‘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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Neonatal Updates #30

Posted on 19 April 2013 by Keith Barrington

Ichinohashi Y, Sato Y, Saito A, Ito M, Watanabe K, Hayakawa M, Nakanishi K, Wakatsuki A, Oohira A: Dexamethasone administration to the neonatal rat results in neurological dysfunction at the juvenile stage even at low doses. Early Human Development 2013, 89(5):283-288.Dexamethasone, even at a dose considered low for a baby rat, affects brain structure and function in later rat life. First implication is that we shouldn’t give dexamethasone to a rat, unless we want to stop its brain growing and give it learning disabilities, which we probably do want, so maybe we should give dexamethasone to rats. Second implication is that this might be the mechanisms for the problems with dexamethasone in the human, and the same model might give us a clue whether other steroids could be safer.

Kilicdag H, Daglıoglu K, Erdogan S, Guzel A, Sencar L, Polat S, Zorludemir S: The effect of levetiracetam on neuronal apoptosis in neonatal rat model of hypoxic ischemic brain injury. Early Human Development 2013, 89(5):355-360. Another rat brain study, using the Bob Vannucci model of unilateral carotid artery ligation with hypoxia, shows some brain protection with this new anti-epileptic agent. Many years from clinical use, but this looks possibly hopeful, and you saw it here first.

Kumagai T, Higuchi R, Higa A, Tsuno Y, Hiramatsu C, Sugimoto T, Booka M, Okutani T, Yoshikawa N: Correlation between echocardiographic superior vena cava flow and short-term outcome in infants with asphyxia. Early Human Development 2013, 89(5):307-310. Returning to humans this study showed that asphyxiated babies with a poorer short term outcome had SVC flows that were quite a bit higher than those with good outcomes, and that during cooling the differences were accentuated. The numbers were very small, however.

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words fail me

Posted on 19 April 2013 by Keith Barrington

Living not far from the USA but having a much lower rate of gun crime, I am astonished by the success of the gun lobby in the US. Despite 90% of the public being in agreement with the very modest (indeed totally inadequate) proposals in the Senate recently, to see them fail is very disappointing, to me and to anyone who cares about children’s health.

An excoriating item from a US author on his website.

davidsimon.com/dead-children-and-monied-politicians/

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Supporting SUPPORT

Posted on 18 April 2013 by Keith Barrington

A great editorial in the PNEJM today from Jeffrey Drazen, he deconstructs the OHRP ruling about the SUPPORT trial consent form. He ends with this phrase ‘We are dismayed by the response of the OHRP and consider the SUPPORT trial a model of how to make medical progress’.

Also yesterday the PNEJM published a letter from the investigators of the SUPPORT trial. Wally Carlo and colleagues note ‘The infants in both treatment groups had lower rates of death before discharge (16.2% in the higher-oxygen-saturation group and 19.9% in the lower-oxygen-saturation group) than did those who were not enrolled (24.1%) and historical controls (23.1%), and rates of blindness did not differ between the treatment groups.’ So one of the major criticisms of the OHRP which is : ‘It would have been appropriate for the consent form to explain (i) that the study involves substantial risks’ is shown to be baseless, participation in the trial was less risky than not participating.

Even the higher mortality group, the lower saturation group, had lower mortality than the non-enrolled infants, and lower than the historical controls.

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No ethical breakdown here

Posted on 16 April 2013 by Keith Barrington

As I mentioned at the end of my first post about this, the New York Times have jumped into the fray with an editorial entitled ‘An ethical breakdown‘ published today.

They take as ‘gospel’ the OHRP findings concerning the study, and show their lack of understanding of this kind of research, they note the following:

But, in this case, the federal Office for Human Research Protections concluded that the consent forms failed to reveal that there was a greater risk of dying in the low-oxygen group and a greater risk of severe eye damage in the high oxygen group. The form also stated that, because both groups would receive oxygen within the standard of care, there would be no predictable increase in risk no matter which group a baby was in.

But the federal agency found that many infants could have faced greater risks by participating. For example, if a baby whose clinical needs might ordinarily have led doctors to deliver a relatively high level of oxygen was enrolled in the study, the infant might be randomly assigned to receive lower levels of oxygen.

