PAS 2018 No5: the trial with no name… propranolol for early RoP, a proper trial.

As far as I can see, this trial has no acronym, which isn’t a big deal, but it also doesn’t show up on trial registry searches, which is a big deal. Trials must be registered before starting them, it ensures that protocols, sample sizes, outcomes, analyses, and so on, do not change without explanation. And it ensures that trials don’t end up being hidden and unpublished. The trial may have been registered, I just can’t find it.

I would call this trial PROPER, Pre-threshold RoP, Evaluation of pRopranolol! The authors can have that acronym for free if they want! How generous I am; unfortunately my Spanish is not good enough to generate a Spanish acronym.

In a single center trial, Aldo Bancalari and colleagues from Concepcion in Chile randomized 62 VLBW infants with stage 2 or 3 RoP in zone 2 or 3 (without plus disease) to oral propranolol or control (I am not sure if there was a placebo or not).

Progression to treatment thresholds (laser or intravitreal anti-VEGF treatment) was much less frequent with propanolol, with 28/31 (90%) having a favourable evolution, compared to 17/31 (55%) of controls. Which is a big difference unlikely to be due to chance alone. One of the propranolol babies was hypoglycemic on day 1, and there were no other side effects noted.

As I was creating this post, I realized that it actually looks like the authors have already published the results of this trial at an earlier stage, when they had enrolled 47 babies. That is really not appropriate; repeated analysis and presentation of results as they accumulate inflates risks of bias, dramatically. I was quite excited by this trial when I first saw it, but it looks now that it might not be a good use of my acronym, and perhaps it isn’t that proper!

**UPDATE, I have now received the full text of the previous publication, and that publication seems to refer to a cohort of treated babies that they compared to a historical control group (as mentioned by Ben Stenson in his comment below) and therefore this is probably a PROPER publication after all, I apologize to the authors if I mischaracterized this trial***

I think it is clear that we need… A Large Multicentre Trial of Propranolol in the Early Stages of RoP to Prevent Progression. Which we could call  “PREPARE” the PREvention of the Progression of REtinopathy trial. I claim priority for this acronym. PORKY would work too, if we could work out how to get the k in there.

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PAS 2108 No4: you little SCAMP!

In the part of England where I was born and spent the early years of my life, and where my parents are from, the Manchester region, ‘scamp’ was a sort of affectionate term for a young child who had done something wrong, so if a toddler emptied a milk bottle on the floor by accident they would be referred to as ‘a little scamp’.

https://upload.wikimedia.org/wikipedia/en/4/48/The_Scamp_%281957_film%29.jpg This 1950’s English movie was a lot darker than that.

The SCAMP study was also small and irritating!

It was registered at NCT01994993

I am still looking to see if the protocol was published anywhere..

This was a multicenter randomized controlled trial to answer a really important question in neonatology. What are the appropriate antibiotics in complicated intra-abdominal infections? (Disclaimer, we were part of this trial, and Julie Autmizguine of our center was one of the investigators).

This was a difficult trial to do; when an infant <34 weeks gestational age and <121 days postnatal age was eligible, with either necrotizing enterocolitis with pneumatosis, or a perforation or peritonitis associated with other diagnoses, they were randomized to one of 3 antibiotic regimens; ampicillin, gentamicin, and metronidazole (group 1); ampicillin, gentamicin, and clindamycin (group 2); or piperacillin-tazobactam and gentamicin (group 3). The study was registered at NCT01994993

Part of the rationale was Julie Autmizugine’s observational study that seemed to show an increase in intestinal stenosis among infants with NEC who received anaerobic coverage, which may have been due to the fact that mortality was a bit lower, so there were a few more babies alive to develop strictures (or maybe not, it was an observational study after all).

Of the 182 patients reported in the abstract, 2/3 were randomized, the others were a simultaneous observational cohort. Mortality was similar between groups, but differed by a maximum of 3% (between about 8 and about 11%), that is not a big numeric difference, but is a large enough difference to influence antibiotic choice if it is real.

Treatment success was defined as being alive, with a negative blood culture and “a clinical cure score >4” which I can’t see defined in the abstract, nor is it mentioned in the registration document, and, as I said, I can’t find a published protocol. After a bit of googling around I did find the clinical cure score in an online pdf of a presentation somewhere by the presenting author. Each element of the score was evaluated and assigned a score of 0 or 1. So if you were extubated, with a lower FiO2, not on dopamine, not oliguric or acidotic, and seizure free, you would score 6.

