Plug the Lung Until it Grows: the FETO RCTs of antenatal diaphragmatic hernia intervention.

What was at one time called PLUG, and, with the change from open to endoscopic intervention, is now called FETO (fetal endoscopic tracheal occlusion) is a way to harness the normal physiology of the lung in congential diaphragmatic hernia (CDH) to improve lung growth and architecture in order to improve outcomes. Lung growth is partially dependent on the rhythmic increases in fetal intrapulmonary pressures which occur because of the active production of fetal lung liquid and intermittent breathing movements of the fetus associated with partial adduction of the vocal cords. Numerous fetal animal studies showed that interrupting this process (with phrenic nerve section or tracheotomy, for example) leads to pulmonary hypoplasia, while increasing the intrapulmonary pressures, by ligating the trachea, caused pulmonary hyperplasia. Finally animal models of diaphragmatic hernia followed by tracheal obstruction showed at least partial normalisation of lung growth. Interventional obstetricians and paediatric surgeons have attempted to temporarily obstruct the fetal trachea in some fetuses with CDH and very high predicted mortality. Initial attempts were apparently successful, but with a risk of preterm labour and delivery.

The improvements in technique and change to purely endoscopic approaches have led to lower complication rates (importantly prematurity), but it remained unclear whether, overall, survival was improved.

The recent publication of the results of 2 parallel trials in high-risk and moderate-risk patients has largely answered that question.

Deprest JA, et al. Randomized Trial of Fetal Surgery for Severe Left Diaphragmatic Hernia. N Engl J Med. 2021.
Deprest JA, et al. Randomized Trial of Fetal Surgery for Moderate Left Diaphragmatic Hernia. N Engl J Med. 2021.

This was a remarkable undertaking, a truly international collboration in a group of mothers carrying a fetus at extremely high risk of dying. And here, as an aside, I always feel a little uncomfortable with the way we talk about these interventions. Although it was indeed “fetal” surgery, there happens to be a woman in the way! Perhaps we should rather talk about “maternal-fetal” interventions. Even the pretty pictures below represent the mother just as an abdominal and uterine wall to be pierced…

As you can see from this summary, there was a dramatic improvement in survival. I do think it is important to emphasize that there is still a very high mortality of 60% in the treatment group; this is a terribly high risk group of babies. The eligibility criteria included a ratio of observed to expected lung-head ratio (O:E LHR) of less than 25%, predicting a mortality of about 82%, very close to the 85% actually seen in ther controls. The median age of delivery for the FETO babies was 34.6 weeks compared to 38.4 for the controls; this doesn’t sound like a huge difference, but 16 FETO babies delivered before 34 weeks compared to 0 controls, and 10 of them delivered before 32 weeks. Managing moderately preterm babies with CDH is very difficult. It seems likely that if we can find ways to prevent the rupture of membranes and preterm labour impacts of FETO, the benefits would be even greater.

The other trial was run in parallel, it enrolled mothers carrying a fetus with an observed lung to head ratio that was 25.0 to 34.9% of the expected, irrespective of liver position, or 35.0 to 44.9% with intrathoracic liver herniation. This was calculated to lead to a survival of 55% and sample size calculated for a 20% improvement.

The primary outcome was actually changed early on by the DSMC of the trial, which was initially designed with a primary outcome of BPD, or oxygen dependence at 28 days, with survival to discharge as a secondary outcome. I think the DSMC did exactly the right thing here, I don’t know who thought that 28 day oxygen requirement was important for infants with CDH, but to have given that priority over survival would have been a major problem. Perhaps that was initially chosen as the investigators are Obstetricians, not Neonatologists (he typed with tongue in cheek)?

Survival to discharge was higher in the FETO group, 62 of 98 treated compared to 49 of 98 controls, RR 1.27 (95%CI 0.99-1.63), as the confidence intervals for the RR just includes 1.0 the intervention was deemed not to show a significant benefit.

The impact on prematurity was very similar to the high-risk group trial, with the median gestational age at delivery being 2 weeks earlier with FETO than control, but both groups being about 2 weeks later than the other trial, that is 36 weeks for the FETO and 38 weeks for the controls. The relative risk and risk difference of being born before 37 weeks was very similar in the 2 studies.

Although this was a “moderate” risk trial, there was still a huge mortality of 50% in the controls (showing again that the O:E LHR is a reliable predictor of mortality), 20% of both groups required ECMO, and they had between 1 and 3 months of hospitalisation (average about 48 days in each group).

The division into “severe” and “moderate” risk groups (perhaps better termed “extreme” and “severe”) was completely arbitrary. A threshold of 25% O:E LHR could easily have been set to 30, or 31.5%. Such a threshold would have included more infants in the extreme trial, and I can guess would not have changed the result to a “non-significant” result.

In fact I don’t have to guess, because if these trials had been run as a single trial and included all the babies eligible for the two trials, with subgroups of extreme and severe risk, then the total survival to hospital discharge would have been 78 of 138 FETO babies and 55 of 138 controls; p=0.0081 (chi-square with Yates correction). In that case the conclusion would have been that FETO is beneficial for babies with an O:E LHR of < 35%, and for babies with intrathoracic liver with an O:E LHR of <45%, perhaps with a subgroup analysis showing a greater effect in the most severely affected fetuses.

It is evident that, at some point, the increased relative risk of prematurity (which was similar between the trials) will outweigh the benefit of the procedure, but we cannot from these data conclude that below a threshold of 25% O:E LHR, FETO is overall a beneficial intervention, but that above 25% it is not beneficial. Unfortunately, I think that is how the data will be interpreted. A secondary analysis of the overall survival benefits of FETO according to baseline O:E LHR needs to be performed, otherwise mothers carrying fetuses who would benefit will not be offered the intervention.

There are not many conditions in medicine for which a trial of 80 patients will show a dramatic and reliable difference in outcome between groups. The substantial benefits of this intervention for a profoundly serious condition mandate that all centres that have potential links to an experienced FETO centre should find a way to offer the intervention to mothers carrying an eligible fetus.

Currently, mothers who have had the procedue need to stay within reach of the FETO centre until the balloon is removed, for very good reasons. This creates limitations for many families, which may be insuperable, our FETO centre for example is 550 km away, for some mothers for other parts of the province it will be 2000 km away! Moving to live in Toronto for 8 weeks is not necessarily feasible for some mothers, especially as health care costs are all covered by our provinicial systems, but not daily living expenses. I wonder if we could create satellite centres who would develop the expertise required to remove or puncture the balloon in case of preterm labour, or routinely at 34 weeks, including the team, the equipment, and the protocols. Then a mother could travel to the FETO centre for the procedure, stay a couple of weeks in the region, and then return to be close to a satellite centre for the rest of the pregnancy. I have no relevant expertise in the interventions, but it seems to me that ultrasound guided balloon puncture is not that different to many of the interventions performed by our MFM specialists, at least compared to fetal bronchoscopy which seems to me to be a greater level of complexity.

