The Microbiome and NecrotiSing Enterocolitis

Posted on 6 October 2013 by Keith Barrington

Fortunately Pubmed speaks both English and American, if you search on Pubmed for necrotizing enterocolitis it also gives you articles about correctly spelt gut diseases in preterm infants as well. As a North American transplant my spelling has become a bit haphazard, so sometimes its hemoglobin sometimes haem…

This fascinating new article has examined the development of the stool microbiome in preterm sets of multiples. I was delighted to read that the stool was ‘salvaged directly from the nappy’ from 12 sets of twins and 1 set of triplets from birth until discharge.  Stewart CJ, Marrs ECL, Nelson A, Lanyon C, Perry JD, Embleton ND, Cummings SP, Berrington JE: Development of the preterm gut microbiome in twins at risk of necrotising enterocolitis and sepsis. PLoS ONE 2013, 8(8):e73465 (free access). Basically the authors took the stool, (and also some breast milk) extracted DNA, amplified the 16S rRNA gene and then figured out what kind of bugs were present; on a subset of samples they did pyrosequencing to get more detail (if that sounds like I know what I am talking about, I do a bit. We are currently collaborating with Kelly Grzywacz, a fellow in peds GI, and doing some similar stuff in a lactoferrin trial, we do unfortunately have to use diapers, we couldn’t get any nappies. More on that study when we get to publishing our results).

Twins had intestinal colonization that was more like their co-twin than the unrelated babies. They were also more like their own mother’s breast milk microbiome than other breast milk. One of the babies developed NEC, and 5 days before that the microbial diversity became much less, and was then significantly less diverse than the co-twin. The co-twin also had an episode of getting antibiotics, which led to a smaller reduction in diversity which then recovered.

There have been other studies showing similar things in the past as noted in a review article last year, although not all the studies have shown the same thing. They consistently show changes in the microbiome prior to development of NEC.  Wang Y, et al. (16s rrna gene-based analysis of fecal microbiota from preterm infants with and without necrotizing enterocolitis. ISME J 2009, 3(8):944-954.) also showed a reduction in bacterial diversity. Whereas Josef Neu’s group showed a change in bacterial patterns and the appearance of a new potential pathogen, but no loss of diversity.

It seems from this new study that a baby’s gut colonization is strongly affected by the mother’s microbiome, particularly the microbiome of her milk, more than the environment of the NICU, but then we can really mess that up with antibiotics.

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Not just a diagnosis; a baby, with a family.

Posted on 4 October 2013 by Keith Barrington

A new publication in Acta Paediatrica is written by 3 mothers (Thiele P, Berg SF, Farlow B: More than a diagnosis. Acta Paediatrica 2013 seems to be open access). All 3 of them have previously written about their experiences with the medical system following a diagnosis of a serious chromosomal abnormality, and the lack of support and compassion that they confronted. But no, I am not complaining about duplicate publication! I think these 3 highly educated and articulate women have experienced attitudes that remain unfortunately widespread, and their stories deserve the widest distribution. These 3 women, 3  mothers, are from 3 different countries on 3 different continents. But they have all experienced the same lack of comprehension and lack of, sometimes refusal to, help. The common thread in their stories was that they valued the life of their child, even though they knew that life would have serious limitations and would probably be very short. They valued the life of their child even though they had a diagnosis that has been referred to in the past as ‘universally lethal’ and even though some physicians have decided that instituting active care is ‘clearly against the child’s best interests’ and that physicians who do so are ‘abdicating’ their ethical responsibilities.

The mothers point out that they want, and have a right to expect, an approach to the care of them and their children which goes beyond identifying the diagnosis and then deciding that all children with such diagnoses will not receive medical interventions. I have been privileged to learn from these women and others with similar stories; it seems to me that all they want is to be treated, and have their children treated, as individuals. To have their wishes, desires, hopes, and values listened to and considered, to have all reasonable options explained and then take a decision, open and transparently shared with their caregivers.