This was adjudicated 30 days after antibiotic treatment, and was similar between groups, 73%, 83% and 74% respectively had a succesful treatment because they were alive and scored less than 4. The group with the highest success though, had the highest mortality… which brings me back to, yes, composite outcomes, and what a problem they are!

If I work this out, in the 1st group, 92% were alive, but another 20% had cure scores of 4 or less, which surprises me 30 days after the antibiotics. Still being ventilated and having a higher FiO2 I would think happen frequently, but, being on inotropes or oliguric or acidotic or having seizures, to have so many with at least 2 of those is unexpected.

In the second group, there were 89% alive and another 6% with a low cure score. This is again a complicated study, only partially randomized, and unblinded. There were a lot of babies who had pharmacokinetics, and a lot of important data will come out of the trial over the next years, I think. And a design for future larger better trials, I hope. This is one of the first trials to address this difficult subject, lets hope we can move forward from this.

 

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PAS 2018 No3: Should we TOLERATE the PDA?

This was another large multicenter trial, designed to determine if routine attempts to close a moderate to large PDA at the end of the first postnatal week decreases the duration of patency, and the incidence of the combined outcome “need for ligation or need for post-discharge PDA follow-up”. The comparison group, the “conservative approach” required pre-specified respiratory and hemodynamic criteria before rescue treatment.

The trial was registered as NCT01958320 but I can’t see a publication of the protocol.

At 1 to 2 weeks of age there were 855 infants of those who were screened (about half of the screened babies were eligible for the trial) who had a moderate/large PDA shunt and required at least 0.25 FiO2 and either ventilation non-invasive ventilation CPAP more than 2 L/min high-flow.

Echo criteria were internal ductus diameter ≥1.5 mm/kg (or PDA:LPA ratio ≥0.5), ductus flow velocity ≤2.5 m/s or mean pressure gradient across the ductus <8 mm, LA/Ao ratio ≥1.5, left pulmonary artery diastolic (or mean) flow velocity >0.2 (or >0.42) m/sec, respectively, and/or reversed diastolic flow in the descending aorta. Those are the criteria copied from the registration, I don’t know how many were needed to be eligible.

202 babies between 23 and 28 weeks gestation were randomized between 6 and 14 days of age half of whom were intubated. Half of them got immediate treatment, and the other half were in the conservative arm.

As fas as I can tell the pharmacologic treatment of the PDA could be either indomethacin or ibuprofen. The criteria for later treatment in the conservative arm are not in the registration document, nor in the abstract. Apparently nearly 2/3 of the conservative arm met treatment criteria (62%), but only half of the group (48%) actually received it.

The primary outcome was needing ligation (criteria not given) or being discharged with an open PDA (confirmed by a pre-discharge echo). That outcome was less common with early treatment (Relative Risk 0.72, no confidence intervals in the abstract). PDA ligation was the same in both groups at 12%, as there is no overlap between, ligation and PDA patency at discharge that means the difference is there, being in the later treatment group means your duct is more likely to stay open at discharge. I would guess that this is both among those who actually were treated (as treatment is known to be less effective later) and among those who didn’t actually receive the later treatment even though they met criteria.

In other outcomes, more of the conservative group received dopamine for 3 days or more. In our unit receiving dopamine (or another catecholamine) after 5 days of age, which was the entry limit for the study is very unusual, even among the subgroup who showed the greatest effect for this secondary outcome, those under 26 weeks. It would be interesting to know if there were standardized criteria for this, or if babies were getting dopamine because their diastolic pressures were a bit low…

Also of interest in the secondary outcomes, mortality and late onset sepsis were more frequent among the early treatment group, with relative risks of 1.79 and 1.52 respectively. These effects were more evident in infants of 26 weeks or more. Feeding progression was slower with early treatment, but again that might be because of unit specific guidelines for holding or slowing feeds during PDA treatment, rather than a problem with feed tolerance.

An important study, but the limitations of the abstract format, and the lack of a published protocol preclude much more in the way of definitive interpretation. Also there are several other trials which are in progress, examining similar questions. If earlier treatment (by these criteria) really does lead to increased mortality then the rest of the results are really irrelevant; being alive with an open PDA, I think anybody would agree, is better than being dead with a PDA firmly closed!

Should we tolerate the PDA? Probably; but how tolerant, and when to become intolerant, are still unclear.

