Neonatal Updates: more nutrition

Posted on 10 April 2014 by Keith Barrington

It is not surprising when I write a blog post about nutrition in the preterm neonate to find that at least one, and on this occasion two, of the articles are from the productive pen of Johannes van Goudoever.

Vlaardingerbroek H, Vermeulen MJ, Carnielli VP, Vaz FM, van den Akker CHP, van Goudoever JB: Growth and fatty acid profiles of vlbw infants receiving a multicomponent lipid emulsion from birth. Journal of Pediatric Gastroenterology & Nutrition 2014, 58(4):417-427.

SMOFLipid is a new-ish lipid emulsion which is made from several different sources, and as as result contains omega-3 fatty acids, as well as omega-6. It has been approved in Canada for TPN in adults, and has been approved in Europe also for neonates. Which I find a bit surprising as we had a recent presentation from our pharmacy, and the total published data from several small trials came to about 100 treated preterm babies, and 100 controls.

The NICU team in Rotterdam now add to that data, they have performed a clinical RCT comparing clinical outcomes among infants randomized to either SMOFLipid or Intralipid. 96 VLBW babies were randomized within 6 hours of birth, starting at 2 g/kg/d on day 1, and 3 g/kg/d on day 2.

The growth on SMOFLipid was improved, and the fatty acid profile was also improved with the DHA and EPA levels being maintained and significantly higher than the controls. There were no adverse effects noted. There were fewer cases of late onset sepsis, 27% rather than 40% had this complication. This is not individually significant, but some of the same authors have previously published a meta-analysis, which showed a 25% reduction in LOS based on 2 small trials and barely significant. If you add the new numbers to the data already in the literature, which which they do in their discussion, you now have a reduction in sepsis of 28% and the upper limit of the 95% CI is 0.94. So a very interesting finding, for which there is some theoretical/basic science support, which needs to be replicated in further larger trials.

I think there is good theoretical justification for using an emulsion which includes omega-3 fatty acids, and if we were to design the first ever intravenous lipid for a trial today we would probably have something like SMOFLipid in mind. However, I think we really should demand robust efficacy and safety data in comparison to the current standard before changing over. Even with the knowledge that when intralipid was introduced for preterm babies there was really no good controlled evaluation. I don’t think there is a single RCT against placebo of intralipid as a component of TPN in preterm infants, which is not that unusual for things that were introduced in the 50’s and 60’s. What to do about that is not entirely clear to me, but I don’t think the answer is to switch to a newer therapy after a few very small RCT’s. I think the time is now to ensure that we have big simple RCTs comparing current usual care to any innovation, even is the current usual care is based on very little, or almost no, data.

Olsen IE, Harris CL, Lawson ML, Berseth CL: Higher protein intake improves length, not weight, z scores in preterm infants. Journal of Pediatric Gastroenterology & Nutrition 2014, 58(4):409-416.This secondary analysis of data from a trial of a concentrated liquid human milk fortifier shows that there was a correlation between higher protein intakes and better length at 28 days.

Christmann V, de Grauw AM, Visser R, Matthijsse RP, van Goudoever JB, van Heijst AFJ: Early postnatal calcium and phosphorus metabolism in preterm infants. Journal of Pediatric Gastroenterology & Nutrition 2014, 58(4):398-403. How much calcium and phosphorus should we supply, and what should be the ratio between them? The answers to these questions are still not entirely clear to me. Avoiding early hypocalcemia, and/or hypophosphatemia, and then ensuring later good bone mineralisation may need different answers to those questions. The data in this study supports the idea that you need a lower calcium/phosphate ratio in the first couple of days, and that gradually changes afterward.

An accompanying editorial gives some guidance, much of which needs confirmation in other studies.

Posted in Neonatal Research | Tagged , , | Leave a comment

Zinc supplementation: should we be galvanized into action?

Posted on 10 April 2014 by Keith Barrington

I wasn’t sure how many non native-English speakers would get that joke, and jokes are rarely improved by explaining them, so if you don’t get it, just keep on reading.

