Not Neonatology: Oh Canada…. Warbler

Still on my trip to Ecuador, where I saw my first ever Canada Warbler. I know it is just a name, but it was most pleasing to find this bird, which does indeed migrate to Canada each year but I had never encountered, and passes the Canadian winter here.

I have completely changed the design of my other blog keithbarrington.com hopefully it is easier to navigate and see anything that might interest you.

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Not neonatology: a trip to Ecuador

A break in blogging for a couple of weeks, while I take a trip to Ecuador, with the main purpose of birdwatching and photography. Ecuador is the country with the greatest avian biodiversity in the world, and with and amazingly knowledgeable guide, I’m having a great experience.

I am blogging about the trip as I go, mostly in order to post photos. Please visit https://keithbarrington.com/, in addition to the home page, I will add various other pages of photos, for now, there is just the page “All the Tanagers of the Trip” which you can find by clicking a link at the top of the page.

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How much protein should we provide to the preterm in the first days of life?

Extremely preterm infants become catabolic rapidly after birth, with the sudden interruption of their trans-placental nutrient supply to the fetus, who becomes a baby that has tiny stores of fat or glycogen. We progressed in neonatology from starving preterm babies in the first few days, to supplying them with just a glucose solution, to providing sick babies unable to full feed with TPN starting almost in the delivery room! This has been based on physiologic principles and the best guess of nutrient needs, and short term physiologic studies. In my NICU, we start with a solution of 3% AA in 10% dextrose, which the babies get at about 80 mL/kg/d (up to 100 if they have no arterial catheter) and so they receive amino acids at a rate equivalent to between 2.4 and 3 g/kg/d of on day 1, the next working day they have a formal TPN prescription, which will progress the amino acid amount up to 4 g/kg/d over a few days.

I have written recently about the PEPANIC trial, and have referred to trials of older children and adults, in whom early TPN after ICU admission increases complication rates, in particular hospital acquired sepsis. That is true even among adults who are considered malnourished on admission.

Extreme preterms are, of course, a different species, and we should not extrapolate any of those data to the preterm, but we can certainly learn from them.

In the ProVIDe trial, (Bloomfield FH, et al. Early Amino Acids in Extremely Preterm Infants and Neurodisability at 2 Years. N Engl J Med. 2022;387(18):1661-72), 434 ELBW infants (<1000g) who were admitted <24 hours and had a UAC placed, were randomized to either get 8.4% amino acid solution or 0.45% saline as the solution in their umbilical arterial catheter, running at 0.5 mL/h. Which would have given a 1 kg baby 1 g/kg/d more amino acids, and given a 500 g infant 2 g/kg/d of amino acids extra.

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Which is the first thing I don’t understand here, the authors state that they did it this way to ensure that the intervention babies received 1 g/d more protein; the babies should, with a birth weight averaging 780g have received on average about 1.3 g/kg/d more protein in the intervention group, for as long as the UAC was in place, to a maximum of 120 hours. But, in fact, they received a supplement which was inversely proportional to their birth weight I am not sure really how relevant this is to any kind of practice that I would consider instituting. I understand the technical simplicity of designing the study this way, but surely just adding an extra 0.5 mL/kg/h of the solution would have been simple and much more clinically relevant. Then every baby would have received 1 g/kg/d extra for the intervention period.

This makes it very difficult to figure out what this means; the results showed, overall, in the intervention group, very slightly lower mortality (18% vs 19.4%, consistent with random variation) before follow up, but worse, and slightly lower, Bayley language, cognitive, and motor scores. Here below are the scores on the 3 composites, showing the numbers tested (about 93% of the surviving infants), the mean score and 1 SD, with the intervention group first, the controls second and then the adjusted mean difference with the 95% CIs.

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The intervention group babies received an average of 0.8 g/kg/d of protein when calculated and averaged over the 1st week of life, but, as mentioned, that supplement will have been very variable. A 400 g baby, for example will have received 2.5 g/kg/d of additional amino acids, up to a total of 12.5 g/kg over the maximum 5 days of the study. This calculates to 1.4 g/kg/d when averaged over the 1st week. Others may have received very little; a 1kg baby having their UAC removed at 48 hours of life would have had an additional 2 g, or when calculated over the 1st week, 0.3 g/kg/d. It might seem strange to calculate the supplements over the first week, when the intervention lasted a maximum of 5 days, but the authors also did the calculations that way for the table in the supplement, which showed that all of the other nutritional intakes, of macronutrients and energy, were identical between groups.

The primary outcome was a new word, “neurodisability”, which really meant… it is not immediately obvious as it is not clearly defined in the publication, you have to download and read the protocol to be certain. To save you that extra work, I have copied the definitions below.

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As is usual in studies of follow up in the very preterm infant, the majority of abnormal outcomes were due to low Bayley scores. In the control babies, 5.5% had CP, 0.6% were “blind” and 1.2% were “deaf”, therefore, most of the 37% with so-called “neurodisability” were classified as such because of a low score on one or more of the Bayley 3 composites.

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This is the part of the results table showing the proportion of tested babies with scores below 85 (“mild”), and below 70 (“moderate or severe”), on each of the composites, and the adjusted relative risk and 95% CI. You can see that most of the 95% CI included no difference, apart from the proportion with a Bayley cognitive composite <70.

The finding which is emphasized in the graphical abstract above, “of moderate to severe neurodisability” was defined posthoc: “Because few disabilities were classified as severe or moderate, these categories were combined post hoc into a single category”.

Giving additional protein, with the same amount of energy, led to an increase in serum ammonia (with 95% CI which included zero) an an increase in urea concentrations, which suggests to me that the babies weren’t utilizing all the extra protein. At the same time there was a metabolic response, as more of the intervention group babies became hypophosphataemic and hypercalaemic, which is a phenomenon that occurs after birth most frequently in babies with Intra-uterine Growth Restriction, and has been called different things in the literature, but which is analogous to the re-feeding syndrome. Babies with this occurrence often also are hypokalaemic and hypomagnesaemic, and may be hyperglycaemic, but I can’t see if those are reported in this trial.

As I mentioned above, early TPN in the PICU leads to an increase in hospital acquired sepsis, which was true for the overall group in the PEPANIC trial, and was especially true for the babies of <1 week of age. In this new trial there were no major individual changes in neonatal complications, apart from an increase in PDA needing treatment, from 42 to 54%, (aRR=1.3, 95% CI 1.05- 1.6). There was only a small increase in the proportion of babies with at least one episode of culture proven late onset sepsis, from 31 to 36% (aRR=1.19, 95% CI 0.51- 1.96). There was a small transient impact on weight gain, with the intervention groups having slightly higher body weight z-scores at 4 weeks of age, but there was no difference at discharge or at 2 years. They also performed executive function testing (BRIEF-P) and a behavioural evaluation (CBCL), which showed no striking differences.

I still don’t know, after this trial, what is the optimal amount of protein to start in the TPN of the very immature baby, and actually, I don’t think the trial helps me very much. The control babies received, when averaged over the entire first week of life, an average of 2.9 g/kg/d of protein, and about 76 kcal/kg/d. Adding somewhere between 1 and 2.5 g/kg/d for the first few days in a manner which is inversely proportional to birth weight, without changing anything else, did not have any positive impact, and there is some suggestion of a negative long term change in development. So I won’t be doing that.

I would be fascinated to see an analysis of these data by the actual amounts of extra protein received. The highest risk babies (lowest birth weight) will have received relatively more additional protein, and, if the additional protein is the cause of those potential impacts on developmental progress, then it should be more evident in those infants.

There are very few studies to put this new trial in context, in terms of large randomized trials of early nutritional interventions in the very preterm with clinical outcomes. A study from Rhode Island, (Balakrishnan M, et al. Growth and Neurodevelopmental Outcomes of Early, High-Dose Parenteral Amino Acid Intake in Very Low Birth Weight Infants: A Randomized Controlled Trial. JPEN J Parenter Enteral Nutr. 2018;42(3):597-606) enrolled 168 babies under 1250 g birth weight, to receive either 1-2 g/kg/d on day 1 increasing to 4 g/kg/d by day 5, or 3-4 g/kg/d on day 1, increasing to 4 g/kg/d by day 2. The primary outcome was from a neurological exam and developmental assessment at 2 years, and it showed no difference between groups. The Cochrane review of higher vs lower amino acid intakes of amino acids included about 20 other studies which were of various different interventions, had differing outcomes, and were all small or tiny. It showed no clear difference in any outcome.