Thank you to the mothers who were prepared to be randomised in this trial, which will have a major impact for many future babies. Your willingness to help others is enormously appreciated.

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What is critical in a “critical sample”?

It is common practice in the evaluation of neonatal hypoglycaemic episodes, especially if unusual or prolonged, to perform a “critical sample”. This is performed to rule out underlying metabolic or endocrine disorders. But what should the critical sample consist of?

I have looked at several recommednations, and there is great variability in what is included in such samples; it is near universal that a lab glucose, a serum cortisol, insulin and growth hormone are included, but after that there is little consensus.

One exception to those inclusions is the American Pediatric Endocrine Society, who are quite minimalist, recommending that the critical sample includes a glucose, bicarbonate, Beta-hydroxy-butyrate and a lactate. They further recommend that plasma be kept in reserve for further tests (and give the following as examples: plasma insulin, FFA, and C-peptide : total and free carnitine and acyl-carnitine), they don’t even overtly mention cortisol and growth hormone as part of the critical sample. Their recommendation is meant for screening for neonates but is also meant for older children, and it therefore ignores the relative incidence of the various causes of hypoglycaemia in the neonatal period. With substrate deficiency (transitional hypoglycaemia) and hyperinsulinaemia being much more common than other causes, and endocrine causes being next and relatively speaking fairly uncommon.

Beta-hydroxy-butyrate is recommended by many to be included in initial screen, it is the most commonly measured of the ketone bodies, and is depressed in hyperinsulinaemic infants, but is low also in infants with transitional hypoglycaemia, so is really only helpful as a flag for endocrine deficiencies and for the rarer glycogen storage diseases, where it is raised during hypoglycaemia.

Ketones, such as beta-hydroxy-butyrate, are increased during hypoglycaemia due to growth hormone or cortisol deficiency. The diagnosis of those entities is sometimes tricky, growth hormone secretion being pulsatile and the range of normal serum cortisol being wide. Often, also, when an infant has a critical sample performed because the bedside glucose is low, the lab glucose will be taken a few minutes later and often ends up being low normal, either because of the delay, and/or because bedside glucose is inaccurate and usually lower than the lab glucose. So, a serum cortisol which is on the low side of normal on a critical sample with a lab glucose of 2.8 (for example) what does that mean? Knowing that the ketones were high would be a good clue that further endocrine evaluation is required.

Ketones are also elevated in ketotic hypoglycaemia, which is one justification for measuring them in some guidelines, but it is not on the differential of neonatal hypoglycaemia, becoming important in older children.

Free Fatty Acids are also in many recommendations, and mainly serve to distinguish fatty acid oxidation defects, where they are elevated during hypoglycaemia despite low ketone bodies, the total incidence of all those disorders is probably about 1:10,000 births, but they are treatable, and picking them up when an infant is hypoglycaemic in the first few days of life is probably beneficial, and may well improve outcomes. I think we should keep them in our critical sample, but I don’t know the proportion of babies with fatty acid oxidationn defects who present with hypoglycaemia in the first few days of life, so diagnosing them from a critical sample is likely to be very uncommon.

Some recommend including a C-peptide measurement, with the idea that a high insulin with a low C-peptide is evidence of exogenous insulin administration. As that is an extremely unlikely scenario in the neonatal ward or NICU I think we can drop the C-peptide, (especially as some varieties of commercial insulin do not even register with some insulin assays). It is mostly paediatric endocrinologists who seem to want a C-peptide, and as part of the work-up of an older child it might be more relevant.

Many recommendations suggest growth hormone and cortisol estimation in the critical sample, and these seem to be the next most likely to lead to a diagnosis, after high insulin concentrations. Inappropriately low concentrations have led to a diagnosis in several babies I have seen over the last few years.

The Canadian Paediatric Society recommends obtaining a critical sample, but does not mention what should be measured in the sample. Others have suggested IGF binding protein-1 levels, without a good explanation why, and then several suggest other tests in later work up depending on the initial findings, including ammonia, urine organic acids and serum amino acids, triglycerides, carnitine and acylcarnitine profiles.

The volume of blood required is an issue for most blood sampling in the newborn, so I think the tests required for specific diagnosis of other rare conditions that rarely present with neonatal hypoglycaemia can be left out of the initial “critical sample”.

The other consideration is that you can get an idea whether a hypoglycaemic infant is hyper-insulinaemic from the amount of glucose that they are requiring. Those that require very high glucose intakes to remain normoglycaemic (more than 8 to 10 mg/kg/min) are likely to be hyper-insulinaemic. That includes a proportion of those who are Small for Gestational Age, or with birth asphyxia as well as infants of diabetic mothers or LGA infants. Of course the uncommon babies with congenital hyperinsulinism syndromes will fit this picture.

Putting all this together, I think the most appropriate critical sample when it is required; that is, unexplained, prolonged, or recurrent hypoglycaemia, should measure the following, and if blood volume is a problem, start with the first 2 items on the list and work down:



Serum Cortisol

Growth Hormone

Ketones (either Beta-Hydroxy-Butyrate or ketone bodies depending on your lab)

Free Fatty Acids

If you can get enough blood, then do a blood gas with bicarbonate and lactate concentrations.

After that, if you still don’t have an answer and hypoglycaemia is recurrent, a call to your helpful local paediatric endocrinologist would be a good idea!

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Two amazing trials, at the opposite ends of the spectrum. What a weird world.

In the most recent NEJM two trials impacting newborn/paediatric care. One including 3,211 preterm infants, which shows that a very simple intervention could save, I estimate, tens of thousands of lives each year at almost no cost; the other with 50 infants, of one of the highest tech interventions possible, and which could make life immeasurably better for a tiny number of children, but which will probably have an extremely high price tag.

The prosaic first study was a randomized trial in “five tertiary-level hospitals in Ghana, India, Malawi, Nigeria, and Tanzania. All live-born infants in the participating hospitals whose birth weight was between 1.0 and 1.799 kg, regardless of gestational age, type of delivery, or singleton or twin status, were eligible for inclusion” WHO Immediate KMC Study Group. Immediate “Kangaroo Mother Care” and Survival of Infants with Low Birth Weight. N Engl J Med. 2021;384(21):2028-38. This trial randomized the low birth weight infants to either standard care, which involved separation of the mother and baby, with the baby placed in an incubator or with a radiant heater for at least 24 hours with no kangaroo care, then once they started to recover, defined as “CPAP not required, SpO2 90-94% on low concentration of additional oxygen (FiO2 <30% by nasal prongs), Tolerating partial enteral feeds (maybe on partial IV fluids)”, at which point the mother “will come to the SCNU to provide brief sessions of KMC a few times a day”.

