Oxygen is good for you

Of course you can have too much of a good thing, but you should also try and stay above the minimum.

The COT trial investigators, led by Christian Poets, have published a secondary analysis of the results, examining in particular data from the study oximeters. Despite the relatively low fidelity of the oximeter data (1 sample each 10 seconds) they were able to analyze the number and duration of hypoxic episodes among the 1020 babies who were randomized and who survived to 36 weeks PMA.

An episode of hypoxemia was diagnosed when the saturation was below 80%, and of bradycardia when below 80. There was a clear correlation between a longer time with a saturation under 80 and poorer outcomes at 18 months PMA. Cognitive and Language scores below 85 on the Bayley version3, motor disability and severe retinopathy were all associated with longer durations of hypoxia.

The effects were mostly associated with longer episodes, so when the authors looked at hypoxic episodes where 6 or more consecutive readings (taken as you recall every 10 seconds) were hypoxic, the effects were substantial, whereas shorter episodes of 5 readings or fewer, were less important.

What causes these hypoxic episodes? Most are probably due to apnea of prematurity, although those occurring during assisted ventilation may additionally have other mechanisms, including forced expiration and loss of lung volume.

I have published 2 articles (here and here) trying to determine if there is a relationship between apnea and long term outcomes, both seemed to show a relationship. The improved outcomes in the CAP trial among preterm babies who were treated with caffeine, could also have been due to the babies having fewer hypoxic episodes, although there were no recordings of oximetry to confirm that.

I also wonder if the problem with prolonged episodes may be related to post-desaturation hyperoxia, I and others have shown that apneas are often followed by hyperoxia, possibly leading to re-oxygenation injury, and free radical mediated CNS injury. In my 2 studies that I published only as abstracts, I analyzed recordings of babies who usually had saturations below 95%, and showed that after apneas, they were often over 95%. I thought that the FiO2 of the babies was probably being increased by the bedside staff in response to the apneic hypoxia, but I couldn’t be sure as we didn’t have FiO2 recorded. A much better study was published last year, van Zanten HA, et al. The risk for hyperoxaemia after apnoea, bradycardia and hypoxaemia in preterm infants. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014. in that study babies on nCPAP who had apneas often had hyperoxia after the apnea, and the hyperoxia was much longer than the hypoxia! The hypoxia (less than 80%) lasted on average 2 minutes, and the post-apneic hyperoxia lasted 13 minutes.

The always perceptive Lex Doyle has written an editorial to accompany the article, he points out that the association may not be causative, and that we really have only a limited number of ways to prove whether it is. A therapy proven to reduce the number and duration of hypoxic episodes, and then prospective randomized trials to demonstrate whether outcomes are improved. We are already part way there with the CAP trial, but most of the babies in this new trial will have been getting caffeine, for substantial periods of time, and they were still having lots of hypoxic episodes.

Higher doses of caffeine have been touted, but the concerning results of a pilot trial which showed an increase in cerebellar injury should make us pause. Other agents such as doxapram are suggested by Christian Poets in the discussion section of the article, which sort of brings me full circle, as I made my start in clinical research studying doxapram. But while it is effective in reducing apneas, long term effects are uncertain, infants who received doxapram have been reported in observational studies to have worse outcomes. Which again of course, does not mean causation, but does mean that any studies should be performed with adequate safety protections, and long-term outcome evaluations.

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How the mighty are fallen

It is sad to see a venerable publication like Pediatric Research publishing total drivel.

For reasons that escape me, the latest, August 2015, edition starts with an “overview of the systematic reviews of acupuncture in children“.

The problem with a high quality journal, dedicated to good science, publishing this sort of nonsense is that it gives the impression that it is worth considering that acupuncture might have a real effect.

It is quite clear that acupuncture is nothing but a theatrical placebo. There is no physiologic basis for any real effect, there is no anatomic basis to the supposed existence of acupoints, and despite a whole slew of studies, no evidence of a real effect, for any disease.

Indeed it has been clearly shown that the tiny effects obtained in some studies are obtained no matter where you put the needles, or even if you don’t use needles at all, either not puncturing the skin or using toothpicks. Untrained operators are just as (in)effective as those with years of experience, effectiveness is related to how pleasant the person is who is sticking needles into you, not on where they put them, or how many or how often.

The published overview concludes that further studies are necessary because those published so far are crap, and non-one has actually died. I think that is a very poor justification for wasting time and resources and the goodwill of families. The authors of this overview do show that better quality systematic reviews show less effect, which is a clear red flag.

