How much phosphorus does a preterm baby need?

Posted on 1 October 2015 by Keith Barrington

Brener Dik PH, et al. Early hypophosphatemia in preterm infants receiving aggressive parenteral nutrition. J Perinatol. 2015;35(9):712-5. This group of neonatologists in Buenos Aires routinely give 3 g/kg/d of lipid, 3 to 3.5 g/kg/d of amino acids, 40 mg/kg/d of calcium gluconate and 20 mg/kg/d of glycerophosphate starting on day 1 to their babies under 1250 grams. By day 6 the babies were often hypercalcemic and hypophosphatemic, especially the IUGR babies. Babies who were more unwell in the first days of life were also more likely to have a low phosphate. 40 mg of calcium gluconate is slightly less than 0.1 mmol of calcium, 20 mg/kg/d of sodium glycerophosphate is about 0.1 mmol/kg/d of phosphorus.

Boubred F, et al. Extremely preterm infants who are small for gestational age have a high risk of early hypophosphatemia and hypokalemia. Acta Paediatr. 2015. In Sweden they give less nutrition on day 1; 2 g/kg/d of protein, 1 g/kg/d of lipid and 6 g of glucose, and then ramp it up over 4 days. On day 1 they give very little phosphorus, thereafter the babies were receiving about 0.6 mmol/kg/d of calcium, and between 0.5 and 0.6 mmol/kg/d of phosphorus. The IUGR babies were much more likely to develop low serum phosphates, and again the peak seems to be about day 4.

Moe K, et al. Administering different levels of parenteral phosphate and amino acids did not influence growth in extremely preterm infants. Acta Paediatr. 2015;104(9):894-9. In this observational study from Copenhagen they report 3 cohorts of preterm babies, in the middle cohort there was an error in their TPN software, so they gave much less phosphorus to the babies, especially during the first 3 days of life, when there was about 0.07 mmol/100 ml of TPN. The babies who got this regime had much more hypophosphatemia, especially if they were IUGR; the authors didn’t find a difference in growth during the first month of life.

Three other recent articles address these issues also :

Bonsante F, et al. Initial amino acid intake influences phosphorus and calcium homeostasis in preterm infants–it is time to change the composition of the early parenteral nutrition. PLoS One. 2013;8(8):e72880. This article (free access) reports a cohort study with varying protein intakes in preterm infants, the babies were all treated in the University hospital in Dijon, but, interestingly none of the authors’ current affiliations are with that hospital, they are from Réunion, Italy and Belgium. They show that the babies who received more amino acids had more hypophosphatemia, even though they also received more phosphorus. The high AA group received 21 mg/kg/d of phosphorus which is about 0.67 mmol/kg/d.

Christmann V, et al. Early postnatal calcium and phosphorus metabolism in preterm infants. Journal of pediatric gastroenterology and nutrition. 2014;58(4):398-403. In this study from Nijmegen babies received much more calcium and phosphorus, quickly getting up to 3 mmol/kg/d of calcium and 1.92 mmol/kg/d of phosphorus, by day 3. By day 4 to 5 many of their babies were hypophosphatemic, and hypercalcemic, at which time they had almost no phosphorus in the urine. So although they were getting lots of phosphorus, it looks like the ratio was not correct.

Pereira-da-Silva L, et al. Early High Calcium and Phosphorus Intake by Parenteral Nutrition Prevents Short-term Bone Strength Decline in Preterm Infants. Journal of Pediatric Gastroenterology & Nutrition. 2011;52(2):203-9. This is the only reference in today’s post that is actually an RCT, from Lisbon this time. About 40 preterm babies per group were randomized to different intakes of Calcium and Phosphorus in their TPN. They either got 45 mg/kg/d of calcium (1.1 mmol) with 36 mg/kg/d of phosphorus (1.16 mmol)  or 75 mg/kg/d of calcium (1.9 mmol) and 44 mg/kg/d of phosphorus (1.42 mmol), which usually started on day 1. The enteral feeds were not changed, so by the end of the first week there was little difference between the groups, and the macronutrient supply was also similar. From week 3 to week 6 there was a progressive reduction in bone strength in the low mineral group, and no reduction in the high group. The authors do not report the incidence of hypophosphatemia.

