Hydrocortisone, with backup dexamethasone, to prevent Bronchopulmonary Dysplasia

Posted on 28 March 2022 by Keith Barrington

A trial that has been awaited for a while has just been published (Watterberg KL, et al. Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia. N Engl J Med. 2022;386(12):1121-31). It was a multi-centre RCT of hydrocortisone in 800 very preterm babies at elevated risk of developing chronic lung disease. Eligibility criteria were a GA at birth of <30 weeks, being intubated for more than 7 days, and still receiving invasive assisted ventilation at 14 to 28 days postnatal age. They had not previously received steroids for lung disease (it seems that a short prior course of steroids for other indications was acceptable according to the protocol, but many exclusions were of babies who had previous short course steroids). The study was performed with 2 primary outcomes, a short term outcome of “BPD or death”, BPD being defined as “moderate or severe BPD”, that is, needing oxygen or positive pressure ventilatory assistance at 36 weeks PostMenstrual Age.

The long term primary outcome was “NDI or death” NDI being a BayleyIII cognitive or motor composite <85, cerebral palsy with a GMFCS of >1, blindness or deafness.

The intervention was hydrocortisone at a starting dose of 4 mg/kg/day (iv or enterally) and weaned over a total of 10 days or placebo. The intervention also included the possible use of open-label dexamethasone (DEXA), in either group, at least 4 days after the hydrocortisone was stopped.

The relevant section of the protocol reads as follows : Infants who remain successfully extubated are not to be treated with open-label glucocorticoids as therapy for BPD. This will be a protocol violation. (ii) Infants who are not extubated during the study treatment period or who are subsequently re-intubated may be treated with open-label dexamethasone after ≥ 4 days following the last dose of study drug. Open-label dexamethasone will be encouraged to be prescribed as described by Doyle.

Forty per cent in each group received DEXA. Those who received DEXA got a median of 10 days treatment. There were another 15% of babies who received non-study systemic steroids (presumably mostly DEXA) during the “14 day study period”, that is, the 10 days of hydrocortisone and the 4 days delay before DEXA was allowed by protocol, therefore they were protocol violations; the proportion was similar in the 2 groups, 14% of the hydrocortisone group, 16% placebo. Its not clear how many of the protocol violation babies also received open-label DEXA by protocol, and there is likely to be some overlap, but probably around 50% or more of each group received a course of DEXA.

At 36 weeks there was a small survival advantage to the hydrocortisone group (mortality 4.8% compared to 7% in controls) but this difference was even smaller by discharge (8.8% vs 10%).

The babies in the hydrocortisone group were more likely to be extubated during that 14 day study period, but, as you can see from the overall results above, this did not lead to a lower proportion of babies with “moderate to severe” BPD.

I put the “moderate to severe” in quotations as, of course, this is what in the past was just referred to BPD. Is this the outcome we should be focusing on, in large important trials like this?

There is little correlation between having a 36 week diagnosis of BPD and longer term respiratory problems, in one study from the CNN and CNFUN (Isayama T, et al. Revisiting the Definition of Bronchopulmonary Dysplasia: Effect of Changing Panoply of Respiratory Support for Preterm Neonates. JAMA Pediatr. 2017;171(3):271-9), only 10% of babies with this as a diagnosis had “serious respiratory morbidity” after discharge, which was defined as “either (1) 3 or more rehospitalizations after NICU discharge owing to respiratory problems (infectious or noninfectious); (2) having a tracheostomy; (3) using respiratory monitoring or support devices at home such as an apnea monitor or pulse oximeter; and (4) being on home oxygen or continuous positive airway pressure at the time of assessment between 18 and 21 months corrected age.” That does seem like fairly serious respiratory morbidity, and having oxygen or respiratory support at 40 weeks led to 16% of the babies having this outcome, rather than 10% at 36 weeks. The 3 or more hospitalisations was used in this definition based on it being the 95th percentile, which I think is not the best way to define “adverse respiratory outcome”, wouldn’t it be better to ask parents what they think is an adverse respiratory outcome, and use that to determine how much impact postdischarge respiratory morbidity has on a family?

To return to the new trial publication, the neurological and developmental outcomes at 2 years corrected age were very similar between the groups, the supplementary data file has this table:

In other words, slightly better cognitive outcomes with hydrocortisone, slightly better motor outcomes with placebo, but no convincing difference in either, and all compatible with random variability.

The average GA of the babies was just under 25 weeks, and the stratum of babies 22 to 26 weeks GA had a similar primary outcome (i.e. no real difference) to the more mature babies. The mean oxygen requirement at enrolment was 50%, even though there was no minimum FiO2 requirement for eligibility. The high mean FiO2 at enrolment suggests to me that those babies who were considered close to extubation, perhaps on low settings and close to 21% oxygen, may not have been enrolled.

The study is therefore a comparison of hydrocortisone with backup dexamethasone, to placebo with backup dexamethasone, in a very high risk group of babies. It would be interesting to see the long term outcomes of babies who did not receive dexamethasone in the two groups, such a comparison might help to reassure that hydrocortisone used like this is safe. As it is, the very frequent treatment with DEXA in both groups may have diminished the ability to find a long term negative (or positive) impact of hydrocortisone, as well as dramatically diluting any potential advantage of hydrocortisone on lung injury.

Comparing this trial to the previous trial which is the most similar, STOP-BPD, in that trial the steroid dose was slightly higher to start with (5 mg/kg) and continued for twice as long (22 days total),was started earlier (7 to 14 days), and had more restrictive entry criteria (respiratory index by the end of the study (MAP x FiO2) >2.5). You will remember that the entry criteria were modified during the performance of that trial, as many babies who had a respiratory index which was not high enough to satisfy the initial entry criterion (>4.5) were being treated with hydrocortisone outside of the trial. 2.5 means 25% oxygen with a mean airway pressure of 10, for example. But in fact the babies were not as sick as those in the new trial, the average respiratory index at enrolment was around 4, in the new NICHD trial it was over 5.5. (The methods of calculation are slightly different, either using FiO2 as a fraction or as a percentage, so just multiply or divide by a hundred).

In STOP-BPD, rescue steroid use was with open-label hydrocortisone, rather than with DEXA, and was also very frequent, but, in contrast to the new trial, there was a big difference in rescue steroid use between groups, 28% in the active treatment group, 57% in the placebo group.

That study also had neurodevelopmental follow up at 2 years corrected age. The trends all were in favour of the hydrocortisone group, with both BayleyIII cognitive and motor scores slightly favouring the hydrocortisone group. Unfortunately this was only published as a research letter in JAMA (Halbmeijer NM, et al. Effect of Systemic Hydrocortisone Initiated 7 to 14 Days After Birth in Ventilated Preterm Infants on Mortality and Neurodevelopment at 2 Years’ Corrected Age: Follow-up of a Randomized Clinical Trial. JAMA. 2021;326(4):355-7), so it is a short publication, without much detail, and there is no additional analysis of the babies according to treatment actually received.

