A CPS statement thought experiement

Its been a while since I ranted about the CPS position statement regarding decision making around extremely preterm delivery. But I am currently in Europe where certain countries have specific thresholds for willingness to provide intensive interventions, thresholds which are somewhat more rigid than the guidelines of the CPS, which are often ignored. This made me think (dangerous I know) about what justification you could have for giving a specific threshold in completed weeks of gestational age below which stabilization and active intensive care for an extremely preterm baby would not be offered.

I think that for such an approach to be rational you would need 2 things, you would need to be able to know the gestational age with certainty, and you would also need to show that there was some substantial change in outcomes (survival or another outcome that you thought was important) at that precise moment. Then you could justify intervening at say 24 weeks and 0 days, but not at 23 weeks and 6 days. Or using the threshold of the CPS position statement, be sometimes willing to offer intervention at 23 weeks and 0 days, but never at 22 weeks 6 days.

We know that the second criterion is not satisfied, there is no step-wise change in outcomes at any particular date, and certainly not at the end of an arbitrary 7 day cyclical period known as a week. There is a gradual progressive change in survival with advancing gestational age, and major effects of birth weight, sex and other variables. In contrast there is little or no effect of gestational age on long term neurodevelopmental outcomes among survivors.

Which led me to think of the following story:

Suppose a mother pregnant with twins following IVF was in threatened labour. She has passed 22 weeks, and has been seen by the neonatologist. She wishes institution of intensive care, but is told by the neonatologist that it is not an option before 23 completed weeks; the consensus of the hospital where she is being looked after is that they should follow the CPS guidelines, and be prepared to intervene actively at 23 weeks, (but only after the mother has had the litany of possible negative outcomes related to her), whereas prior to 23 weeks, life-saving interventions are not offered.

Her contractions continue and the cervix dilates.  Just before midnight on the day she reached 22 weeks and 6 days she delivers a little girl, who is placed in her arms for comfort care. 30 minutes later, just after midnight, the little boy delivers, and is intubated and taken to the NICU.

Would you actually do that? If you were to follow the CPS statement, the answer should be yes. Even if you are prepared to be flexible with twins, and treat them as a ‘package deal’ what about 2 mothers in adjoining rooms who deliver before and after midnight?

And what if the next day the mother comes to you and tells you that she had the Egg retrieval for her IVF at 2 pm in the afternoon. Oh no! The boy is actually only 22 weeks 6 days and 14 hours! We should not have intervened, maybe we should switch to comfort care…

You then find out that mother is referring to the original egg retrieval a couple of years ago, the obstetrician had known that and calculated the dates from the transfer of her embryos, which had been done at midnight because of a power failure during the day. Phew! So she really was exactly the gestation that they thought. we did the right thing after all.

The next day the obstetrician phones you sheepishly, to tell you that the mother actually had transfer of 5-day blastocysts not 3-day embryos. Which means that she had been actually 2 days further advanced in her pregnancy than they thought, so the little girl had actually been 23 weeks and 1 day gestation. So she should have been offered intensive care… Too late now.

This may seem absurd, but arbitrary limits to intensive interventions based on completed weeks of gestational age lead to such absurdities. When you add in the uncertainties of gestational age, the absurdities are multiplied.

This is a plea to recognize messiness. There are too many unknowns, and too many variables to have simplistic rules. Some of the variables can be quantified with precision, such as birth weight, some can be quantified but are imprecise (gestational age), and some can not be quantified at all, such as the values of the parents. We have to do the best we can, for the families we care for, making the best decisions possible in the uncertainties of real life.

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Brain Food for Preterms

All food is brain food when your brain is making 250,000 new neurones every minute.

In a small two-center trial first published in 2013 50 very preterm babies were randomized to different parenteral nutritional intakes. The main differences between the groups were that the controls started at 2 g/kg/d of protein, compared to 3.5 in the intervention group. The controls started at 0.5 g/kg/d of lipid given as ClinOleic, the intervention group started at 2 of SMOFLipid; both gradually increased to a max of 3.4. One they were receiving 110 mL/kg/d of milk the fortification was different between the groups, with the enhanced group getting an extra 0.8 g/kg/d of protein, to achieve 4.4 g/kg/d, and getting extra omega 3 fatty acids to arrive at a total of 166 kcal/kg/d, compared to 146. (which is a whole lot of calories!)