Terrin G, Berni Canani R, Passariello A, Messina F, Conti MG, Caoci S, Smaldore A, Bertino E, De Curtis M: Zinc supplementation reduces morbidity and mortality in very-low-birth-weight preterm neonates: A hospital-based randomized, placebo-controlled trial in an industrialized country. The American journal of clinical nutrition 2013, 98(6):1468-1474. A multi-center RCT enrolled nearly 200 VLBW infants at 7 days of age to receive a zinc supplement (intravenous and oral) or placebo. The zinc supplement gave much more than the current recommendations, around 10 mg per day, while the controls received around 1.3 mg/day, which is consistent with some guidelines, but a bit less than some newer guidelines (which recommend about 2-2.2 mg/kg/d). The authors were interested in clinical outcomes, as zinc has multiple actions, being incorporated into several enzymes, and having effects on immune function and maybe cerebral development. The zinc supplemented group had no cases of NEC (compared to 6% in the controls), but a few more cases of late-onset sepsis; they had less PVL, slightly less BPD and no RoP >stage 2 (compared to 3% in controls). The primary outcome of the study was a composite including the development of at least one of those complications, which was significantly reduced by zinc supplementation, 27% vs 42%. There were quite a few deaths in the study after enrollment, and I think the authors should have included mortality in their composite outcome. There were, however, more deaths in the controls, 17/96 vs 5/97, which was also significant, and I assume that a combined outcome of death or morbidity would have been significant.

An editorial accompanying the article gives some interesting background, and notes that zinc reduces copper absorption, and when high doses of zinc are given, also inhibits iron absorption. It is appropriately cautious, and states that we should be ensuring that babies receive zinc according to current recommendations, and that further research on higher, ‘pharmacologic’ doses of zinc will be important.

As far as I can work out, current human milk fortifiers added to human milk don’t seem to give enough zinc, they add about 0.72 to 1.2 mg of zinc per 100 mL of milk, depending on which you use, it appears that we should probably be giving more, just based on balance studies.

Posted in Neonatal Research | Tagged , , , | 2 Comments

Bugs and Breast Milk

Posted on 9 April 2014 by Keith Barrington

Neonatology recently published a commentary asking the following question about routine probiotic supplementation, ‘what will it take to change practice?‘

This was immediately followed by another commentary, from Neena Modi, explaining why she is still reluctant. Although I have a great deal of respect for Neena, I must say, on this issue, she is wrong.

She reports her unit’s use of fresh colostrum, and the extensive use of fresh breast milk. Now at the risk of receiving howls of protest from the breast milk police (I am one of them myself!) there are stronger data for the efficacy of probiotics than for fresh breast milk, when it comes to prevention of NEC. Indeed one of the mechanisms for the activity of breast milk is probably the frequent ‘contamination’ of breast milk with probiotic organisms, as she mentions herself. I certainly agree that there are also theoretical advantages of other components breast milk, such as the fucosylated oligosaccharides, lactoferrin, and lysozyme. Also secretory antibodies (Rogier EW, et al: Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression. PNAS 2014 a new study in a mouse model showing the probably beneficial effects of sIgA on promotion of a normal microbiome).

One place where I disagree with her are the examples she uses that ‘some therapies initially embraced enthusiastically and widely believed to be safe – for example routine oxygen administration at resuscitation, and antenatal antibiotics for women in spontaneous preterm labour with intact membranes – were ultimately shown to be of no benefit or to have harmful long-term consequences’. As I pointed out during my recent presentation in Scottsdale (which you can download if you wish), therapies which fall into that category have a common feature, that they were adopted without much, or without any, evidence from randomized controlled trials. They were adopted based on ‘expert opinion’ or, more commonly, based on fashion.

Which is actually the opposite of what we see with probiotics. In this instance we have extensive evidence from RCTs, of efficacy and of safety, and yet they have not been ’embraced enthusiastically’.