One thing this review has taught me is that the reporting of mineral intakes and metabolism in preterm infants is often really unclear, even when the study is concentrating on minerals. Could we all please report intakes and balances in mmol?

The other things that are clear, (and I must claim clairvoyance because our TPN standards here have said this for years) is that the requirements for calcium and phosphorus in the first few days of life are not the same as later on in the life of the preterm. The ratio between calcium and phosphorus should be higher for the first few (3-4?) days. Phosphorus is important for cellular metabolism as well as for bone growth. In those first few days we should aim to give enough phosphorus for those requirements, and to avoid hypophosphatemia. At the same time avoiding hypercalcemia and hypocalcemia are important. We might need to give as much as a 1:1 ratio of calcium to phosphorus just after birth, and then progressively switch to a ratio of about 1.6:1 (in mmol).

In fact the paper by Bonsante (a great name for a physician!) suggests something similar, they propose that the appropriate P intake (in mg/kg/d) might be calculated by dividing the Ca intake (also in mg/kg/d) by 2.15 and adding the amino acid intake (in g/kg/d) -1.3 multiplied by 9.8. If a baby is getting 2.5 g/kg/d of amino acids, and 40 mg (1 mmol)/kg/d of calcium this would work out to about 31 mg of phosphorus, which is almost exactly 1 mmol. If they are getting more protein, they would receive a bit more phosphorus, which is consistent with the data from those studies above.

Once the baby starts to grow consistently, then more phosphorus is laid down in bone, and we should probably aim for a ratio of nearer to 1.66 :1 (in mols), which is the ratio of calcium to phosphorus in new bone.

The recommendations of ESPGHAN published in 2005 (available free on-line) only discuss requirements during the growing phase of the preterm, and not during the first few days. They refer to a calcium phosphorus ratio of between 1.3:1 and 1.7:1 (in mols). The total intake they suggest is to vary according to weight gain, and to give 4 mmol of calcium for every 20 g of weight gain. Which I think is difficult to put into practice, as this suggests that you can only decide on how much calcium and phosphorus to give after the babies have already received the TPN and you see how well they grow!

The increased risk of hypophosphatemia in IUGR babies is similar to a “refeeding syndrome” although Bonsante’s group suggest not using that term, they suggest “placental interrupted feeding syndrome” instead, in order to note that you don’t have to be severely malnourished to develop these findings, they occur in AGA preterm also. Do IUGR babies, in the first days of life, need more phosphate? Do they need a higher ratio of phosphorus to calcium? Or both? I think some more observational studies with a higher P administration and an appropriate ratio might help us to know.

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Not neonatology: John Oliver and the refugee crisis

Posted on 1 October 2015 by Keith Barrington

If you have the time, and if you have a heart, watch this:

 

I hope Nageem gets to see this, and one day, maybe she will become an astronaut, who knows.

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Cochrane review featured on their website

Posted on 29 September 2015 by Keith Barrington

Our recently published Cochrane review of resuscitation training programs is now a featured review on their website.

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Photos of preterms

Posted on 29 September 2015 by Keith Barrington

A Québec photographer by the name of Red Méthot has posted a series of photographs of children and adults who were formerly preterm babies. Each holding a black and white photograph of themselves as a baby. Check it out.

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Treating seizures: bumetanide doesn’t seem to work

Posted on 29 September 2015 by Keith Barrington

One of the many frustrating things in neonatology is the treatment of convulsions.

As Gerry Boylan and Ronit Pressler wrote in the introductory section of the excellent issue of Seminars in Fetal and Neonatal Medicine which was all about neonatal seizures,

“Neonatal seizures continue to pose a challenge for clinicians worldwide because they are difficult to diagnose and treat and are associated with poor outcomes.” We have been using this statement, or something very similar, to introduce the topic of neonatal seizures when we give lectures or write papers for the last fifteen years and in that period of time, unfortunately, very little has changed in the management and outcome of neonatal seizures.

It is hard to know if the treatments we give are much use. Does phenobarbitol actually work? A truly evidence-based answer to that question would be “who the hell knows?” It might be a bit less useless than some other drugs, but I don’t think there is good evidence that it works at all. Clinical seizures stop in around 50% of babies after phenobarb, but maybe they would have stopped anyway. EEG documented, electrical seizures often don’t stop after phenobarb, and babies can even have non-convulsive status epilepticus after phenobarb.

