An Oldie but a Goodie

I discovered several months ago that one of my older presentations is very difficult to get on-line. It seems that at some point, when this article, Barrington K, Finer N. The natural history of the appearance of apnea of prematurity. Pediatr Res. 1991;29(4 Pt 1):372-5. was being digitised, it got mixed up with the article just before it in the journal. I wrote to the current owners of Pediatric Research (the Nature group of journals) and they told me there was nothing they could do. It was digitised before they bought the journal, and so basically they couldn’t be arsed to have someone cut the pdf in two and then index it correctly.

So if you follow the link from the Pubmed Page above it will take you to a web-page that says the article doesn’t exist. If you really try hard and pursue this amazing piece of medical science to its origins, you will eventually find that it is not listed in the table of contents of that issue of Pediatric Research, but that it is stuck onto the back half of an article by Hugo Lagercrantz. Which is never a bad place to be stuck, but still, it is a bit irritating, and deprives the world of a tiny bit of my brilliance (along with a even smaller bit of Neil Finer’s much greater brilliance).

So I have decided as a public service to make this freely available on my blog, and if the Nature journals don’t like it they can just fix the April 1991 table of contents for Pediatric Research and I will take it down.

Here for your delectation and delight is a link which I hope will let you download the article.

Barrington K Pediatr Res 1991

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The last nail in the coffin of permissive hypercapnia?

Thome UH, et al. Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial. Lancet Respir Med. 2015;3(7):534-43.

This German multi-center trial randomized infants 400 to 1000 g birth weight to 2 different CO2 target ranges. The target ranges changed over the first few days of life:

The high target group aimed at pCO2 values of 55–65 mm Hg on postnatal days 1–3, 60–70 mm Hg on days 4–6, and 65–75 mm Hg on days 7–14, and the control target at pCO2 40–50 mmHg on days 1–3, 45–55 mm Hg on days 4–6, and 50–60 mm Hg on days 7–14

The primary outcome variable was survival without BPD. Eligible infants were randomized within 12 hours of intubation and stayed in their group until 14 days of age.

This has been a difficult issue in neonatology, many have been reluctant to allow CO2 to rise in the first few days of life because of observations that infants with intraventricular hemorrhages had higher CO2’s. Prospective studies of allowing CO2 to rise however have not shown an increase in hemorrhage, so accidental or unintentional hypercarbia is a very different kettle of fish, denoting more severe events and so on. The idea of not increasing ventilation to normalize a CO2 is certainly an approach that I have taken for years, while acknowledging that there was no good evidence to say what the CO2 targets should be.

Two other related issues:

One, there is some evidence that respiratory acidosis may be protective in critical illness, so benefits of permissive hypercapnia might extend beyond less lung injury. Also attempting to buffer acidosis may well worsen lung injury. (Higgins BD, et al. Differential effects of buffered hypercapnia versus hypercapnic acidosis on shock and lung injury induced by systemic sepsis. Anesthesiology. 2009;111(6):1317-26Laffey JG, et al. Buffering hypercapnic acidosis worsens acute lung injury. Am J Respir Crit Care Med. 2000;161:141-6)

Secondly, There are many ways to ventilate an infant. Just allowing a higher CO2 does not necessarily mean lung-protective ventilation. You can have a high CO2 with one very large tidal volume every 10 seconds, or with high frequency lower tidal volumes.

This study tried to address the second issue by favouring high ventilation rates (60 to 80 or greater initially) with inspiratory times between 0.25 and 0.35 s, and PEEP between 3 and 6. Initial peak inspiratory pressure was chosen to give ‘minimal to moderate’ chest rise. Once the peak inspiratory pressure was below 14 then ventilator rates could be decreased, and once below 30 inflations per minute the baby could be extubated.

There was an enormous use of bicarbonate. Which I find really strange, as I have not given bicarb to a preterm baby for over 20 years! Half of the babies in each group received at least one bicarbonate bolus. It was ‘allowed’ only if the base deficit was more than 8 mmol/L. They say that use of bicarbonate was “discouraged” which seems a weird choice of terminology when so many actually received it.

There was much less separation between the groups than the protocol would have suggested, (similar to an older trial by Carlo), they did mange to achieve more separation that that older trial.

