Paracetamol for the PDA? Maybe not, this time.

Roofthooft DW, et al. Limited effects of intravenous paracetamol on patent ductus arteriosus in very low birth weight infants with contraindications for ibuprofen or after ibuprofen failure. Eur J Pediatr. 2015:1-8.

In contrast to the previous study that I blogged about, this prospective cohort study of children who had failed ibuprofen, or who had contraindications to ibuprofen (but not iv paracetamol) shows very little evidence of a good effect. The practice in the Erasmus NICU (Rotterdam) was to give 2 courses of ibuprofen for the PDA if there was no contra-indication. Of the 33 infants there were 13 who did not get ibuprofen, and 20 who had previously had some exposure to ibuprofen and had either developed a contra-indication or had completed the 2 courses. All of the babies who had paracetamol after ibuprofen had no effect, and they all went to PDA ligation (except 2 who died). Of those who didn’t have ibuprofen first 6 of them had a response, and the other 7 had either a ligation (5), or were able to get ibuprofen (2), to which they responded.

This is all starting to get messy.

When I use the word “response” it means here that there was a temporal relationship between the drug and the PDA constricting. I don’t know what the natural history of the PDAs in those babies would have been if they had not had the drug in question. We need a placebo controlled trial. Preferably with echos performed by blind individuals (you know what I mean) as well as analyzing important clinical outcomes. And/or a comparative trial, with the same features.

It should be noted that some preparations of paracetamol for IV use contain propylene glycol, which as I noted yesterday is one of those potentially toxic excipients that should be avoided if there is an alternative. One preparation used in Europe has almost as much propylene glycol as it does paracetamol (800 mg for every 1000 mg), which gives high enough serum concentrations to be able to study the pharmacokinetics of propylene glycol in preterm infants. the preparation of paracetamol used in this study, in contrast, contains Mannitol, as well as a bit of HCL, NaOH, some cysteine and some dibasic phosphate for good measure. The version on sale in the USA, which has a different trade name (Ofirmev rather than Perfalgan), but seems to be exactly the same, has nearly 4 grams of Mannitol for each gram of paracetamol (or as we call it, acetaminophen).

Which sounds like a lot.

I have used Mannitol in the PICU for reducing intracranial pressure, I don’t know if that is a good idea in a small preterm baby. The dose used for ICP reduction in the PICU is of the order of 1 g/kg. Mannitol is also used as a diuretic, in a lower dose of around 200 mg/kg or so. An iv dose of 15 mg/kg of acetaminophen would give about 54 mg of mannitol, or a total of 216 mg in a day.

Which is a lot.

I’m starting to get more and more worried about all these things,  I’m glad the ESNEE consortium is working on this issue, we have to find ways to produce medications with fewer excipients, and ones that are known to be innocuous.

It is even possible that the differences in efficacy of paracetamol in the different studies is because some of them contain a diuretic, mannitol (like the study by El-Khuffash and others), and some do not.

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Neonatal Updates

Gaynor JW, et al. Neurodevelopmental Outcomes After Cardiac Surgery in Infancy. Pediatrics. 2015. This is an important study of the issue detailed in the title including 1770 infants who had surgery between 1996 and 2009, and who had Bayley II tests performed at between 6 months and 30 months. All had cardiac surgery requiring bypass at less than 9 months of age. As the authors note there are substantial numbers with low Bayley scores, 15% of the entire group are more than 2SD below the standardized mean of 100, and among those who have aortic arch obstruction it was 20%. There has been a minor improvement over the years of the study, after adjustment for risk factors.

Jakaitis BM, Bhatia AM. Definitive peritoneal drainage in the extremely low birth weight infant with spontaneous intestinal perforation: predictors and hospital outcomes. J Perinatol. 2015.The study evaluated the outcomes of 89 preterm infants who had spontaneous perforation in whom the initial approach was peritoneal drainage without laparotomy. 75% never had a laparotomy. The authors note that, of those who proceeded to eventual laparotomy some had persistent air in the peritoneum, some developed skin fistulas, and some had persistent sepsis. A few were found on pathology to have probable NEC after all, when they had the laparotomy.

Nellis G, et al. Potentially harmful excipients in neonatal medicines: a pan-European observational study. Archives of Disease in Childhood. 2015. A report from 89 NICUS in 21 European countries of what nasty stuff they gave to their babies, when they were trying to only give them good stuff. 27% of medications administered contain things we shouldn’t be giving to newborns. 2/3 of the babies received at least one of these medications. The potentially toxic components include Polysorbate 80, Propylene glycol, Ethanol, Parabens, Benzoates, Benzalkonium, Saccharin and Sorbitol. As the authors note, for many of the sources of these excipients, there are alternatives available which do not contain them.

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Keeping Central Lines clean, very clean.