Bumetanide is a loop diuretic that is an effective anticonvulsant in neonatal rats. Unfortunately it doesn’t seem to work in human neonates. Pressler RM, et al. Bumetanide for the treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an open-label, dose finding, and feasibility phase 1/2 trial. The Lancet Neurology. 2015;14(5):469-77. Although they only entered a small number of infants (14) into the study, they were unable to show efficacy, and they had a higher than expected rate of hearing loss.

I think this is great.

Not the result, of course, it would have been really great to find an effective, safe anticonvulsant. But I think it is great that this study was done, that the group was put together and the infrastructure created to get this very high quality investigation performed. Lets hope that the group will stay active, and will be able to evaluate other agents that are creeping into use without good studies. Like levetiracetam, that I can never spell correctly, (so I hope that the site I just copied that from was correct) or topiramate, that I would vote for as I can remember how to spell it.

 

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NRP Works!

Posted on 23 September 2015 by Keith Barrington

When the neonatal resuscitation program was first introduced I think many of us had mixed feelings. I was concerned that some of the initial recommendations were opinion-based rather than evidence-based  (and they weren’t all consistent with my opinions, which are the correct opinions). On the other hand to have a universal standard that could then progressively be improved upon was a good thing, and that has generally happened, NRP has become generally more and more evidence based, and has stimulated the production of more and more evidence. But does it actually work? Does training people in such a standardized, formal program help them to resuscitate better, and most importantly, does it then lead to more babies surviving, and fewer with serious complications.

A group of us, Gene Dempsey, Mohan Pammi, Tony Ryan and I, have just published a Cochrane review addressing that question. The primary question of interest was whether training programs lead to lower perinatal mortality, and lower neonatal morbidity. The secondary questions were to examine how the training is performed; whether boosters or videos or apps or teamwork training, for example, might improve skills and knowledge acquisition and retention, or performance or clinical outcomes.

We found the following: (SFNRT is the rather ponderous acronym I came up with to avoid saying NRP, it stands for standardized formal neonatal resuscitation training; we didn’t limit the searches to just the NRP program, but any similar training approach)

We identified three community-based cluster-randomised trials in developing countries comparing SFNRT with basic resuscitation training (Early Newborn Care). In this setting, there was moderate quality evidence that SFNRT decreased early neonatal mortality (typical RR 0.88, 95% CI 0.78 to 1.00; 3 studies, 66,162 neonates) and when analysed by the approximate analysis method (typical RR 0.85, 95% CI 0.75 to 0.96; RD -0.0044, 95% CI -0.0082 to -0.0006; NNTB 227, 95% CI 122 to 1667). Low quality evidence from one trial showed that SFNRT may decrease 28-day mortality (typical RR 0.55, 95% CI 0.33 to 0.91) but the effect on late neonatal mortality was more uncertain (typical RR 0.47, 95% CI 0.20 to 1.11). None of our a priori defined neonatal morbidities were reported. We did not identify any randomised studies in the developed world.

There were some problems with the analysis, because cluster randomized trials do not always report the ICC, the intra-cluster correlation coefficient, which you need to do all the analyses, the Cochrane collaboration has some ways around this, but it introduces a bit of extra uncertainty into the results.

We identified two trials that compared SFNRT with team training to SFNRT. Teamwork training of physician trainees with simulation may increase any teamwork behaviour (assessed by frequency) (MD 2.41, 95% CI 1.72 to 3.11) and decrease resuscitation duration (MD -149.54, 95% CI -214.73 to -84.34) but may lead to little or no difference in Neonatal Resuscitation Program (NRP) scores (MD 1.40, 95% CI -2.02 to 4.82; 98 participants, low quality evidence).

These two trials were from the same group, and used the same scale of team activity so we could meta-analyze them. The teamwork training improved team behaviour, but didn’t lead to improve scores on the NRP checklist (which didn’t specifically score team behaviours).

We identified two trials that compared SFNRT with booster courses to SFNRT. It is uncertain whether booster courses improve retention of resuscitation knowledge (84 participants, very low quality evidence) but may improve procedural and behavioural skills (40 participants, very low quality evidence).