The sample size was calculated based on a 20% relative reduction in the primary outcome variable (from 50% to 40%) with a power of 80% and a significance level of 5%, using a two-sided group sequential test with two interim analyses, required a maximum sample size of 830 patients.

And here is the big failure of this important study, it was stopped after “only” 312 infants had been enrolled. Because of slow enrollment the funding agency wanted an interim analysis,

The sequential design’s boundaries had not been exceeded at that time (ie, there were no detectable significant differences). The study design was changed from a three-stage group sequential design into a two-stage adaptive group sequential design with one interim analysis. The amendment was approved by the DSMB and the lead investigator’s responsible institutional review board. The interim analysis was based on 312 completed infants and carried out by an independent statistician. The results were presented to the DSMB, which recommended terminating enrolment. The funding agency’s review board concurred with this recommendation and it was implemented by the study coordinator.

The study showed no significant difference in the primary outcome between the groups, 36% in the high CO2 group, and 30% in the lower target group, Relative Risk is 1·21 (95% CI of 0·90–1·63). The 20% reduction in the adverse outcome that was hypothesized by the investigators seems unlikely given those results, but the early termination does lead to a great loss of an opportunity.

You can see here the grey areas, which represent the target CO2, and the coloured diamonds/squares the actual median CO2’s achieved.

Hypercapnia 2015

What to make of this now?

Well, there are a number of reasons why this study may have shown no difference in outcomes between the groups; perhaps permissive hypercapnia as practiced like this is not protective of the lungs.

The authors screened over 1500 babies for inclusion, and over 400 were not enrolled because they weren’t intubated.

As you notice from that graph above, there was very little difference in the CO2 on the first day of life, which may be the most important period of life for initiating lung injury.

Perhaps the extensive use of bicarbonate infusions was an issue, if bicarbonate is as harmful to the lung as suggested by those experimental studies above, it may be that the use of bicarb in both groups eliminated any difference between groups.

Whatever the reasons, this study showed no clear adverse effect of permissive hypercapnia.  So we have no better idea after this study what the optimal CO2 targets are for very preterm infants. The 2 ranges studied in this trial both seem to be within acceptable limits.

Perhaps we need to think about this differently, babies who are doing well, have a good response to surfactant and can be ventilated with ease may escape serious BPD even if the CO2 is kept within the lower of these 2 ranges. What we need to know I think, is when to increase ventilator settings to try and reduce CO2 and when we should let it go, allow the CO2 to rise rather than keep pushing ventilator pressures (or volumes, or amplitudes). I think there has to be a point when further increases in ventilation cause more damage than benefit. But where that is, and how to investigate it are rather difficult questions.

We will have to find other ways of protecting the lungs of our patients, and not just allowing the CO2 to rise. Minimizing lung injury in the first couple of hours of life, avoiding invasive ventilation, using volume ventilation, and getting babies successfully extubated are a few of the things that we need to investigate further.


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Diaphragmatic Hernia Updates

There have been many publications recently for this group of our patients:

Hagadorn JI, et al. Trends in treatment and in-hospital mortality for neonates with congenital diaphragmatic hernia. J Perinatol. 2015;35(9):748-54. This multi-center cohort study shows, in term babies, that mortality has been improving (which is always a problematic outcome, we don’t know the influence of pregnancy termination for more sever lesions, for changes in referral patterns etc etc) and that this has been associated with less ECMO in the uncomplicated cases, with more sildenafil and milrinone use and more multiple vasodilator use. Despite my comments in parentheses above, there were more cases overall which were complicated, so the trends in survival might not be due to changes in case-mix, but despite those changes. Trends in preterm babies with diaphragmatic hernia were not significant, despite more sildenfail and more multiple vasodilator use there was no improvement in mortality.

Gien J, Kinsella JP. Differences in preductal and postductal arterial blood gas measurements in infants with severe congenital diaphragmatic hernia. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015. You would think someone would have done this before, but apparently not: pre-ductal blood gases are often significantly better oxygenated than post-ductal. So if you use pre-ductal blood gases, you can reduce oxygen therapy and respiratory support and so on. Should be routine whenever possible.

Puligandla PS, et al. Management of congenital diaphragmatic hernia: a systematic review from the APSA outcomes and evidence based practice committee. J Pediatr Surg. 2015. A very interesting systematic review of the literature. Can do no better than quote the results section of the abstract.