These results were obtained with over 100 of the placebo babies having received hydrocortisone, so again, it is not clear if the hydrocortisone was harmful to long term outcomes or not. With so much cross over, it would be very difficult to ascertain in any case, as the sickest babies will have received non protocol steroids, so they are likely to have poorer long term outcomes. But at least in this trial the additional, non protocol steroids appear to have been mostly hydrocortisone, so it might be possible to determine, for example, whether there was a dose-response for developmental outcomes.

What does this all mean for steroid use in preterm babies with evolving BPD?…. part 2 coming soon!

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Dexmedetomidine: new wonder drug or next neonatal disaster?

Posted on 23 March 2022 by Keith Barrington

In many units, including my own, dexmedetomidine (DXM) has been creeping into use. Initially, we noticed in some full term babies who returned from the operating room, the medication appeared in the anaesthesia record, then when infants returned occasionally with an infusion still in place. Eventually we have started using it ourselves for some infants where the short term profile seems to have some advantages. It is a medication that seems very interesting, with sedative, anxiolytic, sympatholytic and analgesic effects, which also seems well tolerated, with the most frequent clinically evident problem being bradycardia, usually responding to a reduction in dose. It appears that the bradycardia is usually a reflex bradycardia, baroceptor mediated, due to vasoconstriction.

One supposed advantage of DXM is that it reduces apoptosis, or at least the apoptosis induced by other anaesthetic agents. A review from 2018 (Andropoulos DB. Effect of Anesthesia on the Developing Brain: Infant and Fetus. Fetal Diagn Ther. 2018;43(1):1-11) described all the then available animal data, and showed that the apoptosis caused by isoflurane, ketamine, and propofol, seemed to be reduced by DXM.

However, one of those studies (Pancaro C, et al. Dexmedetomidine and ketamine show distinct patterns of cell degeneration and apoptosis in the developing rat neonatal brain. J Matern Fetal Neonatal Med. 2016;29(23):3827-33) showed, in contrast, increased apoptosis with DXM, and since then other studies, especially those using prolonged infusion or higher doses, have also shown increased apoptosis, although some continue to suggest protection against apoptosis caused by other agents (such as propofol).

Amazing changes in Brain connectivity between 24 weeks (W24) and term (W40), in these postmortem specimens (Takahashi E, et al. Emerging cerebral connectivity in the human fetal brain: an MR tractography study. Cerebral cortex 2012;22(2):455-64) Normal brain development and maturation requires apoptosis.

Apoptosis is of course a vital part of normal cerebral development, so decreasing apoptosis is not necessarily a better effect than increasing it! It would be better to have a drug which had no impact on normal apoptosis or any other aspect of brain development. It is unlikely, however, that a medication that is sedative and analgesic will have no impact on the brain! Thus, I found the title of this recent article a little humorous, (Cortes-Ledesma C, et al. Dexmedetomidine affects cerebral activity in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2022:fetalneonatal-2021-323411), my first response being, well of course it does, that is why it is used. But the article does have an important message, which is that we know hardly anything about this drug in the newborn, and zero in the preterm newborn. So their findings that amplitude integrated EEG activity was decreased by DXM was not too surprising, but the description of how it is impacted, with an increase in interburst intervals and a reduction in cycling, is really helpful.

More concerning, however, is the reduction in cerebral regional O2 saturation measured by NIRS, that they found, from a mean of 75% to 68%. If DXM was only affecting neuronal activity, then cerebral oxygen consumption should fall, and regional cerebral saturation should increase. This decrease implies a significant reduction in brain O2 delivery, and, as peripheral saturations stayed at 93% and haemoglobin did not change, this means that brain perfusion probably fell, most likely as a result of vasoconstriction. I mentioned at the start of the post that systemic vasoconstriction occurs with DXM, leading to reflex bradycardia, but the doses used in this study did not cause measurable systemic haemodynamic changes, non-invasively measured blood pressure and heart rate were unaffected. This implies that there is local cerebral vasoconstriction with DXM.

This drug, which is creeping into use in the NICU, without any good data regarding safety, either in full term babies or in the preterm, reminds me of several previous neonatal disasters, benzoic acid, chloramphenicol and hexachlorophene, where it took years to discover the very serious harms that they were causing.

As far as I am aware, DXM is not licensed for use in the newborn anywhere in the world, in North America at least, it is not licensed for use in children at all. The current FDA labelling states:

8.4 Pediatric Use
Safety and efficacy have not been established for Procedural or ICU Sedation in pediatric patients. One assessor-blinded trial in pediatric patients and two open label studies in neonates were conducted to assess efficacy for ICU sedation. These studies did not meet their primary efficacy endpoints and the safety data submitted were insufficient to fully characterize the safety profile of Precedex for this patient population. The use of Precedex for procedural sedation in pediatric patients has not been evaluated.

One of our current problems in sedation, and one where DXM has become frequently used, is babies with milder forms of HIE under therapeutic hypothermia. They often seem quite uncomfortable, and review articles have suggested that DXM might be a useful agent, in part because of supposed neuro-protective effects. (McPherson C, et al. Management of comfort and sedation in neonates with neonatal encephalopathy treated with therapeutic hypothermia. Semin Fetal Neonatal Med. 2021;26(4):101264) But, let’s be careful out there, one recent neonatal piglet study showed that DXM combined with therapeutic hypothermia was neurotoxic. (Ezzati M, et al. Dexmedetomidine Combined with Therapeutic Hypothermia Is Associated with Cardiovascular Instability and Neurotoxicity in a Piglet Model of Perinatal Asphyxia. Dev Neurosci. 2017;39(1-4):156-70).

We desperately need good clinical studies of DXM use in newborns, term and preterm. So I was initially excited to see a study with my new favourite acronym T-REX. The published article was, however, an uncontrolled pilot to try and determine efficacy of a particular anaesthetic approach, and only in infants over 1 month. The full T-REX trial (NCT03089905) is underway, with a sample size of 450 and eligibility criteria which include term neonates and infants, with a primary outcome of IQ at 3 years. I can’t see any registered trial on clinicaltrials.gov that really addresses the concerns that I have about potential toxicity in the newborn, the DICE trial (NCT04772222) is a controlled trial in babies being cooled for encephalopathy, with a sample size of only 50, which may be enough for their short term safety outcomes, and even though there is long term follow up planned, not enough power for anything other than enormous effects on development.

