Making intubation safer for the most fragile babies

Posted on 31 October 2022 by Keith Barrington

Many, many years ago, when I was a young trainee physician, we learned almost everything “on the job”. I can’t remember the first patient I intubated, but there were no mannequins, and no simulations, the phrase “see one, do one, teach one” was perhaps an exaggeration, but not far from the truth. When I read, recently, the hilarious book ‘This is Going to Hurt’, by Adam Kay which recounts his time as s junior obstetric trainee doctor in England, it seems that a similar approach continued when he was training, fairly recently.

I don’t remember the first patient I intubated, it was certainly an adult, as I did jobs as a House Officer (intern), then a year as a Senior House Officer in adult medicine before switching to paediatrics. During that year I would often institute intensive care for the most critically ill patients, I remember inserting peritoneal catheters to start dialysis, putting in central lines to start intracardiac pacing, and intubating several patients. The first one, or maybe two, intubations were probably done with an anaesthetist standing by my shoulder coaching me. By the time I did my first neonatal job I was asked if I was able to intubate, and, as I answered in the affirmative, I was given first option on the intubations that occurred in the NICU during my calls. In those days we also intubated in the delivery room all babies born with thick meconium in the amniotic fluid, as we were convinced this would reduce the risks of severe meconium aspiration syndrome. We would repeatedly intubate and suck on the tube as we removed it, until the fluid that returned was clear, so sometimes needing 3 or 4 intubations and sometimes even more. We even tried to stop the babies breathing vigorously as we did the intubations! This meant that I rapidly became an expert at endotracheal intubation in larger babies, and gradually in smaller infants also.

Returning to the present, we now know a lot more about physiologic responses to intubation, and the adverse impacts of failed intubations and multiple attempts (Singh N, et al. Impact of multiple intubation attempts on adverse tracheal intubation associated events in neonates: a report from the NEAR4NEOS. J Perinatol. 2022). For example, having multiple attempts at endotracheal intubation in the delivery room increases the risk of intraventricular haemorrhage (Sauer CW, et al. Intubation Attempts Increase the Risk for Severe Intraventricular Hemorrhage in Preterm Infants-A Retrospective Cohort Study. J Pediatr. 2016;177:108-13), and many babies desaturate severely during intubation. It is critically important to make intubation as safe as possible for at-risk babies. At the same time we have to train new young paediatricians, many of whom will eventually work in hospitals with delivery rooms, where they will be responsible for neonatal resuscitation, and may provide coverage for level 2 neonatal units where intubation skills may be important. We have therefore, a dual responsibility, both to future babies, to ensure that our trainees can care for them adequately, but, most importantly, to the fragile babies currently in our NICU.

My colleagues and friends, the 3 authors of this study, Michael, Christian and Ahmed, (Assaad MA, Lachance C, Moussa A. Learning Neonatal Intubation Using the Videolaryngoscope: A Randomized Trial on Mannequins. Simul Healthc. 2016;11(3):190-3) have been performing a series of studies of the best way to teach intubation skills. Residents now intubate mannequins before they ever touch a baby, and they have a refresher course with a mannequin and the videolaryngoscope at the start of their first NICU rotation. They are supervised performing their first real-life intubations with video laryngoscopy, (Moussa A, et al. Videolaryngoscope for Teaching Neonatal Endotracheal Intubation: A Randomized Controlled Trial. Pediatrics. 2016;137(3):1-8), and most subsequent intubations in the NICU are performed by trainees using the videolaryngoscope. In addition, all intubations in the NICU (except in a major emergency) are premedicated, with atropine, fentanyl and succinylcholine (Barrington K. Premedication for endotracheal intubation in the newborn infant. Paediatr Child Health. 2011;16(3):159-71). Atropine reduces bradycardia, fentanyl reduces pain (and intubation is a very painful procedure) and improves physiologic stability, and succinylcholine shortens the overall duration of intubation (Barrington KJ, et al. Succinylcholine and atropine for premedication of the newborn infant before nasotracheal intubation: a randomized, controlled trial. Crit Care Med. 1989;17(12):1293-6) and reduces the number of attempts required.

Despite these standards, endotracheal intubation remains a procedure with high risk of desaturation, occasional bradycardia, and sometimes requires multiple attempts. Our group decided a few years ago that it wasn’t a good idea to have trainees performing their first intubations with the most fragile babies. We therefore restricted endotracheal intubation of the highest risk babies to only those who had demonstrated competence in the procedure with larger babies. Babies under 29 weeks gestation are only intubated by the “tiny baby” team members, which includes neonatologists and fellows, nurse practitioners, respiratory therapists who are members of the transport team, and residents. In order to be on the team, an intubator had to successfully complete at least 5 intubations on larger infants, 4 of which had to be with either 1 or 2 attempts. These criteria were entirely arbitrary. It was difficult to decide what the criteria should be as there was little previous information to base them on, and if we were too restrictive there would not be enough people around to ensure that there was an intubator on every shift! We have just published our experience with this approach, comparing pre- and post-institution of the tiny baby team. (Gariépy-Assal L, et al. A tiny baby intubation team improves endotracheal intubation success rate but decreases residents’ training opportunities. J Perinatol. 2022). We compared 3 periods, just prior to starting the team, a second period starting 6 months later, and a 3rd period starting 4 years later.

Here is an edited version of table 2 from the publication, showing the overall numbers and results of “ETI” endotracheal intubation, in the 1st 3 columns, then the results for the tiny baby team and the remaining infants. One thing you can see is the reduction in overall intubations, with more babies being managed non-invasively, a change which is most marked <29 weeks.

You can also see that the success rate, on first attempt, among the tiny babies increased when the team started and has remained higher, and the proportion needing more than 2 attempts dropped from 23% to just over 10%. Over these periods, if the first intubator was a junior trainee, they were only usually allowed one attempt, which is why the residents’ success rate is lower than the second attempt success rate in all categories. The number of intubations and the proportion performed by residents have both fallen overall, which has made it even more important to ensure that all forms of training are optimized for future paediatricians to be able to adequately perform the task. One change between T2 and T3 was that residents were prioritized for the intubations of babies >28 weeks. Coupled with enhanced simulation training, their success rate for the larger babies was improved in the most recent period.

This study wasn’t designed to look at the physiologic changes during intubation, but the NEAR for Neos registry has recently published data confirming that serious adverse events are more common with multiple attempts. (Singh N, et al. Impact of multiple intubation attempts on adverse tracheal intubation associated events in neonates: a report from the NEAR4NEOS. J Perinatol. 2022;42(9):1221-7). This is a multicentre registry with data contributed by many hospitals in the USA, Canada and Australia. Those data confirm that more than 1 attempt, and especially more than 2 attempts, are associated with serious adverse events. Severe “TIAE”, tracheal intubation associated events, include cardiac arrest and massage, airway injury, vomiting and aspiration, air leaks, and delayed recognition of oesophageal intubation.