For the future, it would be illuminating to do a similar study to ProVIDe, but to add both protein and an additional energy source, adjusted to give the same per kg supplement to all babies. That might allow better protein utilization and avoid the increase in urea concentrations, at the same time enhancing phosphorus supply, especially among the infants with IUGR, should make this safer.

Should we go lower? Is it possible that babies would have better outcomes if we started with even lower protein intakes than the ProVIDe control group? The answer is, I think, yes, it is possible, but I think we will have to be very careful, we could perhaps randomize babies to intakes which are within the range of those in current use in our NICUs, say 1.5 g/kg/d as starting dose, compared to 3 g/kg/d, with appropriate energy intakes, which also could (and probably should) be different between groups. ProVIDe, and other data, suggest that our outcomes should include PDA, late onset sepsis, and long term developmental progress. Despite the lack of very strong data to support the current practice of extremely early TPN in the very preterm, I don’t think we should return to the days of starting TPN on day 3, with just dextrose administered initially, but rather acknowledge that we are not really sure what is the optimal approach to protein and other nutrient administration in the extremely preterm infant in the first few days of life. Overall, babies do much better in terms of survival, nutritional, growth, and developmental outcomes than they have have before. We are doing somethings right, we need to fine tune to get them “righter”!

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It’s Raining Antibiotics

Early onset sepsis is a serious condition with a substantial morbidity, and, thankfully, a relatively low mortality in recent years. Prompt recognition and early treatment are essential, but early clinical signs and risk factors tend to be non-specific. As a result many infants are evaluated for sepsis and treated empirically while waiting for culture results. The proportion is amazingly variable between hospitals, in an article from a couple of years ago the California Perinatal Quality Care Collaborative showed that the proportion of newborns receiving antibiotics ranged from 1.6% to 43% in various hospitals. Some of which was due to differences in hospital characteristics (and included preterm infants), but much was due to differences in practice patterns.

Among term infants and those very near to term (35 weeks and more) somewhere around 5 to 10 % currently have a sepsis evaluation, which almost always leads to temporary treatment with antibiotics. Despite the very high sensitivity of modern culture methods, it is difficult for some physicians to stop antibiotics when the cultures are negative, so “culture negative sepsis” is a frequent diagnosis. The actual incidence, or even the existence of such a phenomenon is uncertain, as very many studies have used the prolongation of antibiotics as a diagnostic criterion. Which leads to the following circular reasoning:

  • 1. Infants with the following criteria were evaluated for sepsis and then had more than 2 days of antibiotics, therefore they had “culture negative sepsis”,
  • 2. In the future we will use those criteria to define “culture negative sepsis” and treat the babies with a full course of antibiotics.
  • 3. Lo and behold, the babies do well, so we must be doing the right thing,
  • 4. We will continue to use the same criteria to diagnose “culture negative sepsis”

This is all compounded by the use of “inflammatory markers” such as CRP as part of the criteria. The criteria used in many centres are a combination of perinatal risk factors and higher concentrations of CRP, or perhaps procalcitonin, than the concentrations found in healthy normal babies without those risk factors.

Anyone reading this blog for a while will now my attitude to those markers. The new article that I will shortly discuss used a combination of “risk factors” and an elevated CRP >10 or procalcitonin (above “reference intervals for postnatal age”). About 10% of noninfected babies overall have a CRP over 10, I am not sure what the proportion is, however, of non-infected babies from births with “risk-factors” that have an elevated CRP. Especially as nowhere in this publication or in the attached protocol are the risk factors defined. One risk factor for sepsis, which is associated with a very high rate of empirical treatment, and a very low frequency of actual sepsis, is maternal chorioamnionitis. It is known that maternal fever and chorioamnionitis increase neonatal CRP even when the infant is not infected, as do fetal distress, prolonged rupture of membranes, prolonged labour, and meconium aspiration syndrome.

The trial I am discussing, (Keij FM, et al. Efficacy and safety of switching from intravenous to oral antibiotics (amoxicillin-clavulanic acid) versus a full course of intravenous antibiotics in neonates with probable bacterial infection (RAIN): a multicentre, randomised, open-label, non-inferiority trial. Lancet Child Adolesc Health. 2022;6(11):799-809.) with one of the longest titles of recent years, enrolled babies of at least 35 weeks gestation, who had an evaluation for early onset sepsis because of risk factors, or transient clinical signs, and who were well at 48 hours after the blood cultures were obtained, which were negative. As mentioned the risk factors are not defined in this publication, but the reference they give is to the NeoPINS study which defined the risk factors as any one of: maternal GBS positive; ruptured membranes >18h; GA <37 weeks; or maternal chorioamnionitis, defined as either fetal tachycardia or a maternal fever >38.5.

If this trial used those criteria, then 100% of the babies born at 35 and 36 weeks would have had a sepsis evaluation and antibiotics, which I think is crazy, to use the scientific terminology.

The combination of one of those risk factors with a negative culture, a baby who was well at 48 to 72 hours, and either a CRP >10 or a PCT over the postnatal age defined limits, made a baby eligible to be randomized to either continued IV antibiotics, or to switch to an oral suspension of amoxicillin and clavulanic acid.

The worst thing about this trial is labelling these healthy, probably uninfected babies, as having “probable bacterial infection”. They did not.

The primary outcome was the re-infection rate, defined as a clinical infection associated with either fever or hypothermia and an increase in inflammatory markers, prior to 28 days of age.

The primary outcome occurred in 1 of 252 IV and one of 252 po babies.

So if you don’t need antibiotics, it doesn’t matter whether you get them intravenously or orally.

The current AAP recommendations are to stop antibiotics in well-appearing infants after 48 hours if the cultures are negative and not to continue simply based on lab results (such as a raised CRP or abnormal white cell count). That is an evidence-based recommendation that I firmly agree with, and would have meant that the large majority of the infants in the RAIN trial, probably all of them, would have been sent home without antibiotics.

Many infants in the RAIN trial would not have had a sepsis work up at all if they had used a sepsis calculator instead of these simplistic perinatal risk factors (Achten NB, et al. Association of Use of the Neonatal Early-Onset Sepsis Calculator With Reduction in Antibiotic Therapy and Safety: A Systematic Review and Meta-analysis. JAMA Pediatr. 2019;173(11):1032-40), probably about half of them would never have been evaluated, and large numbers of the 35 and 36 week infants would have escaped antibiotics.

Systemic antibiotic therapy in the newborn, especially when prolonged, is not benign.

Messing up the neonatal microbiome, which has evolved along with us over many millions of years, should not be taken lightly. Oral antibiotics may even be worse than intravenous, depending on the IV antibiotics used, some have little intestinal excretion, whereas amoxicillin clavulanic acid is great at killing bifidobacteria.

The human intestinal microbiome is affected for months when you give that combination to adults. The long term impacts of giving systemic antibiotics, during the phase of initial development of the intestinal microbiome, are only now being appreciated. (Patangia DV, et al. Impact of antibiotics on the human microbiome and consequences for host health. Microbiologyopen. 2022;11(1):e1260).

Some of the derangement in the microbiome after neonatal antibiotic treatment has abated by 12 months of age (Reyman M, et al. Effects of early-life antibiotics on the developing infant gut microbiome and resistome: a randomized trial. Nat Commun. 2022;13(1):893), but the long term clinical impacts are numerous and important.

Neonatal antibiotic exposure has been linked with asthma, other forms of recurrent wheezing, colic, coeliac disease, abnormal development of recognition processes, reduced linear growth, and increased obesity, not to mention eczema, inflammatory bowel disease, and type 1 diabetes. (Duong QA, et al. Antibiotic exposure and adverse long-term health outcomes in children: A systematic review and meta-analysis. J Infect. 2022;85(3):213-300).

The RAIN trial showed that switching to oral antibiotics meant that the child could go home sooner, and had fewer iv attempts and therefore less pain, which are good things. But even better would be just stopping antibiotics when the baby doesn’t need them.

A mentioned above, all the RAIN trial really tells us is that if you don’t need antibiotics, then the risk of possible infection in the first month of life is the same if you give oral or IV antibiotics for a week.