A big question for designing a study in, initially full-term babies, is what the comparison group should be. A placebo controlled trial would be tricky to do, unless you studied routine sedation in intubated newborn. A comparison with another agent might be more practicable. Is there any current alternative agent which is known to be safe in the short and long term? I think, pragmatically we would have to compare to morphine infusions, which are sedative, and widely used, and a study would only include babies for whom a decision that they require sedation has already been made. There is no evidence that supports routine use of sedation (morphine or anything else) for ventilated newborns, so a study of those for whom it is thought to be necessary would be an ethical way of studying DXM. It is possible that DXM is a big advance in neonatal care, allowing sedation and analgesia without adverse impacts, but we really need to find out, otherwise there remains a risk that in a few years we will find out that we have, yet again, been doing the wrong thing.

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Common interventions for common conditions; what do they have in common? A lack of evidence.

Posted on 21 March 2022 by Keith Barrington

There are a number of problems in neonatal care for which good evidence is lacking, and an evidence based approach is therefore not really possible. Two recent reviews highlight this problem.

The first is a systematic review of tactile stimulation for newborn infants with inadequate respiratory drive in the delivery room (Guinsburg R, et al. Tactile Stimulation in Newborn Infants With Inadequate Respiration at Birth: A Systematic Review. Pediatrics. 2022:e2021055067). I think, from years of experience, that it is likely that tactile stimulation does increase respiratory drive in some infants who are apnoeic of have poor respiratory effort in the delivery room. Indeed even many mammals do this, they vigorously lick their newborn offspring after birth, which might be to remove the membranes, at least in some animals, but may also stimulate respiration. I did a quick search to see if there is any data about this in mammals, but I found mostly just opinion.

We should be careful here, though, just because some apnoeic babies start breathing after being stimulated doesn’t mean that it was the stimulation that caused it. I am led to the idea of placebo buttons in elevators. Many elevators have a “door close” button, which often has no real function. In some places the regulations even state that door close buttons are not allowed to have any function, and they are only present because the universal design of the elevator cages has that space. Nevertheless, people press these buttons when they are in a rush, and often bash the button multiple times if the doors don’t close after the first push. Many people are convinced that the button closes the doors faster, even in places where they are not attached! I’ve done this myself; I actually, because I am a nerd, timed how long it takes the elevator doors of my usual elevator at the hospital to close without pressing the button, and it is exactly the same as when the button is pressed. It is still difficult to refrain from pushing the button when I am in a hurry, and usually the doors will then close!

Tactile stimulation could be the same, perhaps it has no actual effect, but, as most babies respiratory drive improves with time (or a decreasing pH in the respiratory centres), the apparent effect could be an illusion. Worse, it might distract resuscitators from intervening with effective manoeuvres when a baby actually needs more help.

Surely, it wouldn’t be too hard to determine if tactile stimulation actually works (i.e. leads to shorter time to adequate spontaneous respiration) and what the indications should be, and what method to use, and when to stop and proceed to more invasive techniques.

Ruth Guinsburg and colleagues new review winnowed the reliable evidence down to 2 observational studies, “the prespecified 3 primary outcomes were the establishment of spontaneous breathing without positive pressure ventilation (yes or no), time to the first spontaneous breath or crying from birth, and time to heart rate >100 beats per minute from birth”. I think those are entirely reasonable, and would be adequate justification for performing tactile stimulation if it was effective for any of those outcomes. Of the two trials they found that had some value, they could only extract somewhat reliable data from one of them, which only included preterm babies. The results suggested that perhaps endotracheal intubation was less frequent among infants who received stimulation, compared to the controls without stimulation; of course as an observational study there are biases which are impossible to eliminate.

Performing a randomized controlled trial of stimulation compared to no stimulation whatever would be difficult. I think it would be ethically acceptable if the no-stimulation group had a control intervention that was of low invasiveness and very safe, such as perhaps mask CPAP or low pressure PPV, but it would be essential to have buy-in from all the delivery room staff. In the days before we put babies in plastic bags after delivery, I used to teach that drying the baby with a towel was adequate stimulation, and if the baby was still not breathing after that, then the next steps should be performed. It was still difficult to stop other team members from flicking feet or rubbing the back yet again, and of course, it seems to be relatively harmless, as long as other procedures are also being performed.

It would probably be easier to perform an RCT comparing different methods of stimulation, foot flicking and back rubbing being the most commonly performed where I have worked. It would also be of enormous clinical significance if one was more effective than the other.

Another problem where there is a distinct lack of good evidence is the treatment of TTN (transient tachypnoea of the newborn) also sometimes known as RFLF (retained fetal lung fluid) which I prefer as being more euphonious, however, unfortunately “riflif” doesn’t work in Québec, where we treat TTNN (tachypnée transitoire du nouveau-né).

Probable TTN, image from Guglani L, et al. Transient tachypnea of the newborn. Pediatr Rev. 2008;29(11):e59-65.

An overview of the systematic reviews of therapies for TTN has recently been published (Bruschettini M, et al. Interventions for the management of transient tachypnoea of the newborn – an overview of systematic reviews. Cochrane Database Syst Rev. 2022;2(2):CD013563). There are numerous problems in studying TTN, in part because of a lack of widely accepted diagnostic criteria, but this is an area wide open for research, for which large amounts of resources are currently used. The image above, I would suggest, is classic for TTN, but there is a great deal of inter-rater variability in the diagnosis even among radiologists.

The overview summarizes six Cochrane reviews of therapy for TTN, and the findings are disappointing. Despite the prevalence of this condition there are few studies, they all tend to be small, and the trials were mostly at high risk of bias. The largest amount of data existed for salbutamol inhalations, with 7 trials. The rationale for salbutamol is the known physiologic effect of beta adrenoreceptor stimulation on increasing lung fluid clearance, but, as endogenous circulating catecholamines are already very elevated after delivery, it is questionable whether further betamimetic stimulation would be effective or safe, the trials show low-quality evidence that tachypnoea may be shortened. For the other interventions there were between 0 and 3 trials, and no convincing evidence for the efficacy or safety of any of them.

The findings were as follows:

Salbutamol may reduce the duration of tachypnoea slightly. We are uncertain as to whether salbutamol reduces the need for mechanical ventilation. We are uncertain whether epinephrine, corticosteroids, diuretics, fluid restriction, or non‐invasive respiratory support reduce the duration of tachypnoea and the need for mechanical ventilation, due to the extremely limited evidence available. Data on harms were lacking.

I have long been sceptical of the value of CPAP and non-invasive ventilation in TTN, CPAP is great for low volume lung diseases, but lung volumes on chest x-ray of TTN are often increased (as in the radiograph above), and whether external positive pressure actually improves lung liquid clearance and clinical resolution is uncertain. This should be a research priority, shortening the duration of intensive care for these babies would benefit many thousands of families, and could save significant resources.

Currently, for apnoeic babies in the delivery room, there is no clear answer to the questions of whether we should use tactile stimulation, how, and for how long. For babies with TTN, we have no evidence-based therapy to improve the resolution of their clinical condition. Research on either of those areas has the potential to have a major impact on neonatal care.