As mentioned, breast milk contains probiotic organisms, so if you use fresh breast milk you are usually giving probiotics anyway, you won’t be giving very many in the first few days, and you have no idea which strains you are administering. There are also, of course, frequently pathogens in breast milk, and mothers who have received antibiotics have a very different microbiome of their breast milk.  A new review article (Latuga MS, Stuebe A, Seed PC: A review of the source and function of microbiota in breast milk. Semin Reprod Med 2014, 32(1):68-73) is a fairly brief read, and summarizes the data about the germs that are commonly in breast milk, and how they get there, including the idea of entero-mammary trafficking, meaning that they might be specifically transported to the breast tissue from the GI tract.

In a new study published on-line in JPGEN the frequency of finding lactobacilli and bifidobacteria in breast milk was lower than in some other studies, and importantly was substantially decreased by giving antibiotics to the woman. (Soto A, Martin V, Jimenez E, Mader I, Rodriguez JM, Fernandez L: Lactobacilli and bifidobacteria in human breast milk: Influence of antibiotherapy and other host and clinical factors. Journal of pediatric gastroenterology and nutrition 2014). Many mothers who deliver extremely preterm have received antibiotics, this study demonstrates, as we would suspect, that the women who received antibiotics had much lower probiotic counts in their breast milk.

And finally another study showing that antibiotics given to preterm infants do actually kill probiotic organisms, promote the growth of resistant pathogens, and increase the later risk of NEC. (Greenwood C, et al: Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of enterobacter. Journal of Pediatrics 2014).

So if you give breast milk to very preterm infants, you administer an unreliable source of the same organisms as if you actually give a probiotic preparation. You may not give any probiotics if the mother received antibiotics, and if the baby is on antibiotics you really screw up their intestinal microbiome and kill any good bugs that they are getting from the breast milk.

The best way to be certain that the baby receives a source of these protective organisms is by giving them a verified source of probiotics, which will decrease the rate of NEC, even among babies with a high rate of breast feeding.

Posted in Neonatal Research | Tagged , , | 2 Comments

Single baby rooms?

Posted on 8 April 2014 by Keith Barrington

Terrie Inder and her colleagues have put the cat among the pigeons (as we say in England, I guess we are not keen on pigeons).

Her (non-randomized) study suggests that babies who were treated in single rooms had poorer language skills than babies treated in a more traditional unit, with large, multi-patient rooms. Depending on bed availability infants were either admitted to large rooms of 8 beds or so, or single rooms. They followed the babies under 30 weeks gestation out to 2 years of corrected age, 83% of the survivors (n=86) returned for neuro-developmental follow up. I won’t mention the EEG and imaging findings which showed some differences, but rather the 2 year Bayley scores, which were worse in the language domain for babies from single rooms, and motor scores were also somewhat worse.

Single room designs have become the norm for new NICU construction based on data which show an increase in parent satisfaction, an increase in parental presence, and expected reductions in health care associate infections, especially a reduction in patient to patient spread of viral diseases.

This new data should make us reconsider carefully how to optimise the neonatal environment.

One of the possible explanations for this finding is that single rooms tend to be very quiet, and they may be too quiet, with not enough auditory stimulation for the development of the auditory pathways. But perhaps this is not generalisable, in the USA maternity leave is usually 1 month without pay. As I understand it, this may vary by state, but if you have a long stay baby in the NICU, being with the baby a few hours every day and talking to them is extremely difficult to sustain unless you are independently wealthy, or unemployed.

In the NICU where these new data come from, parental visiting was an average of 2 hours a day in the open rooms, and 4 hours a day in the single rooms (in the 3rd and 4th week of hospitalisation). This major increase in visiting time may not be enough to counter the 20 hours of very quiet, undisturbed rest, which we usually think of as a benefit.

In other cultures, mothers are able to spend much longer. Parents in Québec can share a year of parental leave, and for the first half of that can qualify for income from a government supported insurance scheme. It may be that in cultures where the parental leaves are more generous, parents will spend longer with their babies in single room designs, that would be interesting to see.