They confirmed that the requirement for multiple attempts was much greater among the most immature babies, and also when the intubator was a paediatric trainee, and was much lower when the baby had received a muscle relaxant. Overall 22% of the intubations required more than 2 attempts.

I was disappointed to see that of the over 6,600 intubations, 3,800 of which were in the NICU, only 2,760 received sedation and a muscle relaxant. Of those that did receive the optimal combination, only 16% needed more than 2 attempts. This is not the first time this group has reported the benefits of sedation with paralysis for reducing “difficult intubation”, and, of all the dozen or so reports I have found of the use of muscle relaxants during intubation, they universally show a reduction in adverse outcomes, depending on what they were measuring, either serious adverse events, desaturation, duration of attempts, or number of attempts. I don’t think there is a good excuse for not giving newborn infants requiring non-emergency intubation in the NICU an adequate pre-medication with a potent rapidly acting analgesic (either fentanyl or remifentanil are the best options) and a muscle relaxant (either succinlycholine or mivacurium, unless you want more prolonged paralysis in which case rocuronium) with atropine to prevent reflex vagally mediated bradycardia. In one recent publication it was reported that it took an median of 16 minutes for the babies to receive the premedications, I find that a little bemusing. We have a “crash cart” in the NICU with the medications easily available, pre-printed charts with the doses already calculated for each step of 100 g of weight, and all the equipment that may be required. Once I say I want to intubate a baby, the crash cart and additional nursing staff arrive, and the baby is often receiving the atropine within 3 minutes, there aren’t many intubations that are so urgent that they don’t receive our cocktail.

The other thing that you can do to improve stability during neonatal endotracheal intubation is to provide a flow of oxygen. My mentor, Neil Finer, was ahead of his time in many ways, he was among the first to study premedication for neonatal intubation, and one thing that was standard in his NICU was the oxyscope, a laryngoscope with an oxygen channel, to which an oxygen source was attached during intubation. I think “Oxyscope” was a trade name which may have been replaced by “Oxiport”, and I am not sure is still being manufactured, but it provided a fresh gas flow near the larynx which decreased desaturation. (Ledbetter JL, et al. Reducing the risks of laryngoscopy in anaesthetised infants. Anaesthesia. 1988;43(2):151-3). Although not using that commercially-produced blade, a much more recent publication (Steiner JW, et al. Use of deep laryngeal oxygen insufflation during laryngoscopy in children: a randomized clinical trial. Br J Anaesth. 2016;117(3):350-7) has confirmed that taping an oxygen cannula to a standard laryngoscope blade also works, and that a video-laryngoscope blade with an integrated oxygen channel exists, which also decreased desaturation in larger children during intubation. These laryngoscopes have only been studied with 100% oxygen flows, usually about 2 litres per minute, and there are of course concerns about brief episodes of hyperoxia that might be associated with their use. However, hypoxia and subsequent re-saturation is probably rather worse for the generation of free radicals than a couple of minutes of hyperoxia, and using a fresh oxygen flow into the pharynx of an apnoeic infant is unlikely to lead to much hyperoxia anyway.

Another way of providing apnoeic oxygenation during intubation is with the use of high-flow nasal cannulae (HFNC), I already posted about the SHINE study from Melbourne using high-flow, here is another trial, a pilot from Dublin (Foran J, et al. Nasal high-flow therapy to Optimise Stability during Intubation: the NOSI pilot trial. Arch Dis Child Fetal Neonatal Ed. 2022:fetalneonatal-2022-324649), as a pilot there were only 43 babies, and 50 intubations included. Infants (who were all premedicated, as in the SHINE trial, with atropine fentanyl and succinylcholine, also known as suxamethonium) had HFNC placed at 6 lpm with 100% oxygen, which is different to the SHINE trial who used a flow of 8 lpm at the same FiO2 as the infant was already getting and only increased to 100% if they desaturated. Another difference is that SHINE was just during the 1st intubation attempt, whereas in this trial they removed the cannulae after the first attempt and put them back if another attempt was required. This new trial had as the primary outcome the duration of desaturation below 75%, which was shorter in the preterm babies (median 29s vs 43s) and not much different in the term babies, as I said, this was a small pilot.

Here is the profile of the median saturations in the <34 week and >33 wk groups.

It seems to show two things, that the babies clearly desaturate faster without oxygen (!) and that someone should have stopped the intubation attempts before they got out to 120 seconds!!! The NRP used to state that an intubation attempt should take a maximum of 20 seconds, Neil Finer showed that was unrealistic Lane B, et al. Duration of intubation attempts during neonatal resuscitation. J Pediatr. 2004;145(1):67-70, that even experienced fellows took an average of 22 seconds, and Colm O’Donnell, when he was in Melbourne (O’Donnell CP, et al. Endotracheal intubation attempts during neonatal resuscitation: success rates, duration, and adverse effects. Pediatrics. 2006;117(1):e16-21), showed that the Australian trainees were slower, averaging 38 seconds for residents, and 32 for fellows. The 7th edition of the NRP handbook continues to state that “the steps of intubation should be completed within approximately 30 seconds”. That is clearly unrealistic, given that the average time for consultant neonatologists to perform a successful intubation in O’Donnell’s study was 25 seconds SD 17s. In experienced hands only about a half of intubations are completed in 30 seconds.

Most babies these days will have a pulse oximeter in place, and hopefully functioning, during an intubation, even in the DR. I think that after 30 seconds there should be an evaluation of the babies status, and if the baby is desaturating and the intubation is not completed by 40 seconds a decision whether to continue or interrupt the intubation, by someone other than the intubator, should be made. This is actually one way that I find the videolaryngoscope useful, I can see if the trainee has a view of the larynx, and is about to insert the tube, compared to the situation with the larynx briefly flying past the screen, and the tube tip heading for the dark hole of the oesophagus.

I don’t know if the combined oxyscope/video laryngoscope would be more or less effective than HFNC to reduce desaturation and adverse events during intubation, but I think someone should find out!

In summary, making endotracheal intubation safer for our most fragile patients requires the following:

  1. Adequate training of all intubators with simulation and video-laryngoscopy
  2. Step-wise introduction of intubators, with video-laryngoscopy, supervision, feedback and repeated training
  3. Ensure that someone with proven competence performs the procedure, by limiting intubation of the highest-risk patients to a restricted list of intubators.
  4. Universal premedication, including muscle relaxation, unless there is a contra-indication, and have procedures in place to administer with minimum delay.
  5. Apnoeic oxygenation, with HFNC, or perhaps an video-oxyscope
  6. Video-laryngoscopy, if you have access to a laryngoscope blade of appropriate size
  7. Ensure supervision of the baby, and their status, by someone who is empowered to stop the procedure if it is going wrong, or is taking too long.
  8. Feedback and further training whenever things go wrong, and even if they don’t.

No more “see one, do one, teach one”!