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Composite outcomes for research; this is how to do it!

Posted on 21 March 2022 by Keith Barrington

As regular readers of the blog will know, I have been very critical of some very important, otherwise excellent, trials over one vital part of their design, that is, the use of composite outcomes such as “death or BPD”, “death or RoP”, or, the worst of all, “death or NDI” which is a composite of composites. The use of these outcomes is, however, understandable for two reasons. Firstly the outcomes are often competing, that is if you die before 36 weeks you can’t have a research diagnosis of BPD, even if you die of lung injury, so a study investigating a method to reduce lung injury has to take into account the babies who die, otherwise the result might be misleading. Secondly composite outcomes may (although this is not always the case, they may do the opposite) reduce the required sample size.

The problems with this approach are numerous, if the components of the primary outcome change in opposite directions then the result may be null, despite a clinically important difference between the treatments. For example the STOP-BPD trial showed no difference in the composite outcome of death or BPD, despite having fewer deaths at discharge. But, surely surviving with BPD is a preferable outcome to dying. In the most famous example of SUPPORT, the result was again null, no difference in the primary outcome of death or severe retinopathy, but there were more deaths in the low saturation group, and less severe RoP. Again, surely being alive and having laser retinal surgery is to be preferred over being dead.

These composite outcomes imply that the parts of the outcomes are equivalent in importance, which those two examples illustrate, is often not true. However, there are alternatives. Several have been proposed, including the win-ratio that I have discussed several times. A few studies have been published using these techniques, although none as yet in neonatology. One that just caught my eye is this new trial in adults with heart failure and preserved ejection fraction. (Shah SJ, et al. Atrial shunt device for heart failure with preserved and mildly reduced ejection fraction (REDUCE LAP-HF II): a randomised, multicentre, blinded, sham-controlled trial. The Lancet. 2022;399(10330):1130-40).

The intervention was the installation of an inter-atrial shunt by catheterisation to decompress the left atrium, an intervention previously shown to have haemodynamic advantages, and potential clinical benefit. It is basically like creating a permanent secundum ASD of 8 mm diameter. There are a number of potentially competing outcomes of clinical importance for patients with this condition, including death, stroke, progression of heart failure and so on. Just as in neonatology, if you die you can’t get worsening heart failure, so the primary outcome was a hierarchical composite and the primary analysis was a form of the win ratio

The primary efficacy endpoint was a hierarchical composite of cardiovascular death or non-fatal ischaemic stroke up to 12 months post-randomisation; rate of total (first plus recurrent) heart failure events (defined as admissions to hospital or urgent visits to a health-care facility for intravenous diuresis, or intensification of oral diuretics) up to 24 months post-randomisation, analysed when the last randomised patient completed 12 months of follow-up; and change in KCCQ overall summary score between baseline and 12 months.

The KCCQ is the Kansas City Cardiomyopathy Questionnaire, and the score is a continuous variable of clinical status. The statistic that was used to compare the intervention and sham procedure groups was the win ratio, and the p-value was calculated using a method that can integrate dichotomous, recurrent, and continuous outcomes, something called the Finkelstein-Schoenfeld approach.

The authors describe the win ratio calculation in the supplementary materials clearly: “The first patient is compared to every patient, one at a time, and this first patient is assigned a score of 1/0/-1 for each comparison if this first patient has a better (did not experience CV death/ischemic stroke and the comparator patient did), same, or worse (experienced CV death/ischemic stroke and the comparator patient did not) outcome, respectively. For every pairwise comparison where the score is 0, the first patient is assigned a score of 1/0/-1 depending on whether he/she has a better (less HF events than the comparator patient), same (same number of HF events as the comparator patient), or worse outcome (more HF events than the comparator patient), respectively. Finally, for every pairwise comparison where the score is still 0, the first patient is assigned a score of 1/0/-1 depending on whether he/she has a better (change in 12-month KCCQ score at least 5 points larger than the comparator), same (change in 12-month KCCQ score within +/-5 points of comparator) or worse (change in 12-month KCCQ 5 at least 5 points lower than the comparator). This algorithm is then repeated for every patient in the study”.

The results showed a win-ratio was 1.0, which means that overall there was no advantage or disadvantage of the procedure compared to a sham procedure on the components of the primary outcome, when considered in this hierarchical fashion. There were very few deaths or strokes in either group, and in both groups the KCCQ score tended to increase (which means an improvement in symptoms).

One of the interesting things about this trial is that the calculated sample size was a manageable 300, despite outcomes which are somewhat uncommon, and relatively small changes in the continuous score, which suggests that this might be easily applicable for neonatal multi-centre RCTs.

One disappointment I do have for this trial is that there is no mention of whether patients or families were involved in developing the outcomes. It has become essential that there is at least some consultation with those impacted by the conditions we are investigating during development of trial designs, especially when it comes to designing the primary outcomes. In addition to assuring that trials collect data on a group of core outcomes, ensuring that the primary outcomes are what matter most to patients (or, in our case, former patients, and families of neonatal patients), and ensuring that any hierarchy in an analysis of a composite outcome follows what they believe to be most important.

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Should we give up on nebulised surfactant?

Posted on 17 March 2022 by Keith Barrington

A new RCT of curosurf given by nebulisation was published shortly after a systematic review of the previous data. The RCT showed no real benefit, whereas the SR suggested efficacy.

The RCT first, this international trial (Dani C, et al. A Randomized, Controlled Trial to Investigate the Efficacy of Nebulized Poractant Alfa in Premature Babies with Respiratory Distress Syndrome. J Pediatr. 2022) randomized 129 babies (28 to <33 weeks GA) into 3 groups, 2 received different doses of Curosurf nebulised by a special device that could be attached to the nasal prongs (either 200 or 400 mg/kg). Eligible babies were those with HMD who needed between 25 and 40% oxygen on CPAP 5 to 8 cmH2O.

The babies in the 3rd group stayed on regular CPAP. The primary outcome variable was needing intubation; for surfactant therapy (over 40% oxygen need) or becoming hypercapnic (pCO2>60 with pH<7.2) or having lots of apneas.

The study was stopped for futility after just over 40 babies per group, which, as always, is disappointing. The relative numbers of babies who had primary outcome criteria in the higher dose surfactant group (49%) was less than the controls (58%). The 95% confidence intervals for the relative risk of “respiratory failure” (the primary outcome criteria) was 0.56-1.26 for the 400 mg/kg dose and 0.68-1.42 for the 200 mg/kg dose.

It took about 30 minutes to nebulise the higher dose (and half that for the lower dose) and the babies tolerated it well. Post-hoc subgroup analyses suggest that the nebulised surfactant was more effective in the more mature babies.