I mentioned in a previous blog that I think that attitudes are changing, one of the comments that was left was ‘not here they aren’t!’ But because attitudes may be changing, that certainly does not imply that they are anywhere near what they should be, or that all caregivers are going to become thoughtful, compassionate and supportive.

Often parents have been told that ‘there is nothing that we can do for your baby’. Annie Janvier and Andrew Watkins have written an article accompanying the mothers’ stories (which also seems to be free access) in one section of it they talk about that frequently heard statement:

There is always something we can do. For some extremely fragile children with several major malformation and /or low birth weight, [life sustaining interventions] can indeed be quantitatively futile, but we can always be there to support families in these tragic moments. We can guarantee that we will do everything in our power to treat any pain of discomfort their child may have. We can tell parents that the most important thing is that this child has parents who care and love him. That we also hope that they will meet their child and be a family for a while. While it is important to not give unrealistic hopes to parents, we can assure them that we will do everything for their child to have the best life possible.

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Informed consent in the NICU

Posted on 26 September 2013 by Keith Barrington

I have watched most of the presentations at the OHRP meeting, so you don’t have to. Many of the critics of SUPPORT make the same mistaken assumption, that usual care in the NICU is to individualize oxygen saturation targets, I don’t understand why these people (in addition to the people I have criticized before, there are 2 adult ICU docs, and the founder and president of something called the Alliance for Human Research Protection, Vera Sharav) couldn’t be bothered to actually ask someone who knows?

I wouldn’t go to a public meeting to criticize a research project in adult hematology and state with confidence that there was no usual care arm in the trial without talking to someone who knew what usual care was! One of the adult ICU docs gives the example of a baby on high oxygen that has a saturation of 92% and states that the usual response would be to reduce the oxygen saturation goals in order to reduce the oxygen exposure. I don’t know how he practices, but I certainly don’t do that. I also didn’t do that for the 15 years that I worked in the PICU either.

Lois Shepherd, another JD who is a bioethics specialist, in her presentation states something like ‘some defenders of the SUPPORT consent forms think that standard of care research means that the study is comparing 2 interventions that are commonly used and within the bounds of good medical practice’ she goes on to state ‘the SUPPORT trial would not fit within that definition either’. As is usual for such comments, she gives no reference or data, but just makes the assertion. She is, of course, wrong.

Some of the presentations, such as the one by Professor Annas, really suppose that the patient is an independent agent who seeks a medical opinion to determine which treatment to have. In such a circumstance they have the right to examine the options available with the various risks and benefits of each alternative. It is based I think on the model of the adult getting a consultation in a doctors office, the one-on-one decision making that is familiar to anyone who has watched doctor movies from the 50’s. The team I lead in my NICU consists of around 500 people (nurses, auxiliaries, RTs, clerks, cleaners, doctors at all levels of training, professionals in other fields as well) who are responsible simultaneously for around 65 babies. A good proportion of those babies would be dead if it were not for the NICU.

In that situation, the model of informed consent, which is so crystal clear to Pr Annas that he doesn’t really understand the controversy, starts to become really murky. Each day on rounds, for a particular patient I might make 10 different decisions, about the rate of feed increase, and when feeds should be enriched; about whether we will wean the rate of the ventilator or the pressures; about whether I will stop the antibiotics, continue for another 3 days, or do a CRP to help me make the decision; about whether I will ask for an echocardiogram, and if the PDA is indeed patent will I start treatment; and so on and so on. I try to make those decisions based on the best available evidence, and to weigh up the risks and benefits of each alternative. Many of the decisions are guided by protocol, because there is some evidence on which to base a protocol, or if not, the protocol is in place because we just want to make an arbitrary agreement. So our feeding guidelines are a protocol for the commencement and advancement of feeds in preterm babies. Most often the protocol works fine, and I do not adjust it, on some occasions I will decide to change the rate of increase of the feeds for certain clinical reasons.