Gentle ventilation with permissive hypercapnia provides the best outcomes. Initial high frequency ventilation may be considered but its overall efficacy is unproven. Routine inhaled nitric oxide (iNO) or other medical adjuncts for acute, severe pulmonary hypertension demonstrate no benefit. Evidence does not support routine administration of pre- or postnatal glucocorticoids. Mode of extracorporeal membrane oxygenation (ECMO (by which they mean VV compared to VA:KJB)) has little bearing on outcomes. While the overall timing of repair does not impact outcomes, early repair on ECMO has benefits. Open repair leads to significantly fewer recurrences. Polytetrafluoroethylene (PTFE) is the most durable patch repair material.

Bojanic K, et al. Survival of outborns with congenital diaphragmatic hernia: the role of protective ventilation, early presentation and transport distance: a retrospective cohort study. BMC pediatrics. 2015;15(1):155.  Less aggressive ventilation associated with permissive hypercapnia led to improved survival, which was not affected by transportation distance. Of course, as a Canadian, I can laugh at the idea that a 280 km transfer is “distant”. More than 1000 km, now that qualifies as a long distance transport.

Huang JS, et al. Thoracoscopic repair of congenital diaphragmatic hernia: two centres’ experience with 60 patients. Pediatr Surg Int. 2015;31(2):191-5. We have been doing this at my center for a while now, with good success, but the procedure seemed to take longer than an open repair, more recent cases have been quicker. Putting in a patch is still a challenge.

Yamoto M, et al. Cardiac fetal ultrasonographic parameters for predicting outcomes of isolated left-sided congenital diaphragmatic hernia. J Pediatr Surg. 2015. The major finding from this study was that the worst outcomes were among cases where the tricuspid valve was relatively larger than the mitral valve. on the fetal echocardiogram in infants with a left-sided hernia.  The larger that ratio (TV/MV) the higher the mortality. To put it the other way around the smaller the left heart, the worse off the patients were.

DeKoninck P, et al. Right-sided congenital diaphragmatic hernia in a decade of fetal surgery. BJOG: An International Journal of Obstetrics & Gynaecology. 2015;122(7):940-6. In this paper, exclusively interested in right-sided hernia in infants with a fetal diagnosis, the prediction of outcome from the lung-head ratio, compared to the same index for left-sided hernias, was worse. It seemed to be improved by fetal surgery using tracheal occlusion.

Spoel M, et al. Pulmonary ventilation and micro-structural findings in congenital diaphragmatic hernia. Pediatr Pulmonol. 2015 Finally when you get your patients through the neonatal period, and they survive to adulthood, their lungs are still not normal. The subjects included int his study had normal oxygen saturation and a reasonably normal FVC.

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Conflicts of interest are not all financial, but they are conflicts none the less. Name change not required.

Another poorly argued article trying to minimize the reality of conflicts of interest in medical research. Cappola AR, FitzGerald GA. Confluence, not conflict of interest: Name change necessary. JAMA. 2015;314(17):1791-2.

If someone stands to have a personal advantage as a result of their research, or their recommendation of a course of therapy, then that is necessarily in conflict with the need to be objective and to analyze data, perform meticulous trials, and objectively review publications.

First, the term conflict of interest is pejorative. It is confrontational and presumptive of inappropriate behavior. Rather, the focus should be on the objective, which is to align secondary interests with the primary objective of the endeavor—to benefit patients and society—in a way that minimizes the risk of bias. A better term—indicative of the objective—would be confluence of interest, implying an alignment of primary and secondary interests. In this regard, the individuals and entities liable to bias extend far beyond the investigator and the sponsor; they include departments, research institutes, and universities.

I don’t think calling a spade a spade is pejorative. It is just accurate. If I am a medical research scientist my primary interest should  be to perform the research to the highest standards, without bias. Any personal advantage that accrues from that research is in conflict with that goal. It also does not presume inappropriate behaviour; to say that someone has a conflict of interest does not mean that they cheated, exaggerated or misled the public. What it does mean is that there is risk that the results of their academic endeavour might benefit them personally, so watch out! There are so many examples that prove the power of such conflicts, which are not necessarily conscious.