The systematic review (Gaertner VD, et al. Surfactant Nebulization to Prevent Intubation in Preterm Infants: A Systematic Review and Meta-analysis. Pediatrics. 2021;148) included the results of that trial (called Curoneb), the numbers are a little different, which seems to be because the SR mixed the results of the pilot and the full trial, so instead of the 129 babies in Curoneb, they report the 152 babies in the combined trials. As you can see from the following Forest plot, the SR overall suggests that nebulised surfactant decreases intubation within the 1st 72 hours of life, but the results are really completely dependent on the Cummings trial, which showed a major decrease by 48% in need for intubation, without Cummings there seems very little there. The I2 shows lot of heterogeneity, but nevertheless, the 95% compatibility limits of the RR from the results of Curoneb overlap with the summary Relative risk, and there is some overlap with Cummings trial.

If we examine the Cummings trial in detail, (Cummings JJ, et al. Aerosolized Calfactant for Newborns With Respiratory Distress: A Randomized Trial. Pediatrics. 2020) it was a strange study, which included babies from 23 to 41 weeks gestation, who were on any mode of non-invasive support between 1 and 12 hours of age, needing, at first, 25 to 40% oxygen, but then later on in the trial that was changed and babies in 21% oxygen were enrolled. There were no objective criteria in the trial design for intubation, or for failure of treatment, even though intubation for surfactant administration within the first 4 days was the primary outcome and the trial was unblinded.

There were actually more late term/posterm babies in the trial than babies under 27 weeks, and there were as many early term babies as those born at 27 or 28 weeks. The following figure, which shows that information, includes 20 babies (which is what the “combined cohorts” means) who were randomized after extubation having already received surfactant while intubated. As you can see most of the babies were more mature infants, over 30 weeks gestation. The babies received 210 mg/kg of Infasurf, via a modified nebuliser via an oral airway.

The major problem with this trial, of course, is the use of a subjective outcome criterion in an unblinded study. In addition, the inclusion of full term babies, makes it difficult to generalize the results.

Overall then, it seems that there might be clinical effects of nebulised surfactant, a proportion of the administered dose is deposited in the lungs, and gas exchange tends to improve. In larger preterm babies, this probably somewhat reduces the need for more invasive surfactant administration, but any other benefits (reduced chronic lung disease, improved pulmonary health in infancy, less nosocomial pneumonia or sepsis, improved family interactions or satisfaction) have not been shown.

The implications of all this are that nebulised surfactant has an efficacy which seems limited, and many babies will still need either MIST/LISA or intubation for surfactant therapy. If you take the group that seems to have the best response, between 30 to 34 weeks, a baby that has HMD and is on CPAP with 25 to 40% oxygen in the first few hours, will progress around about half of the time and need surfactant by direct intra-tracheal administration, but if given nebulised surfactant that decreases to between a quarter and a third.

To really prove that you can avoid intra-tracheal surfactant administration in that proportion of such babies really needs another trial, probably with a non-inferiority design. It would be expensive to do this as a masked trial, with a separate team to care for the baby during nebulisation, so I would think an unmasked trial is more likely to be possible, failure criteria should be objective, and it should really be limited to preterm infants.

Is it actually worth doing such a trial? I’m not sure that sometimes avoiding intra-tracheal surfactant administration by nebulising it instead is an outcome that matters enough in larger preterm babies. Laryngoscopy and endotracheal intubation, or passing a catheter through the cords, isn’t much fun for the baby, but the GA group of babies where there seems to be most efficacy have little in the way of serious complications. I think if you could reduce intubations in babies under 28 weeks, then that is a whole different issue, but there doesn’t seem much preliminary evidence that that would work.

Looking at the minor difference in outcomes in the group of 27-28 week babies in the above graph, and that is despite the potential biases in study design, you would need a huge trial to confirm a similar reduction in intra-tracheal surfactant need in the babies for whom it might make a clinically important difference. Unless there are better ways of ensuring that an effective surfactant can be quickly deposited in sufficient quantities in the terminal air sacs, I think we might have to say goodbye to nebulised surfactant as a great idea that didn’t live up to its promise.

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Hypoglycaemia, symptomatic or non-?

Posted on 15 March 2022 by Keith Barrington

Many algorithms for detection and treatment of hypoglycaemia make a big deal of whether the hypoglycaemia is symptomatic or not. Symptomatic hypoglycaemia is supposed to be more dangerous in the long term, and requires more aggressive treatment. But symptoms accredited to hypoglycaemia also occur in non-hypoglycaemic infants, and many infants with low blood sugars look and act just like their normoglycaemic peers.

So bravo to a group of German investigators who have tried to determine whether clinical signs really discriminate between babies with and without low blood sugars. (Hoermann H, et al. Reliability and Observer Dependence of Signs of Neonatal Hypoglycemia. J Pediatr. 2022)

They video monitored 145 term and late preterm babies, some considered to be at-risk of hypoglycaemia (SGA, LGA, diabetic mothers, late preterm, and respiratory distress), and others at standard risk. 430 videos were taken just before the blood sample, which was analyzed by a bedside “Stat-strip” glucose analyzer. This is, I think, the main limitation of the study, as such monitors are known to be inaccurate, they produce results which tend to be lower than reference methods, when in the hypoglycaemic range. But if we assume that the hypoglycaemic babies were truly hypoglycaemic, which would often be true, then clinical signs, as detected by the 8 nurses and 2 neonatologists who reviewed all the videos, are completely unreliable.

The sensitivity and specificity of any of the clinical signs were poor, with tachypnoea being the clinical sign which was most different between babies with blood sugars above and below 2.5 mM/L (45 mg/dl).

Apart from the very rare baby with blood sugar of zero who is convulsing, clinical signs are really not much use in detecting hypoglycaemia, and there really is no reliable evidence that an infant with a low blood sugar who has some of these clinical signs has any worse prognosis than a baby with a similar blood sugar who is not thought to be symptomatic.

I really question the division of hypoglycaemia into “symptomatic” and “asymptomatic”; as these authors note, there is no good previous data that shows reliably that symptoms of hypoglycaemia are reproducible or readily detected, and nor is there good data that babies with what are considered to be signs of their low blood sugar are worse off in the long term than those without such clinical signs.

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Skin to skin contact reduces pain… in mothers!

Posted on 8 March 2022 by Keith Barrington

Some neonatal interventions for pain relief don’t seem to work in older subjects, sucrose for example doesn’t seem effective out of the neonatal period, a study from our Emergency Room showed no benefit of sucrose for bladder catheterisation in infants (Desjardins MP, et al. A randomized double-blind trial comparing the effect on pain of an oral sucrose solution versus placebo in children 1-3 months old needing bladder catheterization. CJEM. 2021;23(5):655-62).