Unfortunately the planned sample size was not achieved, the study was stopped early because there was more sepsis in the enhanced nutrition group (p<0.04). Stopping a trial for a barely significant difference between groups is really not a good idea, but it is often a difficult decision, especially when the difference is an important adverse outcome. The primary outcome was post-natal growth restriction. The authors were following a number of secondary outcomes as were the data monitoring committee. The risk that one of those outcomes will be ‘statistically significant’ at some point during the data accumulation is enormous. That is why stopping rules should be much more stringent than that. Of course if you continue the study and it turns out that there really is more sepsis at the end of the study, you may then be criticized, and you might feel bad.  You might indeed face totally ridiculous criticisms similar to those that were directed at the SUPPORT trial by Public Citizen, who don’t understand how interim analyses work.

Having said that the authors published a second paper with the growth data; because of the small sample size there was a difference in the birth growth variables between groups, which actually favoured the controls, more SGA babies in the enhanced nutrition group. Despite this there were significant advantages of the enhanced protocol. None of the non-growth restricted babies in the intervention group became growth restricted, compared to 1/3 of the babies in the control group. The z-scores for weight dropped by about 0.3 for the intervention group, between birth and 30 days of age, and by about 0.7 in the controls. Head growth was also better.

A subset of the infants had MRI performed at term, which has just been published, and which is why I am writing this post. Strømmen K, Blakstad EW, Moltu SJ, Almaas AN, Westerberg AC, Amlien IK, et al. Enhanced Nutrient Supply to Very Low Birth Weight Infants is Associated with Improved White Matter Maturation and Head Growth. Neonatology. 2015;107(1):68-75. (yes its the first article of 2015 on the blog). There were differences between the groups. Which is about as much as I can say about head MRI, the mean diffusivity was lower in the intervention group. Which is good, apparently. In just about every region of the brain there were significant differences in what I shall from now on refer to as MD, as if I knew what I was talking about.

So give more food. It makes the babies grow better, including their head, and it improves their MD, which is a good thing to do.

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It’s not enough to be good

You have to keep practicing as well.

The way our health systems are organized has impacts on outcomes. Multiple small centers doing complex surgery and looking after fragile patients only infrequently will likely have poorer outcomes overall. Large centers which gain experience in those procedures, which develop protocols and approaches, and practice frequently are likely to do better, by which I mean to have more babies who are alive at the end.

It seems so self-evident, that to keep saying it should be redundant, but it isn’t; despite all the evidence that is out there, we still see a deterioration in regionalization, some of which is driven by the idea that the medicine is just a business like any other, so we should let the market decide who is going to do critical procedures. The idea, I guess is that if a center kills enough babies, then eventually they will receive fewer referrals.

Or you could take a different approach and say that highly critical care should be restricted to a few centers, and other centers should not be allowed to do those procedures.

These two new publications address this issue.

Karamlou T, Jacobs ML, Pasquali S, He X, Hill K, O’Brien S, et al. Surgeon and Center Volume Influence on Outcomes After Arterial Switch Operation: Analysis of the STS Congenital Heart Surgery Database. The Annals of Thoracic Surgery. 2014;98(3):904-11.

The arterial switch procedure is highly demanding, both in terms of technical skills of the surgeon, and peri-operative support. This article confirms that both the volume of the surgical center and the number of cases performed per surgeon are important in survival rates.

Kastenberg ZJ, Lee HC, Profit J, Gould JB, Sylvester KG. Effect of deregionalized care on mortality in very low-birth-weight infants with necrotizing enterocolitis. JAMA Pediatrics. 2014.

The progressive de-regionalization of neonatal care in some parts of the USA has led to multiple small units with little experience looking after critically ill babies. These data show that high volume, high-level NICUs have significantly lower mortality for infants suffering from NEC.

Which is consistent with a recent article from the EpiCure2 study that I already blogged about, showing that overall, tertiary centers have better outcomes for tiny babies than centers without tertiary NICUs.

None of which should be surprising, but the implications for the organization of our health care are often ignored.

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Neonatal Updates

I haven’t done one of these for a while, getting too verbose I  guess, but here is a selection of interesting recent articles with just a few sentences about them.