Studies of acupuncture in children are unethical. No more should be done. Sticking needles into children rather than giving them effective care, for whatever their illness may be, is a deluded practice that risks delaying appropriate therapy. Maybe no-one died in the studies that these systematic reviews included, but at least 90 deaths have occurred due to acupuncture. Ineffective interventions like acupuncture are certainly not worth dying for.

Steve Novella on the excellent blog “Science Based Medicine” dissects another recent study, and notes that acupuncture promoters have created “An industry of worthless studies“. He notes :

acupuncture should be abandoned as a scientific concept. It is a failed hypothesis that has added no real knowledge to our understanding of health and disease.

Come on Pediatric Research, lets return to reality-based medicine.

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Under Pressure….

Colm O’Donnell once wrote an article with a whole line from a David Bowie song embedded in the article’s title (O’Donnell CPF. Turn and face the strange – ch..ch..ch..changes to neonatal resuscitation guidelines in the past decade. Journal of Paediatrics and Child Health. 2012;48(9):735-9), I think Gene Dempsey is following suit, but using only the title this time, see below! It might have been difficult to include the line “this is our last dance, this is ourselves, under pressure” to treat hypotension.

Faust K, et al. Short-term outcome of very-low-birthweight infants with arterial hypotension in the first 24 h of life. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015. There have been a number of observational studies of the association between hypotension and clinical outcomes in the very preterm infant. The results have been variable, as the accompanying editorial from Gene Dempsey (Dempsey EM. Under pressure to treat? Archives of Disease in Childhood – Fetal and Neonatal Edition. 2015) points out. One of the reasons for that variability has been the variation in the criteria used for the diagnosis of hypotension. There have been several biases in other published studies, and all observational studies risk biases which are not necessarily obvious.

This particular study was well performed, but of course cannot determine causality, and suffers from not being able to report the duration of the hypotension. What they showed was that there was a statistical association between having a lower blood pressure during the first 24 hours of life, and having more complications (specifically IVH, BPD and death). One of the questions that has been asked about previous data is whether the association might be explained by adverse effects of the interventions that were used for the hypotension. In this data set treatment with pressor agents had a very strong association with IVH and BPD, even after multivariate correction. As Gene points out in his editorial, there were many infants who were hypotensive who were not treated with pressors. Hypotension remains very common, depending on the definition, using the common definition of a mean blood pressure less than the gestational age in weeks, there were about half of the babies who were hypotensive, much as shown in other studies. nevertheless less than 9% of the babies received pressor agents.

So the neonatologists in the network were already selecting who to treat based on some factors other than just the blood pressure. One of the nice things about this study is that they analyze their data among those who did not receive BP support in the first 24 hours, they showed a minor increase in risk of IVH, BPD and death in hypotensive babies who did not receive inotropes, compared to the normotensive. The Odds ratios are between 0.95 and 0.97 and are statistically significant. I think that is the first time this has been shown. Of course it doesn’t mean that the hypotension was causally related to those outcomes, and it certainly doesn’t mean that treatment with inotropes improves the risks. Indeed the Odds ratios for those same complications are much greater for treatment with inotropes, 1.5 to 2.4, which might be because the babies were more unwell, or might be due to the intervention.

This valuable additional data reinforces the need to get prospective trials completed, no matter how difficult they may be.

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Am I conflicted?

Are conflicts of interest a big deal?

Although many of us, definitely including myself, think that conflicts of interest are a serious issue in medical and academic medical practice, a recent series of puff-pieces editorials in the previously prestigious New England Journal of Medicine (from now on it will be the PPNEJM) proposed that physicians earning huge income from pharmaceutical companies was really not such a big deal after all.

These pathetic, clearly conflicted, nonsensical editorials in the PPNEJM invented new terms to denigrate those of us who want clarity, transparency and accountability (“pharma-scolds” was one). However, I guess, as someone who wants medical practice to be evidence-based, I should also want CoI responses to be evidence-based. Fortunately that is possible, as a new post in the BMJ blogs , by a lawyer and bioethicist points out

So what is surprising to me in my experience teaching ethics & COIs is how frequently people who (correctly) insist on the significance of following rigorous evidence in terms of clinical practice seem to offer opinions on the effects of COIs that IMO do not sufficiently reflect what the best evidence on motivated bias actually shows.

…the literature shows that relationships between commercial industry and physicians or scientists are extremely likely to influence physician/scientist behavior in a variety of ways. The claim that various barriers to such influence—i.e. individual virtue, institutional management, disclosure—are sufficient to prevent such influence is simply not an evidence based view.