A new publication, however, shows that skin-to-skin care of mother with her baby reduced the pain of perinatal repair after vaginal delivery (Zou Y, et al. Effect of early skin-to-skin contact after vaginal delivery on pain during perineal wound suturing: A randomized controlled trial. J Obstet Gynaecol Res. 2022;48(3):729-38). New mothers were randomized to have the baby in their arms during perineal repair or to have “standard care” where the infant was on an overhead heater during the repair.

The mothers’ pain scores were substantially lower in the skin-to-skin care group than the controls.

I’m sure the babies were happier too.

Image from UNICEF
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Should we feed insulin to preterm babies?

Posted on 8 March 2022 by Keith Barrington

This was an idea I had not heard about prior to seeing this newly published trial (Mank E, et al. Efficacy and Safety of Enteral Recombinant Human Insulin in Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2022). The introduction is very limited on the prior justification for the trial, but the beginning of the discussion gives a lot more background.

The discussion section notes that, in previous animal studies “the small intestinal weight and intestinal disaccharidase activity (ie, lactase, sucrase, maltase) were significantly higher in both piglets and rats treated with either enteral rh (recombinant human) insulin or enteral recombinant porcine insulin relative to controls, suggesting that insulin has a key role in promoting intestinal maturation. The effect of enteral insulin on the intestine seems to be mediated by insulin receptors, which have been observed on both the apical and basolateral enterocyte membrane of various animals” and apparently insulin receptors have been seen in human foetuses up to 19 weeks, but only on the basolateral membrane of the enterocytes, not apically. There is apparently also quite a lot of insulin in human milk in the first few days after delivery, and an interesting prior study from Deborah O’Connor’s group in Toronto showed that standard Holder pasteurization decreases human milk insulin concentrations by about half.

They therefore performed this study to see if adding a new powdered insulin preparation to human milk feeds would improve GI function, as measured by time to tolerating full enteral feeds, among preterm infants <32 weeks gestation.

The first disappointment I had with this trial was that the investigators excluded infants less than 26 weeks gestation. I can’t see any good reason why more immature babies should have been excluded from the trial, more immature babies are more likely to have feeding intolerance, and including higher risk patients improves study power. Also, if it works overall, then surely you would want some evidence that it works in the highest risk patients. Excluding higher risk, more immature, patients from trials means that we cannot develop the evidence base needed to improve their care (Barrington KJ. The most immature infants: Is evidence-based practice possible? Semin Perinatol. 2021:151543). There were several exclusion criteria, including infants significantly SGA, needing more than 60% oxygen, having a blood count suggestive of infection, etc. Babies were eligible within the first 5 days of life if they had started enteral feeds. Babies were randomized to receive either 400 micro-units of insulin per mL of milk, or 2000 micro-units/mL or placebo, in a masked fashion.

The next disappointment is that most of the attached protocol is redacted. Which is truly weird. The study procedures part of the protocol from section 9.1, screening and eligibility procedures to 9.5 discontinuation/withdrawal of infants are blacked out, the 10 pages with the important details of the study protocol look like something from Trump’s White House or a report into parties at 10 Downing Street. I wanted to read the protocol because I wasn’t clear about one part of the published article, where it states that, in babies receiving exclusively maternal milk, treatment was not initiated until 72 hours post-partum. It wasn’t clear to me what that meant for the other infants, and what would happen if the mother wanted to breast feed, but baby received partially banked human milk, which is why I wanted to read the protocol… I have no idea what they are trying to hide.

I think the delay in maternal breast milk fed babies is because there is a lot of insulin in human milk in the first 3 days, so they wanted to avoid an overdose in those babies. Presumably the intervention was started immediately after randomization in the other babies.

The primary outcome of the trial was the time to full enteral feeds, defined reasonably as 3 consecutive days of at least 150 mL/kg/d of milk. The sample size was calculated based on a reduction from 8 days to 6.6 days, as shown in a pilot study. I find that outcome a bit problematic, it isn’t a terrible idea, but really, who cares? I think the reason for caring about time to full feeds is that more prolonged feeding intolerance is associated with increased other complications, such as late-onset sepsis, cholestasis and increased costs. 1.5 days less of partial parenteral nutrition is really only of clinical significance if it is, firstly, clearly very safe, and secondly leads to reduced other complications. I understand that powering a trial for those other complications is going to lead to very much larger sample sizes, but that is also the only way to be sure that the intervention is safe. If even a small proportion of babies have an adverse secondary effect of enteral insulin, then a reduction of 1.5 days of time to full feeds becomes irrelevant. I think at this stage of investigation, time to full feeds was a reasonable compromise, but doesn’t give me a strong reason to consider introducing a new intervention.

The sample size calculation arrived at 150 babies per group, in a multicentre design, with 2 gestational age strata. After 225 babies were randomized, an interim analysis showed that the calculated power for finding a reduction of 1.5 days in time to full feeds was <35%, so the DSMC proposed stopping the trial. By the time the trial was actually stopped 303 babies had been randomized. In another move which is not fully explained, babies who were in the trial, but had not yet reached full feeds had the intervention stopped, in addition, there were some babies who had the intervention stopped because they were transferred to non-study centres. As a result there are only data about the primary outcome for 261 infants.

Although the trial was stopped early for futility, the final results actually show what is potentially a valuable reduction in time to full feeds in the insulin groups. Median time to full feeds was 10 days in each of the insulin groups compared to 14 days in the controls. Which was twice as great as the hypothesized difference. The difference looks unlikely to be due to random effects, the 95% compatibility intervals were 1 to 8 days shorter time to full feeds. Other outcomes were not much different between groups, if you put the 2 insulin groups together, mortality was about the same 3% insulin vs 4% control, late-onset sepsis was slightly lower with insulin 12% vs 15% and NEC was lower, a difference which, if confirmed in future larger trials, might be a clinically important difference, 5% vs 10%. My back of the envelope calculation shows that difference to be compatible with no real impact of insulin on NEC, or, obviously, with a major reduction.

Early stopping of trials for futility is a common occurrence which seems to be getting more frequent. There are scientific and ethical reasons for questioning the practice, which are illustrated by this trial. Scientifically speaking, the risk of stopping early for predicted probable futility is exactly what this trial has shown, that the trial, when fully analyzed, may show a real difference between treatments, even a difference greater than hypothesized, but being stopped early, of course, reduces the power of the trial. It is easy to imagine situations in which a similar trial may be stopped and show a difference which is not quite convincing, and reported as “not statistically significant” but if it had been continued, and accrued the expected number of participants would have been a positive trial.

Other trials have had similar occurrences, the following figure, for example, is from a cancer trial (for which futility analyses are common) The calculated power of the trial to produce a significant result is plotted over time, which shows that it varied substantially as the results accumulated, the point at which the power dropped was when the pre-planned futility analysis was performed which led to stopping the trial. The lower graph shows the actual primary outcome (for PFS, progression free survival) at the end of data collection, which was better with the new regimen than the old one.

