Not neonatology: Snow Goose migration

Every year at least 1 million snow geese migrate from the Canadian arctic tundra towards the Carolinas. Many of them stop in Quebec especially around the region of Cap Tourmente, not far from Quebec city. There they eat the rhizomes of the American Bullrush, which few other large creatures eat, the energy stores in the rhizomes are important for the calories they need for the migration.

I went last weekend to see the tail end (!) of the migrating hordes, here mixed with Green-Winged Teal (Canada’s smallest duck). According to the official count/estimate there were over 16,000 geese that day.

Most of the birds are like the white morph on the lower left of this photo, the dark morph makes up a few percent of the flocks.

They sometimes pose for a portrait.

And sometimes fly in huge clouds as they head to roost in the evening.

We were also fortunate to see one of the last Belted Kingfishers before the water freezes and they head southerly. The white dots on the photo are a few flakes of snow that were falling.

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Clunk/click every hip

For those of you who are not of a certain age, and brought up in England, that title will not mean very much. When seat belts in cars were first made compulsory in the UK there was a widely quoted government advertising blitz, with the sound of a car door closing followed by the sound of a seat belt being fastened, the motto of the campaign was “Clunk Click every trip”.

Résultats de recherche d'images pour « clunk click every trip »

(Those hands probably belong to Jimmy Savile, the spokesman of the campaign; who later, mostly after his death, became recognized as a serial sexual predator, whose victims were in the hundreds)

But back to neonatology and the tricky problem of detecting hip dysplasia. As a young trainee I was taught the Ortolani and Barlow manoeuvres, and to differentiate between a “clicky hip”, common and, we were taught, associated with ligamentous laxity due to fetal exposure to maternal progestins, and a “clunk”, a feeling of movement of the joint associated with dislocation/subluxation of an unstable hip or reduction of a hip already subluxated. When I was in that phase of my development, oh these many years ago, there was no such thing as hip ultrasound and we sent hips with suspected “clunks” for x-ray.

Despite 40 years of practice the number of babies in whom I have personally detected an abnormal hip, in the absence of other associated conditions, i.e. those who should be picked up by a universal physical exam screening program, is tiny, perhaps 2. To be fair, I haven’t spent much time covering the term nursery during those years. I certainly started to teach other juniors how to examine hips before I had ever detected a new case myself!

A new editorial (Hall DM, Sowden D. Hip hip: no hurray. Arch Dis Child. 2018)
points out that I am not alone, many junior pediatric staff never see a case, and in the lifetime of a family practitioner maybe they will see 2 or 3. The editorial was written to discuss a program in Scotland that reports some results in the same issue of ‘Archives’. (McAllister DA, et al. Enhanced detection services for developmental dysplasia of the hip in Scottish children, 1997-2013. Arch Dis Child. 2018). Two regions in Scotland introduced enhancements to the neonatal screening programs and showed a reduction in the need for surgical treatment of hip dislocation, whereas in other regions the number of surgical cases were stable. Unfortunately it is not entirely clear what the enhancements in service really entailed, in one region a physiotherapist personally examined many hips, and did a lot of teaching, awareness promotion, and a clinic for secondary examinations. In the other region a physician set up a specific clinic providing secondary examinations and ultrasounds and helped to train medical and maternity staff how to examine the hip. There aren’t many more details about what they actually did, how many patients they saw directly themselves, what proportion had ultrasounds etc. In the region with the physician 31% of the babies over a 9 year period had “expert examination and ultrasound” but it would be impossible to try to copy these programs without much more detail, or to know which parts are most likely to be important.

This graph shows the different risks of surgery for “DDH” developmental dysplasia of the hip, in the 2 regions with the programs, where roughly one fifth of Scottish babies are born, where surgery became less frequent, about a 50% drop, and the remainder of Scotland over the same years where it remained stable.

https://adc.bmj.com/content/archdischild/103/11/1021/F2.large.jpg

As far as I can tell surgery included both open and closed reductions of unstable hips, so it seems that these enhanced programs are associated with less surgical reduction, which is certainly a worthwhile goal, as long as all necessary surgeries are being done, and the long term outcomes are good.