A commentary in Acta Paediatrica is written by one of the investigators of the Stockholm RCT of Family Centered Care. In that study infants stable enough for intermediate care were randomized, one part of the family care intervention was a single room. I can’t see from that report how long the parents stayed with their infants, and there was no long term follow up.

The thoughtful commentary (Örtenstrand A. The role of single-patient neonatal intensive care unit rooms for preterm infants. Acta Paediatrica. 2014;103(5):462-3) refers to a systematic review that I was not aware of. The SR includes 10 articles, only one of which, the Stockholm study, was an RCT. The others are various observational designs with potential biases, but which suggest a range of benefits of single rooms.

I think it is possible that the effect shown in the study from St Louis is a real effect. I would be a little surprised if the single room was actually quieter than being in utero, so I would guess that it is the nature, rather than the intensity, of the sounds that may be important.

Which brings me back to the issue of the mother’s voice, and the importance of the mother speaking to her baby. Babies born at term recognize certain features of their mother’s voice from very early after their birth, almost certainly because the antenatal experience of the mother’s voice has impacts on the development of central auditory processing. I think this suggests that the potential adverse effects of being in a single room might have to do with reduced exposure to voices, and that maybe we can counter this effect by encouraging mothers to talk to their infants whenever they are present, and to use recordings of the mothers’ voices when they can’t be there.

Posted in Neonatal Research | Tagged , | Leave a comment

Presentation in Scottsdale AZ

Posted on 7 April 2014 by Keith Barrington

For anyone who was at the AAP workshop in Scottsdale, and anyone else who might be interested. I have put the powerpoint presentation on this blog, under ‘Presentations from our group’ the first heading is AAP Scottsdale AZ 2014. If you click on that you will find the powerpoint. Feel free to download and use any slide that you think is useful to you.

Posted in Neonatal Research | Leave a comment

Do preterm babies need their thyroid?

Posted on 7 April 2014 by Keith Barrington

Now I am very confused. I thought I knew that many very preterm babies had low serum thyroxine levels (this study confirms that). It seems to be a variant of sick euthyroid syndrome, levels tend to fall for about the first week of life then start to increase again. I thought it was well established that infants with a low thyroxine had poorer outcomes, in terms of long term impairments. To my mind it was not clear whether this association was causative, and randomized replacement trials have been generally negative, with no benefit demonstrated, but further appropriate trials were warranted.

Now a new study (Scratch SE, Hunt RW, Thompson DK, Ahmadzai ZM, Doyle LW, Inder TE, et al. Free Thyroxine Levels After Very Preterm Birth and Neurodevelopmental Outcomes at Age 7 Years. Pediatrics. 2014) suggests the opposite.  In this group of babies, from the incredibly productive group in Melbourne, those babies that had higher thyroxine levels had worse outcomes. The main difference between this study and the previous ones is that the infants were studied at 7 years, so such things as language development can be examined in more detail. The babies were probably less sick than in some of the older studies, as very preterm babies are generally less sick than they used to be, and many of the older studies had less antenatal steroid use, and no surfactant. But I am still a bit confused by the reversal of the finding.

The authors note that recent models suggest that the sick euthyroid syndrome may well be adaptive and beneficial, rather than dangerous. If this is true, and higher T4 is a sign of poorer adaptation, then why the older studies showed the contrary remains a puzzle.

The authors also note that the method they used those several years ago to measure T4 is no longer considered optimal (and may be affected by low serum proteins which are common in the preterm). It would be interesting to have a new study, using the best modern assays, with cohorts from Australia, where high T4 seems to be bad for you, and from the US and Holland where low T4 seems to be the problem!