Shepherd EG, et al. Significant Reduction of Central-Line Associated Bloodstream Infections in a Network of Diverse Neonatal Nurseries. The Journal of pediatrics. 2015. This is an observational study from a group which includes a large number of neonatal beds. They report the results of their quality control efforts specifically for central line associated blood stream infections (CLABSI, as we are now calling them). They show a dramatic reduction over the period from 2003 to 2007, and a progressive continued improvement since then, down to very low current levels of  less than 1 infection per 1000 catheter days. The patients include small preterm infants as well as a large number of surgical patients. There has also overall been a reduction in the number of central line days per 1000 admissions.

One issue I have with this study is the question of definitions of CLABSI; they state that they used the definitions which were in place at each time, approved by the national surveillance programs. But it is very hard to find out exactly what those definitions were. The current definition for CLABSI caused by “skin commensals” (including coagulase negative staph) requires 2 blood cultures with the same organism, taken at separate times, less than 48 hours apart. Was that always the case? If not it could have a major impact on the implications of these numbers. They also don’t report the data in the highest risk subgroups, such as the very preterm baby, nor the overall rate of BSI that are not CLABSI. If the infections among extremely immature babies have just shifted from CLABSI to BSI without CL (which I think is probably not the case, but you can’t tell from these numbers) then that has not necessarily benefited the babies.

These issues have to be taken into account when we try and compare rates and approaches over time, and between hospital systems. For example, the Canadian Neonatal Network reports CLABSI as any positive blood culture, including CoNS, in association with a CL; in order to acknowledge that many of the time babies have a single culture, followed by the start of antibiotics. They won’t necessarily have another positive culture, as the antibiotics are already working, so even though they may be clearly infected, they would not be counted as a CLABSI according to the definition used in this paper. The large majority of CLABSI occur in the very preterm infant, so differences in patient populations and in catheter use can have a major effect on CLABSI rates. The CNN data also show somewhat more variability in CLABSI than in overall rates of late-onset infection, reflecting different patterns of catheter use I think, and that some of the variability of CLABSI is offset by occurrence of non-CLA BSI in the very preterm infant.

I think we really need to have data on CLABSI, non-CLA BSI, those numbers among infants of less than 29 weeks, and the numbers if you accept a single CoNS culture (maybe with some other evidence that it is a real infection); in order to be able to really compare results.

Nevertheless these are impressive results, the methods they followed are all available in the appendix on-line.

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Annie on the Radio

Annie was interviewed live on air this morning on a CBC radio show called ‘The Current’. She was asked to discuss the NEJM publication from the Neonatal Research Network that I have been blogging about.

I don’t know if this link works outside Canada.

In case it doesn’t here is a summary:

The program starts at the birthday of Dominica, a baby from our NICU born before 23 weeks there is a photo of her, and her Mom, on the CBC web page. There is a brief interview with both her parents, who are grateful they were given the opportunity to have their daughter alive.

Annie then talks about the failings of our current approach to perinatal decision-making, the lack of transparency, the hidden variation from center to center, and the discrimination based on inaccurate gestational ages. She discusses how these things should be open, and be discussed with parents. How we should be making decisions together with parents which are the best for them and their baby, and which should be open to the possibility of active care whenever there are realistic chances of survival.

She introduced the important questions of what gives a life quality, what makes a life worth living, or worth trying to save, and, the converse, what degree of impairment makes a life worse than being dead.

She was asked if having our own very preterm baby changed how she talks to parents, and she said that it made little difference. But that it made her reconsider how we judge the worth of the lives of our patients; that Violette is perfect to us, even if her scores are not perfect, and even if she sometimes doesn’t want to do her homework! (she didn’t actually say that last bit about homework, it’s just in case she’s reading this).

She was followed by another ethicist who made some general points that were reasonable, and some that needed clarification and debate, but this unfortunately isn’t a debate show. He implied, for example, that Annie was suggesting that it is the physicians who take these decisions, which is exactly the opposite of what Annie said and what she thinks. It is in contrast, what the CPS statement actually recommends before a best-guess gestational age of 23 weeks: that parents should not be given an option. He goes on later to contradict himself, saying that it is OK for hospitals not to offer active treatment for some babies, without defining whether parents should know that another hospital, not 2 kilometers away, might be prepared to offer life-sustaining intervention.

He suggested, and I can only agree, that parents should be given the opportunity to talk to other parents, and that the decision of whether a life with neurologic or intellectual limitations is worthwhile should be left to the parents. Of course, putting this into practice is another issue at 2 am in the morning…

He also emotionally loads his responses, by talking about “chances of some kind of more reasonable life”, and only when the hospital decides that these chances are high enough should the parents then have a right to decide. An argument which, as I said, contradicts his points about parental decision making. He is then asked about cost, and his answer shows he doesn’t know the literature, that NICU is far more cost effective than any other form of ICU. He then starts to use highly emotive and inaccurate language about “putting babies through a grueling experience to have a dismal quality of life”, at which point I was tempted to switch off, but I persevered.