A Cochrane review of hip screening programs was unable to find enough good quality evidence to inform evidence-based recommendations.

Many screening programs are introduced without the kind of hard evidence that is needed and should be required prior to subjecting babies to the intervention. Even though the evidence for pulse oximetry screening for critical congenital heart disease is to my mind now quite convincing, the way in which the process of evaluating the programs started was really not optimal.

A very large randomized trial comparing standard detection algorithms in the real world, compared to the new screening approach, either as an add-on or as a replacement, should be the way these things are introduced. Blinded performance of the add-on method in the standard screening group adds to the data that can be generated, but is not essential.

Several jurisdictions have now introduced universal hip ultrasound screening for developmental dysplasia. Again without the kind of high-quality evidence that would be preferable, I wonder, for example  if universal screening is better than just screening girls, or just screening girls who were in breech? I wonder what is the sensitivity and specificity of a clinical hip exam, and what would be the gold standard for such an evaluation, presumably hip ultrasound? But minor degrees of hip abnormalities on ultrasound are known to sometimes improve. I also wonder what the best outcome measure for such a study should be?

I think I would like to know, when comparing approaches to screening, which approach leads to the lowest proportion of children who end up with disability. If disability is equivalent with 2 methods, then a smaller number of surgeries required to achieve the results would clearly be a benefit, if those numbers are also equivalent, then few children with splinting and non-surgical interventions would be of value for the child and families.One problem with this of course us that, with modern surgical methods very few children end up with significant disability, so a study would need to be huge. As you can see from the graph above, requirement for surgery is somewhere between 0.5 and 1.3 per 1000 live births, so even s study investigating surgical rates would need to be very large.

One of the randomized trials, performed in Norway of a universal ultrasound screening program (Holen KJ, et al. Universal or selective screening of the neonatal hip using ultrasound? A prospective, randomised trial of 15,529 newborn infants. J Bone Joint Surg Br. 2002;84(6):886-90), found a reduction in the rate of late detected hip dysplasia with an RR of 0.2 (1 case out of 7,500 compared to 5 cases per 7,500) , which is a major reduction, but given the rarity of this outcome even such a large reduction may have been due to chance (95% CI 0.03-1.45).

A new publication from a center involved in a universal ultrasound screening program Biedermann R, et al. Results of universal ultrasound screening for developmental dysplasia of the hip. Bone Joint J. 2018;100-B(10):1399-404. reports the results of screening over 28,000 infants in their center. They report no cases of late diagnosis, an overall treatment rate (mostly Pavlik harness or a similar device) of 1% of babies, and 25 total (or 1 per 1000) who had surgery.

A review article published last year (Paton RW. Screening in Developmental Dysplasia of the Hip (DDH). Surgeon. 2017;15(5):290-6) came to the following conclusions :

  • Sonographic selective screening of all ‘at risk’ hips has not reduced the rate of ‘late’ presenting irreducible dislocation when compared to universal clinical hip screening.
  • The General Practitioner hip screening examination is ineffective in diagnosing many cases of pathological DDH in its present form.
  • Spontaneous resolution of clinical and sonographic abnormalities makes the diagnosis of ‘pathological’ hip dysplasia difficult.
  • Sonographic hip dysplasia is a poor outcome measure, as the most robust outcome measure continues to be irreducible hip dislocation.
  • The diagnosis of clinically normal but sonographically diagnosed abnormal hip joints may lead to over diagnosis and potentially over treatment of the condition.
  • Pathological DDH is mainly a female condition and most males are not ‘truly’ at risk if the hip joints are clinically stable.
  • Previously accepted risk factors are not ‘at risk’ i.e. CTEV (Congenital talipes equino-varus), Postural TEV (Talipes equino-varus) Oligohydramnios, Caesarean section, IUGR (intra-uterine growth restriction), Miscellaneous foot problems.