I have corrected the title of the trial :

Efficacy and safety of switching from intravenous to oral antibiotics (amoxicillin-clavulanic acid) versus a full course of intravenous antibiotics in neonates who probably are not infected (RAIN), unfortunately without an untreated control group: a multicentre, randomised, open-label, non-inferiority trial.

Which we could rename as RAINING (Reduction of intravenous Antibiotics In Neonates, In a Non-infected Group).

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Do omega 3 fatty acids make preterm babies smarter?

It seems that they do, perhaps a little bit!

There are now a confusing array of trials of supplementation of polyunsaturated fatty acids in preterm infants. They have compared various control diets to differing PUFA supplements. Many of them have used a long chain omega-3 fatty acid, Docosahexaenoic acid (DHA), and sometimes also Eciosapentaenoic acid (EPA), rarely ALA (alpha-linolenic acid). Some of the studies have also used arachidonic acid, an omega-6 PUFA, and they all try to make sure that the essential FAs, linolenic and linoleic acid are supplied in sufficient quantities.

This new publication (Gould JF, et al. Neonatal Docosahexaenoic Acid in Preterm Infants and Intelligence at 5 Years. N Engl J Med. 2022;387(17):1579-88) notes in the introduction that the current dietary recommendations for DHA intake of about 20 mg a day, are lower than the usual in utero accretion of DHA, most of which goes to the brain and is incorporated into neuronal membranes and is needed for synaptic function. There are a couple of previous tiny trials of DHA supplementation in term babies which suggest that Bayley Scores and problem solving might be improved with a bit more DHA among formula fed babies. The new publication is a follow up study to N3RO which was a multicentre RCT in about 1200 preterm babies <29 weeks gestation with the primary outcome being BPD. BPD was actually more frequent with the DHA supplementation, against all expectations. DHA in that study was started by oral supplementation within 3 days of starting oral feeding, which supplied an additional 60 mg/kg/d.

As you can see from the main outcome table from the original publication which is below, there was less mild BPD, but more moderate or severe BPD, and more BPD overall, with DHA supplementation.

The new publication is of a study in a subgroup of 480 Australian babies from the original trial with similar numbers and similar baseline characteristics in the 2 groups. The primary outcome for this study was the full scale IQ on the WPPSI at 5 years corrected age. Because of COVID a few evaluations were performed outside of the originally specified time window, and a few were unable to be tested.

The main results are below:

What they call “General Cognitive Impairment” is a WPSSI score less than 85 (it is a standardized score, so that is 1 SD below the mean) and “Severe Cognitive Impairment” is <70. In a sample with a normally distributed result, one would expect 16% to have General and 2.5% to have Severe Impairment.

One can see that the full scale scores are shifted up a few points in the DHA group, so that the mean is a little higher and fewer infants fall below those thresholds, and that the main difference is in verbal comprehension.

What should we do with these findings? First of all let’s try and put them in the context of other trials, the MOBYDick trial supplemented breast-feeding mothers of babies <29 weeks. The babies’ intake of DHA was probably less than in N3RO: supplementation increased the percentage of DHA in breast milk from 0.3% to just under 1% of total fatty acids, which remained at about 35 mg/mL, in other words a baby getting 100 mL/kg/d of breast milk from a supplemented mother would receive somewhere around 30 mg/kg/day of DHA compared to about 10 mg/kg/d in the controls. That study also showed an increase in BPD with supplementation, which was why they stopped the trial early, as the results of the N3RO trial appeared, and in combination with the increase in BPD on interim analysis of this trial they realized they were extremely unlikely to show a benefit. The 18 month follow up of that study (Guillot M, et al. Maternal High-Dose DHA Supplementation and Neurodevelopment at 18-22 Months of Preterm Children. Pediatrics. 2022;150(1)) showed no real differences between groups, with a slightly higher Bayley language composite score in the DHA supplemented group. On a subgroup analysis of that trial the scores were more improved in the more immature babies, but the statistical test for interaction suggests that might just be a random difference between the subgroups.

Another much smaller trial of DHA and AA supplementation in around 100 VLBW infants followed the babies to 6 months with the Ages and Stages questionnaire, which was improved on one subscale in the supplemented group, then to 2 years with Bayleys, and then to 8 years for IQ testing. The Bayley and IQ results were similar between the groups.

The DINO trial was an RCT, also from Australia, which enrolled infants of up to 33 weeks gestation, with both maternal supplementation or supplementation in formula milk, with the primary outcome being developmental outcomes. They showed no overall difference in Bayley scores at 18 months were similar between groups, with perhaps higher MDI scores by about 5 points in the supplemented girls.

This seems overall to suggest that there might be a slight benefit, overall, on developmental progress, of supplementation of the diet with DHA in very preterm infants, and at the least, there is unlikely to be a negative effect. It may be that there is a pro-inflammatory effect while receiving supplementation though, leading to an increase in oxygen needs at 36 weeks, and therefore the diagnosis of BPD. There is almost no longer term pulmonary follow up reported, however. The new report does mention that almost half of the babies in N3RO had a respiratory hospital admission before 5 years of age, with an average of just over 2 admissions; there was no real difference between the groups.

These studies point out again the major limitations of using “BPD” as the indicator of lung damage in the preterm infant. There is relatively poor correlation between BPD and longer term pulmonary outcomes which are of importance. It seems that supplementation with DHA may increase “BPD”, but does not increase long term pulmonary morbidity. It might make the babies a little bit smarter though.

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Making intubation safer for the most fragile babies

Many, many years ago, when I was a young trainee physician, we learned almost everything “on the job”. I can’t remember the first patient I intubated, but there were no mannequins, and no simulations, the phrase “see one, do one, teach one” was perhaps an exaggeration, but not far from the truth. When I read, recently, the hilarious book ‘This is Going to Hurt’, by Adam Kay which recounts his time as s junior obstetric trainee doctor in England, it seems that a similar approach continued when he was training, fairly recently.

I don’t remember the first patient I intubated, it was certainly an adult, as I did jobs as a House Officer (intern), then a year as a Senior House Officer in adult medicine before switching to paediatrics. During that year I would often institute intensive care for the most critically ill patients, I remember inserting peritoneal catheters to start dialysis, putting in central lines to start intracardiac pacing, and intubating several patients. The first one, or maybe two, intubations were probably done with an anaesthetist standing by my shoulder coaching me. By the time I did my first neonatal job I was asked if I was able to intubate, and, as I answered in the affirmative, I was given first option on the intubations that occurred in the NICU during my calls. In those days we also intubated in the delivery room all babies born with thick meconium in the amniotic fluid, as we were convinced this would reduce the risks of severe meconium aspiration syndrome. We would repeatedly intubate and suck on the tube as we removed it, until the fluid that returned was clear, so sometimes needing 3 or 4 intubations and sometimes even more. We even tried to stop the babies breathing vigorously as we did the intubations! This meant that I rapidly became an expert at endotracheal intubation in larger babies, and gradually in smaller infants also.

Returning to the present, we now know a lot more about physiologic responses to intubation, and the adverse impacts of failed intubations and multiple attempts (Singh N, et al. Impact of multiple intubation attempts on adverse tracheal intubation associated events in neonates: a report from the NEAR4NEOS. J Perinatol. 2022). For example, having multiple attempts at endotracheal intubation in the delivery room increases the risk of intraventricular haemorrhage (Sauer CW, et al. Intubation Attempts Increase the Risk for Severe Intraventricular Hemorrhage in Preterm Infants-A Retrospective Cohort Study. J Pediatr. 2016;177:108-13), and many babies desaturate severely during intubation. It is critically important to make intubation as safe as possible for at-risk babies. At the same time we have to train new young paediatricians, many of whom will eventually work in hospitals with delivery rooms, where they will be responsible for neonatal resuscitation, and may provide coverage for level 2 neonatal units where intubation skills may be important. We have therefore, a dual responsibility, both to future babies, to ensure that our trainees can care for them adequately, but, most importantly, to the fragile babies currently in our NICU.