It is obviously much more understandable that a journalist does not comprehend the issues, but they lay out in those two segments the findings of the OHRP, which points out how misguided they are. The consent form could not reveal those different risks, because we didn’t know about them before the trial. The idea that neonatologists somehow know which baby has clinical needs that require a higher level of oxygen, and that the baby might be denied that because of the study would be concerning if it were true, but it is not. Firstly we did not have any reason for choosing one level of oxygen over another, as there had been no prior studies to help us choose. Secondly if there were such a situation the ethical imperative is to take the baby out of the study and treat them according to their clinical needs. There is no reason to believe that would not have been done to these babies; it is reported as a protocol violation, and counted at the end of the study.

Earlier on in the editorial they report the usual saturation limits used in most US NICUs as being 85 to 95%. They don’t seem to realize that the ranges tested in SUPPORT were all within those limits.

I am very concerned about this ruling, (as you can see from 3 posts). I think it is a stain on the reputation of the researchers, it calls into question the integrity of their IRBs, and puts at risk other clinical research in the NICU which might possibly be shown to have unexpected outcomes. Furthermore the other oxygen studies, including COT which will be presented at this year’s PAS meeting, will likely also be tainted by association.

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How to show you don’t understand research in critical patients

Posted on 16 April 2013 by Keith Barrington

To continue with my diatribe about the OHRP decision concerning the SUPPORT trial:

At one point in the document sent to the University of Alabama, the OHRP quote an editorial by Jay Greenspan:

‘…Although maintaining ranges of hemoglobin oxygen saturation in the vulnerable preterm population in the proximity of 85% to 90% is gaining increasing acceptance, marked variability in opinion exists.”  In short, the research and data analyses that had occurred prior to the SUPPORT study demonstrated that the use of higher versus lower levels of oxygen could significantly affect the likelihood of a premature infant developing ROP and other aspects of morbidity and mortality.’

Although they quote the editorial they clearly show by this statement that they have not understood it. All of the research and the analyses prior to support demonstrated that it was completely uncertain whether the use of higher versus lower levels of oxygen could significantly affect the likelihood of a premature infant developing ROP and other aspects of morbidity and mortality. They also refer to the Cochrane review of oxygen therapy in the preterm infant. Again they have not understood this sentence, the final one of the abstract

‘The results of this systematic review confirm that (the now historical) policy of unrestricted, unmonitored oxygen therapy has potential harms without clear benefits. However, the question of what is the optimal target range for maintaining blood oxygen levels in preterm/LBW infants was not answered by the data available for inclusion in this review.’

As I noted in the previous post, the prior studies were completely uninformative for modern neonatology.

Further on in this letter the OHRP notes that the study

‘specifically enrolled very premature infants and randomized them to one of two levels of oxygen. For many of those infants, the level of oxygen they received was different from what they would have received had they not participated in the study’

This seems to be the crux of the OHRP argument, because we had no idea if either of these ranges were preferable, and therefore some babies were haphazardly being exposed to higher or lower oxygen targets in their NICUs, it was somehow problematic to systematically randomize them. That is, doing this ethically, and collecting the data was somehow worse than allowing the on-going uncertainty. Because some babies who would have had high sat ranges with an increased risk of RoP, would instead have received less oxygen to achieve low saturations with an increased chance of dying. And vice versa.

The OHRP notes that the consent form includes the following: “It is possible that using lower pulse oximeter ranges will result in fewer babies with severe Retinopathy of Prematurity (ROP).” But then they castigate the investigators for not saying ‘that being in the upper range group may result in the greater risk of developing ROP.’ Now I don’t know about you, but if being in the lower range may decrease the risk, then it seems self-evident that the contrary is true!

I know that the early history of clinical research was sullied by several examples of unethical research practice, and that we need to protect human subjects. I know that introducing new medications and innovative practices do need to be carefully regulated to avoid the patients and parents that voluntarily participate in our trials being harmed.  But the standards for consent to participate in research comparing 2 differing standard approaches, either of which is within the limits of usual clinical practice, and which are in current use in NICUs with high quality care, have to be different.

If not how will we determine whether volume ventilation is really better, in terms of important clinical outcomes, than pressure ventilation; or whether permissive hypotension is better than treating everyone with a low blood pressure with dopamine? Sure it may turn out that pressure ventilation is associated with higher mortality, or with lower mortality. We don’t have any reason to believe that right now, but the only way to be sure is to do good research like SUPPORT.

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