 

Posted in Neonatal Research | Tagged , | 2 Comments

ETT position

Posted on 5 April 2014 by Keith Barrington

I was very fortunate to do my fellowship in neonatology with Neil Finer. One of the (very many) things which he taught me, about the 3rd day of the fellowship I think, was how to determine ETT position. He showed me this technique, with a finger in the suprasternal notch, moving the tube slightly, you can determine if the ETT is in good position. I have used it ever since and tried to teach others. The way I do it is to make sure the infant’s head is in neutral position, then put an index finger in the notch, and you should be able to feel the firm resistance of the tube. Then you slowly pull the tube back until you feel the tip. Then advance the tip of the tube until it is just as far you can feel, just above the manubrium. I have never performed a study of this, but I have never had an endobronchial intubation in many years using this technique. It is very simple and accurate in small preterm infants, but a little more difficult to be sure of the detection of the tube tip in a large term baby.

Several years later Neil published a randomized study demonstrating the utility of the technique (Jain A, Finer NN, Hilton S, Rich W. A randomized trial of suprasternal palpation to determine endotracheal tube position in neonates. Resuscitation. 2004;60(3):297-302).

In a new trial, (Saboo AR, Dutta S, Sodhi KS. Digital palpation of endotracheal tube tip as a method of confirming endotracheal tube position in neonates: an open-label, three-armed randomized controlled trial. Pediatric Anesthesia. 2013;23(10):934-9) infants were randomized to have either tube position determined by either a weight based calculation, calculation plus palpation by ‘specially trained neonatology fellows’ or calculation plus palpation without extra training. There were many fewer malpositioned tubes in the second group.

This technique is simple, easy to learn, non-invasive and quick. It can practically eliminate endobronchial intubations, and ensure that surfactant is delivered via a tube above the carina. It should be more widely taught and used.

 

 

Posted in Neonatal Research | Tagged | 2 Comments

Neonatal Updates

Posted on 2 April 2014 by Keith Barrington

Gephart SM, Spitzer AR, Effken JA, Dodd E, Halpern M, McGrath JM. Discrimination of GutCheckNEC: a clinical risk index for necrotizing enterocolitis. J Perinatol. 2014. The Pediatrix group have developed a scoring system for predicting the risk of NEC; points are given for a number of different items, and then added. The process of developing it is well described, it took me a while to find where is the cut off for the score, but in figure 3 it is noted that the threshold is 32. If you have a score more than that you at increased risk, less than that you are at decreased risk. Interestingly, the positive risk factors, which reduce the risk, include probiotics! Also interestingly the background incidence of NEC in the individual NICU is by far the most important risk factor. Human milk feeding on both days 7 and 14 was another protective factor. Many of the risk factors are not modifiable, but those 2 certainly are.

van Ganzewinkel C, Derijks L, Anand KJS, van Lingen RA, Neef C, Kramer BW, et al. Multiple intravenous doses of paracetamol result in a predictable pharmacokinetic profile in very preterm infants. Acta Paediatrica. 2014. In much of the world, intravenous paracetamol (acetaminophen) is available. This study gives important pharmacokinetic data.

Hitzert MM, Van Braeckel KNJA, de Bok M, Maathuis CGB, Roze E, Bos AF. Functional outcome at school age of preterm-born children treated with high-dose dexamethasone. Early Human Development. 2014;90(5):253-8. Arie Bos is one of those exceptionally productive but self-effacing individuals who drive a large body of neonatal research. In this study the group he works with have analyzed outcomes of very preterm babies who received dexamethasone, compared to control infants. Overall cognitive and motor development were worse, with less effect on language skills. As always from observational data, it is not certain whether this is causative or not, but it is certainly biologically feasible.

Rollo DE, Radmacher PG, Turcu RM, Myers SR, Adamkin DH. Stability of lactoferrin in stored human milk. J Perinatol. 2014;34(4):284-6. Refrigerating breast milk decreases lactoferrin concentrations, but not by much. Freezing it has more of an effect, prolonged freezing at -20  reduces levels by half. The fresher the better, at least for lactoferrin.

Pathak G, Upadhyay A, Pathak U, Chawla D, Goel SP. Phenobarbitone versus phenytoin for treatment of neonatal seizures: an open-label randomized controlled trial. Indian pediatrics. 2013;50(8):753-7. An RCT in about 110 babies with seizures. Clinical seizure control was better with phenobarb. Unfortunately no EEG data.