In our current trial there were no safety issues identified at all, no evidence of harm. Also it is hard to believe that oral insulin powder is a hugely expensive intervention, which might be an issue with continuing some cancer trials, especially industry sponsored trials where the medication might be extremely costly and potentially toxic.

Ongoing monitoring of trial outcomes to reduce risks of the trial to participants is very important. But where there are no identified risks of the intervention, and where being in the trial does not prevent the participant from receiving other interventions, (I can imagine in cancer trials that some of the considerations are different), then the threshold for stopping a trial should be much higher.

From an ethical point of view, I think we have a responsibility to families that participate to ensure the trial is as useful as possible to the community. To expose families to the stress and potential risks of an intervention, and then stop a trial before you have any reliable answers is very questionable. In particular, I think it was wrong in this trial to stop the intervention in babies who had already been randomized and started the intervention. Those families had already consented to be part of the trial, and had started the intervention (insulin or placebo) but then had the intervention stopped part way through, meaning they were exposed to the stress and to the risks of an RCT but were not permitted to contribute to the final results. Surely, once babies are randomized they should have continued in their randomized group until they reached primary outcome criteria, and for the 28 day intervention period.

I think if the DSMC had found increased risks for the insulin group, that would have been an entirely different situation. Also, if the primary outcome results were clearly going in the wrong direction, with an increase, rather than the expected decrease, in time to full feeds with the insulin, then I think the decision to stop for futility would make more sense. Instead we are left with a trial which did not reach planned sample size, in which 42 of the 303 enrolled babies did not even contribute to the primary outcome. A trial which is, therefore, only suggestive of a benefit.

Imagine if the trial had continued to the planned sample size, it is quite possible that an important reduction in NEC might have been found, as well as a potential reduction in late-onset sepsis. At least we would have had more reliable data to proceed with more investigations.

The next disappointment is that the study finished in 2018, and only short term outcomes are reported. Why did it take 4 years to get this in press? It seems an unnecessarily long delay.

The final disappointment is that many of the babies did not receive milk from optimal sources. Although the study started in 2016, and human milk banks were not as widely available as they are now, there were several babies who received formula alone, and many who received a combination of milk sources; the “mixed” category in the results includes babies who received both maternal and banked milk, as well as those who received both human and artificial milk, and it is not clear how many received artificial milk. As the standard of care is now maternal milk feeding, and banked human donor milk when sufficient maternal milk is not available, for preterm babies at risk of NEC (such as all the babies in this study) it is important to know if these potential advantages of enteral insulin apply to babies who received only human milk.

The potential advantages of adding insulin to the feeds of very preterm babies suggested by this study are such that further trials are definitely worthwhile. Those trials should only study babies receiving milk from optimal milk sources, they should include the higher risk babies (less than 26 weeks, small for gestational age, abnormal antenatal dopplers) and should have much stricter rules for terminating the trial for futility. They should be powered to investigate clinically important outcomes such as late-onset sepsis and NEC.

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Does Gastro-Oesophageal Reflux matter in BronchoPulmonary Dysplasia?

Posted on 6 March 2022 by Keith Barrington

The title is deliberately a bit vague as I wanted to discuss whether GOR contributes to the pathogenesis of BPD, and also whether it is important in infants with established BPD.

Does GOR contribute to the development of BPD? There is so little reliable data to answer this question that I can only offer the old Scottish verdict of “not proven”. It is a possibility that GOR and aspiration of refluxed intestinal contents could contribute to lung inflammation and damage. I don’t think it would be too difficult to prove, actually, intubated infants could have recurrent endotracheal aspirates examined for pepsin (which should ordinarily not be in the lungs) and a correlation between evidence of aspiration and the development of lung injury. As far as I know, this has only been done once, (Farhath S, et al. Pepsin, a Marker of Gastric Contents, Is Increased in Tracheal Aspirates From Preterm Infants Who Develop Bronchopulmonary Dysplasia. Pediatrics. 2008;121(2):e253-9) with a rather unconvincing increase in pepsin concentrations among infants who developed BPD compared to those without BPD. You can see the figure below, and although the difference is “statistically significant” it doesn’t look very useful with a major overlap between cases and controls. Of note, 92% of their samples (and all of the babies at least once) were positive for pepsin, suggesting that micro-aspiration is universal, the results suggest that perhaps that having a bit more pepsin in the lungs increases lung injury (at least using oxygen at 36 weeks as the indicator of lung injury).

Apart from that study I can find no real evidence that suggests that recurrent micro-aspiration is important in the pathogenesis of BPD. Even if we strongly suspected it to be true, the next question would be what to do about it? If the culprit were gastric acid, then gastric acid blockade should decrease BPD, but that has never been shown. If it was due to other enzymes and inflammatory responses then actually decreasing episodes of reflux should decrease BPD, but we don’t know how to do that. One observational study from a center which sometimes uses transpyloric feeds showed that those where the neonatologist decided to start transpyloric feeds in the first week of life had shorter duration of assisted ventilation and a little bit less “death or bpd” but there are major problems with this study design. Although the authors attribute this difference to reduced GOR and reduced aspiration, there is no evidence that transpyloric feeding in preterm infants actually decreases reflux. In a study in older children with transpyloric feeds, they all had at least one episode of reflux on impedance pH monitoring, and some had very frequent episodes despite receiving transpyloric feeds. Critically ill adults with transpyloric feeds almost all have reflux of duodenal contents into the stomach, and almost all have gastro-oesophageal reflux and pulmonary aspiration, with only minor differences to controls randomized to gastric feeding. The latest version of the Cochrane review of transpyloric feeding in the newborn notes an increase in mortality, more GI disturbances, no change in aspiration pneumonia/pneumonitis, no data on BPD, and an overall poor quality of available data.

Even if BPD were clearly more common among babies with recurrent micro-aspiration there is no evidence-based way to prevent, or even reduce, that phenomenon in the newborn.

But what about after lung injury has developed? Do babies with BPD have more reflux than those without? Does GOR adversely impact respiratory function or clinical progress in infants with BPD? Does treating reflux improve clinical outcomes in babies with established BPD?

In 1989 a publication compared acid reflux to the proximal oesophagus between preterm infants (on full feeds, at about term) with and without BPD. They actually found less reflux in the BPD infants. A more recent study from 2004 also using pH-metry found the same thing, less reflux among babies with BPD compared to controls of similar gestational and post-menstrual age without BPD. A 2015 study, using impedance as well as pH monitoring showed no difference in reflux events between BPD and control babies who all had “symptoms consistent with GOR”. That study was only able to find a difference after multiple quantile regression analysis, and only in pH-only events, that is, events which dd not show evidence of bulk fluid movement into the oesophagus.

