Neonatal Research

This post is  a bit of a catch up, to mention articles that are worth reading, but which I didn’t have time to write a full post about, in particular studies that could have a positive impact on clinical care.

Let’s stop monitoring gastric residual volumes… please!

Measuring how much liquid is left in the infant’s stomach, just before the next feed, is a practice based on good intentions, but no evidence. Good-intention-based-medicine has, unfortunately, often been proved ineffective, or even harmful, especially when compared to evidence based medicine. This study from Israel (Riskin A, et al. The Impact of Routine Evaluation of Gastric Residual Volumes on the Time to Achieve Full Enteral Feeding in Preterm Infants. The Journal of pediatrics. 2017;189:128-34).  showed the same as other studies, that the only clinically detectable impact of measuring gastric residuals is to slow down how fast babies are progressed to full feeds, without any clinical benefit.

If you give babies more nutrition, they grow more.

One of many studies that show that being more “aggressive” in early nutrition has positive impacts on weight growth, but also head circumference growth, and, perhaps, long term body composition.

Genoni G, et al. Nonrandomised interventional study showed that early aggressive nutrition was effective in reducing postnatal growth restriction in preterm infants. Acta Paediatr. 2017;106(10):1589-95. Approaching recommended standards for nutritional intakes improves usual measures of postnatal growth restriction, which are based mostly on weight.

The word “aggressive” bugs me here, the idea that trying hard to approach an intra-uterine delivery of nutrients, and approximate intra-uterine growth is somehow “aggressive” strikes me as wrong-headed. If we are to reduce the obvious negative impacts of being born far too soon, we must ensure that corporal and cerebral growth approaches normal values; not just in terms of quantity, but also quality. You can certainly have quantity without quality, but can you have adequate good growth, without enough overall weight gain?

If they grow more, are they smarter?

The next study addresses some of the same issues: Raghuram K, et al. Head Growth Trajectory and Neurodevelopmental Outcomes in Preterm Neonates. Pediatrics. 2017. Infants who had better head growth in the neonatal and the post-discharge follow up period had better developmental outcomes, Infants with poorer head growth in the neonatal period, up to discharge, were affected (i.e. had poorer developmental outcomes), and their head growth correlated with their body weight increase.

I think the first barrier to overcome is to ensure that weight, head, and length growth are close to normal intra-uterine values, then we need to evaluate what that means for details of body composition and developmental outcomes. I will come back to this issue soon!

At last, something better than amphotericin B?

This planned phase 3 study was stopped early because of inadequate numbers. Which is  a great shame as we really needed to know if there was something better than AmphoB, which there probably is. In this study, micafungin was as effective as Amhpotericin B, and did not have more adverse events. Benjamin DK, Jr., et al. A Phase 3 Study of Micafungin Versus Amphotericin B Deoxycholate in Infants with Invasive Candidiasis. Pediatr Infect Dis J. 2018.

I have often seen minor adverse effects of Ampho B, and doses are often limited because of the concern about adverse events, most AE’s are minor, but a safer, equally effective antifungal would be a great addition. The echinocandin group, including micafungin, seem to be good candidates, with known pharmacokinetics, and a good safety profile. This phase 3 comparative trial showed little difference in efficacy or safety, but was underpowered for both, with only 30 babies in total (2:1 micafungin:amphotericin). Hats off to Danny Benjamin for trying to get this done, but a great problem in our community that we cannot do adequately powered trials to answer important question like this.

One of the initiatives in our NICU is the implication of former parents of NICU patients; we have been examining ways of integrating former parents as support/resource/information sources for parents who arrive in neonatology with little idea of what to expect.

I remember, as a medical student, visiting the NICU for the first time and being blown away by how unique it was, how different to anything I had experienced before (and I had already done an adult ICU attachment), imagine how much harder it must be for a parent! Annie Janvier and her colleagues here at Sainte Justine have recently published an overview of how former NICU parents (“veteran resource parents”) are integrated into neonatal programs Bourque CJ, et al. Improving neonatal care with the help of veteran resource parents: An overview of current practices. Seminars in fetal & neonatal medicine. 2018;23(1):44-51. Parents have been involved in several different roles, in clinical care, but also in research and in education.

We have been trying to ensure that families are involved in every part of what we do, with the overall objective being to provide optimal care to babies that is consistent with the values of the community. Many of our research projects now include parents in various roles (including editing consent forms), they are also involved in teaching, including in simulations, and in helping new parents adjust to the NICU.

We have support from Prema-Quebec for some parts of the program, but parent-partners who are involved sometimes engender costs that aren’t being covered. So we have set up a fund with our foundation and are raising money to support the parent/partners initiative. I will be running a 10k this year, as I haven’t trained enough to do the half marathon, mostly as a result of my serial viral illnesses.

Please consider making a donation; it is very simple, just click here  then click on “donate now” next to my name, Scotia bank and the foundation cover all the administrative costs, so every penny donated goes to our PAF-fund. (PAF is for Parternariat-Famille) If you go to the team page you can see the names of the team members, many of whom are NICU parents, as well as some NICU patient siblings and even one or two ex-NICU patients! Along with nurses, doctors, other healthcare professionals and 3 Barrington-Janvier kids.

There has been a lot of activity recently around a case that happened several years ago. In a hospital in the UK a boy with trisomy 21 was admitted, with signs of infection, and he deteriorated and died. Several signs of his deterioration were present, but did not receive adequate response, finally he had a cardiac arrest and died. The senior trainee was eventually arrested and put on trial for criminal negligence causing death, a charge that can lead to prison time.