The facebook page for the program has a nice tag-line for this show, a quote from Annie “‘I’m advocating that we treat patients so that they have a great quality of life, and a great quality of life is not just IQ.’ Dr. Annie Janvier”

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The meaning of life

At the end of the article written by a parent that I blogged about recently, there was a link to their blog. Their latest post is a musing about the answer to the question “what is life all about?” It is very profound, and very simple at the same time, certainly worth reading.


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The Swedish Express

To follow on somewhat from the last post, I wanted to discuss the most recent data from the Swedish EXPRESS study. If you remember, this study has examined the outcomes of less than 27 weeks babies from across Sweden, and has previously shown substantial differences in survival between regions.

One great feature of these data is the inclusion of data from mothers from the time they are admitted to hospital, so stillbirths who deliver at 22 weeks to 26+6 are included. This particular new study concentrates on the data from 844 babies who were alive when their mother was admitted to the hospital. 137 of whom were stillborn. 70% of the live born infants survived to get followed up.

Interventions were variable between regions of Sweden, for example the proportion of babies who were delivered after antenatal steroids varied between regions from 40% to 72%, and cesarean delivery between 29% and 60%. Neonatal interventions were also varied, such as giving surfactant quickly, intubation in the DR, and having a neonatologist in the DR.

The authors created a therapeutic intensity score, and then examined whether being more active improved or worsened survival and long-term outcomes.

The results showed that increasing obstetric interventions increased live birth, and among those born alive, increasing neonatal interventions improved survival. When they examined the infants at 2.5 years, they found that among the survivors, there was no increase in “NDI” with more active care, in fact, what differences there are are in the other direction, fewer babies from highly active regions had “NDI” overall, especially among the 22 to 24 week subgroup, 38% compared to 48%. (NDI was any CP affecting walking, deafness, visual impairment and Bayley 3 below -2SD on any scale, compared to the scores of a local full-term control group).

If you put the 2 outcomes together, the famous “death or NDI”, regions of Sweden that practiced higher intensity perinatal care had significantly less adverse outcomes than lower intensity regions. The Odds ratio for the group as a whole were 0.70, that is, the Odds of having a bad outcome were decreased by 30% in highly active regions, and for the most immature infants (22, 23 and 24 weeks gestation), the OR was 0.43 (0.48 after statistical adjustment) so a greater than 50% reduction in the Odds of adverse outcome, by providing  more active care.

This should comfort anyone involved in care of such infants, if you work harder at getting them to survive, you end up in general with results which are at least as good among survivors than less active centers, at least in the range of actions that were examined in this study.

Here is a very striking figure from that article, showing the survival curves for infants born in high activity, versus low activity regions. The differences are striking. Its hard to imagine any other part of medicine where this survival difference would not be considered to be a major advance.

Express Survival


What were the extremely intensive interventions that were different between the regions? Well, very simple stuff really, its just the willingness to do them that is important

4 key obstetric indicators (delivery at level III hospitals, complete course of antenatal steroids, cesarean delivery, tocolytic treatment) and

4 key neonatal indicators (surfactant within 2 hours after birth, delivery attended by a neonatologist, intubation immediately after birth, infants admitted for intensive care [out of infants alive at 30 minutes after birth])

Of course not all these babies need to be intubated after birth, and it certainly wasn’t 100% in any region (actually varied from 35.6% to 75%), but the difference in proportions of the babies intubated was substantial, showing a greater willingness to do so in some areas than in others.

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Before 24

The latest New England Journal of Medicine has a fascinating article the first author of which was a medical student who was working with Ed Bell in Iowa (I say was a medical student as I believe he has now graduated, with an MD and an epidemiology PhD, and is going on to great things in Wisconsin). It recounts the differences in rates of active treatment of babies by their assigned gestational age at birth, and the subsequent survival and 18 to 20 month outcomes, between the hospitals in the NICHD neonatal research network between 2006 and 2011.

Rysavy MA, et al. Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants. The New England journal of medicine. 2015;372(19):1801-11.

Among the hospitals in the Neonatal Research Network, rates of active treatment at 22 and at 23 weeks GA were very variable. At 22 weeks between 0% and 100% of babies born alive received active intervention, at 23 weeks it was between 25% and 100%. By 24 weeks there was very little difference, 65% in one hospital, but the rest being over 90%. Not surprisingly babies that were so immature did not survive without intensive care, also not surprising therefore, the major factor determining survival was whether or not you were actively treated.