We identified two trials on decision support tools, one on a cognitive aid that did not change resuscitation scores and the other on an electronic decision support tool that improved the frequency of correct decision making on positive pressure ventilation, cardiac compressions and frequency of fraction of inspired oxygen (FiO2) adjustments (97 participants, very low quality evidence).

The cognitive aid was a poster in the delivery room, it didn’t make a difference mostly because the participants ignored it. The electronic tool is a tablet “app” which when plugged in to the appropriate sensors tells you what to do next to follow the NRP algorithms.

The NNTB that we calculated in those results, means that for every 227 deliveries occurring in a setting where healthcare workers have been trained in SFNRT programs, there is one fewer neonatal death. Which is huge, and very cost effective. SNFRT is not very expensive, but it’s not free either. The equipment, staff time, staff transportation, outreach and so on all have to come from health care budgets which in many parts of the world are severely under pressure. If you only have 10 dollars per year per member of the population to spend (like in Uganda), then you have to choose wisely. Or you could cut down on military spending and corruption, but that is another issue. High fidelity simulations do not seem to have much greater effect than standard training with a Baby Anne manikin and enthusiastic teachers, so the extra expense can be avoided in low and middle income countries.

Spending on SFNRT programs is effective, reduces death, and does not increase disability. It should be a priority for low income countries.

 

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Many unethical pain studies in newborns

Posted on 23 September 2015 by Keith Barrington

Carlo Bellieni and Celeste Johnston (Conflict of Interest flag, I have collaborated with both of them) have just reviewed a couple of recent years research of analgesic interventions in the newborn. Of 46 randomized studies of painful procedures, 70% had an untreated control group, either placebo or without analgesic intervention.

I have ranted about this before: Pain research in the newborn, what is ethical?, well actually having re-read that post it isn’t really a rant, but a lucid, well-considered and well-argued plea to stop randomizing babies to pain.

The new review shows that the article that I was referring to was not a ‘one-off’ but a persistent pattern. A persistent pattern of unethical research. The discussion section ends like this;

we encourage researchers to perform further studies on new pain treatments by comparing them with with those that have already been validated. we are urging parents and ethics review boards to refuse studies that do not provide acceptable analgesia to all babies enrolled in studies… In addition we are calling on medical journals to refuse to publish studies that deny pain relief to control infants undergoing painful procedures.

I think that editorial guidelines of paediatric journals should be revised to include a clear statement that untreated control groups in studies of painful interventions are not ethical and that articles describing studies with such groups will not be accepted.

I only have one disagreement with the article, and it is the statement that for eye examinations there is ‘no validated treatment that exists’. In fact there are interventions which can significantly reduce pain responses, it is true that they are not perfect, and babies still experience discomfort. But there is a systematic review of local anesthetic drops which shows effect (Dempsey E, McCreery K. Local anaesthetic eye drops for prevention of pain in preterm infants undergoing screening for retinopathy of prematurity. Cochrane database of systematic reviews (Online). 2011;9(9):CD007645).

And multi-modal interventions do have some benefit also (O’Sullivan A, et al. Sweeten, soother and swaddle for retinopathy of prematurity screening: a randomised placebo controlled trial. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2010;95(6):F419-F22.)

The data on sucrose alone are somewhat variable, but as many of the studies are small it is not surprising that some do not show an effect,but many do (such as : Boyle EM, et al. Sucrose and non-nutritive sucking for the relief of pain in screening for retinopathy of prematurity: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2006;91(3):F166-8).

I think an RCT of pain relief for eye examination that did not incorporate most of these items would also be unethical. A control group should have sucrose, a soother, swaddling, and local anesthetic. The efficacy of this combination is not complete, so a randomized addition of other interventions would be a valuable addition to the literature and to the comfort of our babies.

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An astounding betrayal

Posted on 21 September 2015 by Keith Barrington

Some of us may have heard of the problems with the data concerning SSRIs (a commonly used class of antidepressants) and, in particular, young people. It appears that drug companies hid and distorted data from controlled trials, in order to make it appear that the data were positive, and hide the fact that there appeared to be an increase in suicides during the initial phase, at least, of treatment in younger patients.