Several articles in a recent BMJ address the issues surrounding the case, which ended up with the trainee being found guilty, and sentenced to a 2 year suspended jail sentence. She also initially had her medical licence suspended, but it has now been completely revoked after the General Medical Council in the UK thought that temporary suspension wasn’t a severe enough punishment and appealed the suspension.

There is a very thoughtful article in The Times about the case, entitled “Are Hospitals Doomed to Repeat Their Mistakes?” The author  notes that there were multiple factors in the case that increased the likelihood of errors, the Dr involved had just returned from maternity leave, was not oriented to her new role in an acute assessment unit, was covering several other physicians who were not available, eventually covering six hospital services over 4 different physical floors of the hospital; and she actually told the covering consultant physician that the baby had a pH of 7.07 and a lactate of 11, but the supervising consultant escaped any criticism because his trainee had not emphasized that the values were worrying.

I hope that in a similar case in my hospital, the multiple problems with the case would be addressed. I think the processes in place here, in general, would have addressed many of the systemic issues, rather than blaming a trainee. In fact blaming trainees is unlikely here, and certainly a trainee who informed her supervisor of seriously abnormal results would not have been blamed.

Trainees are supposed to be just that, to be under supervision. If a resident told me that a baby had a lactate which had risen to over 11 with a consistent serious metabolic acidosis, then, as soon as I knew that, the response to the abnormalities becomes my responsibility. If I fail to respond then there should be in place processes to ensure that there is follow-up, and not with the resident, but with me!

The author of The Times article draws parallels, as has often been done before between the culture of learning from mistakes in aviation, and the risks of a blame based culture, which the courts are designed to promote.

In the aftermath Bawa-Garba (the trainee involved) talked through the case with her consultant, an important process that enables doctors to reflect and learn from their experiences. To her credit, she confided in the consultant that she could have done better. This was a tribute to her candour. Everyone can get better. Everyone can improve. Yet that one sentence from a confidential reflection was later used against her in court. Her honesty provided a key plank of the prosecution argument. If she could have done better, doesn’t that imply she was somehow negligent?

It is difficult to exaggerate the significance of this case, not just to Leicester (where the incident occurred) but the entire NHS. Preventable medical error kills thousands every year. The only way to reduce these figures is to learn from every single one. This cannot happen if professionals are so fearful of being penalised for entirely honest mistakes that they live under a cloud of fear. Why would a doctor be open, a key prerequisite for institutional learning, if they could be put through years of hell for doing their very best in the most trying of circumstances?

Matthew Syed (the author of the piece) notes that there were no fatal jet plane crashes last year in the entire world (that is right not one), a result of the aggressive quality control initiatives that seek out correctable failings in the system, and where pilots and crew are encouraged to report every minor failing in the system, knowing they will not be automatically individually blamed.

I know that I have made significant errors in my career, one of which (many years ago) led to a child having a second surgery, because a new procedure with a new use of a medication was not interpreted correctly by me. I prescribed a dose of heparin which was 10 times too high, and I then went and checked on the dose as it seemed too much, but by the time I returned to correct the prescription the nurse had already given the excessive dose (which I did not realize at the time), and during the night afterward the patient started to bleed excessively and had to go back to surgery.  The next day I clarified with the consultant that it was my error and not the nurse’s, and there were then safeguards put in place to prevent similar future events. If I had known there was a risk of a criminal prosecution, which would have ended my career, I might have been much more reticent about whose fault it was.

We can reduce medical errors if there is a culture of openness and transparency, if everyone is encouraged to report failures without a risk of individual blame, and if the response to an error is to find a solution, rather than to find the individual responsible.

After several years of preliminary investigations,  a huge RCT has been published from India (Panigrahi P, et al. A randomized synbiotic trial to prevent sepsis among infants in rural India. Nature. 2017;548:407.) which enrolled babies over 2 kg birth weight between 24 and 96 hours of age to receive a synbiotic mixture, Lactobacillus plantarum with a fructo-oligosaccharide, which they received for 7 days. This followed studies showing that this mixture led to stool colonization for several weeks of life. All the babies were breast-fed, although a few received additional liquids by mouth, including water and honey.

The babies were then followed for up to 60 days to see if they needed evaluation for sepsis, which was diagnosed by WHO criteria. The primary outcome of the trial was the combined outcome of death or sepsis.

They planned to enrol over 8,000 babies, but stopped early after “only” 4,556 babies for efficacy.

The combined outcome of death or sepsis was reduced from 9% in the controls to 5.4% in the synbiotic group. The entire difference being in sepsis, as mortality was low (<0.3%), there was a reduction in gram-negative sepsis, gram-positive sepsis and lower respiratory tract infections, as well as in culture-negative sepsis.

The study was a remarkable achievement, an individually randomized, placebo controlled trial in over 150 villages in India. The study excluded smaller babies, and those thought to be under 35 weeks, as well as 254 suspected to be septic at the time of screening for study entry, and those whose mothers appeared to have perinatal infections. The total number of exclusions came to 2,506. The synbiotics were supplied in capsules with “mixing containers and syringes with needles” initially kept at -20 degrees Celsius then distributed with cold packs. I am not sure exactly how the synbiotics were administered, which I think is an important detail for future wide implementation. I presume the syringe and needle were used to inject a solvent (?sterile water) into the capsules and then aspirate it prior to administering the liquid into the mouth of the baby.

The technical difficulties in distributing and administering this synbiotic preparation as a routine will need to be addressed, but this is an intervention with little or no risk that could improve outcomes for millions of babies around the world.