I agree with most of those points, but the evidence for some is weak, especially the first. Remeber that babies with any one of several congenital syndromes, and preterm infants are excluded from this discussion.

I think there is a case to be made for universal ultrasound screening, and the true impact on over-diagnosis and over-treatment is unclear, but very few cases are missed. On the other hand, screening all girls, all boys with a breech presentation, and all those with a first degree relative with a history of developmental dysplasia of the hip would dramatically decrease the number needing screening  with very little impact on the numbers detected.

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Moral Distress in the NICU, a webinar.

Trisha Prentice is a neonatologist in Melbourne who has been working with Annie Janvier and Peter Davis examining the occurrence and causes of moral distress in the NICU. They have already published a systematic review of the subject (Prentice T, et al. Moral distress within neonatal and paediatric intensive care units: a systematic review. Arch Dis Child. 2016;101(8):701-8) and the first in what will be a series of publications about her research (Prentice TM, et al. Always a burden? Healthcare providers’ perspectives on moral distress. Archives of disease in childhood Fetal and neonatal edition. 2018;103(5):F441-F5). Of which a one sentence summary is : all professionals in the NICU experience moral distress, that it is usually when parents want to continue care after the caregiver thinks that it would be preferable to redirect to comfort care, and most caregivers think that it is inevitable in a setting such as ours that moral distress will occur, and indeed it may have value as a stimulus for us to examine our preconceptions.

She will be presenting a webinar on Wednesday 24th of October at midday Kansas CIty time, as part of the excellent series of pediatric bioethics webinars run out of the Kansas City Children’s Mercy Hospital Bioethics Center, under the direction of John Lantos.

You have to register in order to participate in the webinars, which you can do from here https://www.childrensmercy.org/bioethics/webinars-and-podcasts/ but they are free and open to all.

 

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All that pneumatoses is not NEC

OK, I know pneumatose is not a verb, but I thought it was a cute title.

What is NEC, anyway? Necrotizing Enterocolitis, of course, you might reply. But it’s not as simple as that. The very preterm baby who deteriorates after being stable (usually after introduction of feeds), with abdominal distension, ileus, intestinal dilatation, obvious pneumatosis on x-ray, air in the portal venous system, who progresses to perforation and on laparotomy has skip lesions of necrotic bowel, such a baby is a clear case of classical NEC; but may be in a minority.

I have seen babies who present clinically exactly like that but on laparotomy had a strangulated internal hernia or other diagnoses. Full term babies also develop similar clinical and radiologic findings, but they almost always have other major risk factors. Infants with spontaneous perforation would have been classified as NEC in the past, but are now clearly recognized as a separate group.

Even among those with apparent ‘premie NEC’ there are major problems in diagnosis. Previous studies have shown that the radiologic diagnosis of pneumatosis is very uncertain, with inter-observer variability very high. A new study has looked at whether diagnosis of NEC made by local investigators can be supported when the files are reviewed by other experts.

Challis P, et al. Validation of the diagnosis of necrotising enterocolitis in a Swedish population-based observational study. Acta Paediatr. 2018.

This is a publication from the EXPRESS cohort that we have covered here on several occasions. Over a 3 year period all the babies of less than 26 weeks probable gestation born in Sweden were followed; and for many publications, they also followed stillbirths and counted mothers who were admitted with threatened extremely preterm delivery.

For this publication the data from the 707 live born babies was examined, and the 602 who survived more than 24 hours were included. All babies with a diagnosis of NEC in the database were reviewed, in addition any baby who had a sudden reduction in their feeding intake, to less than 10% of total fluid intake for more than a day (or if they never exceeded 10% in the first 10 days). The hospital records were obtained of these babies to see if independent neonatologists would confirm the diagnosis or not.

There were 39 babies identified in the database as being cases of NEC of which 16 after review were not definite cases of NEC, even 5 of the babies who had surgery were re-classified as no-NEC, 3 spontaneous perforations, one volvulus, and one meconium ileus.  Two babies were classified as no clinical suspicion of NEC, and 11 as possible NEC (referred to as Bell’s stage 1) which didn’t fit the case definition.