One study in particular stands out, study 329. This study stands out because it was a very high profile study, of which many questions have been asked, but also because Glaxo Smith Kline eventually agreed to allow complete access to all of the original patient data.

That access has resulted in a new publication in the BMJ, which shows that, in contrast to the original publication, if the data are analyzed as the original protocol specified, and if all the adverse outcome data were appropriately collated, then there was no benefit from the use of the agent in question, paroxetine. Indeed the results show no benefit but an increase in serious adverse events, including suicide attempts.

The original publication reported that the outcomes were positive, but it seems they chose outcomes that appeared positive that were never specified in any of the protocol versions. There was also incomplete, very incomplete, summation of adverse outcomes, leading to erroneous claims of safety.

How could all of this happen? Well the data were all controlled by the company (a predecessor of GSK) who organized the analyses, and employed a ghost writer to draft the first version of the paper. The physicians who eventually were listed as the authors edited the introduction and discussion (making what were mostly “cosmetic” changes). There is a fascinating case study (in a journal I wasn’t aware of called “accountability in research”) of the way this article made it to submission and publication, which contains the following “gems”

 The first draft contained a significant distortion of outcome whereby the list of primary outcomes was expanded from two to eight, four of which separated paroxetine from placebo. This change gave plausibility to the claim that “paroxetine is effective.”

And

(‘Laden’ is the second name of the ghost writer)

Our analysis of the progression of drafts shows that there are few substantial differences between the final published article and the first draft prepared by Laden (Jureidini, 2007). Large portions of the introduction and discussion were re-written, but these changes add little to the substance of the article, and most other changes are little more than copy editing. Throughout the many drafts of this article, the conclusion persists that paroxetine is safe and effective for adolescent depression despite the fact that it failed on both primary and most secondary outcome measures.

That review of the initial publication process also noted that the serious adverse events were downplayed. The new re-analysis of all the original data shows that they weren’t even counted correctly; there were several instances of breaking the blinding of the medication, and coding of the SAE’s varied from one case to another, even when similar events occurred. The evaluation of whether the SAE was related to the medication was sometimes made after the blind had been broken. So, for example, one case of an SAE was ascribed to the study intervention after it was known that the patient was in the placebo arm.

Some of the reported SAE’s were never even transcribed into the study data sheets.

The authors of this re-analysis also note the difficulties with actually performing it, they were allowed a single remote desktop to access files, were not permitted to print anything, and had huge difficulties getting it done as a result. After many thousands of hours of work, I think we can all be grateful that this re-analysis, which could be considered a case study in how to re-analyze publicly available datasets, and also an object lesson in why such datasets should be fully available to the appropriate persons, and not just the extremely limiting access that these authors had, that this re-analysis was as scrupulously done as this.

If anything points out the desperate need for the Alltrials campaign to be successful, it is this publication. How many other articles have been distorted by the sponsors to make their drug seem effective and safe, when in fact they are neither?

In a commentary in the BMJ, accompanying the publication, Peter Doshi is scathing about the response of the journal where the article was originally published, the professional association responsible for the journal, and the university where the first author (that’s the person who is listed as first author, not the person who wrote the article!) works; where he is still head of psychiatry.

The article is still in the literature, still with the same conclusions of efficacy and safety. GSK, you might remember, were sued 3 billion dollars for promoting paroxetine beyond the approved indications, including promotion for adolescents, partly based on this article.

The original article is an astounding betrayal. The authors betrayed the individuals and families who consented, the public in general, including all the subsequent adolescents who have been treated with paroxetine, and the whole world. The big phamaceutical companies are hugely profitable, but they also make huge investments to bring new molecules to market, which subjects them to enormous pressures, to make results of clinical research seem as positive as possible, and minimize the negatives. When the ‘positives’ and ‘negatives’ are the health of patients, the implications are profound. Far more so than for a new children’s toy, or new scent for a perfume range; but the same corporate thinking motivates their actions.

We cannot escape corporate funding for trials of new therapeutic agents, we have to put in place mechanisms to ensure that those trials are well designed, adequately analyzed, and appropriately reported.

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Burping babies

Posted on 17 September 2015 by Keith Barrington

It is very satisfying sometimes, to sit a baby on your knee, lean them forward slightly and rub or pat their back until a loud pleasing burp is heard.