Daniel Goldberg, the blogger concerned, presents a CoI Bingo card, which includes most of the excuses and responses to questions about CoI that are commonly heard.

He also has a blog, which is worth visiting, he has a lot of insights into the evidence regarding cognitive bias, and in particular on “motivated bias”. Evidence that was completely ignored in the PPNEJM editorials that I referred to earlier.

One quote from Professor Goldberg

It is not evidence-based to claim that these kinds of entanglements do not have an influence on our behavior.  They do.  We know that they do.  Across a population of actors subjected to these entanglements, a significant percentage of them will modify their behavior in ways favorable to the commercial entity.

His post on the influence of Coca-Cola on professional recommendations and position statements about sugary drinks is a classic.

Indeed he has a whole series on the issue. One point that he makes repeatedly, and which I wholeheartedly endorse, is that simply revealing conflicts of interest is not enough. Transparency about connections with industry, or other financial conflicts is the absolute minimum that we should expect. Reducing conflicts and their undeniable influence on decision-making and policy also needs to be a priority.

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Politeness pays

Does being rude stimulate people to do better, or does it have adverse effects on performance, and team functioning? And how to prove it on way or another?

This really interesting, innovative paper from a team in Israel has performed an RCT to address the problem. Riskin A, et al. The Impact of Rudeness on Medical Team Performance: A Randomized Trial. Pediatrics. 2015. The authors created 24 NICU teams and arranged for them to receive some comments from a supposed visiting expert from the USA. Half of them included some mildly rude comments, which the team received either just before or midway through a simulated resuscitation of a newborn manikin.

Just before the simulation, to the rudeness exposed group, the “expert” stated that he was “not impressed with the quality of medicine in Israel”. Ten minutes later the simulation was stopped and the participants heard that “medical staff like those observed wouldn’t last a week in his department”. He added that he “hoped that he would not get sick while in Israel”.

The study found substantial negative effects of what they refer to as “mild incivility” on both diagnosis of problems during the simulation and on procedural performance. For example the subjects were much less likely to correctly verify the position of a tube when they had been the target of the rudeness.

They also showed that the rude comments affected information sharing within the team, and on whether the team  members sought help from each other.

I must say I have been exposed to rudeness, sometimes much more direct and biting than the comments in this research, at many times during my career, and have, to be honest, also occasionally been rude to others myself. Sometimes a transient irritation or annoyance can lead to comments or attitudes that are negative and to “incivility”. In a very high stress environment like the NICU, making snarky comments when things don’t go well is a common reaction.

I think that we should all try even harder to avoid such responses, not just because they may hurt feelings and harm morale, but because it actually looks like they can have adverse effects on the medical care that our patients receive.


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Growth in the VLBW; could do better!

Among over 300,000 VLBW infants in the Vermont Oxford Network database between 200 and 2013, the weights at discharge were plotted against the Fenton percentiles. Horbar JD, et al. Weight Growth Velocity and Postnatal Growth Failure in Infants 501 to 1500 Grams: 2000–2013. Pediatrics. 2015. To be included, babies had to be hospitalized for between 15 and 175 days. Over the period studied the babies had slightly better growth moving from 11.8 to 12.9 g/kg/day. The number with postnatal growth restriction fell significantly, which means I guess that the NICUs included are doing a better job. But. In the last year of the study, 50% of the babies were discharged with a weight below the 10th percentile, and 27% below the 3rd percentile.

Which is not good. And can be improved.

19.9% of the babies were below the Fenton 10th percentile at birth.

The article defines postnatal growth failure (PNGF) as a discharge weight below the 10th percentile, which I don’t think is quite right. If a child is born on the 2nd percentile and discharged on the 9th percentile, you can’t really call that PNGF. We need a better definition of PNGF.

In our study, which we have presented at PAS, we called PNGF being discharged below the 10th percentile if you were born above the 10th percentile, and your z-score decreased by 0.5 or more. I am not sure if that is perfect either, as a baby born at the 60th percentile who falls to the 15th would not be defined as PNGF by either definition, but probably should be.

About 5 years ago we introduced enhanced nutritional protocols. We have examined and presented our outcomes for 2 years worth of babies under 1300g (therefore at slightly higher nutritional risk than the VON data) of whom 19% were under the 10th percentile at birth (using the same Fenton standards) so almost identical as a percentage to the VON data. When I look at our data using the VON definitions, there were 27% discharged below the 10th percentile and 6% below the 3rd percentile at discharge. Which is a substantially lower proportion than the VON data, but still, I think we can do better.