Among the 74 babies who had an episode of feeding reduction/interruption there were 4 with definite NEC, 2 had surgery and had reported findings consistent with NEC, 1 had NEC at autopsy, and 1 had clear x-ray findings. Another 7 babies were thought to have possible, stage 1, NEC and were therefore classified as no NEC.

This, to me, points out 2 things; firstly, sometimes data in clinical databases is unreliable, if a baby with findings on autopsy of NEC can be in the database as a case of ‘no NEC’, and a baby with volvulus is a case of ‘NEC’ then we have to be very careful to interpret our databases. Precise definitions, quality control of data entry, secondary verification of critical diagnoses, are important to improve reliability. Secondly, even for cases that are not clearly errors, in a diagnosis such as NEC there is a lot of inter-rater variability (or you might call it subjectivity) in deciding whether an x-ray shows pneumatosis, or other findings consistent with stage 2 NEC. One of the things that has changed (relatively) recently is the appearance of abdominal ultrasound to try to help in management of the condition. We have had cases which never had pneumatosis on x-ray, but an abdominal ultrasound was reported as showing “pneumatosis”, they were then entered into our database as cases of NEC, despite the fact that strict application of case definitions in use at the time did not include ultrasound findings.  The newer version of the definitions we use  now states “or other imaging modality” which I think is a mistake.

A recent systematic review of the diagnostic accuracy of abdominal ultrasound for diagnosis of NEC has been published. (Cuna AC, et al. Bowel Ultrasound for the Diagnosis of Necrotizing Enterocolitis: A Meta-analysis. Ultrasound Q. 2018;34(3):113-8). As all systematic reviews/meta-analyses it suffers from the limitations of the primary publications, but it does give some guidance as to the likely usefulness of the technique. The systematic review found 6 prospective cohort studies, with 462  infants with suspected NEC who had both radiographs and ultrasound studies. For such studies you have to decide what is the “gold standard” which is of course staging as Bell’s stage 2 or more using radiography. I can’t think of  a way of getting around this at present, but the “gold standard” is more like a tarnished silvery coloured metal. The review showed that among infants with confirmed NEC, ultrasound was relatively insensitive for most findings (portal venous gas, pneumatosis, free air, bowel wall thickening, bowel wall thinning, absent peristalsis, ascites and focal fluid collection) but was reasonably specific, mostly over 95%. The exceptions being pneumatosis at about 90%, and for bowel wall thickening at 67%.

So among the babies in these studies, even when there was a clinical suspicion of possible NEC, 10% of the time when the ultrasound showed “pneumatosis” the baby did not have a final diagnosis of Bell’s stage 2 NEC. 1/3 of the babies with bowel thickening did not have NEC.  I have seen kids having an abdominal ultrasound for other reasons, and having no symptoms, being reported as showing pneumatosis. In contrast I am sure there are babies where pneumatosis is not clearly seen on radiography, but ultrasound suggests that it is there, who do really have NEC. What is the place of ultrasound then? I think there are data that show that many more babies with NEC will have portal venous gas on ultrasound than on x-ray, and I think that finding is probably a very good indicator that they really do have the disease. Free air is a pretty definite indication that something serious is wrong(!) but is obviously not restricted to NEC; ascites with lots of junk in the liquid (to use the technical terminology) is usually not a good thing to find. Colour doppler investigation of bowel perfusion might help in decision making, but you really need to be a bit sceptical, I have seen more than 1 infant have a laparotomy, partly based on analysis of bowel perfusion, who had healthy looking bowel when the surgeons opened, and closed again, his/her abdomen.  Of course that can also happen without ultrasound/doppler, knowing when the bowel is necrotic, and needs to be resected, is notoriously difficult.