My colleagues and friends, the 3 authors of this study, Michael, Christian and Ahmed, (Assaad MA, Lachance C, Moussa A. Learning Neonatal Intubation Using the Videolaryngoscope: A Randomized Trial on Mannequins. Simul Healthc. 2016;11(3):190-3) have been performing a series of studies of the best way to teach intubation skills. Residents now intubate mannequins before they ever touch a baby, and they have a refresher course with a mannequin and the videolaryngoscope at the start of their first NICU rotation. They are supervised performing their first real-life intubations with video laryngoscopy, (Moussa A, et al. Videolaryngoscope for Teaching Neonatal Endotracheal Intubation: A Randomized Controlled Trial. Pediatrics. 2016;137(3):1-8), and most subsequent intubations in the NICU are performed by trainees using the videolaryngoscope. In addition, all intubations in the NICU (except in a major emergency) are premedicated, with atropine, fentanyl and succinylcholine (Barrington K. Premedication for endotracheal intubation in the newborn infant. Paediatr Child Health. 2011;16(3):159-71). Atropine reduces bradycardia, fentanyl reduces pain (and intubation is a very painful procedure) and improves physiologic stability, and succinylcholine shortens the overall duration of intubation (Barrington KJ, et al. Succinylcholine and atropine for premedication of the newborn infant before nasotracheal intubation: a randomized, controlled trial. Crit Care Med. 1989;17(12):1293-6) and reduces the number of attempts required.

Despite these standards, endotracheal intubation remains a procedure with high risk of desaturation, occasional bradycardia, and sometimes requires multiple attempts. Our group decided a few years ago that it wasn’t a good idea to have trainees performing their first intubations with the most fragile babies. We therefore restricted endotracheal intubation of the highest risk babies to only those who had demonstrated competence in the procedure with larger babies. Babies under 29 weeks gestation are only intubated by the “tiny baby” team members, which includes neonatologists and fellows, nurse practitioners, respiratory therapists who are members of the transport team, and residents. In order to be on the team, an intubator had to successfully complete at least 5 intubations on larger infants, 4 of which had to be with either 1 or 2 attempts. These criteria were entirely arbitrary. It was difficult to decide what the criteria should be as there was little previous information to base them on, and if we were too restrictive there would not be enough people around to ensure that there was an intubator on every shift! We have just published our experience with this approach, comparing pre- and post-institution of the tiny baby team. (Gariépy-Assal L, et al. A tiny baby intubation team improves endotracheal intubation success rate but decreases residents’ training opportunities. J Perinatol. 2022). We compared 3 periods, just prior to starting the team, a second period starting 6 months later, and a 3rd period starting 4 years later.

Here is an edited version of table 2 from the publication, showing the overall numbers and results of “ETI” endotracheal intubation, in the 1st 3 columns, then the results for the tiny baby team and the remaining infants. One thing you can see is the reduction in overall intubations, with more babies being managed non-invasively, a change which is most marked <29 weeks.

You can also see that the success rate, on first attempt, among the tiny babies increased when the team started and has remained higher, and the proportion needing more than 2 attempts dropped from 23% to just over 10%. Over these periods, if the first intubator was a junior trainee, they were only usually allowed one attempt, which is why the residents’ success rate is lower than the second attempt success rate in all categories. The number of intubations and the proportion performed by residents have both fallen overall, which has made it even more important to ensure that all forms of training are optimized for future paediatricians to be able to adequately perform the task. One change between T2 and T3 was that residents were prioritized for the intubations of babies >28 weeks. Coupled with enhanced simulation training, their success rate for the larger babies was improved in the most recent period.

This study wasn’t designed to look at the physiologic changes during intubation, but the NEAR for Neos registry has recently published data confirming that serious adverse events are more common with multiple attempts. (Singh N, et al. Impact of multiple intubation attempts on adverse tracheal intubation associated events in neonates: a report from the NEAR4NEOS. J Perinatol. 2022;42(9):1221-7). This is a multicentre registry with data contributed by many hospitals in the USA, Canada and Australia. Those data confirm that more than 1 attempt, and especially more than 2 attempts, are associated with serious adverse events. Severe “TIAE”, tracheal intubation associated events, include cardiac arrest and massage, airway injury, vomiting and aspiration, air leaks, and delayed recognition of oesophageal intubation.

They confirmed that the requirement for multiple attempts was much greater among the most immature babies, and also when the intubator was a paediatric trainee, and was much lower when the baby had received a muscle relaxant. Overall 22% of the intubations required more than 2 attempts.

I was disappointed to see that of the over 6,600 intubations, 3,800 of which were in the NICU, only 2,760 received sedation and a muscle relaxant. Of those that did receive the optimal combination, only 16% needed more than 2 attempts. This is not the first time this group has reported the benefits of sedation with paralysis for reducing “difficult intubation”, and, of all the dozen or so reports I have found of the use of muscle relaxants during intubation, they universally show a reduction in adverse outcomes, depending on what they were measuring, either serious adverse events, desaturation, duration of attempts, or number of attempts. I don’t think there is a good excuse for not giving newborn infants requiring non-emergency intubation in the NICU an adequate pre-medication with a potent rapidly acting analgesic (either fentanyl or remifentanil are the best options) and a muscle relaxant (either succinlycholine or mivacurium, unless you want more prolonged paralysis in which case rocuronium) with atropine to prevent reflex vagally mediated bradycardia. In one recent publication it was reported that it took an median of 16 minutes for the babies to receive the premedications, I find that a little bemusing. We have a “crash cart” in the NICU with the medications easily available, pre-printed charts with the doses already calculated for each step of 100 g of weight, and all the equipment that may be required. Once I say I want to intubate a baby, the crash cart and additional nursing staff arrive, and the baby is often receiving the atropine within 3 minutes, there aren’t many intubations that are so urgent that they don’t receive our cocktail.

The other thing that you can do to improve stability during neonatal endotracheal intubation is to provide a flow of oxygen. My mentor, Neil Finer, was ahead of his time in many ways, he was among the first to study premedication for neonatal intubation, and one thing that was standard in his NICU was the oxyscope, a laryngoscope with an oxygen channel, to which an oxygen source was attached during intubation. I think “Oxyscope” was a trade name which may have been replaced by “Oxiport”, and I am not sure is still being manufactured, but it provided a fresh gas flow near the larynx which decreased desaturation. (Ledbetter JL, et al. Reducing the risks of laryngoscopy in anaesthetised infants. Anaesthesia. 1988;43(2):151-3). Although not using that commercially-produced blade, a much more recent publication (Steiner JW, et al. Use of deep laryngeal oxygen insufflation during laryngoscopy in children: a randomized clinical trial. Br J Anaesth. 2016;117(3):350-7) has confirmed that taping an oxygen cannula to a standard laryngoscope blade also works, and that a video-laryngoscope blade with an integrated oxygen channel exists, which also decreased desaturation in larger children during intubation. These laryngoscopes have only been studied with 100% oxygen flows, usually about 2 litres per minute, and there are of course concerns about brief episodes of hyperoxia that might be associated with their use. However, hypoxia and subsequent re-saturation is probably rather worse for the generation of free radicals than a couple of minutes of hyperoxia, and using a fresh oxygen flow into the pharynx of an apnoeic infant is unlikely to lead to much hyperoxia anyway.

Another way of providing apnoeic oxygenation during intubation is with the use of high-flow nasal cannulae (HFNC), I already posted about the SHINE study from Melbourne using high-flow, here is another trial, a pilot from Dublin (Foran J, et al. Nasal high-flow therapy to Optimise Stability during Intubation: the NOSI pilot trial. Arch Dis Child Fetal Neonatal Ed. 2022:fetalneonatal-2022-324649), as a pilot there were only 43 babies, and 50 intubations included. Infants (who were all premedicated, as in the SHINE trial, with atropine fentanyl and succinylcholine, also known as suxamethonium) had HFNC placed at 6 lpm with 100% oxygen, which is different to the SHINE trial who used a flow of 8 lpm at the same FiO2 as the infant was already getting and only increased to 100% if they desaturated. Another difference is that SHINE was just during the 1st intubation attempt, whereas in this trial they removed the cannulae after the first attempt and put them back if another attempt was required. This new trial had as the primary outcome the duration of desaturation below 75%, which was shorter in the preterm babies (median 29s vs 43s) and not much different in the term babies, as I said, this was a small pilot.

Here is the profile of the median saturations in the <34 week and >33 wk groups.