We also calculated the average change in z-scores (again derived from Fenton’s work) which is probably a better overall indicator of nutrition for the whole group. Our new protocols resulted in a reduction of z-score between birth and discharge of 0.39 compared to a reduction of more than 1 with our previous protocols.

We had 13% infants with postnatal growth failure by our definition. Which is still too high, I think. Also these definitions are based on body weight ; length and head circumference should also be measured (although measuring length accurately is a challenge) as indicators of skeletal growth and body composition. Our babies, with our enhanced nutritional protocols, had a head circumference z score change between admission and discharge of only -0.1, much better than the previous -0.6, but had a length z-score change of -1.5 compared to -1.7.

Continuing to improve these outcomes will probably require an increase in protein intakes; a review of our standards revealed that many babies were receiving less than the 4 g/kg/d of enteral protein for a growing preterm which is now recommended. We are in the process of further enhancing our intakes to try to further increase protein administration, with the hope that a further improvement in length outcomes, and in head circumference, but without an increase in adiposity will result.

Interestingly our enhanced protocols are similar to the standards suggested in a recent review article from Germany. Maas C, Poets CF, Franz AR. Avoiding postnatal undernutrition of VLBW infants during neonatal intensive care: evidence and personal view in the absence of evidence. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014. The main difference between their recommendation to start breast milk fortification at “no later than 100 mL/kg/day” and or protocol which starts when the babies receive 25 mL/day (which we chose so as to prepare a whole days feeds with at least one sachet of fortifier, and not throw away breast milk). That review article quotes 5 studies which all had good growth outcomes, and were all quite similar to our results, meaning I think that just about any NICU should be able to achieve similar nutritional/growth outcomes.


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Choosing Wisely

Many of you will have heard of the “Choosing Wisely” campaign, an attempt to improve decision making, by clarifying efficacy and risks of common procedures or therapies. Many specialty societies have come up with lists of the Top-5 questionable practices that should be reconsidered. The AAP has just published a list of 5 neonatal practices that they say should be avoided. It is interesting that some of the other societies have made very clear recommendations to not do certain things (“Don’t do….” a particular test, for example). The AAP list instead states to “Avoid Routine…” for each one of the 5 practices. I think for a couple of their practices they could have been more forthright.

  1. Avoid routine use of antireflux medications for treatment of symptomatic GERD or for treatment of apnea and desaturation in preterm infants.

This is one where that prior comment applies. I think this should have been stated “Do not use antireflux medications in the newborn”. The reason being that there is no such animal. There is no medication that has been shown to reduce reflux. There is no way clinically to diagnose abnormal reflux. There is no effect of antireflux medication on apnea or desaturation. All the medications in use are toxic.

Now if by antireflux medications, they include anti-gastric acidity medications (and when you look at the supplemental materials it seems that they do) then I guess you could temper those comments a little. It is possible that sometimes acid-caused reflux disease is an issue, and the agents are effective at reducing gastric acid production, even in the newborn. Whether they improve any acid-related disease findings is less certain, most of the rare small RCTs have shown no clinical benefit. They are also associated with more infections, more NEC and increased mortality. So maybe in a baby after diaphragmatic hernia repair, or after Oesphageal Atresia repair they could be indicated, but it would be great to have some actual data.

  1. Avoid routine continuation of antibiotic therapy beyond 48 hours for initially asymptomatic infants without evidence of bacterial infection.

Again I think this could be a stronger statement, given the 2 provisos that the babies are initially asymptomatic and that they have no evidence of bacterial infection. In other words it is for babies with risk factors for infection, but who develop no clinical signs. In those babies you could appropriately say “Stop antibiotics at 36 hours”.

  1. Avoid routine use of pneumograms for predischarge assessment of ongoing and/or prolonged apnea of prematurity.

I think this is appropriately stated, there may be indications for selective predischarge pneumograms, for diagnostic rather than screening purposes, so “Avoid routine” is about right.

  1. Avoid routine daily chest radiographs without an indication for intubated infants.

I agree with this, I didn’t know it was a common practice in the NICU. Some babies are intubated for months, that would be an awful lot of radiation.

  1. Avoid routine screening term-equivalent or discharge brain MRIs in preterm infants.

Again I agree with this, as many of you will already know! The justification given however, is that there is no evidence that they improve long term outcome. While that is true, I don’t think that is why they are being done, not many people think a few minutes in a magnet will make the babies better. The data show a poor positive predictive value of abnormal findings for long term outcomes, which make them of questionable value.

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