Mola-Schenzle E, Staffler A, Klemme M, Pellegrini F, Molinaro G, Parhofer KG, et al. Clinically stable very low birthweight infants are at risk for recurrent tissue glucose fluctuations even after fully established enteral nutrition. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014. VLBW and ELBW babies continue to have unstable blood sugars, with low and high values even when you think it was safe to stop monitoring them so closely. What do we do about this? I sure don’t know.

Okumus N, Beken S, Aydin B, Erol S, Dursun A, Fettah N, et al. Effect of Therapeutic Hypothermia on C-Reactive Protein Levels in Patients with Perinatal Asphyxia. American journal of perinatology. 2014(EFirst). Asphyxiated babies under hypothermia have elevated CRP. Asphyxia, and/or cooling is one of the many things that makes your CRP rise.

Hauglann L, Handegaard BH, Ulvund SE, Nordhov M, Rønning JA, Kaaresen PI. Cognitive outcome of early intervention in preterms at 7 and 9 years of age: a randomised controlled trial. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014. At 7 to 9 years of age the authors could find no benefit of their early intervention program on cognitive outcomes. I do not think this means that we should ditch the programs. They will be harder to justify, but I think we should still be helping families to learn how to help out their premies at home, and we need to focus on subgroups that have ore benefit, which in other studies are those with lower socio-economic status.

Meyer MP, Hou D, Ishrar NN, Dito I, te Pas AB. Initial Respiratory Support with Cold, Dry Gas versus Heated Humidified Gas and Admission Temperature of Preterm Infants. The Journal of Pediatrics. 2014. We don’t use cold dry gases to ventilate our premies at any other time, so why in the delivery room? This is a multi-center RCT examining the question. Using Warmed humidified gases resulted in more infants being normotthermic on admission to the NICU, especially the very preterm babies. With 100 babies in each group there were no other significant differences in clinical outcomes, but most differences were in the direction of a beneficial effect of warming and humidifying the gases. A larger study is worth doing I think but will be hard to fund with these modest differences between groups.

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Comparing Currently Used Treatments

The idea that we should actively and scientifically compare treatments that are in widespread use, but currently with haphazard variations based on poor or no evidence, is a vital part of improving medicine.

In my own field, the care of the critically ill newborn, there are huge variations in some outcomes. Survival differences between centers are much larger than the survival differences ever demonstrated in simple clinical trials. We must find out which of the variations in practice lead to better outcomes.

Without the trials that compare such treatments there will be limited improvements in medical care.

Comparative effectiveness research therefore needs to be promoted and supported.

I knocked off a blog post recently about the proposed OHRP guidelines for consent for such trials. Which, although a specifically USA initiative, will affect all of us in time. I focused on how difficult they are to understand or operationalize. But a deeper appreciation of the potential  impacts has been published in the PNEJM. The commentary by John Lantos effectively destroys the reasoning of the OHRP. It is brief and worth reading in full.

One particularly pertinent phrase is the following which refers to potential research subjects (or parents):

They should not be misinformed into thinking that their doctor’s preferred treatment is always and necessarily the safest and most efficacious and thus that any alteration from that treatment adds risk

This is in fact the crux of many of the criticisms of SUPPORT, that being in the trial prevented doctors from exercising their best judgement, and therefore increased risk, because doctors somehow know best (even in the absence of data). It is the crux of the criticism of the ARMA trial by Dr Natanson (who spoke at the OHRP meeting about SUPPORT) and the criticisms of many (non-physician) ethicists also.

John Lantos puts a bit of reality back in the discussion, Doctors only know best if they have good data to tell them what is best. Being in a randomized trial is no more, and much data suggest less, risky than not being in a trial. If you have a similar chance of receiving a treatment outside of a trial as within the trial, then how can you state that the trial is causing an increase in risk?

The editors of the NEJM (I will drop the prestigious bit I think, as it is getting tedious) are equally scathing :

We disagree with the proposed guidance because it suggests that within the standard of care there is a known differential between treatments. But it is precisely because no net differential is known that the research is being conducted. The fundamental nature of research equipoise means that doctors are uncertain as to whether there is benefit or risk that is predictably associated with one treatment or another. The goal of the research is to determine whether such a net differential exists. To report a differential risk or benefit in the informed-consent documents of standard-of-care research suggests that there are known differences between one standard treatment and the other.

