RCT I have difficulty answering any of them

1. Registration. Was this trial registered? No information given, and I can’t find an entry on the meta-register of RCTs.

2. Eligibility. The authors state that the infants had to be ‘physiologically stable, i.e., no ventilator use, absence of apnea, bradycardia, or desaturation with or without oxygen use at post-menstrual age (PMA) of 36 weeks’ and ‘hospital discharge prior to PMA of 44 weeks’ but the babies were enrolled at an average PMA of age of 34.5 weeks, that is before they were eligible! Also they use BPD as an outcome criterion, and even use it in their sample size calculation, when by definition infants with BPD were not eligible.

3. Intervention. There were 3 groups, controls who got regular developmental care in the hospital, a clinic based intervention group, and a hospital based intervention group. I can’t really tell you what the intervention was, they say they got feeding support, massage and parent support and education. They also talk about family centered care, but there is no real details given for any of this bundle of interventions.

4. Outcomes. There is no primary outcome mentioned anywhere in the document. The table of results shows 18 outcome measures with significance testing on each. They have selected 2 which they say were significant, RoP grades 2 and 3, and desaturation during feeding. Now my gentle readers all know, I am sure, that this is horse dung. I don’t understand why the reviewers of this article didn’t know that. Clearly if you test 18 outcomes and for each one you use a significance level of 1 in 20, its pretty likely that you will find one to be significant.In fact the probability that at least one will be significant is 1-(0.95^18) (I think) which is 0.6 (ish). So in any study if you do 18 significance tests and use 0.05 as your threshold for significance, you will find something positive 60% of the time, even in a completely random set of numbers.

Also interesting is that more advanced RoP was an exclusion criterion. So they knew that most of the development of retinopathy occurs before they were even in the trial, but then they use it to show an effect of the intervention.

This study makes no sense! The authors note in the discussion that the study was unable to show an effect on duration of ventilation, when the infants were only eligible if they weren’t being ventilated.

How on earth did this get published? I went on the website of the journal ‘Early Human Development’ to see if their instructions for authors mention the CONSORT statement. That is a statement giving standards for the reporting of RCTs, which most quality journals have signed up to; they require conformity with its standards prior to accepting a report of an RCT. Any comparison of this report with CONSORT would be a clear and obvious fail.

The instructions for authors page is blank. Interesting.

But even the CONSORT statement doesn’t say that you can’t use outcome variables that are diagnosed before you enter the study, or that you can’t use eligibility criteria that occur after the babies are enrolled. I guess the CONSORT group never thought about that, maybe it should be in the next version?

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