The NeoGluCO trial

This trial was a modestly sized RCT of low dose diazoxide for treatment of persistent or severe hypoglycaemia in newborn infants of at least 35 weeks gestation. I say “modestly sized” as a descriptor, not a criticism, because I think this trial is potentially very important. It included 75 babies admitted to the NICU in the first week of life who had ≥3 episodes of blood sugar <2.6 mmol/L in a 48 h period, or a persisting episode <2.0 mmol/L despite gel on 2 occasions, or any episode with a blood sugar <1.2 mmol/L, AND ongoing treatment for hypoglycaemia, which meant IV dextrose, continuous or
frequent feeds (≤2 hourly), inability to wean formula

• Babies were randomized to either 5 mg/kg of diazoxide followed by 1.5 mg/kg q12h, or placebo.

After the first 2 doses further doses were adjusted according to the following schema, the doses are given in mL/kg as it was a masked trial, but the drug was concentrated so that 1.5 mg/kg was 0.15 mL/kg.

The primary outcome was a complicated one, evidence of stabilised glucose metabolism, as shown by: established enteral bolus feeds (either breast or bottle); no IV fluids for at least 24 hours, and all glucoses in range (2.6 to 5.4 mmol/L with at least 4 of them prior to a feed).

The primary outcome was shorter with diazoxide, but not statistically different between groups (2.8 days with diazoxide cf 3.7 days in controls). Nevertheless, there seemed to be some major advantages of being in the diazoxide group. Only 2 of the diazoxide group had a mild hypoglycaemia after the loading dose was given, whereas, in the control group, 53% had ongoing hypoglycaemia, 21% had recurrent or severe episodes, 16% had hypoglycaemia after initial stabilization, 29% had study drug dose increases, and 3 required open label diazoxide to achieve control.

They redefined the outcome variable after the study (always a dangerous thing to do) to be a bit simpler, “Time to resolution of hypoglycaemia AND full enteral bolus feeding AND no IV fluids for ≥24 hours”, and that was substantially shorter in the diazoxide group, who had no adverse effects (2 babies with blood sugar in the high normal range) and, importantly, had many fewer heelsticks, a median of 15 instead of 20. In comparison many control babies had repeated and/or severe hypoglycaemia after the initiation of the trial: 53% had ongoing hypoglycaemia, 21% had recurrent or severe episodes, 16% had hypoglycaemia after initial stabilization, 29% had study drug dose increases and 3 required open label diazoxide to achieve control.

They also noted that babies had an IV infusion for a shorter time, and there was no recurrence of hypoglycaemia when the diazoxide was stopped. I think this warrants further investigation, especially in the severe group, less than 1.2 or multiple samples <2.0. And always remember that bedside glucometers are very inaccurate in the hypoglycaemic range, often over-diagnosing hypoglycaemia, as yet another study showed, presented as a poster in this meeting. The Auckland group have always used reliable methods in their studies, with high quality lab analyses (usually with a blood gas analyser or the EPOC device), which of course, have to be available very rapidly for this problem.

ESC-NOW secondary analysis

The ESC-NOW trial was a multicentre investigation of using ESC (Eat Sleep Console) instead of the Finnegan scale for neonatal opiate withdrawal. This secondary analysis showed that maternal buprenorphine treatment was associated with much less neonatal morphine use, and shorter medication use and shorter hospitalisation than maternal methadone treatment.

The ESC approach was advantageous in both groups, shortening hospitalisation from 11 to 7 days in the buprenorphine group and from 17 to 10 days in the methadone group. Need for medications in the babies was decreased from 39% to 15% with ESC in the buprenorphine group, and from 63% to 31% in the methadone group. As far as the impacts on the baby, it is clear that using buprenorphine is preferable to methadone during pregnancy. For an individual mother, of course, there may be enormous numbers of other considerations.

The Dove study

This was a single group study of the use of High Frequency Oscillation with the Draeger VN500 in pressure and then volume guarantee mode. The study was all funded by Draeger, and seems to have been done largely to try and get approval as a medical device in the USA. Subjects were 24 to 30 weeks infants in the 1st 4 days of life who still needed more than 25% oxygen after surfactant with an MAP of 7 or more. Initially the MAP was increased by 2 when the baby was switched, and the initial pressure amplitude was 15-20 cmH2O, which was adjusted by eye, looking for a chest jiggle that appeared right! TcCO2 was used and early blood gases to avoid hypocapnia.

Although not randomized, there was a concurrent control cohort, and outcomes were all very similar to those who stayed on conventional ventilation. Except for pneumothorax which was 4% in the HFO group, and 11% in the conventional group. 11% seems very high to me, after surfactant there are usually far less than that, but not knowing how the control cohort was enrolled makes it difficult to comment.

CO2 fell after the change in ventilation mode, with a mean about 45 mmHg at 2 hours, and a SD of about 4, which means that a mean -2SD is about 37, and there will be occasional babies with more severe hypocapnia. After stabilisation the babies were switched to Volume Guarantee Mode, which, just as in conventional ventilation means that the ventilator adjusts the pressure to give the volume that you set. The mean volume used was close to 2 mL/kg.