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PAS 2018 No2: let’s STOP-BPD

The STOP-BPD trial was a multicenter trial from Holland, (registered as NTR2768) over 180 babies were randomized to each arm of this trial, they were <30 weeks or less than 1250 g at birth, and were still ventilated at 2 weeks of age.  They had a respiratory index of more than 2 (which you get by multiplying the mean airway pressure by the FiO2). They actually changed the eligibility criteria during the trial as many infants with a respiratory index between 2 and 3.5 (the original criterion) were still developing BPD. A respiratory index of 2.1 therefore would be achieved by having a mean airway pressure of 10 in 21% oxygen, roughly, therefore, anything more than a mean airway pressure of 10 would make you eligible, or lower pressures with higher FiO2.

Infants in the hydrocortisone group received hydrocortisone 5 mg/kg/day Q.I.D for 7 days, followed by 3.75 mg/kg/day T.I.D. for 5 days, then one dose less per day every 5 days. This led to a duration of therapy of 22 days and a cumulative dose of 72.5 mg/kg hydrocortisone. The protocol was published here.

The results, as presented at PAS 2018, showed no difference in the primary outcome, which was survival without BPD. In contrast there were many fewer deaths, 16% vs 24%, and no change in moderate or severe BPD, 65% vs 66% with the hydrocortisone treatment compared to placebo. We don’t have long term neurologic or developmental follow up as yet, but to be honest I am not sure how important that is, if there is an increase in survival. Even if there are more survivors with low Bayley scores, there are more survivors! Also important, survival as reported in the abstract was survival to 36 weeks, they don’t mention survival to discharge which is much more important; with such a big difference in survival to 36 weeks, survival to discharge might well be improved. I don’t remember in the presentation if survival to discharge was reported.

These 2 studies, SAIL and STOP-BPD) illustrate really well the problem with these combined outcomes in neonatal studies. Especially this particular common outcome, combining oxygen needs at 36 weeks PMA with death, I think this is really a big problem.  The two outcomes are not of equivalent value to families, nor to me. What are you supposed to do with those data, to say to parents: “we could start steroids now, but that doesn’t change the probability of your baby surviving to discharge without needing oxygen at 36 weeks. Jacob is more likely to survive if we give him hydrocortisone, however…”

The 2 studies both have a null outcome, but in reality, the STOP-BPD trial intervention appears to be (at least potentially until the peer reviewed publication appears) a major benefit to babies. SAIL is the opposite, a study had a null outcome, but what seems to be a serious negative impact of the intervention. There are other ways of designing and analyzing these trials, analysis of survival as a first step, and then presenting morbidities among survivors would be much more useful for future families. Even profound impairments with limited communication skills, should be separated from mortality, as different families have differing attitudes to survival of the most handicapped infants.

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PAS 2018 No1: SAIL away (and another mention by a science journalist).

For some reason there is a small epidemic (n=2, that’s a pico-epidemic) of articles about probiotics and necrotising enterocolitis this year in the mainstream press. I was interviewed, and I am mentioned again, in this article on the NOVA “next” website, which is open access ww.pbs.org/wgbh/nova/next/body/probiotics-for-preemies 

I have just returned the PAS meeting, where I sometimes get invited to lunch to eat with groups of amazing neonatal fellows, such as the fellows from Columbia, who, with the leadership of Tina Leone, are doing great work. Thanks for lunch, and the stimulating interactions.

Also it is where this year there were several large important neonatal trials being presented, I usually only post about studies after peer review, but the large clinical trials don’t usually change much between PAS presentation and final publication. So I will post about SAIL, STOP-BPD, TOLERATE-PDA, SCAMP, and a randomized trial of propranolol for treating retinopathy, which sadly doesn’t seem to have an acronym.

I decided I would write a few posts and divide them up as the mood takes me…

Here is the first, the SAIL trial, a very high quality trial of a very important issue.

SAIL is a trial of sustained inflations in preterm infants during resuscitation. This was a multicenter trial (registration NCT02139800 ) of which theprotocol has been published (and is open access); extremely preterm babies 23 to 26 weeks were enrolled at birth if they needed respiratory assistance at birth.

In the control arm the babies were ventilated as usual, in the sustained inflation arm they had one or two prolonged sustained inflations, 20 cmH2O for the first, and 25 for the second (if needed) and then they continued NRP.

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The primary outcome was BPD or death. The study was stopped about 2/3 of the way through, with 425 babies analyzed. At that point there was no “statistically significant” difference in the primary outcome, but an excess of early deaths in the SI group, 7.5% compared to 1.4% of controls died within 48 hours of birth, which was considered to be highly unlikely to be due to chance (p<0.002).