Once a control group baby was more stable, defined as “when the following criteria are met for at least a continuous period of 24-hours:
(i) Breathing spontaneously without additional oxygen, and oxygen saturation on room air >90%
(ii) No need for CPAP
(iii) Respiratory rate 40 to <60 breathes per minute
(iv) No apnoea
(v) Heart rate 80 to <180 beats per minute
(vi) Axillary temperature 36.0 to 37.4°C
(vii) No need for intravenous fluids”

they were transferred to the Mother-NICU, units which were specially renovated spaces where Kangaroo Care was facilitated. These standards for the control babies followed current WHO guidelines.

The Mother–NICUs “included mothers’ beds and reclining chairs, were built or converted from existing NICUs. All equipment, staff, and care provision in the Mother–NICUs remained the same as in the control NICUs. At two sites, completely new Mother–NICUs were built in a nearby location and the existing NICUs were retained as the control NICUs. At the other three sites, modifications were made to convert half the existing NICUs to Mother–NICUs, and the other half served as the control NICUs. Infants receiving kangaroo mother care were secured firmly to the mother’s chest with a binder that ensured a patent airway.”

Babies randomized to the intervention were admitted as soon as possible after birth to the Mother-NICU, being randomized either before birth or as soon as possible afterwards, with a mean age of enrollment of about 30 minutes. The goal was to have the babies in KC for 20 hours a day, by the mother or a designated female relative (fathers are not allowed in the majority of the units!) Each had a KC support person who ensured they had access to food and toilets (as did the surrogate) and had routine obstetric postnatal care. The same approaches to neonatal care were employed as in the controls. The countries involved were, clearly very poor; the mothers enrolled had an average monthly family income of about 170 US dollars, and they were in countries where per capita annual health expenditures were as low as 35$ in Malawi, up to about 80$ in other involved countries.

The 28-day mortality in the controls was 15.7%, which was reduced to 12.0% with the immediate kangaroo care intervention. The study was, in fact, stopped early because of the mortality benefit in the intervention group, with no evidence of any harmful effect. The relative risk of death was 0.75 with KC, 95% CI 0.64, 0.89.

Previous studies of KC in low-income countries have also shown a benefit in reducing mortality, the Cochrane review notes a 40% reduction in mortality, but most studies were started after the baby was “stabilised” and therefore excluded a large number of deaths, those occurring soon after birth.

This intervention has the possibility of dramatically decreasing neonatal mortality in low and middle-income countries (NNT=27) at almost no cost; there may be some initial costs related to the logistics, which will not be huge, but may need specific budgets assigned in countries with such low health care expenditures. India and Nigeria, two of the countries involved in this trial, have the highest numbers of neonatal deaths in the world, with a combined 800,000 annual deaths of babies <28 days, much of which is related to low birth weight.

At the absolute opposite end of the health care spectrum, and in the same issue of NEJM, it now looks like gene therapy can “cure” children with ADA deficiency Severe Combined Immunodeficiency (ADA-SCID). Kohn DB, et al. Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency. N Engl J Med. 2021. This is a disease with an incidence somewhere around 1 per million live births, with the Adenosine Deaminase enzyme being hypo- or non-functional, leading to serious life-threatening, life-shortening, immune deficiency. Some of the states in the USA perform universal screening for this disorder, not because it makes any sense to screen, but because of family advocacy. That is a side issue, but it explains why the average age of patients in the 3 studies, reported together here, is much lower in the USA than in the UK. It is easy to understand why parents wanted neonatal screening, diagnosis is usually delayed until after the first couple of serious infections; however, there was previously no treatment, and the extreme rarity of the condition made it a questionable part of the routine neonatal screen. In the last few years, enzyme replacement therapy has been available and has improved the quality of life of the affected infants, which makes screening a bit more reasonable. This new study shows that administering gene therapy can provide long term improvement in ADA levels, prolonged high-quality survival and cessation of enzyme replacement. The study was partially supported by a commercial enterprise, Orchard Therapeutics, but with major funding by the NIH and the English Medical Research Council and other foundations.

Forty-eight of the 50 children studied had a sustained increase in their ADA levels, and had clinical improvements in their immune function. It is an amazing advance for the tiny number of infants with this condition, with a good probability that their lives may be almost normal after the intervention.

But I worry about what this might cost, and if crowd-funding initiatives will be necessary to get treatment for affected children; the example of Werdnig-Hoffman, Spinal Muscular Atrophy, does not give one much hope.

I also fear that the annual budget expenditure for one case of ADA-SCID in a high-income country may be more than the entire costs needed to implement immediate kangaroo care across the whole of Malawi.

Unfortunately the world makes no sense.

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What do you think are meaningful long term outcomes for preterm infants? Give your opinion!

Annie Janvier is part of a group of collaborators who are trying to get multiple opinions about meaningful outcomes in preterm babies. It is part of a project being run by the Canadian Follow-up Network CNFUN, which is called Parent-EPIQ.

If you want to participate you can follow this link

Feel free to answer from wherever you are in the world, I just completed and it took less than 5 minutes.

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Which is worse; death or a low Bayley score? Comparing composite outcomes between groups, taking into account clinical priorities.

I keep harping on about this issue as I think we make a mistake in the design of our research studies when we include death and a much less important outcome in composite outcomes. For example in the STOP-BPD trial, the primary outcome “death or BPD at 36 weeks” was “not significantly different” between groups, but death before 36 weeks was somewhat lower in the steroid group than controls. There were more survivors to 36 weeks in the steroid group but exactly the same proportion of survivors with BPD in each group (65% vs 66%), therefore there were numerically more babies with BPD in the steroid group. Surely being alive with BPD is better than being dead! The distribution of moderate and severe BPD also favoured the steroid group, but that is not factored into the primary outcome analysis.

Methods exist for analyzing not only death, but the severity of the BPD, and giving a greater importance to death than to severe BPD, and lesser importance again to moderate BPD. Those methods can also take into account time to an event, so that, for example, a baby who no longer has oxygen at 6 months of age, is considered less severe than a baby who still needs oxygen at 12 months.

Death between 36 weeks and discharge is not better than death before 36 weeks, all deaths before discharge (there are very few after discharge in the first years of life) should be considered an equally adverse outcome, which is worse than surviving with BPD. Of course in adults, many of whom in cardiac research studies are even older than me, delaying death is a good thing to do, indeed it is the main aim of many interventions, preventing death is not an option! In newborn infants delaying death a few days or weeks is not necessarily a good outcome.

The problem of composite outcomes with differing clinical importance is not only a problem in neonatology, in cardiac research the outcomes often include death and hospitalisation for cardiac reasons, for example. In those studies the time to the adverse outcome may included in the analysis, and ways of comparing patients, so that a patient who dies is considered a worse outcome than one who survives but is hospitalised, and one who is hospitalised 2 years after intervention is considered a better outcome than one who is hospitalised after 2 weeks; also the time to a patient dying is clearly important.

As a result, ways of analysing composite outcomes that take into account the clinical importance of the outcome have been developed, in particular the Win Ratio. Patients are compared in pairs and if one has a longer survival than the other then the treatment they received is considered the winner, if the next pair has one patient dying and the other being hospitalised, then instead of a traditional analysis in which “death or hospitalisation” is the primary, and both patients are considered to have equivalently bad outcomes, in win ratio analysis the patient who survived despite being hospitalised is considered the winner, and their treament is given an extra point and so on.