It seems to show two things, that the babies clearly desaturate faster without oxygen (!) and that someone should have stopped the intubation attempts before they got out to 120 seconds!!! The NRP used to state that an intubation attempt should take a maximum of 20 seconds, Neil Finer showed that was unrealistic Lane B, et al. Duration of intubation attempts during neonatal resuscitation. J Pediatr. 2004;145(1):67-70, that even experienced fellows took an average of 22 seconds, and Colm O’Donnell, when he was in Melbourne (O’Donnell CP, et al. Endotracheal intubation attempts during neonatal resuscitation: success rates, duration, and adverse effects. Pediatrics. 2006;117(1):e16-21), showed that the Australian trainees were slower, averaging 38 seconds for residents, and 32 for fellows. The 7th edition of the NRP handbook continues to state that “the steps of intubation should be completed within approximately 30 seconds”. That is clearly unrealistic, given that the average time for consultant neonatologists to perform a successful intubation in O’Donnell’s study was 25 seconds SD 17s. In experienced hands only about a half of intubations are completed in 30 seconds.

Most babies these days will have a pulse oximeter in place, and hopefully functioning, during an intubation, even in the DR. I think that after 30 seconds there should be an evaluation of the babies status, and if the baby is desaturating and the intubation is not completed by 40 seconds a decision whether to continue or interrupt the intubation, by someone other than the intubator, should be made. This is actually one way that I find the videolaryngoscope useful, I can see if the trainee has a view of the larynx, and is about to insert the tube, compared to the situation with the larynx briefly flying past the screen, and the tube tip heading for the dark hole of the oesophagus.

I don’t know if the combined oxyscope/video laryngoscope would be more or less effective than HFNC to reduce desaturation and adverse events during intubation, but I think someone should find out!

In summary, making endotracheal intubation safer for our most fragile patients requires the following:

  1. Adequate training of all intubators with simulation and video-laryngoscopy
  2. Step-wise introduction of intubators, with video-laryngoscopy, supervision, feedback and repeated training
  3. Ensure that someone with proven competence performs the procedure, by limiting intubation of the highest-risk patients to a restricted list of intubators.
  4. Universal premedication, including muscle relaxation, unless there is a contra-indication, and have procedures in place to administer with minimum delay.
  5. Apnoeic oxygenation, with HFNC, or perhaps an video-oxyscope
  6. Video-laryngoscopy, if you have access to a laryngoscope blade of appropriate size
  7. Ensure supervision of the baby, and their status, by someone who is empowered to stop the procedure if it is going wrong, or is taking too long.
  8. Feedback and further training whenever things go wrong, and even if they don’t.

No more “see one, do one, teach one”!

Even in our NICU, with most of this in place, over 10% of the very immature babies need more than 2 attempts to intubate, we have to find ways to do better than that, to reduce the number and the consequences of failed intubation attempts. During the study that I referred to, of the tiny baby team, we did not have a video-laryngoscope blade that worked for the extremely low birth weight baby, newer technology, and perhaps ever-more realistic high-fidelity mannequins, may help us to further reduce failure rates.

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Time to stop placebo injections in neonatal research projects

Randomized controlled trials are the bedrock of evidence-based medicine. If a treatment has a good theoretical rationale, and preclinical data showing efficacy, the only way to prove efficacy in the human is to randomise patients to the treatment, compared to an alternative, which should usually be some sort of standard therapy, and compare clinically important outcomes. In order to be reliable, randomisation should be masked, which means that, once the patient is enrolled in the trial, and prior to pressing the “randomise” button, the investigators are unaware of which group they will be enrolled.

Masking of the actual intervention is not always possible, for example when comparing different modes of assisted ventilation, and there is less empirical evidence that it makes a difference to results. In particular, in neonatal research I don’t think there is any comparative evidence that shows whether the results of masked trials are systematically different to unmasked trials of the same intervention. The placebo effect, or the improvement in outcomes of control groups, is often misinterpreted as being evidence that the human body has great powers of self-healing, some people even talk about “harnessing the placebo effect”. But, when the outcomes of interest are objective outcomes, the majority of the placebo effect is in fact, “regression to the mean”, or simply that extreme findings usually become less extreme with time, and that most patients recover from most illnesses.

As an example, an uncontrolled trial of a drug (or any intervention) for apnoea will usually show an improvement in apnoeic spells, for a number of reasons. Babies tend to be enrolled in studies when their apnoea is troublesome, and they will therefore, usually, have fewer apnoeas after enrolment. In addition, in this particular example, apnoeas get better with time, so any trial without controls will tend to show improvement over time. But there is really no reason to think that treating babies with a placebo will have any more effect on apnoeic spells than simply not treating them with anything, as long as an objective measure of apnoea is used. Uncontrolled trials of medications for hypotension, as another example, will enrol babies who have blood pressures lower than average; overall such babies will subsequently have higher blood pressures, even if the drug has no effect. But having no treatment, compared to having a placebo infusion will not change that occurrence, both non-treatment and a placebo will have identical effects.

In studies with objective outcomes therefore, one could question the importance of masking the intervention. In my Cochrane review of inhaled nitric oxide for term and late preterm infants, as one example, the outcome “death or ECMO” is very similar between the masked and the unmasked trials. There were a few of both, and I compared the RR and confidence intervals between the masked and the unmasked trials, the results being very similar with the RR for the outcome “death or ECMO” being 0.66 for the masked studies, and 0.7 for the unmasked trials.

This question becomes extremely important when the intervention is a parenterally administered medication. In babies with no IV access in place, or when the medication must be given by another route (IM, subcutaneous…) the tendency in older publications was to give placebo injections, which inevitably create pain. For example, in a trial of erythropoietin prophylaxis published in 1994, control babies received placebo subcutaneous injections 3 times a week for up to 6 weeks. It seems to me to be highly unlikely that subcutaneous saline has any impact on erythropoiesis, not even a “placebo effect”, so the up to 18 painful injections were completely unnecessary. The more recent trial of Juul et al (and some older trials by Ohls and colleagues) used placebo injections for the intravenous phase of the trial, and when an IV was no longer in place, they avoided placebo subcutaneous injections by using sham procedures, in which curtains were drawn around the bed, and a bandage placed where the injection would have been.

This may be inconvenient, compared to just supplying vials with masked information on them and giving the unknown contents by injection, and it may be more costly, but the huge advantage of not inflicting pain on control babies must surely be worth it. A recent article in Acta Paediatrica discusses this issue, and also concludes that placebo injections are neither necessary nor ethically acceptable.

One recent article, which describes a potentially important improvement in RSV prophylaxis, was this one Griffin MP, et al. Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants. N Engl J Med. 2020;383(5):415-25. The authors randomized preterm infants not eligible for RSV prophylaxis in their home countries, to receive either nirsevimab or placebo, 969 received active drug and 484 were randomized to have an intramuscular injection of saline. IM injections hurt. We should only give an IM injection to a newborn infant if there is some benefit to them. The primary outcome of the study was RSV infections requiring medical assistance, which were dramatically reduced from 46 (9.5%) to 25 (2.6%), hospitalisations from RSV were also reduced, from 4% to just under 1%.

Nirsevimab is potentially a significant advance in RSV prophylaxis, a single injection appearing to provide protection for the entire RSV season. Nevertheless, 481 infants received an intramuscular injection of saline. There is no possible benefit to the infant of this painful procedure. The published protocol notes that the blinding was performed at each individual centre, therefore there was an individual who was unblinded at each participating centre. The unblinded individual could easily have been the healthcare worker giving the injection, who could have performed a sham procedure on the control babies.

Even if blinding of the intervention is considered essential (and I hesitantly suggest that it was not, surely RSV infections would be identical in an open-label untreated control group and a masked control group) the blinding could have been maintained by placing an adhesive dressing on the thigh of the control babies, rather than subjecting them to a painful IM injection.

Another recent example is this Rosenfeld WN, et al. Stannsoporfin with phototherapy to treat hyperbilirubinemia in newborn hemolytic disease. J Perinatol. 2022;42(1):110-5, full term babies with a diagnosis of hemolytic jaundice were randomized to stannsoporfin or control, with the primary outcome being changes in serum bilirubin concentration. The 30 control babies received IM saline. I can think of no good reason for subjecting the control babies to the pain of the placebo; surely the lab tech analysing the serum for bilirubin concentrations will not be influenced by knowing which group the infant was in? Even if it was thought that other important secondary outcomes might be influenced by knowing which group the infant was assigned to, the intervention could equally well have been masked by a sham procedure without painful injection. But the only secondary outcomes listed all depend on the serum bilirubin concentrations. There is a plan to perform long term neurodevelopmental outcome evaluation in the infants; I guess it was thought to be just about feasible (and I would challenge that assumption) that knowledge of treatment group could have an impact on neurological or developmental outcomes. Even if this is the reason for maintaining masking of the intervention, such masking does not require intramuscular placebo injections.