Even in our NICU, with most of this in place, over 10% of the very immature babies need more than 2 attempts to intubate, we have to find ways to do better than that, to reduce the number and the consequences of failed intubation attempts. During the study that I referred to, of the tiny baby team, we did not have a video-laryngoscope blade that worked for the extremely low birth weight baby, newer technology, and perhaps ever-more realistic high-fidelity mannequins, may help us to further reduce failure rates.

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Time to stop placebo injections in neonatal research projects

Posted on 27 October 2022 by Keith Barrington

Randomized controlled trials are the bedrock of evidence-based medicine. If a treatment has a good theoretical rationale, and preclinical data showing efficacy, the only way to prove efficacy in the human is to randomise patients to the treatment, compared to an alternative, which should usually be some sort of standard therapy, and compare clinically important outcomes. In order to be reliable, randomisation should be masked, which means that, once the patient is enrolled in the trial, and prior to pressing the “randomise” button, the investigators are unaware of which group they will be enrolled.

Masking of the actual intervention is not always possible, for example when comparing different modes of assisted ventilation, and there is less empirical evidence that it makes a difference to results. In particular, in neonatal research I don’t think there is any comparative evidence that shows whether the results of masked trials are systematically different to unmasked trials of the same intervention. The placebo effect, or the improvement in outcomes of control groups, is often misinterpreted as being evidence that the human body has great powers of self-healing, some people even talk about “harnessing the placebo effect”. But, when the outcomes of interest are objective outcomes, the majority of the placebo effect is in fact, “regression to the mean”, or simply that extreme findings usually become less extreme with time, and that most patients recover from most illnesses.

As an example, an uncontrolled trial of a drug (or any intervention) for apnoea will usually show an improvement in apnoeic spells, for a number of reasons. Babies tend to be enrolled in studies when their apnoea is troublesome, and they will therefore, usually, have fewer apnoeas after enrolment. In addition, in this particular example, apnoeas get better with time, so any trial without controls will tend to show improvement over time. But there is really no reason to think that treating babies with a placebo will have any more effect on apnoeic spells than simply not treating them with anything, as long as an objective measure of apnoea is used. Uncontrolled trials of medications for hypotension, as another example, will enrol babies who have blood pressures lower than average; overall such babies will subsequently have higher blood pressures, even if the drug has no effect. But having no treatment, compared to having a placebo infusion will not change that occurrence, both non-treatment and a placebo will have identical effects.

In studies with objective outcomes therefore, one could question the importance of masking the intervention. In my Cochrane review of inhaled nitric oxide for term and late preterm infants, as one example, the outcome “death or ECMO” is very similar between the masked and the unmasked trials. There were a few of both, and I compared the RR and confidence intervals between the masked and the unmasked trials, the results being very similar with the RR for the outcome “death or ECMO” being 0.66 for the masked studies, and 0.7 for the unmasked trials.

This question becomes extremely important when the intervention is a parenterally administered medication. In babies with no IV access in place, or when the medication must be given by another route (IM, subcutaneous…) the tendency in older publications was to give placebo injections, which inevitably create pain. For example, in a trial of erythropoietin prophylaxis published in 1994, control babies received placebo subcutaneous injections 3 times a week for up to 6 weeks. It seems to me to be highly unlikely that subcutaneous saline has any impact on erythropoiesis, not even a “placebo effect”, so the up to 18 painful injections were completely unnecessary. The more recent trial of Juul et al (and some older trials by Ohls and colleagues) used placebo injections for the intravenous phase of the trial, and when an IV was no longer in place, they avoided placebo subcutaneous injections by using sham procedures, in which curtains were drawn around the bed, and a bandage placed where the injection would have been.

This may be inconvenient, compared to just supplying vials with masked information on them and giving the unknown contents by injection, and it may be more costly, but the huge advantage of not inflicting pain on control babies must surely be worth it. A recent article in Acta Paediatrica discusses this issue, and also concludes that placebo injections are neither necessary nor ethically acceptable.

One recent article, which describes a potentially important improvement in RSV prophylaxis, was this one Griffin MP, et al. Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants. N Engl J Med. 2020;383(5):415-25. The authors randomized preterm infants not eligible for RSV prophylaxis in their home countries, to receive either nirsevimab or placebo, 969 received active drug and 484 were randomized to have an intramuscular injection of saline. IM injections hurt. We should only give an IM injection to a newborn infant if there is some benefit to them. The primary outcome of the study was RSV infections requiring medical assistance, which were dramatically reduced from 46 (9.5%) to 25 (2.6%), hospitalisations from RSV were also reduced, from 4% to just under 1%.

Nirsevimab is potentially a significant advance in RSV prophylaxis, a single injection appearing to provide protection for the entire RSV season. Nevertheless, 481 infants received an intramuscular injection of saline. There is no possible benefit to the infant of this painful procedure. The published protocol notes that the blinding was performed at each individual centre, therefore there was an individual who was unblinded at each participating centre. The unblinded individual could easily have been the healthcare worker giving the injection, who could have performed a sham procedure on the control babies.

Even if blinding of the intervention is considered essential (and I hesitantly suggest that it was not, surely RSV infections would be identical in an open-label untreated control group and a masked control group) the blinding could have been maintained by placing an adhesive dressing on the thigh of the control babies, rather than subjecting them to a painful IM injection.

Another recent example is this Rosenfeld WN, et al. Stannsoporfin with phototherapy to treat hyperbilirubinemia in newborn hemolytic disease. J Perinatol. 2022;42(1):110-5, full term babies with a diagnosis of hemolytic jaundice were randomized to stannsoporfin or control, with the primary outcome being changes in serum bilirubin concentration. The 30 control babies received IM saline. I can think of no good reason for subjecting the control babies to the pain of the placebo; surely the lab tech analysing the serum for bilirubin concentrations will not be influenced by knowing which group the infant was in? Even if it was thought that other important secondary outcomes might be influenced by knowing which group the infant was assigned to, the intervention could equally well have been masked by a sham procedure without painful injection. But the only secondary outcomes listed all depend on the serum bilirubin concentrations. There is a plan to perform long term neurodevelopmental outcome evaluation in the infants; I guess it was thought to be just about feasible (and I would challenge that assumption) that knowledge of treatment group could have an impact on neurological or developmental outcomes. Even if this is the reason for maintaining masking of the intervention, such masking does not require intramuscular placebo injections.

Surely it is time to abandon additional unnecessary pain in research participants. We could start with banning placebo skin-breaking injections. Studies in newborn infants, who obviously don’t know themselves which group they are in, could be performed unmasked if the primary outcome variable is objective. If there is some subjectivity in the determination of the major outcomes than masking can be maintained by the use of sham injections.