Wilson-Ching M, Pascoe L, Doyle LW, Anderson PJ. Effects of correcting for prematurity on cognitive test scores in childhood. Journal of Paediatrics and Child Health. 2014. I think that you should always correct for prematurity. It just has less and less impact as the child ages. 3 months of correction makes a big difference to a 2 year old, and not much for a 10 year old. But at least we all then talk about the same thing.

Posted in Neonatal Research | Leave a comment

Apneas are bad for you (probably), this might be part of the reason

Posted on 1 April 2014 by Keith Barrington

I have published two articles that looked a the relationship between apneas and long term outcome. One was taken from pre-discharge recordings of very preterm babies. We compared the long term neurodevelopmental abilities of preterm babies 18 months later, and compared them to the pattern of apneas that babies, who were ready to be discharged, had on their recordings.

Infants with the more severe apneas had worse outcomes at long term.

Another study examined the number of days that apnea was recorded by the bedside nurse in the hospital chart, and again compared this to long term outcomes. There was a significant correlation, the more days of apnea, the worse the outcomes.

Quantifying apnea from hospital charts is fraught with risk. Many apneas are not noticed by the bedside nurse, especially obstructive apneas; overall about half of apneas are not noted in the charts. That is the reason we decided not to try to count apneas in the CAP trial, the only really reliable method is continuous recordings, which are then analyzed objectively.

Nevertheless, it is probably true that there is a correlation between the apneas recorded in the chart and the true number of apneas that a baby has had. The more ticks in the chart, the more apneas the baby had, probably.

So as a sort of surrogate of  true apnea incidence the number of recorded apneas, or the number of days of apnea, as we studied, is probably of some value.

A newly published study compared the total numbers and severity of bradycardia of apneas as derived from the hospital charts, as well as whether they received stimulation or vigorous stimulation, of extremely low birth weight babies, and their neurodevelopmental outcomes, using the Bayley 3 scales. They found worse language development in infants who had more severe, or more frequent apnea, at 8 months corrected, and at 20 months corrected age. From what I can tell, the authors did a large number of regression analyses, which makes a type 1 error more likely, nevertheless, the results are in the same direction as my older studies, as well as others by Pillekamp et al, and the CHIME study group. CHIME showed that both preterm and preterm babies who had serious apneas at home, had worse developmental outcomes.

Why this might be is presumably related to the frequent hypoxia/re-oxygenation episodes preterm infants experience, episodes which are less frequent with caffeine. This is presumably the reason for the beneficial effects of caffeine (even though other effects, on inflammation, for example, have been shown also.)

One other thing which I noticed previously, and have published 2 abstracts about, is that it is not rare, after an apnea, for a baby to become hyperoxic. I noted that some babies who had an average saturation in the low 90’s before an apnea, would oversaturate after they started breathing again. Although there are one or two possible reasons for this, I thought that some of it, at least, was probably due to caregivers increasing the FiO2 when the baby desaturated. From my data I wasn’t able to be sure, as I didn’t have a record of the oxygen concentration being administered, which is why I never proceeded to produce a full publication. And now I have been beaten to it!

In a study from Leiden the authors analyzed recordings of babies on CPAP who developed apnea, and noted whether they had an increase in SpO2, and whether the FiO2 had been changed around the episode. They found that FiO2 was increased around 11% of the apneas, and when that happened a large majority of the time (79%), the babies became hyperoxic (SpO2>95%) after the apnea, this lasted for an average of 13 minutes! The authors don’t tell us, I think, what happened to post-apneic hyperoxia if there was no change in FiO2, how common it was if the FiO2 was unchanged isn’t described.

It clearly doesn’t help to increase FiO2 if the baby is not breathing. Few of these apneas were likely to have been obstructive, as the babies were on CPAP, so oxygen was increased probably either when the baby was apneic, or afterward during the recovery phase. I guess that most often it was probably when the SpO2 wasn’t coming up as quickly as the nurse expected, so she(he) increased the oxygen, and then took on average 14 minutes to get it back down to the previous concentration.