Surely it is time to abandon additional unnecessary pain in research participants. We could start with banning placebo skin-breaking injections. Studies in newborn infants, who obviously don’t know themselves which group they are in, could be performed unmasked if the primary outcome variable is objective. If there is some subjectivity in the determination of the major outcomes than masking can be maintained by the use of sham injections.

A major problem is the way painful procedures are evaluated by ethics review committees. One of the worst studies in terms of pain inflicted on the neonatal participants was another RSV prophylaxis trial, the MAKI trial, where infants were subjected to either monthly palivizumab, or monthly IM placebo injections, to a maximum of 5 intramuscular injections of saline. Unusually, this trial was also the source of an article trying to justify its ethical approval. That article concluded

The Institutional review board (IRB) concluded the study has high clinical relevance because the benefit of 50% chance of protection by palivizumab outweighs the risk of side adverse events due to intramuscular administration of placebo.

It is actually impossible to argue with that conclusion, the study was indeed of high clinical relevance, and the “risk of side adverse events” from up to 5 IM saline injections is negligible. But only if you think that pain is not an adverse event. If you include pain as an adverse event the “risk” of adverse events was 100%.

The authors try to justify the use of the IM placebo, without ever mentioning pain, as follows “A placebo controlled control group was necessary because the primary objective will depend on parent-reported daily scores of wheezing along with information from parent-reported questionnaires”. Firstly, I question that rationale, is there any reason to believe that parents would provide biased scores of daily wheezing based on whether the child actually had a placebo injection compared to being enrolled in an untreated control group? Even if there were some evidence of such an effect, the placebo injections could have been replaced by sham injections.

The book from the Institute of Medicine “Ethical conduct of clinical research involving children” has a chapter “Defining, Interpreting, and Applying Concepts of Risk and Benefit in Clinical Research Involving Children” describing how to determine risks, and tries to define “minor increase over minimal risk”, in research with children as research participants. It includes a table which illustrates the hidden way in which pain is taken into account. The table lists “routine history taking” and a “complete neurological examination” as procedures with minimal risks, which we surely cannot argue with. But in the same category is included “venepuncture/fingerstick/heelstick”.

From a purely “risk” point of view, if pain is not considered a risk, then I guess that makes sense, but surely examining a baby and sticking a needle into them should be considered differently? The table also includes, as a minor increase over minimal risk, a lumbar puncture. Lumbar puncture is an extremely low risk procedure in the otherwise stable newborn, why is it given a higher risk status? Is it because we know it hurts, a lot? The only place pain is mentioned in that table is for two other “minor increase over minimal risk” procedures: skin punch biopsy and bone marrow biopsy, where “topical pain relief” is added as part of the name of the procedure. One might wonder why pain relief is not mentioned for heelstick or for lumbar puncture. In another part of the book it is stated “children should always be given the option to receive a topical anesthetic to reduce needle-stick pain”, but I can find no mention of routine analgesia prior to painful procedures in the newborn. The only mention of intramuscular injections is that they are more risky in children with hemophilia

A new publication from Ruth Grunau and the group in Vancouver who have performed amazing research into the adverse impacts of pain, and how to minimize it, has just appeared. McLean MA, et al. Association of Neonatal Pain-Related Stress and Parent Interaction With Internalizing Behaviors Across 1.5, 3.0, 4.5, and 8.0 Years in Children Born Very Preterm. JAMA Netw Open. 2022;5(10):e2238088. This study examined child behavioural patterns at the ages mentioned in the title, and determined the association with painful procedures in the neonatal unit. There was a clear correlation, after correcting for multiple other factors including gestational age, between having more painful experiences and having more internalizing behaviours, across all of those ages. They also showed that a more supportive, positive, and less stressed family environment could mitigate those impacts.

This study, among many others, emphasizes that we need to do all we can to reduce pain in the neonatal period, and any additional avoidable pain should be prohibited. This must include the use of placebo injections in research, which can always be avoided.

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Protein pump inhibitors cause coeliac disease and asthma, and they are unnecessary.

OK, that title is perhaps slightly too definite, the publications that I wanted to discuss are observational studies, which can only prove associations, but it would be hard to perform the prospective controlled trials that would be necessary to prove (or disprove) causality. A trial for PPIs and coeliac disease would need an RCT of about 2400 per group, which will clearly never be done; for asthma the sample sizes I calculated were even larger, around 5000 per group.

So what this first study shows (Boechler M, et al. Acid Suppression and Antibiotics Administered During Infancy Are Associated with Celiac Disease. The Journal of Pediatrics. 2022) is that from a huge database, the military healthcare system database, the Hazard Ratio of having coeliac disease was 3.37, and after adjustment was 2.23, for infants who had a prescription for a PPI prior to 6 months of age; a risk that was also shown for histamine receptor blockers (adjusted HR 1.94) and antibiotics (1.14). Having all 3 was the worst risk (adjusted HR 5.43). They also showed that the longer the infant received a prescription for acid suppression, the higher the risk. In this database about 2% of all the babies got a prescription for a PPI during the 1st 6 months of life.

The other article is also from an administrative database and shows, using propensity score matching, an increase in the frequency of asthma diagnoses and of prescriptions for asthma medications among children who had a PPI prescription. (Wang YH, et al. Association Between Proton Pump Inhibitor Use and Risk of Asthma in Children. JAMA Pediatr. 2021;175(4):394-403), with the hazard ratio being about 1.5 for the various drugs, being highest in the first 6 moths after prescription and then decreasing.

In a recent study from Scandinavia rates of PPI prescriptions were given to up to 8% of all infants under 1 year of age in Denmark in 2017. There must be a global epidemic of hyperacidity. (Lyamouri M, et al. Proton pump inhibitors for infants in three Scandinavian countries increased from 2007 to 2020 despite international recommendations. Acta Paediatr. 2022;111(11):2222-8).

Why on earth are so many babies and infants receiving a PPI? We seem to have become intolerant of babies spitting up, or being irritable, or having colic, all of which can be rather disturbing things for new parents, but which do not usually need, or respond to, any medication!

In the NICU this is usually done because someone thinks a baby has pathological reflux, and gets a label of Gastro-Oesophageal Reflux Disease, which then leads to treatment with a protein pump inhibitor and/or other medications. A recent review article (Sawyer C, et al. Neonatal gastroesophageal reflux. Early Hum Dev. 2022;171:105600) is generally well done, I thought, but it is not intended just for the NICU or for preterm and former preterm infants.

Overall, available evidence does not support the routine use of PPIs or H2RAs to treat classically associated GERD symptoms in post-term infants, although some sub-populations may benefit from treatment. Outside of proven acid-reflux, treatment with a PPI should be time limited and all caregivers should be aware of possible side-effects. Acid-suppression therapy should not be used in preterm infants given the risk of severe side effect.

To put it simply, I think of this as follows:

  1. The only reliable clinical sign of reflux in the newborn is regurgitation, but having regurgitation does not mean that a baby has significant reflux, most babies regurgitate. No other clinical sign discriminates between babies with more or less reflux, either the total number of episodes, or the number of acid reflux episodes. When the nurse tells you they think the baby has significant reflux, either based on using a clinical score, or based on their personal evaluation, there is no correlation with objective measures of reflux.
  2. You cannot diagnose reflux with a laryngoscope.
  3. Diagnosis of abnormally frequent reflux requires objective evaluation, using multi-luminal impedance with pH monitoring.
  4. Most reflux in newborn infants is not acidic, as shown by such studies.
  5. Diagnosis of GOR DISEASE requires evidence, in addition, that the reflux is actually causing clinical problems; this is rarely due to acid in the newborn.
  6. Apnoea spells are not triggered by reflux, for the great majority of cases, but sometimes reflux may be triggered by apnoeas, especially obstructive apnoeas.
  7. Bronchopulmonary dysplasia is not clearly worsened or caused by reflux.
  8. Blocking gastric acid production does not decrease reflux, it just changes it from being majority non-acid to being a very large majority non-acid. It is possible that PPI use actually increases reflux, in several animal models they cause relaxation of the lower oesophageal sphincter.
  9. Gastric acid is there for a reason. Blocking it changes the intestinal microbiome, and increases the risk of respiratory infections, systemic sepsis and NEC. PPIs reduce calcium, magnesium, and iron absorption, and seem to cause coeliac disease, asthma, and increase the risk of fractures.