Maybe Annas and Lois Shepherd will consider me negligent, but I do not discuss most of those options with the parents! Most of those day to day decisions if there is no unit protocol are made based on best guesses, minimization of harm, etc. Each of them might indeed carry risks and benefits that are different to the alternatives. When it is likely that a particular decision changes the risks of important outcomes, then I discuss with the parents. As I wrote several years ago, for example, before giving steroids to a child with severe bronchopulmonary dysplasia we should discuss with parents the possible long term consequences, as well as the short term benefits. As both are to some extent predictable based on published evidence (despite its limitations).

Our patients are often at nearly 100% risk of death if we do not intervene with intensive care, so, in our initial discussion with the parents we will often say that the patient may die despite our efforts. But death is rarely directly a risk of the treatment they are receiving, we dramatically reduce the chance of dying by instituting intensive care. So in the daily decisions about treatment options, if we do not know which of 2 options has the better chance of survival, then how am I supposed to inform the parents about the ‘material risk’ of death (which Dr Annas uses as an example of a risk that must always be disclosed)? For most of my decisions the risk of death is probably not particularly different between the alternatives but other important outcomes might be, and there will be some risk of death whatever I do.

If I were to design a trial to compare different feeding protocols, because I am truly uncertain whether one might be better than the other (and there are many, many different protocols out there), then I would do that because an evaluation of the evidence shows that use of either protocol would be an entirely reasonable clinical decision, even in the absence of the trial. Also, it must be crystal clear, if a baby is not tolerating their particular protocol, and I think they should deviate from it, then that is what happens. Research or no research.

Some of the presentations at OHRP such as George Annas and the entirely over the top Vera Sharav (who is tearfully outraged that we study fragile preterm babies) seem to think that we become unthinking, uncaring automatons, blindly imposing research protocols on our helpless patients the moment the misleading consent form is signed. Well, no. The parents assent to NICU care for their baby, and place a great deal of trust in me to make many hundreds of small and large decisions for their babies. Even some of the larger decisions, such as an intubation for surfactant, are not discussed with the parent beforehand to obtain their consent if it is clearly in the best interest of the baby. If a research protocol imposes a course of action that is not in line with those interests then we deviate from it. Without worrying about it. Every large study has some protocol violations, many of those are because someone in the team thinks the study directed approach is not consistent with the best interest of the patient. Even after informed consent for the trial.

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Prebiotics, to support growth of Probiotics, and how to kill them

Posted on 25 September 2013 by Keith Barrington

Ishizeki S, Sugita M, Takata M, Yaeshima T: Effect of administration of bifidobacteria on intestinal microbiota in low-birth-weight infants and transition of administered bifidobacteria: A comparison between one-species and three-species administration. Anaerobe 2013, 23(0):38-44. In this study the investigators report 3 sequential periods in their NICU, one without probiotics, one with one strain of bifidobacteria (breve) and one with 3 strains of bifidobacteria (breve, infantis and longum). They gave 5 x 108 bugs for each strain so the last group got 3 times as many. The babies were 1 to 2 kg and feeding by 7 days of age, and got the germs for 6 weeks. They looked at the microbiome with culture rather than molecular techniques and found there was better bowel colonization with bifidobacteria when the mixture was used than the single strain. Also there were fewer clostridia when either probiotic regime was used, and fewer enterobacteriaceae with the mixture.  It was a small study with about 14 babies per group, so no clinical differences would be expected.

Serce O, Benzer D, Gursoy T, Karatekin G, Ovali F: Efficacy of saccharomyces boulardii on necrotizing enterocolitis or sepsis in very low birth weight infants: A randomised controlled trial. Early Human Development 2013. This is the second published randomized study of saccharomyces, a probiotic yeast, in preterm infants, showing no benefit on NEC or sepsis. This could be a problem of power, as there were ‘only’ 208 babies in the trial and a lowish rate of NEC (7%) but it looks like we shouldn’t bother investigating single-strain probiotic administration with this yeast any further. I believe there is another trial that has been presented but not published as yet, also showing no benefit, but I don’t know any details.