One thing that I think is surprising is that we have no idea how to treat apneas. We have some idea how to prevent apneas, using caffeine, and CPAP, (I won’t discuss doxapram for the moment).

But when a baby stops breathing, how should we intervene to get him/her breathing again? What usually happens is that the baby is first stimulated (does this work? if so, how? what kind of stimulation works best?) and then, if still apneic, a variety of other interventions may be tried, including repositioning, suctioning, more vigorous stimulation, assisted ventilation, and increasing oxygen concentrations. Do any of these actually work? Which is best? This is one of the commonest interventions in the NICU, something done many times a day, but we have no idea what is the best approach.

I have a design written for a trial of ‘usual therapy’ compared to what I think might be optimal, that is, keeping a self-inflating bag next to the baby, in the same FiO2 as the baby is receiving, and immediately starting positive pressure ventilation. I think that only a couple of breaths would be required for most babies, that this might reduce post-apneic hyperoxia. Certainly some way of deciding how long to wait before increasing the FiO2 of a baby would be really useful.

Posted in Neonatal Research | Tagged , , | Leave a comment

Oxygen, transfusions, and NEC

Posted on 31 March 2014 by Keith Barrington

What causes NEC! The answer is ‘who knows?’, or perhaps a better one would be ‘its complicated…’ You probably need an immature gut, gut mucosal injury, inflammation and cytokine release, and an abnormal microbiome, all of which probably interact in complex ways.

In a comment on a previous post, John Lantos remarked that the majority of the increased mortality in the SUPPORT trial was from NEC. I replied that he was right, there were more also a few more  deaths from sepsis and from bronchopulmonary dysplasia, but the biggest difference was in NEC deaths, 23 vs 14. There wasn’t a big difference in diagnosis of NEC (stage 2 or 3), 11.9% vs 10.8%, just in mortality from NEC.

I seemed to remember that the pattern was the same in the BOOST 2 trials also, indeed the rate of NEC (requiring surgery or causing death, that is, more severe than in SUPPORT) was 12.2% vs 9.9%, with the new algorithm installed on the pulse oximeters, in the low saturation group compared to the high saturation group. There were 39 deaths from NEC in the low saturation group, and 22 in the high saturation group. There were also more deaths from septicaemia, 28 vs 15, and more deaths from BPD 18 vs 12.

In the COT trial there were also more cases of NEC overall (stage 2 or more) in the low saturation group than the high saturation group, 12.3% vs 9.3%, but I don’t know about causes of death, or whether the difference changed with the re-programming of the pulse oximeters.

The reason for going back over this is twofold, firstly, the observational study about TANEC that I mentioned in that previous post showed that babies who had a lower hemoglobin before their transfusion seemed to be more likely to develop TANEC; secondly a new commentary published in the Journal of Perinatology discusses the ‘limitations of the randomized clinical trial and the end of equipoise’ using the oxygen trials as an example.

That first point makes me think that there may be a common issue, that of intestinal re-oxygenation. If more severely anemic infants have somewhat hypoxic intestinal mucosa, and transfusion improves that, as well as supplying inflammatory mediators, then that could trigger the injury leading to NEC. Also it has been shown that infants in the low saturation arm of the SUPPORT trial had more frequent and severe intermittent hypoxia, with multiple episodes per day of hypoxia, re-oxygenation (and perhaps hyperoxia as well, more about that later). So there may be a common link, how that relates to sepsis or BPD I am not sure.

Although there are some issues in the commentary that I agree with, I think there are some fundamental errors also. The authors state that the oxygen trials were elegant, important, adequately powered, etc, but that clinicians seem reluctant to institute changes in practice, they suggest that this is because we thought that perhaps there would be less RoP with lower oxygenation, but that the mechanisms of the increase in mortality is uncertain. I am not sure that is likely to be true, I think therapeutic intertia is a bigger issue.