In summary, only prescribe acid blocking medications if there is some clear evidence that the baby will be improved with less gastric acid production. A rare occurrence.

The review article that I mentioned and linked to also discusses the evidence against using prokinetics, which I totally agree with:

None of the[prokinetic agents] have been shown to reduce GERD symptoms in preterm infants. Similar to other medical therapies for GERD, most are not well studied in neonates and are associated with significant and concerning side effects. Side effects of metoclopramide and domperidone are primarily neurologic including irritability, drowsiness, apnea, and possible irreversible tardive dyskinesia. Erythromycin is associated with infantile pyloric stenosis and cardiac arrythmias. Given the lack of evidence for efficacy and the potential for significant side effects, the use of prokinetic agents to treat neonatal GERD is not recommended.

The review does discuss the idea that bovine protein intolerance is a factor in GOR; in my evaluation there is some soft evidence for this in older infants, and as a result a therapeutic trial of elimination of cow’s milk protein is sometimes included in treatment guidelines, but, as far as I know, there is no such evidence in the newborn, especially in the preterm newborn.

An article I discussed previously noted that lansoprazole was a drug with a major decrease in use between 2010 and 2018, but over the whole period covered by that study about 5% of all the ELBW babies received at least one course of treatment. There were also about 10% of the ELBW infants received ranitidine, which was taken off the market towards the end of that study, let’s hope its use wasn’t replaced by more PPIs!

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Reducing pain from retinopathy screening

Retinopathy screening is undoubtedly painful for preterm babies, formal evaluation with PIPP scores routinely exceed 10 during screening, and may exceed 14, meaning moderate to severe pain. As a planned procedure there is always opportunity for pre-emptive analgesia prior to and during a screening exam, but what? Many of the interventions studied have limited efficacy.

A new systematic review has examined the efficacy of “pharmacologic” methods of pain control, and therefore, using their definition of “pharmacologic”, excluded breast milk, sucrose, swaddling; I know there has been some debate about whether sucrose should be considered “pharmacologic” or not, but that was the definition they used.

Thirunavukarasu AJ, et al. Analgesia for retinopathy of prematurity screening: A systematic review. Pain Pract. 2022;22(7):642-51.

The review, which is unfortunately lacking in cute Forest plots to copy into this post, confirms that topical anaesthesia has limited effectiveness, there are 4 controlled trials that they found, with a mean PIPP score after local anaesthetic of between 10 and 15, reduced by an overall 1.6 points, which although not likely to be due to chance, is a very small reduction.

The other studies they reviewed all used topical anaesthesia in both groups, and examined other additional analgesia. They found 3 trials with acetaminophen (paracetamol to the Europeans) compared to control or placebo or sugar or milk. Overall, 2 of the trials showed a reduction in PIPP scores during the procedure, the 3rd reported PIPP scores after the procedure, which ere also reduced. The 3 trials used 15 or 20 mg/kg of acetaminophen given either 30 or 60 minutes prior to the procedure. As for opiates there were 2 trials of oral morphine which show relatively little effect, and one of intranasal fentanyl which appeared effective, when given in combination with sucrose and topical anaesthesia compared to that combination without fentanyl (Sindhur M, et al. Intranasal fentanyl for pain management during screening for retinopathy of prematurity in preterm infants: a randomized controlled trial. J Perinatol. 2020;40(6):881-7). That was a nice masked study with 50 babies per group, and has the advantage over acetaminophen that it works quickly, I don’t think it has become widespread, but why not?

You can see from that figure, taken from the aforementioned publication, that intranasal fentanyl was rather effective. You can also see from the controls that despite topical anaesthesia, swaddling, and sucrose, retinopathy screening examinations still hurt.

Other interventions that have been tried include nitrous oxide, in a controlled trial by my friend Romain Mandel and our colleagues (Mandel R, et al. Nitrous oxide analgesia during retinopathy screening: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2012;97(2):F83-7) which didn’t have a benefit, Also breast milk, compared to sucrose, which showed that neither was better than placebo control for the acute pain response, but the breast milk babies apparently returned to baseline a bit faster than the sucrose, at least that is what the authors write (Şener Taplak A, Erdem E. A Comparison of Breast Milk and Sucrose in Reducing Neonatal Pain During Eye Exam for Retinopathy of Prematurity. Breastfeed Med. 2017;12(5):305-10), but I can’t see any data in the article to support that contention, the post procedure PIPP scores were lower in the 2 intervention groups compared to control, but there are no reported data about time to recovery.

What I make of all this is that topical anaesthetic is of limited efficacy, but I would still give it anyway, it seems 100% safe, and there is probably a small beneficial effect. Sucrose does very little if anything, but perhaps the babies return to baseline a little faster with either sucrose of breast milk, at the age when the babies are getting screened they are receiving much less sucrose for other procedures, so it will probably be safe to give; the use of breast milk as an alternative does not seem much more effective. Adding a pacifier/soother/dummy usually makes sucrose more effective, but for eye screening this has not been shown for sure, on the other had giving sucrose, with a soother/pacifier/dummy and swaddling does have some impact (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).

I think that either acetaminophen or nasal fentanyl given before the procedure warrants either routine introduction or more study. I’d like to see confirmation of the efficacy and safety of routine intranasal fentanyl before introducing the practice to large numbers of stable preterm infants, but it does seem effective from that one study, and the dose of 2 microg/kg as a single administration in the nose appears from other data to be safe. The reduction of pain scores with acetaminophen is interesting but it isn’t apparently as effective as fentanyl, although a comparative trial would be nice.

My optimal protocol for the present would be, administration of 15 mg/kg of acetaminophen 30 to 60 minutes prior to the procedure, at the time of application of topical anaesthetic and mydriatic, swaddling of the baby and administration of sucrose 2 minutes prior to the procedure, a second dose of sucrose with a soother just prior to speculum insertion, then repeated sucrose if the procedure takes more than 2 minutes, and trying to avoid scleral depression if possible.

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What dose of caffeine to use?

The dose of caffeine that we used for the CAP trial was the dose that was being widely used at the time. It seemed to be a safe dose, that did not require serum concentration surveillance, but was not based on a large number of high quality dose ranging trials, indeed it was identical to the doses used in the very first publication of caffeine use in the preterm infant, published in 1977 by Jack Aranda, from Montreal (the McGill side of the mountain). (Aranda JV, et al. Efficacy of caffeine in treatment of apnea in the low-birth-weight infant. J Pediatr 1977;90(3):467-72), they used 20 mg/kg of caffeine citrate as a load, and 5 to 10 mg/kg/dose once or twice a day, starting 48 to 72 hours after the load.

The maintenance dose gradually stabilised over the years, although there have been repeated questions about whether it is the optimal dose. There were some pharmacokinetic studies, but few quality pharmacodynamic studies, those that existed rarely used objective quantification of apnoea frequency, which is essential to be able to say much about the impacts on apnoea, nursing records of apnoea spells being notoriously unreliable.

The CAP trial remains the standard, which showed an improvement in medium term, and very long term, outcomes after caffeine use among infants of less than 1250 g birth weight, less than 10 days of age started on caffeine (or placebo) because the attending physician thought they needed caffeine. The dose in that trial was 20 mg/kg of caffeine citrate as a load, and 5 mg/kg daily, that could be increased to 10 mg/kg of caffeine citrate daily if the physicians thought the baby needed more. I submitted an abstract to a PAS meeting which showed that babies who had the dose increase had the same advantage of caffeine as those who remained on the initial dose, which I never fully published (sorry!) but I think was reliable information that the higher dose of caffeine was safe.

Clearly if some caffeine is good, then it is possible that much more caffeine might be even better. If we can keep babies extubated for longer periods of time, and knowing that several animal models show brain protective effects of caffeine, then what dose of caffeine should we give?