Westerbeek EAM, Slump RA, Lafeber HN, Knol J, Georgi G, Fetter WPF, Elburg RM: The effect of enteral supplementation of specific neutral and acidic oligosaccharides on the faecal microbiota and intestinal microenvironment in preterm infants. Eur J Clin Microbiol Infect Dis 2013, 32(2):269-276. This was an RCT of prebiotic supplementation with the molecules noted in the title. They found that prebiotics in the milk did indeed increase intestinal colonization in 113 VLBW infants, compared to placebo. The biggest effect though was the use of broad spectrum antibiotics, which wreck all the bugs in the gut.

Gupta RW, Tran L, Norori J, Ferris MJ, Eren AM, Taylor CM, Dowd SE, Penn D: Histamine-2 receptor blockers alter the fecal microbiota in premature infants. Journal of Pediatric Gastroenterology & Nutrition 2013, 56(4):397-400. A case control study of infants from a prospective evaluation of normal microbiome development in the preterm. Of the 76 babies in the study there were 25 who had received H2 blockers for a mean of 19 days before the stool sample. None of them had recently received antibiotics. The babies that were on H2 blockers had less bacterial diversity, more Proteobacteria (some of which are bad)  and fewer Firmicutes (some of whom are good, including lactobacillae). The authors don’t talk about the Actinobacteria which includes Bifidobacteria.

As the authors state:

Many Proteobacteria, especially of the family Enterobacteriaceae, are known pathogens, such as Klebsiella, Shigella, Escherichia coli, Citrobacter … They are Gram-negative, facultative anaerobes, often motile, and capable of producing toxins, adhesins, and capsular antigens. They have the ability to undergo antigenic phase variation, type III secretion, and exchange antimicrobial resistance genes. Some have been associated with epidemics or anecdotal cases of NEC. An overabundance of such organisms in an immature GI tract is cause for concern.

I was happy to note tonight doing rounds, that, as usual, there isn’t a single preterm infant in the intensive care part of my unit who is receiving an H2blocker, or a PPI. Gastric acid is there for good reasons.

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Maybe CRPs are not CRaP? Not entirely convinced yet.

Posted on 25 September 2013 by Keith Barrington

This is  a nicely done study, with interesting data, but I am not sure I agree 100% with the conclusions.

Lots of newborn babies get antibiotics for suspected infection, they are usually stopped at 48 hours if the cultures are negative, which is much the most frequent outcome. New recommendations are to stop the antibiotics at 36 hours if the cultures are negative, and the baby is without signs of sepsis.

The authors of this study measured CRP with a bedside machine at 18 hours and then kept the results masked from the caregivers. The idea was to see if using a negative CRP was sufficiently predictive that antibiotics could be stopped earlier, after about 18 hours. There were preterm, late preterm and term babies in the study, 1202 of them. Which makes it quite big. There were 16 babies who actually had positive cultures. Which shows how many babies are unnecessarily exposed to antibiotics. In addition there were 107 babies who are called possible sepsis, as their mothers had received antibiotics and they were treated for more than 72hours. Most of the possible sepsis babies were probably not infected, but some may have been.

The CRP threshold that was used was 10 mg/L. Of the babies with an elevated CRP, only 14% had possible or proven sepsis, and under 3% had proven sepsis. Demonstrating once again the low specificity of CRP. There was only one infant with definite early onset sepsis who had a negative CRP, but another 43 who may have been infected, using their definition. Interestingly the negative CRP may be more useful for the late preterm and term baby, as all the babies more 34 weeks gestation who were asymptomatic at 18 hours of age and who had a CRP less than 10 were uninfected except one, whose mother had a positive blood culture.