They then discuss whether there might be situations in which  a lower saturation target might be right for an individual baby,

The authors of the commentary use a very limited view of EBM

The idea of evidence-based medicine is straightforward—the clinician needs to use the best available evidence to determine optimal therapy for his or her patient

David Sackett, in contrast, puts it this way

Evidence Based Medicine is the integration of clinical expertise, patient values, and the best evidence into the decision making process for patient care. Clinical expertise refers to the clinician’s cumulated experience, education and clinical skills. The patient brings to the encounter his or her own personal and unique concerns, expectations, and values. The best evidence is usually found in clinically relevant research that has been conducted using sound methodology.

Which is a much richer understanding, and which actually addresses much of what they discuss. They make much of the fact that a particular RCT may not address the issues of an individual complex patient, which is obviously the case, and is the reason why exploratory sub-group analyses are performed on large RCTs, to try and identify patients for whom further investigation may be required. I emphsize, further investigation is required, subgroup analyses are fraught with problems and have sometimes been proved unreliable when those further studies are done.

They conclude with the following:

What we do as clinicians with the newest evidence about oxygen-saturation targets and ELGANs remains to be seen. As the product of elegantly designed and conducted international multicenter RCTs, the evidence for the benefit of higher oxygen saturation targets will be heavily weighted. But as the product of an RCT it may not necessarily be the best practice for every individual ELGAN.

I would respond to that: tell me when you think it is better for a baby to have lower saturation limits. Under what circumstances, for this particular issue should you expose the baby to higher risks of death, and lower risks of RoP? Of course it is likely to be true, as they point out in the commentary, that some babies who developed RoP would have escaped it if they had been in the lower group, and they may not have been the same babies who would have died. In other words, an individual baby, if you knew from the day of their birth that they would survive, and would not develop NEC or sepsis or BPD, but were at risk of severe retinopathy, would be better in the low oxygen group.

If you know how to identify such babies, then you should design an RCT to enroll them, and prove that they are indeed safer with lower saturations.

I can actually see that could be true, it could be that in a particular clinical situation a lower saturation might be beneficial. But unless you can define and test that possibility there doesn’t seem to me to be any reason to expose babies to the increased risks of death (from NEC sepsis and BPD) which accompany the lower saturations.

And to be honest, in their NICU do they really go round every day and decide which babies should have saturation targets of 85 to 89, 88 to 93, or 90 to 95%? I really doubt it, I don’t know anyone who does that. So their argument just falls flat, for this particular issue; I would bet you that they have standard oxygen saturation target ranges for preterm infants in their NICU, because we have no evidence for doing anything else. Of course clinical expertise is important in neonatology, and it is an essential part of evidence based practice, but I have no idea what kind of clinical expertise ‘cumulated experience, education and clinical skills’ you could use for assigning a different oxygen saturation target for an individual-complex baby, to use their term.

The authors discuss research equipoise and clinical equipoise as if they were different. I do not agree with their evaluation. Equipoise just means that there is a therapeutic choice and you do not know which is best for an individual baby. In such a circumstance it is appropriate to design an RCT or enter the baby in an RCT, or, if there isn’t one approved just make your best guess, by adding up all the pros and cons, and try and decide the least worst option.

For oxygen saturation targets we no longer have much uncertainty, the higher saturation targets decrease mortality and we can be 99% confident that this is true. If you are still using lower saturation limits then I think you should inform parents about this evidence and explain why you are have decided to use lower saturations.

Which brings me back to a sentence earlier in the commentary

‘If one were to consent parents to a trial arm for which there is now evidence for increased mortality, would any parent reasonably be expected to provide permission for their child to be enrolled?’

If the authors think is unlikely that parents would consent for such a trial, why should parents be expected to consent for individual treatment according to a standard ‘for which there is now evidence of increased mortality’? If my baby were in an NICU and the neonatologist informed me of that evidence, and then said, ‘but I have decided with my clinical experience that your baby should nevertheless have lower saturation targets’ I think we would have some serious discussions.

Posted in Neonatal Research | Tagged , , , , , | Leave a comment