The article does, however, point out the importance of other non-financial conflicts of interest.

For example researchers involved in a large multi-center trial for which they have invested much time and public money, may be very reluctant to stop such a trial even when the results of other similar trials become conclusive. This has happened more than once, including in neonatology. It is entirely understandable, and I do not believe necessarily a conscious bias. It is usually possible to find a reason why “the science is not yet settled” and continue a trial, even when it has become crystal clear that the science actually is settled to clinicians outside the trial.

This is partly why Iain Chalmers wrote an article a couple of years back that data-monitoring committees of similar trials should share data (Chalmers I, et al. Data sharing among data monitoring committees and responsibilities to patients and science. Trials. 2013;14(1):102.)

The JAMA article refers to his pressure as being “the prospect of fame”, which I don’t actually think is that big an issue, depending on what you mean by “fame”. Neonatologists do not become celebrities, in general, but the recognition of your peers, the satisfaction of getting an article published in a high profile journal, the feeling that you have performed the best, most complete research, adding to your total of entries in PubMed, getting promoted at your university, and so on, are drivers of academic conflicts of interest. Such conflicts are not often revealed, and indeed are hard to define.

It has happened many times in neonatology that several simultaneous trials investigating the same issues have been performed almost simultaneously. Whereas one larger trial could answer the questions with more precision, and do so faster. Sometimes this has been because of funding issues, but it has sometimes been because of academic conflicts of interest.

I think the answer to such conflicts is transparency, and finding ways to work together. Co-funding of trials from multiple agencies could get us much further, but has been hard to organize as yet. The CIHR ha been very open to allowing inclusion of non-Canadian centers in research projects, but that doesn’t increase the funding available. Hopefully in the future we will be able to perform larger trials, co-funded by several agencies, and everyone involved will get appropriate recognition of their contributions, without having to be first author on the article, and that we can work for the good of our patients and their families, with fewer conflicts of interest.

Yes conflicts, not confluences.

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Retinopathy: up or down?

The oxygen saturation targeting trials showed more retinopathy with higher oxygen saturation targets. Will this translate into more retinopathy in actual practice? Many units have increased their saturation targets as a result of those studies. This may indeed lead to more RoP, and the expected result seems to have happened, in Melbourne at least. A before and after study showed that there was an increase in retinopathy, both overall and of stage 2 or more. They evaluated the outcomes in babies under 30 weeks or under 1250 g who survived to get retinal screening, about 150 before they changed and nearly 200 afterward. They saw more total RoP. There were very few babies who needed laser, 1 before and 3 after, which may have been due to chance, with such small numbers, but it certainly didn’t go down. Among infants of less than 28 weeks, the stage 2 disease incidence went from 16% to 34%.

What can we do to counter this? Which is likely to be repeated in many different units who have raised their saturation limits. What interventions are there that can reduce retinopathy? Well, we know that poor early neonatal growth is associated with an increased risk of retinopathy. So optimizing neonatal nutrition in at-risk infants should help, although that hasn’t been proven in randomized trials, as far as I am aware.

An RCT from Poland (with the collaboration of Michael Sherman) suggests that a mixed lipid source, including some fish oil/omega-3 fatty acids may reduce RoP in very preterm infants. They randomized infants <1250g and less than 32 weeks. The 70 control infants received a mixture of soy and olive oil lipids (Clinoleic, which is used in Europe, but I don’t think is licensed in North America). The 60 babies in the intervention group received half Clinoleic, and half Omegaven (the fish oil emulsion with lots of omega-3 goodies) by volume, but the Clinoleic is a 20% emulsion, the Omegaven is a 10% emulsion. So they had about 1/3 omegaven, 2/3 the other stuff.

It was an unblinded study, apart from the ophthalmologist who was apparently… uuh…blinded. (Sorry about that). The primary study outcome was “an assessment of ROP severity and whether laser photocoagulation was required to save vision” which isn’t a primary study outcome, of course, you can’t have a study outcome which is an “assessment of” something. The sample size was calculated based on an extremely high frequency of retinal ablation in the controls, of 27%, and a massive reduction to 7.5% in the fish oil group. so we will call that the primary outcome variable.