A major problem is the way painful procedures are evaluated by ethics review committees. One of the worst studies in terms of pain inflicted on the neonatal participants was another RSV prophylaxis trial, the MAKI trial, where infants were subjected to either monthly palivizumab, or monthly IM placebo injections, to a maximum of 5 intramuscular injections of saline. Unusually, this trial was also the source of an article trying to justify its ethical approval. That article concluded

The Institutional review board (IRB) concluded the study has high clinical relevance because the benefit of 50% chance of protection by palivizumab outweighs the risk of side adverse events due to intramuscular administration of placebo.

It is actually impossible to argue with that conclusion, the study was indeed of high clinical relevance, and the “risk of side adverse events” from up to 5 IM saline injections is negligible. But only if you think that pain is not an adverse event. If you include pain as an adverse event the “risk” of adverse events was 100%.

The authors try to justify the use of the IM placebo, without ever mentioning pain, as follows “A placebo controlled control group was necessary because the primary objective will depend on parent-reported daily scores of wheezing along with information from parent-reported questionnaires”. Firstly, I question that rationale, is there any reason to believe that parents would provide biased scores of daily wheezing based on whether the child actually had a placebo injection compared to being enrolled in an untreated control group? Even if there were some evidence of such an effect, the placebo injections could have been replaced by sham injections.

The book from the Institute of Medicine “Ethical conduct of clinical research involving children” has a chapter “Defining, Interpreting, and Applying Concepts of Risk and Benefit in Clinical Research Involving Children” describing how to determine risks, and tries to define “minor increase over minimal risk”, in research with children as research participants. It includes a table which illustrates the hidden way in which pain is taken into account. The table lists “routine history taking” and a “complete neurological examination” as procedures with minimal risks, which we surely cannot argue with. But in the same category is included “venepuncture/fingerstick/heelstick”.

From a purely “risk” point of view, if pain is not considered a risk, then I guess that makes sense, but surely examining a baby and sticking a needle into them should be considered differently? The table also includes, as a minor increase over minimal risk, a lumbar puncture. Lumbar puncture is an extremely low risk procedure in the otherwise stable newborn, why is it given a higher risk status? Is it because we know it hurts, a lot? The only place pain is mentioned in that table is for two other “minor increase over minimal risk” procedures: skin punch biopsy and bone marrow biopsy, where “topical pain relief” is added as part of the name of the procedure. One might wonder why pain relief is not mentioned for heelstick or for lumbar puncture. In another part of the book it is stated “children should always be given the option to receive a topical anesthetic to reduce needle-stick pain”, but I can find no mention of routine analgesia prior to painful procedures in the newborn. The only mention of intramuscular injections is that they are more risky in children with hemophilia

A new publication from Ruth Grunau and the group in Vancouver who have performed amazing research into the adverse impacts of pain, and how to minimize it, has just appeared. McLean MA, et al. Association of Neonatal Pain-Related Stress and Parent Interaction With Internalizing Behaviors Across 1.5, 3.0, 4.5, and 8.0 Years in Children Born Very Preterm. JAMA Netw Open. 2022;5(10):e2238088. This study examined child behavioural patterns at the ages mentioned in the title, and determined the association with painful procedures in the neonatal unit. There was a clear correlation, after correcting for multiple other factors including gestational age, between having more painful experiences and having more internalizing behaviours, across all of those ages. They also showed that a more supportive, positive, and less stressed family environment could mitigate those impacts.

This study, among many others, emphasizes that we need to do all we can to reduce pain in the neonatal period, and any additional avoidable pain should be prohibited. This must include the use of placebo injections in research, which can always be avoided.

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Protein pump inhibitors cause coeliac disease and asthma, and they are unnecessary.

Posted on 24 October 2022 by Keith Barrington

OK, that title is perhaps slightly too definite, the publications that I wanted to discuss are observational studies, which can only prove associations, but it would be hard to perform the prospective controlled trials that would be necessary to prove (or disprove) causality. A trial for PPIs and coeliac disease would need an RCT of about 2400 per group, which will clearly never be done; for asthma the sample sizes I calculated were even larger, around 5000 per group.

So what this first study shows (Boechler M, et al. Acid Suppression and Antibiotics Administered During Infancy Are Associated with Celiac Disease. The Journal of Pediatrics. 2022) is that from a huge database, the military healthcare system database, the Hazard Ratio of having coeliac disease was 3.37, and after adjustment was 2.23, for infants who had a prescription for a PPI prior to 6 months of age; a risk that was also shown for histamine receptor blockers (adjusted HR 1.94) and antibiotics (1.14). Having all 3 was the worst risk (adjusted HR 5.43). They also showed that the longer the infant received a prescription for acid suppression, the higher the risk. In this database about 2% of all the babies got a prescription for a PPI during the 1st 6 months of life.

The other article is also from an administrative database and shows, using propensity score matching, an increase in the frequency of asthma diagnoses and of prescriptions for asthma medications among children who had a PPI prescription. (Wang YH, et al. Association Between Proton Pump Inhibitor Use and Risk of Asthma in Children. JAMA Pediatr. 2021;175(4):394-403), with the hazard ratio being about 1.5 for the various drugs, being highest in the first 6 moths after prescription and then decreasing.

In a recent study from Scandinavia rates of PPI prescriptions were given to up to 8% of all infants under 1 year of age in Denmark in 2017. There must be a global epidemic of hyperacidity. (Lyamouri M, et al. Proton pump inhibitors for infants in three Scandinavian countries increased from 2007 to 2020 despite international recommendations. Acta Paediatr. 2022;111(11):2222-8).

Why on earth are so many babies and infants receiving a PPI? We seem to have become intolerant of babies spitting up, or being irritable, or having colic, all of which can be rather disturbing things for new parents, but which do not usually need, or respond to, any medication!

In the NICU this is usually done because someone thinks a baby has pathological reflux, and gets a label of Gastro-Oesophageal Reflux Disease, which then leads to treatment with a protein pump inhibitor and/or other medications. A recent review article (Sawyer C, et al. Neonatal gastroesophageal reflux. Early Hum Dev. 2022;171:105600) is generally well done, I thought, but it is not intended just for the NICU or for preterm and former preterm infants.

Overall, available evidence does not support the routine use of PPIs or H2RAs to treat classically associated GERD symptoms in post-term infants, although some sub-populations may benefit from treatment. Outside of proven acid-reflux, treatment with a PPI should be time limited and all caregivers should be aware of possible side-effects. Acid-suppression therapy should not be used in preterm infants given the risk of severe side effect.