A much better way of clinically confirming mucosal injury, and its severity, would be great. Unfortunately all the biomarkers that I have seen investigated (from memory that includes calprotectin, PAF-1, fatty acid binding proteins, various interleukins, neutrophil surface markers, and Something About Amyloid called SAA) have been of very limited value. A recent review article about calprotectin suggests that one reason for that is that NEC is not one single disease, it may also be that, in my humble opinion, most biomarkers are a waste of time, if they are sensitive enough to be useful they are not specific, and if they are specific enough to rule out other diseases they are not sensitive! (a much more thoughtful review of biomarkers for NEC is available) A prospective study from Groningen looking at the usefulness of serial calprotectin for predicting NEC showed that levels are very high in preterm babies just after birth, and then vary widely, not being useful for prediction of NEC.

And of course all of these studies suffer from almost never being sure that a baby actually has NEC! The closest we really get to a gold standard diagnosis is in those babies who have laparotomy and bowel resection with pathology. In less severe cases the diagnosis will often be surrounded by question marks. The study from Sweden confirms this again.

There are only a few ways an immature bowel, with highly abnormal microbiome, limited circulatory reserve and underdeveloped Paneth cells (to name a few issues) can respond to an insult. Blood in the stools, ileus, and pneumatosis can occur in other conditions than classical premie NEC, and other associated conditions must be eliminated. The baby with a strangulated internal hernia did very well after the surprise finding on surgery, followed by resection and repair. In contrast babies with severe NEC requiring surgery continue to have a very high mortality, with about 5% in many series never going to surgery and dying, and 20% to 40% dying after surgery.

Those numbers are one of the reasons this subject comes up so often on this blog, and that doesn’t even touch on the adverse effects of the serious inflammatory insult and the associated nutritional difficulties on brain development.

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Richard Ehrenkranz 1946-2018

I am very fortunate in many ways in my life, including having met, and become friends with, many of the greats of neonatology.

One of the those greats was Richard Ehrenkranz, a neonatologist who spent most of his professional life at Yale, and who was extremely productive. As a junior faculty, he worked with Laura Ment in the Yale neonatal neurology lab, and he became very interested in long term neurological and developmental outcomes of preterm infants.

He was a major part of the NICHD neonatal network, and helped the network become the force that it now is.

For the last 30 years or so he became the person to go to for evidence about the influence of nutrition of outcomes of extremely preterm babies. He used the NICHD neonatal database to show that nutrition in the first few weeks of life of the extremely preterm infant has lifelong impacts on how their brains develop.

He died this August, an obituary is here. His enormous contributions to the wellbeing of preterm babies can be seen here : https://www.ncbi.nlm.nih.gov/pubmed/?term=ehrenkanz+r

Thank you, Richard.

Good Bye.

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Mother’s milk is best, but how best to use it?

A survey of practices in Germany, Austria, and Switzerland (the German speaking part) demonstrates the range of practices for handling mother’s own breast milk in very preterm babies. Klotz D, et al. Handling of Breast Milk by Neonatal Units: Large Differences in Current Practices and Beliefs. Front Pediatr. 2018;6:235.

The authors wanted to know what the units did for CMV surveillance and inactivation, bacterial cultures and responses to cultures, and how they managed fortification. About half of the 300 or so units replied.

Most units performed some sort of maternal CMV screening, but 66% fed raw colostrum from sero-positive mothers for at least a couple of days. After that 58% performed some sort of CMV inactivation for milk from sero-positive mothers, either standard Holder pasteurization, high temperature short duration pasteurization, or freezing and thawing the milk, usually until about 32 weeks.

Nearly half of the units cultured the breast milk, and then either pasteurized it or threw it out based on bacteria found and bacterial counts; there were 30 different thresholds for those actions in the different units.

Fortification was individualized using breast milk analysis in only 16 units (5 of those in a trial, only 6 did it as a routine, the remainder in selected cases). Fortification was usually with commercial multi-component fortifiers, but additional use of protein was common, additional lipids and carbohydrates were also sometimes used.

Units started putting babies to the breast mostly at 32 weeks, sometimes at 33 or 34 weeks.