Parenting websites, and MDs, nurses, and midwives often promote burping as way to reduce regurgitation or avoid colic, We have web-pages dedicated to the different, sometimes contradictory, techniques. But does it work? There are some communities in the world where they just don’t do it, and their babies seem very happy (as an evidence-based person I have to confess that I am not sure if that is true, it’s hard to find data, but there is at least one essay written by someone who lived in Mongolia that never saw parents burping their babies, I’ve tried searching Google to find studies, but so far no luck.)

So we should do an RCT right?

Well, fortunately, I don’t have to because these people did. (Kaur R, et al. A randomized controlled trial of burping for the prevention of colic and regurgitation in healthy infants. Child: Care, Health and Development. 2015;41(1):52-6.) they compared regurgitation and colic in babies whose mothers received parenting advice either with or without burping information. The babies in the burping group had more regurgitation, and there was no difference in colic.

This looks like a good way to reduce reflux, no more toxic drugs, just stop burping the little blighters.

Unfortunately I am pretty sure this won’t make any difference. I am sure it will take more than a few facts to change years (centuries? millenia?) of practice. There are a few voices in the wilderness, Robin Barker, the author of the best selling Australian baby care book, apparently says not to bother with burping.

I agree.

 

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Do Blood transfusions trigger NEC? This month the answer is no.

Posted on 16 September 2015 by Keith Barrington

OK, not exactly this month, but “towards the end of last year” wouldn’t have been as good a title.

Three case-control studies, with some differences in design and implementation, but all 3 with the same result, no evidence that red cell transfusion causes NEC. So you could say that in Stanford, Gainesville Florida, and Riyadh transfusions don’t trigger NEC but in some other places they do, and in still other places they may even be protective.

Sharma R, et al. Packed red blood cell transfusion is not associated with increased risk of necrotizing enterocolitis in premature infants. J Perinatol. 2014;34(11):858-62.

Wallenstein MB, et al. Red blood cell transfusion is not associated with necrotizing enterocolitis: a review of consecutive transfusions in a tertiary neonatal intensive care unit. The Journal of pediatrics. 2014;165(4):678-82.

AlFaleh K, et al. Association of packed red blood cell transfusion and necrotizing enterocolitis in very low birth weight infants. J Neonatal Perinatal Med. 2014;7(3):193-8.

I think the most appropriate answer is “unproven”, I also think its great that these 3 negative case-control studies were published. There is probably less publication bias in neonatology for RCTs, although publishing negative trials can sometimes be a challenge, and sometimes doesn’t occur. Publication bias of observational studies is, I think a major problem, so kudos to these authors and journals. Even “completion bias”, a new term I just invented, is a real problem. If I run through a local database, and find no apparent association with NEC in my NICU, am I going to take the time and effort required to complete an IRB approved research project? Probably not, but if my first glance at the data looks positive, well then I might get a good publication out of it, and I’m much more likely to try to complete it.

I think that especially the first reports of an association, such as the association between NEC and blood transfusions, have a high likelihood of being biased, just because of such a completion bias. What I mean is that if someone has seen 3 babies in a row get NEC after a blood transfusion, they then might think, I wonder if blood transfusions might trigger NEC, and then search their local data and find that there are more episodes of NEC after transfusion, there is a high likelihood that it might just be due to the fact that they are searching a database that includes the cases that they have just seen.

Replications of that investigation by others would not have the same detection bias, but might well have the “completion bias” that I just described.

Many of the observational study articles have suggested that we need large randomized trials to be sure about whether this is a real effect or not, while I agree, I don’t think a trial of blood transfusion in at-risk neonates should be done just to address this issue. A randomized trial of differing threshold of transfusion would have other outcomes to investigate also, but an important secondary outcome to be prespecified should be NEC.

In the PINT trial, we did give fewer transfusions to one group compared to the other, an average of 4.9 in the low transfusion group, and 5.7 in the high group. The low group actually had more NEC 8.5% vs 5.3% (not statistically significant).

I don’t know if any future trial is likely to get more separation in hemoglobins, or in transfusion frequency than PINT, but powering such a trial to see if there is a difference in NEC would mean that the trial would have to be very large, and very expensive. Making large trials simpler, and less expensive is a major priority for the future.

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