I haven’t been able to find any reliable evidence to address the second and third questions, which are obviously linked. Even though GOR does not appear to be more common in babies with BPD compared to control preterm infants, it could still be associated with worse lung injury and babies could possibly benefit from treatment, and evidence of an adverse impact would be strongest if reducing GOR actually improved lung function. The big problem of course is the lack of effective treatments of GOR. Although commonly referred to as anti-reflux treatments, acid blockade with histamine receptor antagonists or proton pump inhibitors do not, of course, reduce reflux. Unless symptoms are only due to acidic GOR they will have no effect. There is no good evidence to support the use of any prokinetic agent, those that have been investigated are as likely to show an increase in reflux as a decrease.

The recent article about medication use in the NICU that I already discussed was somewhat reassuring that there had been a decrease in the use of lansoprazole between 2010 and 2018, (and of ranitidine, but that had been taken off the market). I couldn’t see much else on the list that is being used to replace them, there is rare use of famotidine and omeprazole. I was surprised to see both sucralfate and simethicone on the list of NICU drugs, which maybe are being given for perceived GOR symptoms, but simethicone doesn’t even work for colic, the usual indication, at least as according to the only placebo controlled RCT that was performed; Sucralfate is 21% aluminium by weight, so probably not a good idea to give to developing brains.

In summary then, there is no good evidence that GOR and microaspiration are important in the pathogenesis of BPD, there is no good evidence that infants with BPD have increased GOR compared to other preterm infants, and there is no good evidence that GOR has an impact on respiratory function in established BPD.

Even if, in an individual patient, you thought that GOR might be contributing to their pulmonary symptoms, I reiterate that there isn’t much you can do about it. There is no evidence-based effective medication that safely decreases GOR or GORD. Thickening feeds has a minor effect on reflux, but has never been shown to improve any clinical aspect of GORD. Transpyloric feeding does not eliminate GOR, and, in the only trial in infants with established BPD, transpyloric feeding seemed to increase hypoxic spells. All you can do is try and keep the babies upright especially after feeds (this might have no direct evidence base, but kangaroo care has many benefits, and gravity can be our friend), and wait for improvement.

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What is Gastro-Oesophageal Reflux Disease (GORD, or GERD if you prefer) in the neonate?

Posted on 4 March 2022 by Keith Barrington

All babies have reflux, repeated transient lower oesophageal sphincter relaxations are universal. Almost all babies have overt regurgitation, I often say that if a baby never regurgitates it may be a sign that they aren’t getting enough milk!

So when does GOR become GORD? There are 3 groups of symptoms that are often ascribed to reflux in the NICU: apnoeas and recurrent bradycardias; respiratory deterioration/bronchopulmonary dysplasia; oesophagitis and resulting feeding problems.

There are many studies of the relation between GOR and either apnoeic or bradycardic spells. In order to have any idea of the reality of that relationship we need prolonged multichannel recordings which measure reflux objectively in addition to cardiorespiratory recordings which include airflow. In a study I did a few years ago now in San Diego we used pH recordings and found no relationship evident between apnoeic events and acid reflux. But, of course, most GOR in newborn infants is either neutral or alkaline, so its possible that we could have missed something.

Most of the available studies which have used impedance, and therefore detected non-acid reflux also, show no temporal relationship between episodes of reflux and acute respiratory events, some show that apnoea (particularly obstructive apnoea) may precede reflux events. There are one or two that have reported that acid reflux may trigger apnoeas in some infants, and a couple of studies, usually in small highly selected groups of babies, showing a temporal relationship between GOR events and obstructive apnoeas. One study, for example, in 7 former preterm infants around term found that among the 4 who had extremely frequent obstructive apnoeas (>6 per hour) there were 3 who seemed to have apnoeas preceded by GOR.

One interesting study from Jadcherla’s group in Columbus Ohio used the sort of intensive monitoring I have described, but with oesophageal manometry rather than impedance measures, and then introduced artificial pharyngeal stimulation with up to 0.5 mL of sterile water as a bolus. They found that overall former preterm babies who were evaluated at 36 to 40 weeks PMA with or without recurrent bradycardia had very similar responses to pharyngeal stimulation. A subgroup of the babies had more severe bradycardia after stimulation, the definitions the authors used are rather weird as they are based on the resuscitation guidelines NRP and PALS, which are of course completely irrelevant for episodic bradycardias in otherwise stable infants. Nevertheless, this study does suggest that some babies are more sensitive to pharyngeal stimulation than others and may have more severe bradycardias, but these studies were performed after discharge home, at around term post-menstrual age, and therefore not necessarily relevant to apnoea in the NICU.

Fig. 1

This remarkable image shows a reflux event, using overlaid data from oesophageal manometry in addition to multiple impedance (the white lines). The reflux event starts with a transient relaxation of the LES, lower oesophageal sphincter, and the progressive drop in impedance in a cephalad direction is the bolus of liquid climbing the oesophagus, followed by major increases in pressure which are swallowing movements in the pharynx and then the purple wave of increased pressure moving down the oesophagus to clear the reflux. In the interesting review article from which that image was taken (Badran EF, Jadcherla S. The enigma of gastroesophageal reflux disease among convalescing infants in the NICU: It is time to rethink. Int J Pediatr Adolesc Med. 2020;7(1):26-30). There are other images also which show an association between episodic symptoms preceding a reflux event.

This looks to me as if the arching and irritability, or the grunt, caused the reflux, rather than the other way around! Indeed when symptom scores have been compared with objective recording of reflux in NICU patients, there has usually been no correlation. There are several studies that have almost all failed to show that symptoms ascribed to reflux are actually caused by reflux, four that I quickly found in my files are listed below.

I teach residents and fellows that the only clinical sign which is reliable for the presence of reflux is overt regurgitation. Even though reflux might sometimes cause clinical consequences (GORD) there is no way to determine its presence without prolonged impedance monitoring, which should be combined with pH and multi-channel recordings to have any confidence that clinical events are caused by reflux.

Also vitally important, most reflux in the newborn in the NICU is not acidic, and there is no evidence that the acidity of reflux episodes is associated with the likelihood of a reflux episode causing a clinical event. Using acid blocking medications therefore has no rational basis in the treatment of GORD if the justification for treatment is the presence of episodic cardiorespiratory events. And probably not for other possible respiratory indications either, a subject to which I shall return.

Funderburk A, et al. Temporal Association Between Reflux-like Behaviors and Gastroesophageal Reflux in Preterm and Term Infants. J Pediatr Gastroenterol Nutr. 2016;62(4):556-61. Snel A, et al. Behavior and gastroesophageal reflux in the premature neonate. J Pediatr Gastroenterol Nutr. 2000;30(1):18-21. Kohelet D, et al. Esophageal pH study and symptomatology of gastroesophageal reflux in newborn infants. Am J Perinatol. 2004;21(2):85-91. Mousa H, et al. Testing the association between gastroesophageal reflux and apnea in infants. J Pediatr Gastroenterol Nutr. 2005;41(2):169-77.

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