Practices in different parts of the world might well be very different to those in this survey, but the study pointed out to me how little we know about what we should really do about these issues. In some countries the national recommendation is to pasteurize all maternal breast milk before giving it to the most immature babies. Pasteurization inactivates CMV, and profoundly decreases bacterial counts, but has negative effects on several large proteins, including some of those which may be responsible for the advantages of maternal breast milk. Two trials comparing raw mothers milk to pasteurized mother’s milk (Stock K, et al. Pasteurization of breastmilk decreases the rate of postnatally acquired cytomegalovirus infections, but shows a nonsignificant trend to an increased rate of necrotizing enterocolitis in very preterm infants–a preliminary study. Breastfeeding medicine. 2015;10(2):113-7. A “before and after” study and Cossey V, et al. Pasteurization of Mother’s Own Milk for Preterm Infants Does Not Reduce the Incidence of Late-Onset Sepsis. Neonatology. 2012;103(3):170-6, a Randomized Controlled Trial) both show a trend to more complications if mothers’ breast milk is pasteurized.

Using mother’s own milk is an important factor in improving outcomes for very preterm babies, I think it is about time we knew how to do it.

What are the indications for pasteurizing mother’s own milk? How is it best done to be effective and have the fewest adverse impacts? For which babies do we need to adjust fortification, and is individual breast milk analysis significantly better than just adding more protein (or protein and fat, or…)? Does adding prebiotics improve outcomes? How can we normalize the development of the intestinal microbiome in addition to mother’s milk?

And,just as important:

How can we increase the percentage of mothers who commence breast milk production for their very preterm baby? How can we increase breast milk production over the long term? How can we increase the proportion of babies who go home receiving exclusively mother’s milk?

There are, fortunately, now many investigators around the world researching some of these issues (you can see a list of a selection of recent publications below; sorry I haven’t got time to put a URL attached to each one, but they are all listed in PubMed), but many important questions remain to be answered.

Parker LA, et al. Facilitating Early Breast Milk Expression in Mothers of Very Low Birth Weight Infants. MCN Am J Matern Child Nurs. 2018;43(2):105-10.
Romaine A, et al. Predictors of Prolonged Breast Milk Provision to Very Low Birth Weight Infants. The Journal of pediatrics. 2018.
Cuttini M, et al. Breastfeeding outcomes in European NICUs: impact of parental visiting policies. Archives of disease in childhood Fetal and neonatal edition. 2018.
Tshamala D, et al. Factors associated with infants receiving their mother’s own breast milk on discharge from hospital in a unit where pasteurised donor human milk is available. J Paediatr Child Health. 2018;54(9):1016-22.
Grzeskowiak LE, et al. Domperidone for increasing breast milk volume in mothers expressing breast milk for their preterm infants: a systematic review and meta-analysis. BJOG : an international journal of obstetrics and gynaecology. 2018;0(0).
Haiden N, et al. Comparison of bacterial counts in expressed breast milk following standard or strict infection control regimens in neonatal intensive care units: compliance of mothers does matter. J Hosp Infect. 2016;92(3):226-8.
Hannan KE, et al. Impact of NICU admission on Colorado-born late preterm infants: breastfeeding initiation, continuation and in-hospital breastfeeding practices. J Perinatol. 2018.
Kaya V, Aytekin A. Effects of pacifier use on transition to full breastfeeding and sucking skills in preterm infants: a randomised controlled trial. J Clin Nurs. 2017;26(13-14):2055-63.
Pannaraj PS, et al. Association Between Breast Milk Bacterial Communities and Establishment and Development of the Infant Gut Microbiome. JAMA Pediatr. 2017.
Heon M, et al. An Intervention to Promote Breast Milk Production in Mothers of Preterm Infants. West J Nurs Res. 2016;38(5):529-52.
Tully KP, et al. A Test of Kangaroo Care on Preterm Infant Breastfeeding. Journal of Obstetric, Gynecologic & Neonatal Nursing. 2016;45(1):45-61.
Peters MD, et al. Safe management of expressed breast milk: A systematic review. Women Birth. 2016;29(6):473-81.
da Cunha RDeS, et al. Breast milk supplementation and preterm infant development after hospital discharge: a randomized clinical trial. Jornal de Pediatria. 2016;92(2):136-42.
Belfort MB, et al. Breast Milk Feeding, Brain Development, and Neurocognitive Outcomes: A 7-Year Longitudinal Study in Infants Born at Less Than 30 Weeks’ Gestation. The Journal of pediatrics. 2016.
Kreissl A, et al. Human Milk Analyser shows that the lactation period affects protein levels in preterm breastmilk. Acta Paediatr. 2016;105(6):635-40.
Healy DB, et al. Structured promotion of breastmilk expression is associated with shortened hospitalisation for very preterm infants. Acta Paediatr. 2016;105(6):e252-6.
Post ED, et al. Milk production after preterm, late preterm and term delivery; effects of different breast pump suction patterns. J Perinatol. 2015.
Mörelius E, et al. A randomised trial of continuous skin-to-skin contact after preterm birth and the effects on salivary cortisol, parental stress, depression, and breastfeeding. Early Human Development. 2015;91(1):63-70.