When subjects are paired, by design, then the analysis is actually quite straightforward, if patients are not paired then you can compare every result from the treatment group to every result from the control group, and the analysis gets much more complicated, especially calculating the confidence intervals of the win ratio which seems to require heavy duty bootstrapping. One can also take into account stratification, and only compare within stratified groups.

I thought I would try this out on the recent data from the Inositol trial. The parts of the composite outcome at 2 years are dichotomous, death, yes or no, “NDI”, yes or no, so I did not need the primary data set to do this. In the Inositol group there were 60 deaths, who therefore were losers for all their comparisons to the control babies, except for comparisons with the 39 control babies who died, where there was no preference. Similarly the Inositol babies with “NDI” were winners when compared with the control deaths, but losers when compared to control baby survivors without “NDI”.

As there were 287 Inositol babies with known death or NDI outcomes, and 289 controls, there were 82,943 possible comparisons (which I evaluated one by one of course!!) The controls won 31,901 comparisons, Inositol won 29,171 comparisons and 21,871 comparisons were null. The win ratio therefore was 1.09. (to be honest Excel is very good at copying large ranges and if you know how to use relative and absolute cell addresses it is a bit laborious but not too difficult).

The calculation of the p-value is then not too complex, and using the formulae in the supplementary data of this article I calculated that z=2.45, which gives a p-value <0.01. (I hope I have calculated correctly), I tried to use an SAS program that was supplied to me, but never having used SAS before I have not yet been able to get it working, even though I downloaded SAS and followed some initial tutorials trying to learn it a bit (the things I do for my readers). The same source kindly sent me a program for calculating the 95% CI of the win ratio, but again I could not get it to work, so I used an approximate method from one of Pocock’s publications, which gave 1.02 and 1.17.

If you use the standard methods, as used in the publication, which give equal weight to death and “NDI” (which is mostly low Bayley scores), there is no significant difference between Inositol and control in the combined outcome. If you use the Win Ratio method, that takes account of the fact that being dead is worse than a low Bayley score, you find that the odds of any pair of patients having a better outcome if they were the one that got placebo was 1.09, with a 95% CI 1.02 to 1.17 (p<0.01).

That means you are significantly more likely to be a winner if you get placebo than if you got Inositol; using the same data that say there is no significant difference in “death or NDI”.

It has been said that, for the example of the SUPPORT trial, “does it really matter that the primary outcome variable was not statistically different? Everyone can read that the lower saturation group had more mortality”. My response is that, yes that is true for SUPPORT (even though, in fact, unadjusted comparisons of death using a chi-square, are not “significantly” different between groups), but in fact it is not true for the Inositol trial, that trial was suspended because of a manufacturing issue, and the unexpectedly higher mortality in the intervention group was not significantly greater at the time of evaluation of the primary outcome (50 in the inositol group and 33 in controls, chi-square with Yates’ correction=2.86, p=0.09). The trial also had more RoP in the treated group than the controls which made the combined outcome better in controls.

The great advantage of the win ratio method is that it can be used, as mentioned in the first paragraph, to give more importance to death than to severe BPD, and also more importance to severe BPD than to moderate BPD, etc. We could, preferably, include in a composite, outcomes that are more clinically important, such as numbers of rehospitalisations in the first 2 years, or duration of home oxygen therapy.

Sometimes parts of a composite may be difficult to prioritize, such as non-surgical NEC and severe BPD. Which is worse? They both have adverse long term impacts as well as short term morbidity, I guess that if we asked a group of parents the answers to that particular comparison would be mixed, so they could be given equal weight in the analysis

Trials are now being designed using methods such as this, and methods for sample size calculation have been published. (Redfors B, et al. The win ratio approach for composite endpoints: practical guidance based on previous experience. Eur Heart J. 2020;41(46):4391-9).

Other methods which can be used for composite outcomes which incorporate the clinical importance of the parts of the outcome are also available (Capodanno D, et al. Computing Methods for Composite Clinical Endpoints in Unprotected Left Main Coronary Artery Revascularization: A Post Hoc Analysis of the DELTA Registry. JACC Cardiovasc Interv. 2016;9(22):2280-8) such as the Weighted Composite Outcome method.

The time has surely come to design trials, especially those in which mortality is a potential outcome (the majority of neonatal ICU trials), using methods that take account of the clinical importance of the various outcomes that we are measuring. And to cease the methods that imply that death and BPD, or death and retinopathy, or death and low Bayley scores, are equivalent.

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Renal Function in the very immature preterm, what is a “normal” creatinine

The last time I blogged about this issue, there were a few comments from renal specialists which pointed out some limitations in my interpretation of the data. I defended myself admirably (it is my blog after all!) but I recognize that this is a complex issue.

Two new publications analyse serial serum creatinine in a cohort of preterm babies who all had multiple measures of creatinine concentrations. the first (Rios DR, et al. Creatinine filtration kinetics in critically Ill neonates. Pediatr Res. 2021;89(4):952-7) introduces the concept of creatinine filtration delay, with the idea that newborns have a delay before they start filtering creatinine of varying duration, being longest in the most immature infants. This is why creatinine concentrations take a while to fall and may indeed increase in the first few days of life.

I find this difficult to comprehend, if a baby is producing urine, then surely they must be filtering creatinine, even if GFR is very low (as it is immediately after birth) and tubular function is poor, I don’t think that there can be a selective delay in the filtration of creatinine. Perhaps they mean the term as a way of visualizing something else?

The idea I wrote about last time was that an increase in serum creatinine despite usual amounts of urine output may well be evidence of creatinine being reabsorbed in the tubules, one commenter noter that there is no reported mechanism for the reabsorption of creatinine, challenging that concept (that I must admit was not my idea, but the interpretation of a pediatric nephrologist of their data showing that creatinine clearance was lower than inulin clearance in the newborn rabbit, probably because of “back-leak of creatinine across leaky immature tubules“).

Around the time I posted that previous blog post, there was a publication from one of the commenters on the post (Askenazi D, et al. Acute changes in fluid status affect the incidence, associative clinical outcomes, and urine biomarker performance in premature infants with acute kidney injury. Pediatr Nephrol. 2016;31(5):843-51), which pointed out that infants lose extracellular fluid after birth, and the most immature babies lose the most weight after birth. This postnatal weight loss is due largely to a reduction in interstitial fluid, and thus to total body water. Creatinine is evenly distributed in all the body water compartments, therefore a reduction of total body water, without equivalent elimination of creatinine by the kidneys, will lead to an increase in serum creatinine concentrations.

I realize when re-examining the data from Rios et al, and their story of creatinine filtration delay, that they did not take into account the postnatal weight loss and, as the most immature babies have the highest extracellular fluid compartment (as much as 800 mL/kg, compared to about 400 at term), the impact of postnatal weight loss on serum creatinine concentrations is greatest among that group. I think it is most likely that the majority of the delay in the fall in serum creatinine is because of contraction of extracellular fluid and concentration of the creatinine while GFR is still low, rather than a delay in creatinine filtration.