To put it simply, I think of this as follows:

  1. The only reliable clinical sign of reflux in the newborn is regurgitation, but having regurgitation does not mean that a baby has significant reflux, most babies regurgitate. No other clinical sign discriminates between babies with more or less reflux, either the total number of episodes, or the number of acid reflux episodes. When the nurse tells you they think the baby has significant reflux, either based on using a clinical score, or based on their personal evaluation, there is no correlation with objective measures of reflux.
  2. You cannot diagnose reflux with a laryngoscope.
  3. Diagnosis of abnormally frequent reflux requires objective evaluation, using multi-luminal impedance with pH monitoring.
  4. Most reflux in newborn infants is not acidic, as shown by such studies.
  5. Diagnosis of GOR DISEASE requires evidence, in addition, that the reflux is actually causing clinical problems; this is rarely due to acid in the newborn.
  6. Apnoea spells are not triggered by reflux, for the great majority of cases, but sometimes reflux may be triggered by apnoeas, especially obstructive apnoeas.
  7. Bronchopulmonary dysplasia is not clearly worsened or caused by reflux.
  8. Blocking gastric acid production does not decrease reflux, it just changes it from being majority non-acid to being a very large majority non-acid. It is possible that PPI use actually increases reflux, in several animal models they cause relaxation of the lower oesophageal sphincter.
  9. Gastric acid is there for a reason. Blocking it changes the intestinal microbiome, and increases the risk of respiratory infections, systemic sepsis and NEC. PPIs reduce calcium, magnesium, and iron absorption, and seem to cause coeliac disease, asthma, and increase the risk of fractures.

In summary, only prescribe acid blocking medications if there is some clear evidence that the baby will be improved with less gastric acid production. A rare occurrence.

The review article that I mentioned and linked to also discusses the evidence against using prokinetics, which I totally agree with:

None of the[prokinetic agents] have been shown to reduce GERD symptoms in preterm infants. Similar to other medical therapies for GERD, most are not well studied in neonates and are associated with significant and concerning side effects. Side effects of metoclopramide and domperidone are primarily neurologic including irritability, drowsiness, apnea, and possible irreversible tardive dyskinesia. Erythromycin is associated with infantile pyloric stenosis and cardiac arrythmias. Given the lack of evidence for efficacy and the potential for significant side effects, the use of prokinetic agents to treat neonatal GERD is not recommended.

The review does discuss the idea that bovine protein intolerance is a factor in GOR; in my evaluation there is some soft evidence for this in older infants, and as a result a therapeutic trial of elimination of cow’s milk protein is sometimes included in treatment guidelines, but, as far as I know, there is no such evidence in the newborn, especially in the preterm newborn.

An article I discussed previously noted that lansoprazole was a drug with a major decrease in use between 2010 and 2018, but over the whole period covered by that study about 5% of all the ELBW babies received at least one course of treatment. There were also about 10% of the ELBW infants received ranitidine, which was taken off the market towards the end of that study, let’s hope its use wasn’t replaced by more PPIs!

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Reducing pain from retinopathy screening

Posted on 3 October 2022 by Keith Barrington

Retinopathy screening is undoubtedly painful for preterm babies, formal evaluation with PIPP scores routinely exceed 10 during screening, and may exceed 14, meaning moderate to severe pain. As a planned procedure there is always opportunity for pre-emptive analgesia prior to and during a screening exam, but what? Many of the interventions studied have limited efficacy.

A new systematic review has examined the efficacy of “pharmacologic” methods of pain control, and therefore, using their definition of “pharmacologic”, excluded breast milk, sucrose, swaddling; I know there has been some debate about whether sucrose should be considered “pharmacologic” or not, but that was the definition they used.

Thirunavukarasu AJ, et al. Analgesia for retinopathy of prematurity screening: A systematic review. Pain Pract. 2022;22(7):642-51.

The review, which is unfortunately lacking in cute Forest plots to copy into this post, confirms that topical anaesthesia has limited effectiveness, there are 4 controlled trials that they found, with a mean PIPP score after local anaesthetic of between 10 and 15, reduced by an overall 1.6 points, which although not likely to be due to chance, is a very small reduction.

The other studies they reviewed all used topical anaesthesia in both groups, and examined other additional analgesia. They found 3 trials with acetaminophen (paracetamol to the Europeans) compared to control or placebo or sugar or milk. Overall, 2 of the trials showed a reduction in PIPP scores during the procedure, the 3rd reported PIPP scores after the procedure, which ere also reduced. The 3 trials used 15 or 20 mg/kg of acetaminophen given either 30 or 60 minutes prior to the procedure. As for opiates there were 2 trials of oral morphine which show relatively little effect, and one of intranasal fentanyl which appeared effective, when given in combination with sucrose and topical anaesthesia compared to that combination without fentanyl (Sindhur M, et al. Intranasal fentanyl for pain management during screening for retinopathy of prematurity in preterm infants: a randomized controlled trial. J Perinatol. 2020;40(6):881-7). That was a nice masked study with 50 babies per group, and has the advantage over acetaminophen that it works quickly, I don’t think it has become widespread, but why not?

You can see from that figure, taken from the aforementioned publication, that intranasal fentanyl was rather effective. You can also see from the controls that despite topical anaesthesia, swaddling, and sucrose, retinopathy screening examinations still hurt.

Other interventions that have been tried include nitrous oxide, in a controlled trial by my friend Romain Mandel and our colleagues (Mandel R, et al. Nitrous oxide analgesia during retinopathy screening: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2012;97(2):F83-7) which didn’t have a benefit, Also breast milk, compared to sucrose, which showed that neither was better than placebo control for the acute pain response, but the breast milk babies apparently returned to baseline a bit faster than the sucrose, at least that is what the authors write (Şener Taplak A, Erdem E. A Comparison of Breast Milk and Sucrose in Reducing Neonatal Pain During Eye Exam for Retinopathy of Prematurity. Breastfeed Med. 2017;12(5):305-10), but I can’t see any data in the article to support that contention, the post procedure PIPP scores were lower in the 2 intervention groups compared to control, but there are no reported data about time to recovery.

What I make of all this is that topical anaesthetic is of limited efficacy, but I would still give it anyway, it seems 100% safe, and there is probably a small beneficial effect. Sucrose does very little if anything, but perhaps the babies return to baseline a little faster with either sucrose of breast milk, at the age when the babies are getting screened they are receiving much less sucrose for other procedures, so it will probably be safe to give; the use of breast milk as an alternative does not seem much more effective. Adding a pacifier/soother/dummy usually makes sucrose more effective, but for eye screening this has not been shown for sure, on the other had giving sucrose, with a soother/pacifier/dummy and swaddling does have some impact (O’Sullivan A, et al. Sweeten, soother and swaddle for retinopathy of prematurity screening: a randomised placebo controlled trial. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2010;95(6):F419-F22).

I think that either acetaminophen or nasal fentanyl given before the procedure warrants either routine introduction or more study. I’d like to see confirmation of the efficacy and safety of routine intranasal fentanyl before introducing the practice to large numbers of stable preterm infants, but it does seem effective from that one study, and the dose of 2 microg/kg as a single administration in the nose appears from other data to be safe. The reduction of pain scores with acetaminophen is interesting but it isn’t apparently as effective as fentanyl, although a comparative trial would be nice.