The reason I say in the title of this post that I am not yet convinced is that it seems to me that there is a great risk that there will be unnecessary prolongation of antibiotic courses in uninfected infants if this becomes a routine. I am also not sure about the definition of possible sepsis, it is a real dilemma whether to start and or continue antibiotics in such infants. Many mothers are treated for fever, which becomes frequent the longer an  epidural is in place, many of the mothers don’t have a blood culture done, or other accurate investigations for serious infections.

Anyway overall this confirms what I thought about CRP, that they are very non-specific, but fairly sensitive. If you just focus on proven sepsis in infants who were 35 weeks or more, the sensitivity was 100%. I think it is likely that many of the ‘possible sepsis’ babies did not have sepsis, which is why there was little inflammation. They can be most helpful then in deciding to stop antibiotics (or sometimes making you feel more comfortable about a decision not to start them).

This study also makes me re-question the advice that I wrote about before from NICE, who suggest a CRP at baseline and then a repeat at 12 to 18 hours. I think this study suggests to me that the initial CRP would be a waste of time, if  you are going to do one, and you decide that a low CRP will change your management decision, then you should probably just do one, and do it at 18 hours after starting treatment.

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Fuzzy Images

Posted on 20 September 2013 by Keith Barrington

The title of this post I stole from the title of a newly published article (Mann PC, Woodrum DE, Wilfond BS: Fuzzy images: Ethical implications of using routine neuroimaging in premature neonates to predict neurologic outcomes. The Journal of pediatrics 2013, 163(2):587-592).

The commentary is a critique of the common practice of performing routine head ultrasounds in the first few days of life to predict long term outcomes in very preterm babies.

As I have noted here before, there is very little good data to support the practice. Head ultrasounds are poorly predictive of neurological or developmental problems, and are of no proven value for prediction of serious impairments.

In addition the large majority of studies that have compared head ultrasound results with outcomes have examined the children much too early to make good long term predictions, and (you might be able to guess what I am going to say next) a low 2 year score on the Bayley MDI scale is not an impairment! There is a recent meta-analysis of all the data that the authors could find comparing Bayley scores, mostly performed around 24 months, to later outcomes. They showed that the MDI correlated poorly with later testing, and that variation in MDI explained only 37% of the variation in IQ.

The commentary refers to one of the few follow-up studies of a largish cohort of very preterm babies who had intracerebral hemorrhages (referred to in the original article as periventricular hemorrhagic infarction, and in this commentary as grade 4 IVH) who examined the children at school age. That study from Roze and colleagues in Groningen in the Netherlands, including the extremely productive Arie Bos, showed that although many of the children had a diagnosis of cerebral palsy (16 of the 21 children) there were only 3 who had a GMFCS of 3 or worse. Meaning that the remainder were able to walk. Only 2 of the 21 had a cognitive outcome worse than 2SD below average. These 21 children were from an initial number of 38 infants who had periventricular hemorrhagic infarction, the remainder we are told ‘died in the neonatal period’. Now what that might well include are a number of infants who had withdrawal of life support because of the head ultrasound findings. It is possible that the infants with the worse appearance on head ultrasound were among that group, so we can’t in any of the studies really know what is the prognosis of all babies with this type of lesion, because there are some non-survivors in all of the studies, and it is rarely made clear if life support was withdrawn. In fact the group from Groningen have published a previous report which seems to include the infants in their newer paper, with a follow up to 24 months of age. In that paper they note that there were only 2 infants who died as a result of withdrawal of life support, so it is not such an issue for this cohort, but in some cohorts it could be much more important.

Despite that limitation there are now several studies that show very little effect of intracranial bleeds on outcomes of very preterm babies; including for example another paper by Roze and Bos, a study which followed 106 very preterm babies to school age, and showed ‘The children with cerebral lesions (grade III intraventricular haemorrhage and periventricular haemorrhagic infarction) had similar scores to those without cerebral lesions on total IQ and the Movement ABC’. Also interestingly ‘IQ scores did not correlate with gestational age’ the babies who were born at 24 and 25 weeks had scores not different to more mature babies.