I think this is an important part of the answer to the issues, Askenazi et al give a way of calculating an adjusted serum creatinine concentration accounting for the increased concentration due to weight loss. Which means, for example, that a small preterm baby who has a serum creatinine of 100 μmol/L at birth, the same as her mother, and then loses 13% of their body weight over the first 3 days and then has a re-measured serum creatinine of 120 μmol/L actually has a new adjusted serum creatinine of 100.5; If the baby weighs for example 1000g, and we assume a total body water, TBW, at birth of 800mL/kg then we can calculate the adjusted creatinine as 120 x (670/800) =100.5 (800 being the TBW in grams at birth and 670 being the TBW after loss of 130 g weight).

The total body creatinine, adjusted for weight loss, should be falling if renal function was “normal” to eventually arrive at a value which is appropriate for the size of the infant, but at least the adjustment for weight loss does give us a better indication of the real situation. Then we have to figure out why the adjusted serum creatinine is not falling, despite a urine output that has commenced.

This graph from Askenazi’s paper shows that this is a frequent finding in the very immature baby.

You can see that under 26 weeks, on average serum creatinine rises, but even the “fluid-adjusted” creatinine, taking into account weight loss, does not fall as you might expect; in more mature babies the “fluid adjusted” Serum Creatinine (FA-SCr) falls immediately after birth.

In this study there were 16 babies under 27 weeks of a total of 41 who had aute kidney injury according to the definition of an increase in serum creatinine of at least 27 micromol/L (0.3 mg/dl), 11 of them still had AKI by that definition when using adjusted creatinine values.

Of course, if there is glomerular filtration, creatinine is being filtered (I don’t think that creatinine filtration delay is a real thing) the Fluid-Adjusted Creatinine concentration will vary depending on the balance between GFR, and thus the creatinine clearance, and how much creatinine is being produced. Creatinine is produced by degradation of creatine, which is largely from muscle mass. So tiny preterm babies probably produce very little, but they also have very low GFR especially on day 1.

The other new study I mentioned is a study of 158 ELBW babies from Leuven, which modelled creatinine kinetics (van Donge T, et al. Characterizing dynamics of serum creatinine and creatinine clearance in extremely low birth weight neonates during the first 6 weeks of life. Pediatr Nephrol. 2021;36(3):649-59) and in their model they included a term for creatinine production which averaged 3.55 mg/day (SD 1.44) which is 31.4 μmol in modern units, the average weight of the babies was 820g, so a production of about 38 μmol/kg/d. (An adult produces somewhere around 160 μmol/kg/d).

These are the reference ranges they produced:

The model takes into account the fluid loss and reduction in total body water which leads to increased concentration in serum creatinine, the very low initial GFR, and the ongoing production of creatinine.

I think this is the best explanation of how all those factors interact, and gives reference ranges which can be used. It does use data from a group of babies of widely varying disease severity, some of whom were sick and at risk of kidney injury. However, their data did not seem to show an impact of inotropes, but did show a small impact of ibuprofen use.

How the use of these ranges helps in the definition of clinically important kidney injury will be important in the future. But it starts to explain to me the changes in serum creatinine in the very preterm.

For example: if creatinine clearance is as low as 0.2 mL/min on the first day of life, and an 820 g baby starts with a serum creatinine of 100 μmol/L, then they have a total body creatinine load of (0.820 x 0.8 (TBW) x 100)= 66 μmol. Filtering 0.2 mL/min means they filter 29 μmol of creatinine on day 1 while producing 31 μmol of creatinine, which would lead to an increase in total body creatinine load to 68 μmol, and if they lose 5% of their body weight (and 9% of their TBW) then their serum creatinine concentration will rise to 110 μmol/L.

A baby with a greater weight loss and a somewhat lower creatinine clearance will of course have a greater increase in their serum creatinine concentration..

I don’t know if you could use these data to try and back-calculate the creatinine clearance of an individual baby; then perhaps a certain lower limit of clearance could be used to define Acute Kidney Injury in the preterm. I do, however, think that these data clearly invalidate the definition of neonatal AKI as an increase in SCr of 27 μmol/L (0.3 mg/dL), and even using fluid adjusted SCr with that threshold. I think we need a new definition which is based around creatinine clearance which is lower than the gestational and postnatal age adjusted “normal”, or if that is too complex for routine use, then graphs such as those above with the addition of percentile lines may be enough for a working definition: a baby with a creatinine which rises too fast and crosses percentiles could be considered to have AKI.

I know I went a bit down the rabbit hole with this post, but I like understanding things, and when I don’t I get agitated and follow reference chains until I either get fed up or find a conclusion! I guess the take home message is that creatinine concentrations rise after birth, partially explained by postnatal weight loss, and also by low GFR, but we don’t have a good definition of AKI in the preterm infant.

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Longer-term outcomes: what should we measure? part 2

I have made my concerns about developmental screening tests including the Bayley clear over the years, including in the previous post, which might make what I am going to say now seem odd: I do not think we should stop screening for developmental delay in neonatal follow up!

The problem is not doing the Bayley evaluation, the problem is thinking of Bayley scores as a hard endpoint which diagnoses clinically important impairment.

The tests that we perform in follow up should be adjusted to our goals of follow up. If we wish to screen for developmental delay in order to offer intervention, then that is a worthwhile goal, and performing a test early will identify more babies with low scores, so an 18-month test might be reasonable. Brett Manley and a group of CAP investigators analysed the factors which were associated with an improvement in test scores from 18 month Bayley version 2 scores to an IQ test at 5 years; we found that the major factor associated with having an improvement was the socio-economic environment. Identifying infants at 18 months of age who have delayed development and who are also socio-economically deprived identifies a group of children at high risk of lower IQ scores, and probably therefore of difficulties at school, who could well benefit from early intervention programs, while those who are socially and economically advantaged will usually get higher scores anyway in the future.

On the other hand, if we want to predict later impairment, the predictive value of Bayley scores for later intellectual difficulties is poor, especially at 18 months. The screening tests become more useful with age, but even at 30 months they (at least the Bayley version 3) only correctly identify around about 50% of infants. The table below (from the EXPRESS cohort) shows that, if defined as moderately “disabled” at 30 months of age, which in 2/3 of the cases was as a result of a moderately low Bayley 3 score, 44% of the infants were moderately or severely disabled at 6.5 years, again, mostly because of low cognitive scores, (using the WISC-IV).