My optimal protocol for the present would be, administration of 15 mg/kg of acetaminophen 30 to 60 minutes prior to the procedure, at the time of application of topical anaesthetic and mydriatic, swaddling of the baby and administration of sucrose 2 minutes prior to the procedure, a second dose of sucrose with a soother just prior to speculum insertion, then repeated sucrose if the procedure takes more than 2 minutes, and trying to avoid scleral depression if possible.

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What dose of caffeine to use?

Posted on 9 September 2022 by Keith Barrington

The dose of caffeine that we used for the CAP trial was the dose that was being widely used at the time. It seemed to be a safe dose, that did not require serum concentration surveillance, but was not based on a large number of high quality dose ranging trials, indeed it was identical to the doses used in the very first publication of caffeine use in the preterm infant, published in 1977 by Jack Aranda, from Montreal (the McGill side of the mountain). (Aranda JV, et al. Efficacy of caffeine in treatment of apnea in the low-birth-weight infant. J Pediatr 1977;90(3):467-72), they used 20 mg/kg of caffeine citrate as a load, and 5 to 10 mg/kg/dose once or twice a day, starting 48 to 72 hours after the load.

The maintenance dose gradually stabilised over the years, although there have been repeated questions about whether it is the optimal dose. There were some pharmacokinetic studies, but few quality pharmacodynamic studies, those that existed rarely used objective quantification of apnoea frequency, which is essential to be able to say much about the impacts on apnoea, nursing records of apnoea spells being notoriously unreliable.

The CAP trial remains the standard, which showed an improvement in medium term, and very long term, outcomes after caffeine use among infants of less than 1250 g birth weight, less than 10 days of age started on caffeine (or placebo) because the attending physician thought they needed caffeine. The dose in that trial was 20 mg/kg of caffeine citrate as a load, and 5 mg/kg daily, that could be increased to 10 mg/kg of caffeine citrate daily if the physicians thought the baby needed more. I submitted an abstract to a PAS meeting which showed that babies who had the dose increase had the same advantage of caffeine as those who remained on the initial dose, which I never fully published (sorry!) but I think was reliable information that the higher dose of caffeine was safe.

Clearly if some caffeine is good, then it is possible that much more caffeine might be even better. If we can keep babies extubated for longer periods of time, and knowing that several animal models show brain protective effects of caffeine, then what dose of caffeine should we give?

In this study in 3 day old rats, for example, the animals received 20 mg/kg/d of citrate for 5 days starting the day before a classical carotid-ligation-hypoxia model, and they had less white matter injury. In another study in newborn mice with an IVH model, caffeine at 20 mg/kg/day for 3 days started after the IVH reduced brain injury and brain atrophy. In another study Jack Aranda returns to caffeine 45 years after the first publication (!), comparing neuroprotection in newborn rats who received a dose similar to the usual human preterm dose (20 mg/kg load of Caffeine citrate followed by 5 mg/kg/d) or a larger dose of 80 mg/kg load followed by 20 mg/kg/d for 12 days. They showed similar neuroprotection with the 2 doses.

But before we ramp up the caffeine dose too far, remember the results of the pilot trial from St Louis, which randomized babies to get 80 mg/kg as the loading dose, starting in the first 24 hours of life, compared to 20 mg/kg in the standard dose group. The 80 mg/kg was actually given over 36 hours, as 4 doses, 40 mg/kg as the initial load, 20 mg/kg 12 hours later, then 10 mg/kg 24 and 36 hours after the first dose, the controls received 20 mg/kg then 10 mg/kg 24 hours later. Both groups in that small pilot (n=37 per group) received the same maintenance dose 10 mg/kg/day of caffeine citrate. The results of that trial showed a greater seizure burden with high dose compared to standard dose, and the high dose babies also had more cerebellar injury; fortunately the 2 year and 5 year outcomes were very similar between groups.

This was actually a slower load than in the previous trial by Steer et al who gave a 80 mg/kg bolus over 15 minutes, and then a maintenance of 20 mg/kg/d compared to their controls who got 20 mg/kg load then 5 mg/kg/d. In that study, the 240 babies of <30 weeks gestation were a little older (2 to 12 days of age, average 4 days) when enrolled and the study was designed to look at extubation failure. The primary outcome, extubation failure was less frequent in the high dose group, and there was a little less BPD in the high dose group 34 vs 48% RR 0.72 (95% CI 0.52-1.01). The medium term outcomes at 1 year of age tended to be better in the high dose group, and are described in more detail in this publication. The developmental quotient from the Griffiths scale is a slightly higher in the high dose group, but I don’t see any publication with later follow up.

There are a couple of smaller studies randomizing babies to higher doses of caffeine. In one of them, published in Chinese so I can only read the English abstract, 162 ventilated infants <32 weeks were randomized to different maintenance doses, they all received 20 mg/kg load before 6 hours of age (presumably of caffeine citrate) then either 5 or 10 mg/kg (presumably the daily dose of caffeine citrate); it appears that the higher dose group were less likely to fail extubation, which was mostly because of apnoea. An Egyptian trial (fortunately for me published in English) randomized 120 ventilated babies <32 weeks to receive either a load of 40 mg/kg of caffeine citrate and a maintenance of 20 mg/kg/d, or a load of 20 and maintenance of 10. They showed less extubation failure in the high dose group, but there is no longer term follow up. Another study from China randomized ventilated infants <30 weeks gestation who were over 48 hours of age and thought to be within 24 hours of an extubation attempt to a maintenance dose of either 5 or 10 mg/kg of caffeine citrate starting 24 hours after the load of 20 mg/kg, which was the same in each group. Extubation failure was decreased with the higher maintenance dose.

Putting this together to me this suggests that very early, very high loading doses of caffeine might be risky, that increasing maintenance doses to 10 mg/kg/d is probably safe and beneficial, with an increase in successful extubation and less apnoea, but limited long term outcome data. Increasing the loading doses after the first couple of days of life probably improves extubation success, but without more safety data I would be reluctant to use very high loading doses as a routine.

One of the particular features of caffeine kinetics is a dramatic increase in clearance as babies approach term. Caffeine is mostly filtered by the kidneys unchanged in early postnatal life of the preterm, and there is a gradual development of various pathways of demethylation with maturation, acetylation probably develops even later. The half life, as a result, is often over 100 hours in the early preterm period, falling to about 4 to 6 hours in an adult.

If we are planning to give caffeine to babies who are more mature, as they approach term, doses will therefore probably have to be adjusted. A trial which randomized 95 preterm babies who were stopping caffeine at >33 weeks, to either usual care without caffeine or to restart it 5 days later with a loading dose of 20 and maintenance of 6 mg/kg showed that the babies had fewer intermittent hypoxic spells in the caffeine group, until they reached 37 weeks PMA, by which time there was no longer much impact of the caffeine, I think this may have been partly because of a lack of power, as the controls were having fewer spells, but may also be because caffeine clearance was rapidly increasing and the infants needed more. The authors of this study therefore enrolled a second cohort of 27 similar babies who received higher doses, which they compared to the controls from their first study. The doses in the 2nd publication were started just 24 hours after stopping clinically required caffeine, and were 10 mg/kg/d of caffeine citrate, increased at 36 weeks PMA to either 14 or 20 mg/kg/d, decided by random allocation. The doses were chosen to try and maintain salivary caffeine concentrations at above 20 microg/mL, thought to be a reasonable therapeutic target for efficacy and safety. In this trial there was a reduction in intermittent hypoxic spells compared to the controls from the previous study.

