Humans, after they are born, are supposed to receive their nutrition via the gut. Before that of course, they receive a continuous infusion of nutrition via the umbilical vein. We are far from having an intravenous nutrition mixture for sick preterm infants which closely reflects what the fetus receives from the placenta, but it is clear that we can affect the usual catabolic state of an unfed newly born preterm infant by initiating intravenous nutrition immediately. Whether this is safe and whether it improves clinical outcomes has not been proven in a strictly scientific sense, but immediately starting amino acid solutions for small preterm infants has become the “norm” in the NICU.

Once we leave the immediate neonatal period of course, there is no similar analogy; parenteral nutrition is abnormal, and could well have a different balance of risks and benefits. Which is not to say that we should ignore data from older patients such as these from this new publication.

A high quality new large 3 center RCT (Fivez T, et al. Early versus Late Parenteral Nutrition in Critically Ill Children. The New England journal of medicine. 2016), the PEPaNIC trial, challenges the benefits of early intravenous nutrition in critically ill children, and is consistent with other data in adults. In studies from the adult ICU, early initiation of parenteral nutrition (I will call it PN) may increase infections, had no clear benefits, and, even among those who are extremely high risk of malnutrition, has not been shown to have benefit. This seems to be particularly true in adults who can receive early oral or enteral nutrition, adding early PN may be detrimental.

The new RCT is in  children admitted to the PICU with an expectation that they would have to stay for at least 24 hours. They were randomized to have early PN, or late PN. The protocol for early PN varied among the units, which is both a strength and a weakness of this study, all children received enteral nutrition as soon as it was thought to be safe; in one center the early PN was started on day 1 with an amino acid mixture, the other two centers started with a glucose infusion alone. All 3 centers added lipids on day 2, one of the centers started amino acids on day 2, the third added the amino acids on day 3.

The late-PN group had no intravenous nutrition until day 8.

The main finding of the study was that early PN led to an increase in the proportion of patients who developed a new infection during hospitalisation. The biggest increase was in respiratory infections, which brings me to one question I have about this study; there is no definition of the primary outcome in the paper, nor in the study protocols, which are available from the FPNEJM (formerly prestigious new england journal of medicine). In the supplemental appendix it is noted that the diagnosis of infection was made by “infectious disease specialists” blinded as to treatment allocation, who reviewed the hospital charts of every patient who had more than 48 hours of antibiotics, started after arriving in the PICU. They give a reference at that point, (Horan TC, et al. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. American journal of infection control 2008;36:309-32) which does contain widely used definitions of infections, but the manuscript, and the appendix, don’t explicitly say if those were the definitions that had to be followed in each case. If we assume that to be so, then the blood stream infections are easy-ish, diagnosing respiratory infections is much more difficult, especially in the newborn were there are no validated definitions of ventilator associated pneumonia. If the infectious disease specialists were indeed effectively masked to treatment allocation, this may not produce a bias, but might add some random noise.

I am going into some detail about this study, as, even though it was in a PICU population, 209 of the 1440 patients were newborns who had been born at full term, that is they were less than 28 days old on admission to the study. Subgroup analysis revealed no statistically significant differential effect between the newborns and the remaining patients. By which I mean to say that early PN was just as harmful in the newborns as it was in the older children.

The overall study outcomes were: an increase in new infections from 10.7% with delayed PN to 18.5% with early PN, airway infections increased from 4.2% to 8.2%, and bloodstream infections from 1.4% to 3.2%. Other infections were rarer and not affected. So the Odds ratio for developing a new infection was 0.48. It was 0.47 among the newborn subgroup, (95% CI for the adjusted OR for the overall analysis, 0.35, 0.66).

The other primary outcome was length of PICU stay, which was substantially  longer with early PN, from an average of 6.5 days to an average of 9.2 days. The newborns also had a longer PICU stay if they had early PN.

Among the secondary outcomes, the duration of mechanical ventilation was longer with early PN, 6.4 days on average compared to 4.4 days.

Mortality was almost unchanged in the study, 6.1% with early PN  and 5.3% with late. there was more hypoglycemia with the late PN, but that was the only potential advantage of early PN.