You can also see from the table, that infants with no disability at 30 months still sometimes had moderate or even severe disability at 6.5 years (Serenius F, et al. Neurodevelopmental Outcomes Among Extremely Preterm Infants 6.5 Years After Active Perinatal Care in Sweden. JAMA Pediatr. 2016)

Ideally, a follow-up program should be able to identify infants that will benefit from therapy as well as to determine the outcomes of our neonatal interventions. If 2 arms of study have the same survival, then examining other aspects of the outcomes becomes of interest. Outcomes that affect the function of the child and their family are the ones we should focus on; and the rare infant with a significantly reduced quality of life, if different between arms of a study would also be valuable information. The newer versions of the Bayley scores include an evaluation of function, which in the Bayley version 4 is derived from the Vineland Adaptive Behaviour Scales, a well-supported scale for analysing function.

Outcomes of neonatal trials should be considered in a hierarchical fashion. As almost all survivors have an acceptable, good or excellent quality of life, survival should always be the primary outcome. The second level of the hierarchy should be impairments and clinical difficulties which affect function: disabling CP, blindness, gastrostomy feeding, recurrent hospital admissions, medical instrumentation at home, disruptive behaviour problems. The third level of the hierarchy should be things that affect function little but would be preferable to avoid: chronic medication use, developmental delay, need for physiotherapy. You may notice that I haven’t put in this schema intellectual limitations and learning difficulties, because I do not know where they should go, I think different families, would probably score them differently and different severities of those problems might put them in the 2nd or third priority group.

Ways of analysing trials that prioritize adverse outcomes in that way have been developed, and could be much more useful in deciding between therapeutic approaches than “death or NDI”. I have blogged about this previously, the “win ratio” where results are compared between groups with prioritized outcomes, so death is the worst outcome, survival with serious long term problems is next, and survival with moderately severe problems is next. By comparing the number of winners in the comparisons, Pocock SJ, et al. The win ratio: a new approach to the analysis of composite endpoints in clinical trials based on clinical priorities. European Heart Journal. 2012;33(2):176-82 you can analyse statistically which of two groups have the better outcome.

This is not just a theoretical methodology, there are now several trials, mostly in Cardiology, that have used the win ratio as a way to take into account death as well as non-fatal complications as part of a composite outcome, where death is the most important outcome, but others such as hospitalisation for cardiac events, are given secondary importance. (Redfors B, et al. The win ratio approach for composite endpoints: practical guidance based on previous experience. Eur Heart J. 2020;41(46):4391-9).

There are also logistical reasons for continuing to perform developmental screening tests at around 2 years, keeping infants in a follow-up program needs frequent contact, and waiting until a child has reached 5 years of age, risks losing many more children and decreasing the confidence in the results, funding for trials which can’t report their outcomes for 7 or 8 years is tricky. The CAP trial was for example funded initially for 18-month outcomes, and then repeated grant applications to extend follow up were required, and successfully obtained by Barbara Schmidt and her collaborators.

Finally, I have a question for my readers; is there any trial that has shown no difference in developmental outcomes at 2 years between two groups that has then found an important difference in neurological/intellectual/learning outcomes later on?

If the answer is no, and I can’t think of such a trial currently, them perhaps continuing to evaluate and report on developmental delay at around 2 years of age is reasonable, not as a hard endpoint of any clinical significance, but as a sort of a screen to decide which trials should then get funding for 5 or 6-year outcomes. Studies showing no difference in neurological impairment or developmental delay at around 2 years may be extremely unlikely to show a difference later; while those that show a difference could then be funded to examine clinically important outcomes and outcomes important to families at around 5 or 6 years of age. I think that the analysis of the 2 years outcomes should prioritize survival as the most important of the outcomes, and then as second priority neurological impairments (which are more likely to be long-term problems for the child) and then as third priority developmental delay, that analysis could be done using the win ratio method.

At later follow up we could measure outcomes which have an importance to families at 5 or 6 years, such as indicators of good health, behaviour problems, feeding difficulties, and those which could lead to adjustments in the way they are taught, such as measures of IQ and executive function.

Indeed we should be doing more research to find out which outcomes matter most to parents, such as the studies that Annie Janvier and her collaborators are doing.

Below is a youtube video of a webinar that Annie gave about the outcomes that parents care about, and about her on-going research on the topic.

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Longer term outcomes; what should we measure? part 1.

Many important trials include follow-up to about 2 years in order to ascertain longer-term effects. Such as this one:

Adams-Chapman I, et al. Neurodevelopmental outcome of preterm infants enrolled in myo-inositol randomized controlled trial. J Perinatol. 2021. Ira Adams-Chapman was one of our fellows when I was in San Diego; a wonderful gentle person, who would nevertheless stand up for herself, and for what she thought was right for her patients. I was never able to publish the study in piglets that we did together during her fellowship, as there were several technical issues that we couldn’t correct, but that didn’t stop her (or maybe even helped her!) becoming an important part of the neonatal world. After graduating from our program, she developed her research career in the follow-up arm of the NICHD network. I kept intermittent contact with her over the years, and remember a very pleasant breakfast in Atlanta when I visited a few years ago.

I was stunned to hear that she died towards the end of last year, far too young, having been predeceased by her husband, also far too young.

I mention this because I was pleased to see that, despite being unable to sign off on the manuscript which was submitted shortly after her untimely demise, she is still listed as the first author. I am sure that represents her contribution to this article, and to the high-quality work it represents.

The study is a report of the longer-term outcomes of infants enrolled in a trial of prophylaxis with myo-inositol for retinopathy prevention. Phelps DL, et al. Effects of myo-inositol on type 1 retinopathy of prematurity among preterm infants <28 weeks’ gestational age: A randomized clinical trial. JAMA. 2018;320(16):1649-58. At 2 years of age survivors were examined with the usual panoply of neonatal tests.

The new article notes that there was no difference in the composite outcome of “death or NDI” at 2 years corrected age mong survivors (95% of whom were evaluated; great work!) Which might suggest that either giving inositol or not were equally valid choices. But hang on, mortality was quite a bit higher in the inositol group, 20%, than the controls, 13%. The relative risk of dying was 1.53 (95% confidence intervals 1.08–2.18).

49% in each group of those followed up had neurological impairment or developmental delay (NIDD I will call it) and the summed outcome of NIDD or death was 60% (inositol) vs 56% among controls. As usual, infants with Bayley motor or cognitive scores <85 were the majority of those that had what they call “NDI”.

These results are a perfect example of why we should NOT be using “death or NDI” as the outcome for clinical trials.

More of the control babies survived, but the proportion of survivors with “NDI” was identical in the 2 groups, there were, therefore, numerically, more survivors with “NDI” in the control group, because there were more survivors!

When you then calculate the proportion of survivors without NIDD in the 2 groups, there is no “statistically significant” difference. Here is what that means for this study; in the Inositol group there were 62 deaths, and 14 babies not followed up, among the 289 babies with 2-year outcomes there were 112 with NIDD. In the control group, there were 39 deaths, and 14 babies not followed up, so among the 289 babies with 2-year follow up there were 122 infants with NIDD. This is my graphic of those results, the vertical axis being the absolute numbers of subjects.

If you were to choose betwen treatment 1 and treatment 2, with substantially more deaths in group 2, and exactly the same proportion of infants with low Bayley scores among survivors, I bet there are not many who would choose treatment 2!