In a small short term study like this it is not possible to say whether there was a clinical benefit to the babies of having fewer intermittent hypoxic spells. As far as I can see there is no long term follow up of these babies published, but it would have very little power anyway.

All of which is a preamble to a newly published study from Auckland examining the use of caffeine in late preterm infants. We don’t normally worry about these babies in terms of apnoea of prematurity, even though they clearly very commonly have apnoeic spells, most of the spells are brief and resolve spontaneously. However they are accompanied by episodic hypoxia, and repeated hypoxia and re-oxygenation leads to an oxidative stress, which might have adverse long term effects. We also know that the neurodevelopmental long term outcomes of late preterm babies are different to those at term, with more cerebral palsy, and more schooling difficulties.

The new study was to determine a dose that decreases intermittent hypoxia in late preterm infants (Oliphant EA, et al. Caffeine to prevent intermittent hypoxaemia in late preterm infants: randomised controlled dosage trial. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2022:fetalneonatal-2022-324010); babies born at 34 to 36 weeks were randomized to placebo or one of 4 doses ranging from 5 to 20 mg/kg/d, around 25 babies per group, with the first dose in each case being the double of the maintenance. Caffeine (or placebo) was continued until term, including after discharge, and the primary outcome was the number of intermittent hypoxic spells on an oximetry recording performed at 2 weeks after enrolment.

They showed fewer events at 2 weeks of age with the caffeine dose of 10 or 20 mg/kg/d compared to placebo (but not with 15 mg/kg/d), heart rates and episodes of tachycardia were increased in the caffeine groups. Presumably the lack of effect of the 15 mg/kg dose is just a random effect, as the groups were relatively small and the frequency of intermittent hypoxia spells is very variable.

This study confirms that to have an impact on respiratory drive and hypoxic spells near to term, the doses required are substantially higher. What it does not tell us is whether we should be doing this!

If you are caring for an individual child with troublesome clinically important apnoeas who is approaching term, and you want to treat with caffeine, you will need a higher dose to reduce the number of spells, because of the changes in metabolism.

Routine treatment of babies as they approach term is another question entirely. A higher dose than previously used will be necessary IF prevention of intermittent hypoxia spells near to term can be proven to be important. We have known for years that very preterm babies often continue to have multiple apnoeic spells as they approach term and hospital discharge (Barrington KJ, et al. Predischarge respiratory recordings in very low birth weight newborn infants. J Pediatr. 1996;129(6):934-40). We also know that there is a statistical correlation between more days with apnoeic spells and worse neurodevelopmental outcomes. Janvier A, et al. Apnea is associated with neurodevelopmental impairment in very low birth weight infants. J Perinatol. 2004;24(12):763-8.

What we need to know is whether it is safe and effective to give high doses of caffeine to very preterm infants as they approach term to reduce such spells. Even if, as seems likely, we can reduce intermittent hypoxia with higher doses of caffeine with routine continuation towards term, does it actually improve longer term outcomes. Even more important in some ways, given the very much larger numbers of at-risk infants, is it safe and effective to routinely treat late preterm infants to reduce their frequent hypoxic spells?

I am sure Dr Alsweiler and colleagues in Auckland are hoping to follow up the Latte Dosage trial with a large multicentre RCT examining long term impacts of high dose caffeine in late preterm infants, lets hope they get the funding. We tried a couple of times to get NIH funding for a trial in very preterm babies as they approached term, but the trial, as it was designed, was hugely expensive and never got high enough priority. A simpler pragmatic trial would be very valuable, and could inform our community about what to do with caffeine for the preterm infant approaching term.

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Toxicity of antenatal steroids on the developing brain.

Posted on 4 September 2022 by Keith Barrington

A new study from Finland this time, raises similar concerns to those from a Canadian study. (Raikkonen K, et al. Associations Between Maternal Antenatal Corticosteroid Treatment and Psychological Developmental and Neurosensory Disorders in Children. JAMA Netw Open. 2022;5(8):e2228518). It is an analysis of the same dataset that the authors previously published about; in that previous study they lumped together developmental and behavioural disorders, and did not analyse neurosensory difficulties. Using the same enormous linked databases with over half a million children, of whom just over 2% had been exposed to antenatal steroids (presumably all fluorinated steroids for lung maturation). The authors state that they have previously validated that these cases are all indeed betamethasone in threatened preterm delivery. This is important of course, because people take steroids for all sorts of reasons, even during pregnancy, and most are metabolized by the placenta and have no direct fetal or neonatal impact of note.

This time they also differentiated between those who delivered at term and those who were actually preterm. The graphic below shows that most of the outcomes were similar between preterm exposed and non-exposed to steroids, even though the actual gestational age at birth was lower in the preterm babies who had been exposed to steroids (mean 32.8 (SD3.0) vs 35.5 (SD1.7) weeks). Among the babies who delivered at term the exposed and unexposed had very similar GA (39.3 vs 40.1) and other characteristics, but had more adverse outcomes, in just about every domain, with cerebral palsy being the most striking.

The absolute risks are small, however, for CP, for example, the Hazard Ratio is over 2, but the absolute percentages are 0.4 compared to 0.1.

These results are not dissimilar to data from Ontario (Aviram A, et al. Antenatal corticosteroids and neurodevelopmental outcomes in late preterm births. Arch Dis Child Fetal Neonatal Ed. 2022;107(3):250-5) another database study showing that having received antenatal steroids is associated with an increase in billing codes that reflect suspected neurocognitive disorders.

What should we do about these data? I think that we should be more circumspect about steroid use in the late preterm, especially after 35 weeks when the benefits are small. Also we need to find ways to better target steroids to those who are more likely to deliver preterm.

Maybe we should also be reducing the dose? Well…. maybe not (Schmitz T, et al. Neonatal outcomes for women at risk of preterm delivery given half dose versus full dose of antenatal betamethasone: a randomised, multicentre, double-blind, placebo-controlled, non-inferiority trial. The Lancet. 2022;400(10352):592-604) In this multicentre French RCT, over 3000 mothers with threatened preterm delivery who had received their first dose of betamethasone and were less than 32 weeks gestation were randomized to receive either placebo or betamethasone for the second dose. The primary outcome of the study was the need for surfactant treatment, I guess that is reasonable as a primary, it is probably not the outcome I would have chosen, but I am not sure what would have been!