To go back to the commentary by Mann, their introductory section ends with this sentence

We encourage neonatal practitioners to reconsider whether the perceived screening benefits are valid and the prediction of NDI definitive.

I think they present plenty of reasons to make that sentence much stronger: ‘screening head ultrasounds are of no proven value as predictors of important neurological or cognitive impairments, and it is therefore ethically questionable to use them for decisions regarding life sustaining interventions.  They should be performed only to screen for treatable lesions such as post-hemorrhagic ventricular dilatation.’

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Nous sommes à la télévision!

Posted on 20 September 2013 by Keith Barrington

Yesterday evening on “télé-québec” the first 22 minutes or so were about prematurity; it was all shot in our NICU, and features several members of the team here, nurses, a nurse practioner, neonatologists, RTs and parents. It think it turned out well.

If you want to watch the link is below, although you may well have to sit through an advert when it starts, it is also all in French.

Un reportage sur la prématurité, émis hier soir sur la chaîne ‘télé-québec’. Filmé dans notre unite à Sainte-Justine. Lien en bas, peut commencer avec une publicité.

http://zonevideo.telequebec.tv/media/6912/naitre-a-24-semaines/une-pilule-une-petite-granule

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C’est inSUPPORTable!

Posted on 19 September 2013 by Keith Barrington

A new publication about SUPPORT? Haven’t we heard enough?

Well no, this is fascinating, although not entirely unexpected if you think about it.

One of the 2 comparisons of the SUPPORT trial involved randomization to be either immediately intubated to receive surfactant, or to attempt to keep the baby extubated and on CPAP, unless they exceeded 50% oxygen, or just weren’t able to breathe. At the time, some centers were intubating routinely, based on older trials which showed benefit, but which did not use what we now consider best treatment in their comparison groups. Some centers were trying to keep babies on CPAP, based on prior data from the COIN trial, and on accumulating experience elsewhere. In other words this also was a comparative effectiveness comparison, both approaches were considered within acceptable medical care approaches and both were in common use.

Some centers in SUPPORT had less experience with avoidance of intubation, and starting early CPAP in the DR, so when SUPPORT was active they started to gain more experience with that approach.

This new article shows that babies who were not actually in the trial, but were born in a participating hospital while SUPPORT was being carried out, ended up being treated differently than before the trial.

LeVan JM, Wyckoff MH, Ahn C, Heyne R, Sánchez PJ, Chalak L, Jaleel MA, Burchfield PJ, Christie L, Soll R et al: Change in care among nonenrolled patients during and after a randomized trial. Pediatrics 2013.

Babies born at the Parkland hospital who were under 28 weeks were intubated in the DR 85% of the time before SUPPORT, babies who were not in  the trial were intubated 61% of the time while the trial was on-going, and after SUPPORT had ended the frequency stayed at 61%. This wasn’t a change that everyone adopted at the same time, babies in the Vermont Oxford Network, not involved in SUPPORT, over the same interval did not have much change in their intubation frequency.

This ‘spill-over’ effect is not unexpected, (it is one of the reasons that we sometimes do cluster randomized trials) but this is a very clear example.

One implication of this is that we will need to have an informed consent process for all the non-enrolled patients in clinical trials. As has been pointed out, consent for research and for clinical care have the same requirements, so we will need to inform parents that there are trials gong on in our NICU at the present time, which may change the care that their babies receive whether or not they are enrolled in the trial. Maybe also the consent forms for the trials should have a section which notes that, even if the parents refuse the trial, the performance of the trial might change how their baby gets treated anyway… so they might as well sign up to the trial! How could this happen? Surely doctors know what is optimal care, how could the fiduciary obligation of a doctor to provide optimal care to his patients, who are not in a trial, be affected by a trial being performed? (Paragraph written with tongue firmly planted in cheek: if you are not a native english speaker that means that I am not really serious).