But the abstract of the article just notes: “Treatment group did not affect the risk for the composite outcome of death or survival with moderate/severe NDI (60% vs 56%, p = 0.40)” which suggests that the results are equivalent and that it doesn’t matter which treatment you choose, but which is entirely the wrong interpretation of these data.

For this particuar trial we do have the intial study report which noted that “death or RoP” was more frequent in the inositol group; but other trials may have “death or NDI” as the primary outcome, and many people would read no further than the abstract noting no difference in the outcomes.

From a strictly scientific point of view, one should not change the primary outcome after the data are in; so from that point of view, if the initial plan for the analysis was to compare “death or NDI” between groups, then that is what should be published, and the results as published are accurate. But, from the perspective of someone wanting to determine the best treatment choice for a baby, this is totally wrong; dying and having a low Bayley score are in no way equivalent. The analysis plan should take that into account, giving much more weight to survival than the results of screening tests for developmental delay.

Are there any outcomes that can be balanced against survival? The few studies that have asked this of parents note that they generally think that survival with impairments so profound that the child is unable to communicate would be a category equivalent to mortality. Such outcomes are so rare in the NICU that they will likely never balance differences in survival.

The same considerations apply to any screening test for developmental delay, not just the Bayley; but also to neurological impairment, even if likely to be permanen. Is cerebral palsy with a GMFCS of 3 equivalent to being dead? Is blindness equivalent to being dead? Surely, if they are not equivalent we should design our studies and our analyses to acknowledge that.

Children with impairments have lives that are worth living, and enrich the lives of those around them, despite the major challenges they also bring. I was reminded of this, and also of how bad we are in predicting whether a child will not be able to communicate, when I recently watched this video from ‘Britain’s got talent”

I love that song and that performance. Valuing children (and adults) for who they are regardless of their impairments is the moral of that wonderful anthem. If you only have time to watch the song, it starts at 2:20.

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More thoughts about what to de-adopt

My post about de-adopting certain investigations or procedures in the NICU got a lot of suggestions and responses. Here are a few, either from the comments section or from Twitter. We should de-adopt the following:

  1. Dopamine. This is a suggestion that I have a lot of sympathy with, the 2 major actions of dopamine in the newborn are to cause vasoconstriction and to suppress the pituitary. I don’t think that vasoconstriction is often what we want when we initiate cardiovascular support. All the studies of dopamine with analysis of haemodynamics have shown that if you give enough dopamine to increase blood pressure then you decrease cardiac output. In the occasional baby with vasodilated shock, a vasoconstrictor might be useful, but other agents may be more effective. Dopamine suppresses release of TSH and thus thyroxine, also suppresses prolactin and growth hormone, these actions are probably not beneficial and are not shared by other catecholamines. (Dopamine also suppresses respiratory drive and is associated with an increase in nosocomial sepsis.)
  2. Supra-systemic hypertension to reverse the shunt in PPHN. This is related to the first issue, an older idea about how to improve oxygenation in PPHN was to push the systemic pressures higher than the pulmonary artery pressures. Dopamine, which was for a while almost the only vasopressor that neonatologists used, was shown to cause vasoconstriction in the systemic and pulmonary circulations. A study by Willa Drummond in lambs noted that when extremely high doses of dopamine were given, systemic vasoconstriction exceeded pulmonary (at 270 microg/kg/min), she reported using dopamine in human newborns at 20 to 125 microg/kg/min. The extreme vasoconstriction with such doses impairs myocardial function. A balanced approach, supporting the systemic circulation where necessary without excessive vasoconstriction, and dilating the pulmonary arteriolar bed if needed, makes much more sense.
  3. Hi-FLo. I think that High Flow Nasal Cannulae are overused, and there are some suggestions that centres that have adopted widespread use of Hi-flo have more BPD. Because they are comfortable and well-tolerated by babies and parents I think they tend to get weaned less aggressively, which might lead to more BPD diagnoses. However, I do think that nasal injury is important, and patient comfort and parental wishes are important, so I would say a partial de-adoption, rather than complete, is more reasonable, and don’t forget to wean them whenever you can.
  4. Gentamicin levels after the 2nd or 3rd dose. We have already done this, gentamicin levels in our NICU are only ordered if the gentamicin is continued after 36 or 48 hours, so usually only when the cultures are positive. Which doesn’t happen very often. I also agree that trough concentrations are not very predictive of anything. Vancomycin levels are a similar issue, poorly predictive of either efficacy or toxicity. I think we do many of these levels for medico-legal concerns rather than to help our babies.
  5. Sodium Bicarbonate. I absolutely agree, I have prescribed Bicarbonate once in the last 25 years, when I was being pushed to do so by a cardiologist, I re-reviewed all the data I could find after that, and I won’t be doing it again.
  6. Treating all PDA, or even doing the echo to diagnose them. The example in the tweet regarding echos was an infant on 21%, tolerating feeds and urinating well. This is such a complex issue that I will post something about it soon, in particular in response to a new publication from Montreal. But I certainly agree that many PDAs don’t need to be treated, the question is: which ones?
  7. Checking residuals and stool guiac. Checking residuals can be done away with without any adverse consequences. Routine stool blood testing should also be thrown out, occasionally if you are not sure that there is blood present or not, then maybe confirmation with an occult blood test might be helpful, but if you need the test there can’t be much blood there!
  8. Spironolactone (my own addition). I don’t think there is any indication for the use of this drug in the neonatal period. See my recent post on medication use in BPD.
  9. Long term diuretics to prevent or treat BPD (also my addition). No evidence of benefit, substantial evidence of harm.

And one suggestion from Gil Wernovsky on LinkedIn

Using the term “Pulmonary Hypertension” in isolation. Should always be qualified with 1. Elevated PVR 2. Low PVR with elevated PA pressure due to intrasvascular communcation. As Gil notes, sometimes we end up treating babies with high flow/low PVR pulmonary hypertension with pulmonary vasodilators, which is usually a big mistake! I agree with this: treatment of pulmonary hypertension should always take into account the pathogenesis and the haemodynamics. Discuss it with the cardiologist (just don’t give them bicarbonate; at least not the baby, a bit of oral bicarbonate for the cardiologist might help his dyspepsia).

Also this was a question rather than a suggested addition

Milk thickeners for reflux. There is very little good neonatal data about this, we know that some thickeners (or perhaps just one) have been associated with NEC, specifically Xantham Gum. So avoid that completely. Other thickeners may be safe, that is not clear, but they probably do have some effect in reducing the number of regurgitation episodes, and perhaps the overall duration of acid reflux on pH study. I would say milk thickeners in any baby at risk of NEC should be de-adopted. For infants past term who have major regurgitation and no other risk factor for NEC (not a gastroschisis or congenital heart disease baby) they might be safe and reduce the number of regurgitations. (see Cochrane review)

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Medication use in babies with bronchopulmonary dysplasia

A few recent studies have noted the marked variability between sites in the use of medications in preterm infants with BPD.