Death before discharge was 33% higher in the SI group (relative risk 1.33 95% CI 0.9, 2.0), BPD was not reduced (it was actually 12% more frequent in the SI group), and the primary outcome was somewhat more frequent with SI overall, about a 10% increase in “death or BPD”; which was not “statistically significant” (as  is still often said) because the 95% confidence intervals include a relative risk of 1.0 (the relative risk of “death or BPD” was 1.10, 95% CI 0.9, 1.3).

Part 2 to follow soon…

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Important outcomes after extreme prematurity: what do parents think?

There has been remarkably little study of the response to the question posed in the title: what do parents think is important in the outcomes of the very preterm baby? Physicians have focused on developmental progress, often as measured by developmental screening tests. The group at Sainte Justine (conflict of interest report: the authors are all either friends, or colleagues of mine, or my wife) have been investigating what parents find important, a new publication (Jaworski M, et al. Parental Perspectives Regarding Outcomes of Very Preterm Infants: Toward a Balanced Approach. The Journal of pediatrics. 2018) is from a study where they asked parents about what their concerns were about their baby, and what were the most positive things about their baby.

This is the first Venn diagram I can remember seeing in a medical publication, which makes me think that “modern maths” (as we called it 50 years ago) might not have been a waste of time after all (to be honest I loved maths, and I was rather good at it, unlike latin…).  The A diagram is the positive things that parents said, the B diagram shows their concerns. What I find perhaps most interesting in this publication is the lack of correlation between whether or not the baby actually had neurological impairment or developmental delay and the parents opinions/worries.

As you can see from this table, there was really no difference between the parents whose infants were doing well (by our usual medical criteria) and those who had serious issues (by our usual medical criteria) in their concerns or their positive evaluations. There are only 15 (out of 190) with what they call “severe NDI”, and among that small group there were similar responses to the other parents. The parents who were somewhat more likely to be worried about their child’s development were those in the “mild to moderate NDI” category, where 2/3 of the parents voiced this concern compared to about half of the none or severe categories.

I think the next step needs to be to ask a group of parents what they think we should be trying to measure as neonatal outcomes, both acutely and during follow-up. That next step is already being done, of course, one group that has been working on this is the COIN project, which stands for Core Outcomes In Neonatology, based in London (the UK version of London). You can see on their web page that they are developing a list of Core Outcomes, and the first stakeholder group on their list is “the parents of babies needing medical care”.

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Regular universal antibiotics to reduce infant mortality?

This (Keenan JD, et al. Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. The New England journal of medicine. 2018;378(17):1583-92 Open Access) is a new multicenter cluster randomized trial of giving all infants in a community regular azithromycin. If that sounds crazy, just wait… azithromycin (or placebo) was given to all the infants in the included communities twice a year, if they were between 1 and 59 months of age.  The study was based on observations that children in trachoma prevention trials (using azithromycin) had lower mortality; this study was designed to see if that was a real effect. Communities in Malawi, Tanzania and Niger were enrolled in this stunning, massive, effort, which included hundreds of thousands of infants.

The other stunning fact, that this study reminds us of, is the enormous post-neonatal infant mortality in these countries. In the country with the highest placebo mortality, Niger, the mortality rate was over 27 per 1000 patient years, that is nearly 3% of all their young kids die each year.

The intervention, azithromycin syrup in a single dose twice a year, was studied in the trial which was called MORDOR, which you may recognize from Lord of the Rings as Tolkien’s name for the kingdom of evil, which he derived from the old English word for murder morþor . I guess because the official language of Niger is French they tortured the acronym production machine until it came up with “Macrolides Oraux pour Réduire les Décès avec un Oeil sur la Résistance”.

The result of the trial was actually the opposite of morþor: there was a significant reduction in mortality, especially in Niger, and especially in the youngest kids, in whom the subgroup analysis showed that babies between 1 and 5 months of age had a 25% reduction in mortality with azithromycin compared to placebo. That is a reduction in mortality among all the infants in the community, which is the 3rd time I am going to use the word stunning in this post.

This intervention will probably have some impact on macrolide resistance, but with such infrequent dosing perhaps that will be minimal, and perhaps this might save many thousands of lives in the world’s poorest countries, if we can ensure that those at highest risk can have access. Azithromycin is quite cheap, and was provided for this Bill and Melinda Gates Foundation funded trial by Pfizer. I’d like to believe that their motivation was altruistic, and that they will provide azithromycin free or at production cost for future trials or usage, if the benefit can be shown to be maintained and that resistance does not become a problem. “you may say I’m a dreamer… but I’m not the only one

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