As I mentioned above, the results are similar to other studies in adults, in particular a study of over 4000 adult ICU patients run by the same group from Leuven. In that study adults who were mostly able to tolerate some oral or enteral nutrition were randomized to a similar comparison to the PEPaNIC trial. That study also showed an increase in infections and increased duration of ICU stay with early PN, and no difference in mortality. In contrast another study in 1372 adults with contraindications to enteral nutrition showed no difference in infections and shorter duration of assisted ventilation when they were randomized to early PN, compared to delayed PN. In yet another, much smaller study among 300 adults randomized after 3 days in the ICU if they were receiving less than 60% of their nutritional needs enterally. In that study the group that did better was the early PN group, who actually had fewer nosocomial infections.

Which is all a bit confusing, but in general, I would suggest the following interpretation: it seems to me that if you can get very little or none of your nutrition by the enteral route, that early PN has benefits, with maybe a reduction in ventilator days, and an uncertain effect on infections. If there is no contra-indication to increasing nutrition by the enteral route as quickly as possible, then adding early PN, just to try and get the numbers right in terms of calorie and protein administration, may have a balance of negative effects with an increase in infections.

What are we neonatology folks going to do about this? I don’t know, is the simple answer. I don’t routinely start PN on admission for full-term babies in the NICU, but many of them get started very quickly afterward, often ordered the next morning, unless enteral nutrition can be increased quickly. Some full term  babies with gastrointestinal anomalies who we can’t feed get PN very quickly, and get it increased rapidly

So the question is relevant to our babies, if we delayed PN for a few days while increasing enteral nutrition, might they do better?

How are our babies different to those in PEPaNIC?

In my NICU, most of our full term babies are admitted on day 1 or 2, with a few others through to the end of the first week, thereafter they are admitted to the PICU. Very few of the babies in the PEPaNIC study would have been admitted on day 1, if admission patterns in Belgium (and the 3rd site in Edmonton Alberta) are like ours. How much difference might that make? We worry that a period of low calorie intake after birth leads to a catabolic state, which can be reversed by good PN. But, many acutely sick older children are also catabolic on admission to the PICU. So it may not be that much different a situation.

As for the diagnostic mix, The authors state that diagnostic group did not interact with the benefits of delaying PN.

The frequency of new infections among these children seems high compared to what I can find from NICU publications. In the latest CNN annual report for example, the incidence of blood stream infections more than 48 hours after birth was 1% (The definition is “after birth” not “after admission” so this definition leaves the possibility that there might be a few babies admitted with a diagnosis of sepsis at 3 days of age who would be included in the CNN definition, but not in PEPaNIC) , 64 babies among 6,200 babies of 37 weeks gestation or more admitted to the NICU and surviving more than 2 days. Some of these babies will likely be of lower risk than the babies in the PEPaNIC trial, but I think most term admissions to the NICU have a predicted length of stay of at least 48 hours, and many are critically ill. Having been attending staff in both NICU and PICU, I don’t think PICU very young infants have an overall systematically different severity of illness than the NICU term babies.

Overall, I would guess that I have to say that the newborn stratum of the PEPaNIC trial are potentially relevant to NICU term babies. The differences with preterm infants are much greater, but even there the relevance is not so far-fetched.

As these authors note, prior observational studies showed associations of early nutritional support with improved outcomes. Which shows again the importance of randomized controlled trials.

Which means (drum roll) I think we need a large enough trial in the NICU term population to investigate the risks of early PN. It should be stratified according to whether enteral nutrition is extremely limited or nil, in one stratum, compared to rapidly advancing in the other, and should compare very early PN to PN delayed until…. when? Perhaps for our population, a good date for late starting of PN would be when the nutritional deficits are accumulating, rather a strict number of days; but the size of the potential effects seems quite large, and certainly worth investigating.

If a term NICU trial shows the same adverse effects if early PN as PEPaNIC, then a further preterm trial might be warranted even though, at present, all the data we have supports giving PN immediately in the very preterm; as science-based medicine advocates, we have to always be ready to admit, “I might be wrong”.