Neonatal Updates

Raina A, et al. Treating perinatal asphyxia with theophylline at birth helps to reduce the severity of renal dysfunction in term neonates. Acta Paediatrica. 2016. This was an RCT in 160 full-term babies with perinatal asphyxia and encephalopathy. Babies, who were not cooled, received either a single dose of 5 mg/kg of theophylline or placebo, prior to 1 hour of life. Babies needing assisted ventilation were not eligible.

Despite the Acta Paediatrica website claiming that all RCT reports must follow the CONSORT guidelines, this report does not.

A few examples: the title does not mention that it is a randomized trial; it is not clear what the primary outcome was; there is no CONSORT flow chart; the sample size calculation is poorly explained; there is no trial registration noted, and I could go on. I don’t see how an RCT can be published in a journal claiming to require CONSORT standards when there are so few of those standards being respected.

The sample size was calculated based on a reduction of AKI (acute Kidney Injury) from 40% to 20% “using a power of 85 and confidence interval of 95%.” which doesn’t make sense, power is expressed as a percentage or as a decimal, in fact, if you do the calculations, the sample size of 164 patients is for a power of 80% and an alpha of 0.05. AKI is also not defined. There is a definition for “post asphyxia severe renal dysfunction”, but it is not clear if this was what they meant by AKI.

According to the results section there were 33 deaths, 12 in the theopylline group, and 18 in the placebos (!), In the discussion the deaths in the theophylline group are noted as being 15.

If we assume that AKI is the primary outcome variable, and that the definition of “post asphyxia severe renal dysfunction” is actually AKI, then this was reduced by theophylline, from 48% to 15%.

I think this is a real shame, the authors have performed an RCT of an important clinical issue, and peer review has really failed them. They could and should have been helped to make this a much clearer report, a peer reviewer, and the editor, really should have picked up on the things I describe above.

The relevance of the data to my practice are questionable, but, in the context of the other smaller trials already published, this suggests some improvement in creatinine, and higher urine output in the babies who received theophylline. Whether this would translate to some medium or longer term clinical benefit is unclear, but it may warrant investigation in infants undergoing hypothermia.

Watterberg KL. Hydrocortisone Dosing for Hypotension in Newborn Infants: Less Is More. The Journal of pediatrics. 2016. A great review from Kristi Watterberg about the dose that we might need to treat hypotension (and shock). She reviews the available data regarding the dose requirements to mimic stress steroid release, and the data about potential harms of excessive steroid levels during critical illness. She notes that 0.5 mg/kg should normally give a response if one is going to occur, but that, practically speaking, that might just lead to a delay and a desire to try a higher dose, so as a result:

, I suggest a “test dose” of 1 mg/kg. If no response is seen within 2-4 hours after 1 mg/kg is given, further dosing is not warranted. If the infant’s … cardiovascular status improves over this time frame, subsequent doses of 0.5 mg/kg can be given, with an initial planned dosing interval of 12 hours for extremely preterm infants, and 6-8 hours for late preterm and term infants.

In the absence of trials comparing different doses, I think this is the best we can do, and I plan to follow this guidance.

Tang J, et al. Randomised controlled trial of weaning strategies for preterm infants on nasal continuous positive airway pressure. BMC pediatrics. 2015;15(1):147. How to wean CPAP? This pilot trial of only 60 babies in a 2×2 factorial trial was performed to get some more information before progressing to a larger trial. Once babies needed 5 cmH2O or less they could have their CPAP stopped, or have alternating periods with and without CPAP. With either method they could either have high flow nasal cannulae or not. Babies who had “abrupt” weaning spent less time off CPAP. One important result was that babies in the abrupt weaning with no HFNC group were much more likely to be taken out of the trial by their parents, as they weren’t satisfied with the weaning method. It is interesting to me that a few years ago the parents would have all been satisfied with this method as it is what we always did! So how did the parents develop this attitude? There was no objective finding that the babies were worse off at all.  In some centers it has become almost universal that a period of time on HFNC follows discontinuation of CPAP, maybe that subtly influenced the parents to think their baby wasn’t getting the right care for them; or maybe the parents in this study were sensitive to the needs of their baby in one group that they felt were struggling more, even though the investigators couldn’t see much difference.

There is a tendency to think that HFNC is a benign intervention, but I think overuse of any intervention, including HFNC, is a problem. Effects on development of the lungs, on development of orality, and so on, are understudied.

About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
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