To suggest that there are foreseeable risks in such a study is misleading. A potential trial participant will suffer the false impression that there is a known net difference in risks and that they can avoid risk by not enrolling in the study. Neither impression is true.

Now I do think that research subjects (or parents) should know why we are doing the research, which is going to be because we don’t know of a net difference in outcomes between the treatment arms, and, for future patients to get the best care, we need to know if there is a difference. Which means that, at the end of the study, we might well find out that one mode of treatment is preferable (or sometimes, that we understand better the balance of risks and benefits so that we can better inform future patients). But we need to tell them clearly about these issues, so that they can make an informed decision about whether to participate, without implying that doing so increases their overall risks.

I hope the OHRP are listening to these criticisms, I think they probably are listening, but how much they are willing to be change them is more questionable.

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Feeding and NEC

Necrotizing Enterocolitis remains a devastating disease. One of the major causes of mortality in Very Low Birth Weight Infants, it often strikes when babies are starting to do well. Because it is relatively unpredictable, observational studies are potentially useful, but can easily be misleading. In particular, observational studies which are performed as a result of a perceived change in incidence might easily be biased.

One recent study that was published has received some publicity, I myself received some links on Linked-In pointing to this study, which at first sight seems to show that advancing feeds slowly might decrease NEC. Lets examine the data a bit more carefully.

In 2009 a hospital changed their feeding policies. A paper published in 2014 reported their data from 2009 to 2012. According to the published article the paper was received on July 24th 2014, and accepted on August the 5th. Which immediately makes me wonder two things, why the authors decided to perform this study, and how do they get a paper accepted so quickly? If the authors performed the study because they saw a decrease in NEC, and then decided to do the analysis, that immediately creates a bias, many other hospitals could possibly have made a similar change and not noted any change in NEC, and therefore not looked at their data. Studies such as this are more likely to be reliable if the decision to prospectively collect and try to publish their data is made at the time that the change in therapy is introduced. But then a similar study showing no effect on NEC would be very difficult to publish, and probably not be accepted in under 2 weeks!

There are a couple of concerning things in their findings, one is that after the change in the protocol there was not actually statistically any less NEC overall than before the change in protocol. Only by a subgroup analysis, was the group of babies under 750g significant, and then they did not report the p-value of the interaction, which is really essential. They showed much less NEC in the babies under 750 g birth weight than those between 750 and 1000g. Which really strongly suggests to me that this is just the result of the random nature of NEC incidence, I don’t know any large study that has ever found more NEC in the larger babies.

More worryingly, the new protocol led to babies having later commencement of feeds, longer use of intravenous nutrition, longer use of picc lines, and really horrendous nutritional outcomes, with over half of the babies being under the 10th percentile at discharge (admittedly that was better than the 75% with their older protocol).  The feeding protocol that they introduced is entirely non-evidence based, as I have noted before here, there is no evidence from controlled trials that varying the advancement of feeds has any effect at all on the incidence of NEC.

A slightly older study (from 2009) provides interesting data from the German Neonatal Network, and is, I think, much more reliable. They compared the outcomes of babies from centers where it took on average less than 12.5 days to get their VLBW babies on full feeds, to centers where it took on average more than 12.5 days to get the babies to full feeds.


You can see here the clinical outcomes from the study. The only things that were different between the groups were the late-onset sepsis, which was much higher in the babies with slower feeding. Surgical NEC was slightly (non-significantly) more frequent with slower feeding, and severe retinopathy was also higher, which is entirely consistent with the recent information linking retinopathy with poorer nutrition.


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Frozen poop sounds much more palatable

Fecal transplants are effective in treatment of persistent clostridium difficile infections. The publication showing that, in the small RCT published in the PNEJM, was remarkable in the pre-screened donors who were ready and available to produce a “donation” on demand.

This new study (Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, Capsulized, Frozen Fecal Microbiota Transplantation for Relapsing Clostridium difficile Infection. JAMA. 2014;312(17):1772-8.) takes poop from screened donors and freeze dries it and puts it in capsules: 70% of the small group of patients resolved their diarrhoea after a single treatment. The others almost all resolved after repeat treatment. This way of treating has the advantage of not needing a list of on-call volunteers, and not needing to pass a tube into the intestine. It has the disadvantage that if you forget, and bite down on the capsule….

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