The babies in the study were on average just under 1000g birth weight, and were 28 weeks gestational age. Those in the new-lipid group got much more DHA (docosahexaenoic acid, an omega-3 FA) which they incorporated into red cell membranes. They defined cholestasis as more than 20% of the bilirubin being conjugated; which was very frequent in the controls, 20/70 vs 3/60 in the group with the fish oil. Treated retinopathy was extremely frequent in the controls, 22/70 and decreased to become very frequent in the fish oil group, 9/60.

The proportions of fish oil are not the same with their mixture as with SMOFLipid, a mixture of Soy, Medium chain triglycerides, Olive oil, and Fish Lipids, which is commercially available. In SMOF about 15% of the lipids are fish oil derived.

This looks hopeful, but we will need to be sure that the results are the same with an approved lipid in Canada (SMOFLipid is approved, but not specifically for newborns in Canada), or wherever you are in the world. Also that it is effective in NICUs with a much lower rate of retinopathy needing treatment, then providing enough omega-3 FAs from early life in the very preterm infant might help to counter the effects of keeping the saturations a little higher.

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Neonatal Updates

Gschließer A, et al. Inter-expert and Intra-expert Agreement on the Diagnosis and Treatment of Retinopathy of Prematurity. American Journal of Ophthalmology. 2015;160(3):553-60.e3. The investigators showed 52 retinal photographs to 7 expert ophthalmologists, and then 8 weeks later showed them to the same experts again.

There was little agreement in staging, on the presence or absence of plus disease, on whether there was aggressive posterior disease, on whether the patient needed treatment (using the ETROP) criteria, or on what kind of treatment they would offer. The Kappa agreements were only between about 0.23 and 0.4, between different experts. Even when they looked at the consistency of the scores, by the same experts, they found quite a lot of variability, with Kappa scores mostly between 0.5 and 0.6.

I wasn’t aware of the previous studies that this group refer to in the discussion section of this worrying article. But they describe 3 other studies that show similar things. It seems that there is a lot of variability in the other studies also in terms of diagnosing whether an infant is truly at threshold (needing treatment) there is also disagreement on defining the limits of zone 1. This new study used wider angle retcam images, compared to the previous ones.

Post ED, et al. Milk production after preterm, late preterm and term delivery; effects of different breast pump suction patterns. J Perinatol. 2015. This study compared the efficacy of two different models of breast pump. Just over 60 mothers and babies, (of preterm, late preterm and term infants), who needed to express their milk either pumped with a “sucking” action, and a newer version which generates an irregular suction pattern: it produces periods of 60, 90 or 120 sucks per minute, as well as pauses in suction randomly distributed in time. Mothers were assigned to one group or the other based on equipment availability. There are a couple of things in the report that I don’t understand, they say that mothers were only included if they were pump dependent for at least 7 days, and expressed at least 7 times a day. But they received the equipment when they started expressing, and one of the outcomes was recorded usually before 7 days post-partum. I guess it might mean that there were other mothers who dropped out after starting to pump with one of the 2 devices, but they never got to 7 days, or didn’t pump often enough, so their data were not included. This is a potential bias in the study, but I am not really clear on this.

The mothers who used the irregularly pumping breast pump achieved a 50 mL in a day breast milk production more than 24 hours earlier. More of them were able to produce more than 500 mL a day, and they produced 500 mL or more about 2 days earlier than the comparison group.

Even the controls had a pumping suction pattern which was not regular, they started with a 2 minute stimulation phase of 120 sucks per minute, followed by the expression phase of 60 per minute. Which is already much more like natural sucking than the standard breast pumps we have available, that maintain the same sucking action and frequency throughout, unless you manually vary the frequency. A previous RCT Meier PP, et al. Breast pump suction patterns that mimic the human infant during breastfeeding: greater milk output in less time spent pumping for breast pump-dependent mothers with premature infants. J Perinatol. 2012;32(2):103-10. that I also was not aware of, already showed a benefit of the irregular suction patterns in mothers of preterm babies, the new study with a less rigorous design, suggests the same benefits for milk production in mothers of larger preterm, or term babies.


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International Prematurity Day

A Quebecois photographer, Red Methot has been taking photos of prematurely born children, each one is holding a photo of themselves as a preterm baby.

He has now made a youtube video of his project.

And here is his photo of my little flower.

Violette Red


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