This is still more evidence that we are already in a learning health care system, approaches to care change as a result of many factors other than published best evidence, when you have more exposure and more experience with a particular approach you may start to use it more, even if the evidence does not (or not yet) show substantial advantages. Maybe this is appropriate, maybe not, but it is a reality of modern health care.

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Neonatal Updates #37

Posted on 18 September 2013 by Keith Barrington

Hough JL, Johnston L, Brauer S, Woodgate PF, Schibler AF: Effect of body position on ventilation distribution in ventilated preterm infants. Pediatric Critical Care Medicine 2013, 14(2):171-177. Regional ventilation was measured using computed impedance tomography. The researchers found no effect of gravity on the distribution of ventilation, consistent with their previous work in infants on CPAP or health term babies. The babies were not very sick, with mean O2 requirements of 26%, and no difference in oxygen needs when they were placed prone or supine. It is frequent in babies with sick lungs to find that their oxygen needs a reduced in prone position, perhaps gravity has an effect on the distribution of perfusion, which becomes important in improving VQ matching when the lungs are sick. There are also fewer desaturation events in prone position.

Kidokoro H, Neil JJ, Inder TE: New mr imaging assessment tool to define brain abnormalities in very preterm infants at term. American Journal of Neuroradiology 2013. One of the difficulties in assessing the literature regarding MRI imaging in the preterm infant is that everyone reports them differently, so it is difficult or impossible to compare them. What we need is some sort of standardized reporting system. Behold! Terrie Inder and her group have come up with just that. Lets hope it catches on.

Filippa M, Devouche E, Arioni C, Imberty M, Gratier M: Live maternal speech and singing have beneficial effects on hospitalized preterm infants. Acta Paediatrica 2013, 102(10):1017-1020. Cool: Sick preterm babies have fewer apneas and hypoxic events when their mothers sing to them or talk to them.

Serce O, Benzer D, Gursoy T, Karatekin G, Ovali F: Efficacy of saccharomyces boulardii on necrotizing enterocolitis or sepsis in very low birth weight infants: A randomised controlled trial. Early Human Development 2013 Just over 200 VLBW babies were randomized to a probiotic fungus or control. No benefits were shown, either in reduction of NEC or in sepsis or mortality.

Ruano R, da Silva MM, Campos JA, et al: Fetal pulmonary response after fetoscopic tracheal occlusion for severe isolated congenital diaphragmatic hernia. Obstetrics & Gynecology 2012, 119(1):93-101 It is starting to look like this might actually work. The group in Sao Paolo are now reporting some outcomes from two small randomized trials, with a total of  just over 70 patients randomized. Fetuses had very severe pulmonary hypoplasia, with an observed to expected Lung/Head ratio below 25% and the liver herniated. Only 5% of the controls survived, and over 50% of the intervention group. The particular technique used requires a fetoscopic laryngoscopy, with occlusion of the trachea by balloon, followed, usually by an EXIT procedure, although they have sometimes done a second fetoscopy to remove the balloon. The report of the second trial is free access and has neat pictures. The same group has also done some earlier procedures also with some success. With this approach the gestational age at delivery was pretty close to term on average at 35 + weeks, which is also better than previous reports. If other centers can replicate this success, then we are on our way.

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What are the responsibilities of clinical researchers?

Posted on 18 September 2013 by Keith Barrington

One of the presentations at the OHRP hearings of the HHS was by George Annas, a JD who has an MPH (for those outside of north america that means he is a lawyer, but with a masters in public health). He is an influential figure who made the following statement (or something very like it) ‘physicians have a fiduciary obligation to their patients to provide optimal care; researchers have no such obligation.’ He was very emphatic.

He is also wrong.