This is similar to previous data, that, at 10 Hz, the average volume required is close to 2 mL/kg. Because of those prior findings, and the occasional occurrence of severe hypocapnia in our babies after switching to HFO, we now initiate HFO with Volume Guarantee and a volume of 2 mL/kg. Since starting that approach we have had no severe hypocapnia: I think that makes much more sense than trying to evaluate if the chest is vibrating the right amount. We also try to keep all the preterm babies on 10 Hz, people get confused by the changes in high frequency tidal volumes and DCO2 when you change frequency, so keeping them all at 10 Hz simplifies things. However, with the VN500 you often can’t achieve your desired tidal volumes in larger babies at 10 Hz, and often have to reduce the frequency to 9, 8, or even 7 Hz, to get adequate ventilation.

2 mL/kg is however, just a starting point, some babies will still be mildly hypocapnic, on the first blood gas, which should be done rapidly after switching to HFO, and will need volumes eventually as low as 1.2 mL/kg, others may need volumes as high as 3.5 or occasionally even more.

Long term outcomes of the MINVI trial

Many of you will remember the MINVI trial of cord milking for non-vigorous term infants. That trial had a null primary outcome, but re-analysis using the DOOR methodology showed that short-term outcomes were improved with cord milking compared to immediate clamping.

As you can see from this illustration by Satyan, several outcomes of interest to parents were improved by milking, and there were no adverse effects.

At 2 years of age the babies were evaluated with the Ages and Stages Questionnaire, and with the Modified Checklist for Autism in Toddlers (MCHAT). The proportion of babies with abnormal scores on each domain of the ASQ-3, was identical in the two groups. There were no evident outcome differences between groups. I think this means that cord milking in such babies should be routine, having fewer babies with moderate to severe HIE and/or needing Cooling are substantial benefits. Especially as there were no adverse impacts, and the babies also have a higher red cell mass, and therefore higher iron stores, it may be that other benefits will show up later, as has happened with the term delayed clamping trials, where higher haemoglobin led to better very long term outcomes at 4 years, despite no difference at 1 year.

Long term respiratory outcomes of the Darbe trial

The Darbe trial was a multicentre RCT of darbepoetin among over 640 very preterm infants with the primary outcome being based on an interest in determining whether there was neuroprotection, it hasn’t yet been published in full, but seems to have had no impact on the primary outcome. 23 to 29 weeks infants were included, and the primary outcome is neurological and developmental findings at 2 years corrected age.

P	•650 infants born 230/7 to 286/7 weeks’ gestation •Enrolled ≤24hr of age between 2017-2019 (f/u through 2022)
I	•Darbepoetin 10μg/kg weekly (IV or SC) through 35 weeks’ PMA
C	•Placebo (IV) or sham injection (SC)
All	•Parenteral or enteral iron supplementation per study guidelines •Restrictive protocol for red blood cell transfusions
O	•Primary: Bayley III composite cognitive score at 22-26 months •Secondary: Multiple pre-specified outcomes

The presentation didn’t have a slide saying “not to be shared” so I can copy the above data from the pdf, some of the others had such a slide, so I haven’t cut and pasted any figures or slides for some presentations.

Darbepoetin reduced the number of RBC transfusions compared to controls, the mean transfusion number was 1.9 (2.8) vs. 3.3 (3.6), and the proportion who never had a single transfusion was 46% compared to 24%.

The short term respiratory outcomes showed a reduction in grade 2 or 3 BPD with darbepoetin compared to control, from 46% to 34% among survivors; mortality was similar between groups. They performed a mediation analysis to show that it was possible that the reduction in BPD was mediated by the substantial reduction in transfusions.

Although they have gone to great statistical effort to show the potential mediation of the reduction in BPD by a reduction in transfusion, we should keep in mind that the TOP study, in which there were far fewer transfusions in the low hemoglobin group, showed no difference in BPD, or any other index of lung injury.

Short term respiratory outcomes that are of more interest to parents were, however, not different between groups. The proportion of babies going home on oxygen was the same, 37% vs 38%, and the proportions on respiratory medications at discharge were also very similar. Among respiratory outcomes at 2 years of corrected age, 5% in each group were still on oxygen, and 2% on respiratory support, about 1/3 were getting respiratory medications, and 1/5 had been readmitted to hospital for respiratory complications. There was no difference between groups in any of these outcomes.

Darbepoetin therefore had some effect on respiratory adaptation in the NICU, with babies in the active treatment group needing 7 days less of oxygen supplementation, and 7 fewer days of positive pressure, perhaps having something to do with the transfusion need. But no important impact on any outcome that matters to parents, or, indeed, matters to society in terms of health care resource needs.

Thanks to the NRN and Dr Jensen, for providing yet more evidence that “BPD” is of little value as an outcome variable in clinical trials.

Although there was a major reduction in BPD in this trial, it was because control babies needed oxygen or positive pressure for a little while longer, and thus they were more likely to still be in oxygen at 36 weeks PMA, but, as I already noted, none of the outcomes that we have shown to be concerns of families were affected. I think an ordinal outcome variable including several clinically important signs of lung injury would be much more useful for the future. Such an outcome should be co-constructed with parents (and former preterms, perhaps) and would probably include: discharge delayed because of respiratory difficulties; home oxygen after 40 weeks PMA; respiratory medications at discharge; home gavage feeding after 40 weeks PMA. Somewhere in there should also, be the rarer outcomes of prolonged ventilation past 40 weeks, tracheostomy, and so on.

If we keep using “BPD” there is a real risk that interventions that have no major real impact on lung injury, such as darbepoetin, may be widely used to improve pulmonary outcomes, which, based on these data, would be a big mistake. In contrast, using darbepoetin to reduce transfusions may indeed be something that appeals to parents. I think that being able to avoid transfusion might be something that parents would value, if there are no adverse impacts of the medication, which seems to be the case.