The first interesting tidbit from the results, the frequency of active treatment prior to 24 weeks seems to jump up the last 2 days before the actual week is completed. Many more babies are actively treated at 23 weeks 5 days than at 23 weeks 4 days, and at 22+5, especially 22+6, than at 22 +4.

22 weeks b

At 22 weeks some of the numbers are quite small, with 79 in total getting active intervention, compared to 278 who did not. Survival was 23% for the group overall among those who were actively treated. Six of the 18 survivors had ‘severe NDI’ (‘NeuroDevelopmental Impairment’), 4 of them being a Bayley cognition score under 70, 2 having disabling cerebral palsy. (These numbers are in the supplementary appendix).

This might be repetitive ( I know it is) but a low score on a Bayley evaluation is not an impairment, it is evidence of developmental delay, which may or may not (and often does) catch up in the future. This is still true with the Bayley version 3, as I discussed recently. An impairment is a “loss or abnormality of function”, and I wish the NRN stopped using this term. Disabling CP, death, delay in cognitive or language development, deafness and blindness are all lumped together in the outcome ‘death or NDI’. I don’t think that composite is very useful for parents, nor should it be used for our counseling and decision making with them.

The actual numbers for the individual hospitals are in this figure: It is of interest that the survival at hospitals that treated all their 22 week infants actively are below the 23% I mentioned above, presumably because hospitals that are treating a proportion, but not all, of such infants tend to actively treat infants who are more likely to survive than the average (such as with a higher birth weight, or who have had time to complete steroids).

The legend (slightly edited) to the figure is below.

22 weeks

Relationship between hospital rates of active treatment of extremely preterm infants born at 22, 23, or 24 weeks of gestation and hospital rates of outcomes among such patients. Outcome rates are risk-adjusted to account for differences in infant demographic and clinical characteristics among hospitals. Black dots represent hospital rates of the specified outcome. Gray dots represent the difference between the adjusted hospital rates of survival and survival without impairment and represent an estimate of the adjusted rate of survival with impairment.

It took me a few minutes to figure out the gray dots on the graphs, they are an estimate of the babies who survive with severe impairment or with moderate or severe impairment. (I read it too fast the first time). Most of the ‘moderate impairment’ is a Bayley score between 70 and 84, which has very little significance for long term functioning of these kids.

Jon Tyson has been saying for years, as have we, (and he gave a presentation about this at the PAS meeting that just finished) that our best guess at the fetal gestational age is only one factor that we should be included in our decision-making, and that to have strict rules (even if arrived at by some sort of consensus) based on gestational age alone is irrational.

Part of that irrationality is based on the fact that we never know the GA unless the ovum was fertilized in an assisted reproduction center. The creep up as GA approaches 23 and 24 weeks, is evidence of this irrationality; surely if based on likelihood of survival or ‘survival without NDI’, the frequency of active intervention should increase gradually over the week, and not change as we click past midnight between Thursday and Friday.

Dr Tyson was proposing that we should try and develop thresholds based on predicted outcomes and suggested that we should develop a consensus with parents about which thresholds are appropriate.

I am not entirely in agreement with this approach, especially as his example was to use the composite outcome of ‘survival without severe NDI’.

I think we should be developing methods, along with parents, to ensure that the best decision is made for each family. It won’t necessarily be at the same predicted percentage survival, or ‘survival without severe NDI’ where active intervention becomes the right answer for each family.

I think we should separate the calculation of survival from the discussion of long term outcomes, and that we could investigate, with each family, which outcomes are most important to them, and then try and figure out the likelihood of having, or avoiding those outcomes.

I don’t think that being super precise about the figures is that valuable either: if the risk of death is 21 compared to 31% should that, or would that, make a difference to many families’ decisions? I think the value of the NICHD calculator is to point out the relative importance of non-GA factors, not to give a precise prediction (which is, in any case, already out of date) and then take that figure to the parents bedside, even though that is what is commonly being done (as Bill Meadow’s group showed in an abstract at this years PAS meeting)..

One major missing factor in all this is what I just wrote about a couple of posts ago, the babies who die in utero, because there is no active Obstetric intervention. I know Matt Rysavy is trying to get at this point, but it might be difficult to get good data, unless the NRN starts collecting it prospectively. I wouldn’t be surprised if obtaining this data would make some of the center differences even more striking, as centers with a tendency to actively intervene after birth might also intervene more actively before birth. But maybe not, it would be good to know. Certainly as Neil Marlow notes in his accompanying editorial, the Epicure 2 study showed that “referral to a suitable perinatal center for delivery is a major determinant of survival”.

As John Lantos and Bill Meadow have pointed out, if there was a similar difference between centers in the USA in terms of treatment of other serious diseases (such as metastatic breast cancer as one example), and one center treated all of the patients referred, but another decided that it wasn’t worth it and let them all die, there would be outrage! Especially if some center had long term survival rates of 23%, and others had zero.

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