In this study in 3 day old rats, for example, the animals received 20 mg/kg/d of citrate for 5 days starting the day before a classical carotid-ligation-hypoxia model, and they had less white matter injury. In another study in newborn mice with an IVH model, caffeine at 20 mg/kg/day for 3 days started after the IVH reduced brain injury and brain atrophy. In another study Jack Aranda returns to caffeine 45 years after the first publication (!), comparing neuroprotection in newborn rats who received a dose similar to the usual human preterm dose (20 mg/kg load of Caffeine citrate followed by 5 mg/kg/d) or a larger dose of 80 mg/kg load followed by 20 mg/kg/d for 12 days. They showed similar neuroprotection with the 2 doses.

But before we ramp up the caffeine dose too far, remember the results of the pilot trial from St Louis, which randomized babies to get 80 mg/kg as the loading dose, starting in the first 24 hours of life, compared to 20 mg/kg in the standard dose group. The 80 mg/kg was actually given over 36 hours, as 4 doses, 40 mg/kg as the initial load, 20 mg/kg 12 hours later, then 10 mg/kg 24 and 36 hours after the first dose, the controls received 20 mg/kg then 10 mg/kg 24 hours later. Both groups in that small pilot (n=37 per group) received the same maintenance dose 10 mg/kg/day of caffeine citrate. The results of that trial showed a greater seizure burden with high dose compared to standard dose, and the high dose babies also had more cerebellar injury; fortunately the 2 year and 5 year outcomes were very similar between groups.

This was actually a slower load than in the previous trial by Steer et al who gave a 80 mg/kg bolus over 15 minutes, and then a maintenance of 20 mg/kg/d compared to their controls who got 20 mg/kg load then 5 mg/kg/d. In that study, the 240 babies of <30 weeks gestation were a little older (2 to 12 days of age, average 4 days) when enrolled and the study was designed to look at extubation failure. The primary outcome, extubation failure was less frequent in the high dose group, and there was a little less BPD in the high dose group 34 vs 48% RR 0.72 (95% CI 0.52-1.01). The medium term outcomes at 1 year of age tended to be better in the high dose group, and are described in more detail in this publication. The developmental quotient from the Griffiths scale is a slightly higher in the high dose group, but I don’t see any publication with later follow up.

There are a couple of smaller studies randomizing babies to higher doses of caffeine. In one of them, published in Chinese so I can only read the English abstract, 162 ventilated infants <32 weeks were randomized to different maintenance doses, they all received 20 mg/kg load before 6 hours of age (presumably of caffeine citrate) then either 5 or 10 mg/kg (presumably the daily dose of caffeine citrate); it appears that the higher dose group were less likely to fail extubation, which was mostly because of apnoea. An Egyptian trial (fortunately for me published in English) randomized 120 ventilated babies <32 weeks to receive either a load of 40 mg/kg of caffeine citrate and a maintenance of 20 mg/kg/d, or a load of 20 and maintenance of 10. They showed less extubation failure in the high dose group, but there is no longer term follow up. Another study from China randomized ventilated infants <30 weeks gestation who were over 48 hours of age and thought to be within 24 hours of an extubation attempt to a maintenance dose of either 5 or 10 mg/kg of caffeine citrate starting 24 hours after the load of 20 mg/kg, which was the same in each group. Extubation failure was decreased with the higher maintenance dose.

Putting this together to me this suggests that very early, very high loading doses of caffeine might be risky, that increasing maintenance doses to 10 mg/kg/d is probably safe and beneficial, with an increase in successful extubation and less apnoea, but limited long term outcome data. Increasing the loading doses after the first couple of days of life probably improves extubation success, but without more safety data I would be reluctant to use very high loading doses as a routine.

One of the particular features of caffeine kinetics is a dramatic increase in clearance as babies approach term. Caffeine is mostly filtered by the kidneys unchanged in early postnatal life of the preterm, and there is a gradual development of various pathways of demethylation with maturation, acetylation probably develops even later. The half life, as a result, is often over 100 hours in the early preterm period, falling to about 4 to 6 hours in an adult.

If we are planning to give caffeine to babies who are more mature, as they approach term, doses will therefore probably have to be adjusted. A trial which randomized 95 preterm babies who were stopping caffeine at >33 weeks, to either usual care without caffeine or to restart it 5 days later with a loading dose of 20 and maintenance of 6 mg/kg showed that the babies had fewer intermittent hypoxic spells in the caffeine group, until they reached 37 weeks PMA, by which time there was no longer much impact of the caffeine, I think this may have been partly because of a lack of power, as the controls were having fewer spells, but may also be because caffeine clearance was rapidly increasing and the infants needed more. The authors of this study therefore enrolled a second cohort of 27 similar babies who received higher doses, which they compared to the controls from their first study. The doses in the 2nd publication were started just 24 hours after stopping clinically required caffeine, and were 10 mg/kg/d of caffeine citrate, increased at 36 weeks PMA to either 14 or 20 mg/kg/d, decided by random allocation. The doses were chosen to try and maintain salivary caffeine concentrations at above 20 microg/mL, thought to be a reasonable therapeutic target for efficacy and safety. In this trial there was a reduction in intermittent hypoxic spells compared to the controls from the previous study.

In a small short term study like this it is not possible to say whether there was a clinical benefit to the babies of having fewer intermittent hypoxic spells. As far as I can see there is no long term follow up of these babies published, but it would have very little power anyway.

All of which is a preamble to a newly published study from Auckland examining the use of caffeine in late preterm infants. We don’t normally worry about these babies in terms of apnoea of prematurity, even though they clearly very commonly have apnoeic spells, most of the spells are brief and resolve spontaneously. However they are accompanied by episodic hypoxia, and repeated hypoxia and re-oxygenation leads to an oxidative stress, which might have adverse long term effects. We also know that the neurodevelopmental long term outcomes of late preterm babies are different to those at term, with more cerebral palsy, and more schooling difficulties.

The new study was to determine a dose that decreases intermittent hypoxia in late preterm infants (Oliphant EA, et al. Caffeine to prevent intermittent hypoxaemia in late preterm infants: randomised controlled dosage trial. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2022:fetalneonatal-2022-324010); babies born at 34 to 36 weeks were randomized to placebo or one of 4 doses ranging from 5 to 20 mg/kg/d, around 25 babies per group, with the first dose in each case being the double of the maintenance. Caffeine (or placebo) was continued until term, including after discharge, and the primary outcome was the number of intermittent hypoxic spells on an oximetry recording performed at 2 weeks after enrolment.

They showed fewer events at 2 weeks of age with the caffeine dose of 10 or 20 mg/kg/d compared to placebo (but not with 15 mg/kg/d), heart rates and episodes of tachycardia were increased in the caffeine groups. Presumably the lack of effect of the 15 mg/kg dose is just a random effect, as the groups were relatively small and the frequency of intermittent hypoxia spells is very variable.

This study confirms that to have an impact on respiratory drive and hypoxic spells near to term, the doses required are substantially higher. What it does not tell us is whether we should be doing this!

If you are caring for an individual child with troublesome clinically important apnoeas who is approaching term, and you want to treat with caffeine, you will need a higher dose to reduce the number of spells, because of the changes in metabolism.

Routine treatment of babies as they approach term is another question entirely. A higher dose than previously used will be necessary IF prevention of intermittent hypoxia spells near to term can be proven to be important. We have known for years that very preterm babies often continue to have multiple apnoeic spells as they approach term and hospital discharge (Barrington KJ, et al. Predischarge respiratory recordings in very low birth weight newborn infants. J Pediatr. 1996;129(6):934-40). We also know that there is a statistical correlation between more days with apnoeic spells and worse neurodevelopmental outcomes. Janvier A, et al. Apnea is associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol. 2004;24(12):763-8.

What we need to know is whether it is safe and effective to give high doses of caffeine to very preterm infants as they approach term to reduce such spells. Even if, as seems likely, we can reduce intermittent hypoxia with higher doses of caffeine with routine continuation towards term, does it actually improve longer term outcomes. Even more important in some ways, given the very much larger numbers of at-risk infants, is it safe and effective to routinely treat late preterm infants to reduce their frequent hypoxic spells?

I am sure Dr Alsweiler and colleagues in Auckland are hoping to follow up the Latte Dosage trial with a large multicentre RCT examining long term impacts of high dose caffeine in late preterm infants, lets hope they get the funding. We tried a couple of times to get NIH funding for a trial in very preterm babies as they approached term, but the trial, as it was designed, was hugely expensive and never got high enough priority. A simpler pragmatic trial would be very valuable, and could inform our community about what to do with caffeine for the preterm infant approaching term.

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