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Surfactant by nebulisation

After the PAS meeting I blogged about a presented abstract of nebulized lucinactant, which showed a possible reduction in needing intubation among babies on CPAP who received the surfactant, compared to controls.

A new publication from Perth (Minocchieri S, et al. Nebulised surfactant to reduce severity of respiratory distress: a blinded, parallel, randomised controlled trial. Archives of disease in childhood Fetal and neonatal edition. 2018) reports a similar study, but using poractant and a different type of nebulizer. The authors randomized 64 babies, between 29 and 33 weeks gestation with HMD, to CPAP or to CPAP with the nebulizer placed between the bubble CPAP circuit and the face mask. Infants were eligible if less than 4 hours old, on CPAP of 5 to 8 cmH2O and needed some oxygen, but less than 30%. Treated infants received 200 mg/kg via nebulization, and 100mg/kg if they needed re-treating.

Despite the difficulties, this was done as a masked trial with the surfactant team behind a screen during the administration of surfactant (or equivalent period for the controls).

Failure of assigned treatment was determined by an increase in FiO2 to more than 35% for over 30 minutes, or over 40%, or a respiratory acidosis (CO2>65 and pH<7.2) or multiple apneas or if the physician got fed up (intubation “deemed necessary” but without the other criteria).

The need for intubation within 72 hours was reduced from 22/32 controls to 11/32 surfactant nebulizer babies. This was a short term pilot study, but seems again to show the potential benefit of this intervention, at least for the larger babies; among the babies in this trial, a subgroup analysis suggested benefit only in the more mature babies, but the study was underpowered for such analyses.

The only weird thing about the study is that is was performed between 2010 and 2012, it isn’t clear why it took 6 years to publish it after the end of the trial. I don’t know if that could be related to the fact that the first author has a patent with PARI pharma for the nebulizer.

Many of the intubations, especially of the smaller babies, were because of physician preference. With many of us now being more comfortable having babies on CPAP despite moderate respiratory distress (especially the 29 to 30 week gestation babies) physician preference might well be different if a similar study was redone.

None of the babies developed BPD or IVH or NEC, which makes one wonder, what is the benefit to the infants of avoiding intubation? If our outcomes for such babies are already excellent, is reducing the number or duration of intubation a significant advantage? I would say that in the short term there are advantages, to the baby and the family; intubation is associated with serious physiologic disturbance (and major pain unless you use good analgesia), multiple attempts are often required with increased risks, not likely to show up in a small pilot trial. Seeing a baby intubated rather than on CPAP is probably more stressful for the parents.

Also if we can prove efficacy in the larger early preterm babies, testing the intervention in the more immature babies, and intervening very early, would really be worth doing and may produce further benefits.

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