In neonatology at least, the big majority of trials are performed by physicians who are also researchers. There are a few trials led by epidemiologist/trialists, but even in those trials the local investigators are almost always neonatologists. So what are our ethical responsibilities as clinicians who are also researchers? I think they still include the obligation to provide optimal care, an obligation that has to take into account, as it does in daily clinical practice, the fact that we often do not know what is the optimal treatment. Thus in the NICU, in identical situations, I might choose one treatment one day, and another treatment on the other. That can be consistent with all of my fiduciary obligations, whether I do that because the fellow has made a good argument for one treatment rather than another, and I can’t find any evidence to counter their argument, or because the parents prefer one treatment rather than another, and both are acceptable alternatives, or because it didn’t go well last time, or the phase of the moon has changed…

Professor Annas doesn’t really address that problem in his presentation, but it is addressed in the question session. He doesn’t, however, answer the question when it is posed, he talks about how important people feel it is to be able to choose their own physician. But even if preterm babies chose me as their physician (that really isn’t how it works, by the way) I still often don’t know what is best to do! Annas states that he doesn’t believe that physicians don’t know anything, and that every treatment decision is not a flip of the coin. But nobody said that. Many treatment decisions are evidence based, and many are proven to be better than alternative options. So if a preterm baby with HMD needs to be intubated and still has significant needs for oxygen, we know very well that they should get surfactant. If a full-term baby with hypoxic respiratory failure has an OI that is greater than 25 they should get inhaled NO; whoever they choose to be their doctor, the choice of treatment should be the same. That also has nothing to do with the ethics of uncertainty. Also, in many health care systems you don’t get to choose your doctor, or at least you rarely have an unrestricted choice. In the USA you don’t get an unrestricted choice either, and a baby in an NICU (and his family) really has little or no choice of doctor. That doesn’t change that fiduciary obligation.

Annas talks about the case of the law suit brought in the 80’s by someone who became blind as a result of high O2 levels when he was randomized (with no consent process at all in those days) to the high arm in one of the O2 trials in the 50’s. He describes this atrocious ophthalmologist who repeatedly examined the eyes of the baby every week, watching him going blind and doing nothing about it. He describes this as if it were a case of some ‘Nazi-like’ (my characterization, not his) medical experimentation, and comments that he could only have acted like that if he saw himself as a researcher, and not a physician. But in reality, he could have acted like that while being both, for what was the doctor supposed to do? There was no proof that higher O2 was the cause of RoP, many people doubted it, and there were cases of RoP in both the high oxygen and the low oxygen arms of the trials. Turning down the oxygen would not necessarily have had any effect on the progression of the eye disease (indeed the, much later, STOP-ROP trial showed that it does not). Another baby in the same NICU who was receiving the, then standard, treatment with very high oxygen and also getting repeated eye exams would have been receiving exactly the same care as the baby in the trial, despite being in a ‘fiduciary relationship’ with their physician! And, furthermore, there was no effective treatment; Cryotherapy was not available then, there was nothing anyone could do except watch the retina deteriorating.  Professor Annas has his retrospectoscope on high power, which has created substantial distortion: he seems to think that all the babies in the high oxygen arm of the trial went blind, that switching to low oxygen would have saved the baby’s eyesight, that the doctors knew this and that they were just doing the trial to have a nice publication in order to get famous.

So while I agree that I have a fiduciary obligation to provide optimal treatment, I also have a moral obligation to know what the optimal treatment is, and to know when more than one treatment is equally ‘optimal’, by which I mean equally supported by the current evidence.  I also, simultaneously, have a moral obligation as a researcher to keep trying to find out what the best treatments may be.

I also think that a non-physician investigator, for example Pr Annas, if he decided to do a clinical research project, also has a moral obligation to ensure that the patients in his study are receiving optimal treatment. No-one in a trial is simply a guinea-pig. No-one as a trial subject loses their rights as a person to receive good care. Comparative effectiveness research is a waste of time and money, and is indeed unethical, if we already know that one arm of the trial is optimal therapy and the other is not.

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