Nelin TD, et al. The association between diuretic class exposures and enteral electrolyte use in infants developing grade 2 or 3 bronchopulmonary dysplasia in United States children’s hospitals. J Perinatol. 2021.
Bamat NA, et al. Loop Diuretics in Severe Bronchopulmonary Dysplasia: Cumulative Use and Associations with Mortality and Age at Discharge. J Pediatr. 2020.
Greenberg JM, et al. Respiratory medication use in extremely premature (<29 weeks) infants during initial NICU hospitalization: Results from the prematurity and respiratory outcomes program. Pediatr Pulmonol. 2020;55(2):360-8.
Tan C, et al. Diuretic use in infants with developing or established chronic lung disease: A practice looking for evidence. J Paediatr Child Health. 2020;56(8):1189-93.

The first 3 of these studies are multi-institutional observations, the 4th being from a single centre. Variations in medication use and in particular the use of diuretics are enormous, some centres seem to treat almost all of their babies with loop diuretics, while in others such use is limited. In my centre chronic diuretic use is quite unusual, while intermittent brief courses may be tried in a small percentage of babies.

Why such variation? One of the usual explanations for such variation is an absence of a strong evidence base; so what is the evidence for diuretic use for the prevention or treatment of BPD?

Diuretics were first tried I think because the early phases of BPD show interstitial oedema; so why not use a diuretic? The few mechanistic studies that were performed showed an improvement in some measures of lung mechanics, but little or no effect on gas exchange. One controlled trial of prolonged use in infants with BPD on non-invasive O2 therapy showed some decrease in FiO2, but no decrease in the duration of O2 therapy, and no residual effect after the furosemide was stopped.

Interestingly lung mechanics changes have also been shown in anephric dogs, the ion pump which is inhibited by the loop diuretics (NaK2CL co-transport) is present on the luminal surface of the thick ascending limb of the Loop of Henle. furosemide also inhibits chloride transport in the lungs, which may be relevant to its effects, especially in dogs without kidneys, the mechanism is probably related to Cl Na co-transport. There is a disconnect between diuresis and effects on pulmonary mechanics, for example, inhaled furosemide can improve compliance and resistance in infants with BPD, but without causing a diuresis. Another placebo-controlled study showed effective improvement in lung mechanics with alternate day furosemide, without an overall increase in urine output.

Improving mechanics of course is not really what I want when I prescribe a medication, I want to improve clinical status and clinical outcomes. There is little or no evidence that diuretics of any kind do this. The Cochrane review of loop diuretics in BPD found 6 trials (all furosemide) and no evidence of impact on clinically important outcomes (which weren’t reported in most trials). The Cochrane review of thiazides in BPD (both reviews are authored by Luc Brion, and were last updated in 2011, but I am not aware of any new trials) also showed in six trials no clinically significant effect. The only exception being the RCT of thiazides in intubated babies with BPD which showed less mortality with thiazides, but that trial only included 34 babies, the 15 controls were all boys except one, and with a higher pip and mean airway pressure than the 19 diuretic babies (8 females), therefore a significant chance of a type 1 error.

As a reminder to everyone, the Neonatal Cochrane reviews are all available at the Vermont Oxford Webisite, free of charge for anyone.

What do these new publications say? The first, Nelin et al shows that babies on any diuretic also often receive mineral supplements and that babies on thiazides were more likely to receive them than babies on loop diuretics. That to me is entirely expected, thiazides often lead to hyponatraemia, whereas it is less frequent with furosemide. Chronic thiazide use often is accompanied by chronic sodium supplementation, which is a questionable combination, as you are using the diuretics because they cause natriuresis! Pushing sodium out by the kidneys and simultaneously supplementing it enterally makes little sense. Loop diuretics, however, cause more of a reduction in total body fluid, so less dilution of serum sodium. The study also calls into question the concurrent use of potassium-sparing diuretics, as babies receiving them in addition to thiazides (the most common use in this trial) were just as likely to receive potassium supplements. Again that should be of no surprise, spironolactone does not affect thiazide-induced potassium loss in the newborn infant. An RCT from 2000 showed that adding spironolactone to a thiazide had no additional benefit on lung mechanics, and did NOT spare potassium. Just as many babies received K supplements, and serum potassium was identical with and without spironolactone. As far as I can see, that study is the only scientific data that exists about the value of adding spironolactone to a thiazide, i.e. there is no value.

The second publication, Bamat et al showed, not for the first time, that loop diuretic use is extremely variable, and that the variability is explained by which hospital you are in, rather than the severity of your lung disease. The study examined data from infants with grade 2 or 3 BPD and showed that infants from hospitals that used a lot of loop diuretics did not get home any sooner, (PMA at discharge was around 47 weeks, showing these were quite sick babies) but were more likely to go home on diuretics. The hospitals ranged from use of loop diuretics on 8% of the days between birth and discharge among infants with moderate and severe BPD to 50%.

The third in my list , Greenberg et al is a prospective multicentre cohort of infants born between 23 and <29 weeks gestation, which produced this pretty figure :

Of note, this study was not solely babies with BPD, but nevertheless by 5 weeks of age half of the babies are on furosemide. Also, from the supplemental data, 45% of the babies who did not develop BPD had received furosemide before they reached 40 weeks.

The last of these studies (Tan et al) is a single centre publication from Monash and deals mostly with the thiazide/spironolactone combination. As a single centre study they were able to give some more data pre and post diuretics, which showed that 84% became hyponatraemic and 12% hypokalaemic after diuretics, which did not significantly improve gas exchange but did lead to a slow down in weight gain.

None of this is new. Slaughter JL, et al. Variation in the use of diuretic therapy for infants with bronchopulmonary dysplasia. Pediatrics. 2013;131(4):716-23.Laughon MM, et al. Diuretic exposure in premature infants from 1997 to 2011. Am J Perinatol. 2015;32(1):49-56. Our use of these medications, in particular, the diuretics, is non-evidence-based, extremely variable, off-label, and somewhat irrational.

We should do the following:

  1. Stop all use of spironolactone in the newborn. It does not improve electrolyte status, does not spare potassium, does not add to diuretic effects of thiazides, and has adverse effects, in particular blocking androgen receptors, but also with reports of thrombocytopaenia and agranulocytosis.
  2. Stop routine use of diuretics to prevent or treat BPD. There is no evidence that diuretics reduce the incidence of BPD, and no evidence of clinically important benefits in treatment.
  3. Stop prolonged use of diuretics to prevent or treat BPD. Prolonged use leads to serious electrolyte disturbance, not to mention nephrocalcinosis and bone demineralization, metabolic alkalosis and chloride depletion.
  4. Perform prospective controlled studies to determine potential indications for diuretic use and the balance of risks and benefits. The lack of clinical impact when comparing widespread to restricted diuretic use in these observational studies is clear evidence that equipoise should exist, and clinical trials are essential for these widely used agents.
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