About 60% actually delivered preterm in the study, only 30% prior to 32 weeks gestation, and another 10% prior to 34 weeks. About 20% in each group required surfactant, and the 95% confidence intervals for the difference in surfactant requirements crossed the non-inferiority boundary, leading the authors to conclude that they were unable to show non-inferiority.

Data are all for the primary outcome, need for surfactant

Although this is an important, well-designed study, I do have doubts as I said, about the primary outcome. We don’t really give steroids to avoid giving surfactant, but for all the other benefits on maturation, and most importantly a reduction in mortality in the most immature infants, but a study designed with a mortality outcome would have to be absolutely enormous, so overall, I think needing surfactant is a reasonable proxy outcome.

What about the other important neonatal outcomes?

As you can see there is no clear difference in any of the outcomes, with the exception of the combination outcome among infants who were born within a week of getting the steroids.

It looks like the lower dose is just about as good as the full dose, but, being stringent in our interpretation, they have not shown non-inferiority, the outcome was a little bit more frequent in the low dose dose group, and is consistent with a poorer efficacy. Of note there were only about 250 in each group that delivered within 7 days of receiving steroids.

I was encouraged to read that the study was funded for long term outcomes, with a 5 year assessment including WPPSI and NEPSY subsets and a neuro exam. Also that a Canadian and Australian trial is underway SNACStrial.com with short and long term outcomes being investigated.

It is going to take a while, but we will eventually have good quality data about whether halving the dose of betamethasone is as effective, and potentially safer, than the current dose. If you remember, the currently used dose was derived directly from the original Liggins studies in sheep, and there has never been, until these new trials, any dose response data. It is about time.

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Cord milking and resuscitation, an alternative?

Posted on 2 September 2022 by Keith Barrington

My recent posts about resuscitation with an intact cord were rapidly followed by a publication of another multicentre randomized controlled trial, this time a cluster randomized crossover trial, of cord milking in babies who needed intervention. (Katheria AC, et al. Umbilical cord milking in non-vigorous infants: A cluster-randomized crossover trial. Am J Obstet Gynecol. 2022).

In this trial called “MINVI”, babies of 35 to 42 weeks GA were delivered vaginally or by cesarean, and evaluated during the first 15 seconds, prior to cord clamping. Those with pallor, poor tone, or apnoeic were then exposed to the intervention. If they were vigorous they had usual care (natural cord management).

Illustration from the publication, I don’t see an acknowledgement, but it sure looks like the style of Satyan Lakshminrusimha

Hospitals were randomized to one of two approaches, and, depending on the randomization, babies who qualified then had either early cord clamping (at the latest by 60 seconds) or had cord milking, which was performed with the cord intact, the cord being milked 4 times over a 2 second period each time, and milking about 20 cm of cord. The cord being clamped at a median of 29 seconds in the milking group (IQR 20s- 30s), compared to 20 seconds in the early clamping group (IQR 10s-20s). These durations are presumably estimates, as I don’t think there was someone assigned with a stopwatch to time the interventions (which is why the numbers are suspiciously round numbers!). Once half the study was completed, which took about a year, hospitals then were switched to the alternate approach (with a 2 month “washout” period).

The primary outcome of the trial was admission to the NICU for the following reasons: “respiratory distress (tachypnea, grunting, retractions), bradycardia or tachycardia, hypotonia, lethargy or difficult to arouse, hypertonia or irritability, poor feeding or emesis, hypoglycemia, oxygen desaturations or cyanosis, need for oxygen, apnea, seizures or seizure-like activity, hyperbilirubinemia, and/or temperature instability”. Admission just for observation or for antibiotics or because of low cord pH, for example, was not considered. There were numerous secondary outcomes, including principally HIE, and other outcomes that could reasonably be impacted by the intervention, such as jaundice and hemoglobin levels.

The cord milking group were less frequently admitted to the NICU for the above reasons, 23% vs 28%, however, after adjusting the analyses for centre, the confidence intervals of the adjusted Odds Ratio included no difference between groups, OR 0.69, 95% CI 0.41-1.14. Respiratory distress leading to NICU admission was less frequent with cord milking, other secondary outcomes are shown below

As you can see the cord milking babies were less likely to need respiratory support. There was also less moderate HIE, leading to less cooling, numbers of these neuro outcomes were small which is why there is no adjusted Odds Ratio.

Another illustration from the publication, by Satyan

In the strictest sense this is a null study, with a primary outcome in the two groups being within the usually accepted limits of a possibly random effect. It certainly shows no adverse impact of the procedure, apart from the minor increase in bilirubin.

Anup Katheria, the principal investigator of this study, has previously published a review article (in 2018), which is open access, available via PubMed Central. He reviews the then available data, and the rationale which formed the basis for this study. I must say there is much less data from animal models regarding cord milking, and what is available is not reassuring, one study from Stuart Hooper’s lab, that I recently referred to, studied preterm lambs, (Blank DA, et al. Haemodynamic effects of umbilical cord milking in premature sheep during the neonatal transition. Arch Dis Child Fetal Neonatal Ed. 2018;103(6):F539-F46) and showed that if you did the procedure in one of the two ways they examined, they did not find much evidence that you actually increased blood volume. In that lamb study the milking was done in 2 different ways, the first was to release the cord between milks, so that it could refill from either end of the cord. The second method was to milk the cord, then keep it occluded near the lamb, so that it refilled from the placental end, then it was milked again. With the second method there was a net transfusion of about 9 mL/kg of blood. They also showed major haemodynamic fluctuations during the procedure, with blood pressure shooting up and down during milking.

You can see some of those impacts in this figure, of note there also was no net placental transfusion with physiological based cord clamping.

Although these impacts are concerning, the limitations of this lamb model are demonstrated by the lack of net placental transfusion with clamping after 3 minutes of positive pressure ventilation in the “physiological based clamping” group. Preterm babies with delayed clamping do have higher hematocrits and evidence that they receive a transfusion.

It isn’t clear to me whether the technique used in the MINVI trial is more reflective of the with or without placental refill group in the lamb trial, if I was doing it I think I would tend to hold the baby end of the cord closed with my fingers while the cord refilled from the placental end, (which is what Hooper’s group called WITH placental refill). It may be that the fluctuations in blood pressure and so on are less important in full term babies than they might be in the preterm.

What should be the response to these trials in the clinical realm? It might be too much to ask for a large RCT comparing clamping after PPV to cord milking in babies at or close to term who are non-vigorous at birth. In order to get an adequate sample size, an approach like MINVI, with cluster randomization and deferred/waived consent will be necessary I think.

That is probably the only way to resolve the conundrum, for now, based on these recent trials it looks like either approach would be acceptable, and both seem to be at least as good as early clamping, with no disadvantages of consequence, and all the differences being in favour of the alternative, physiology based clamping or cord milking. Personally, the physiology based clamping is something I find a more pleasing idea, in terms of the physiology, but it looks from MINVI that you can get the majority of the advantages, at least among term and late preterm infants who are non-vigorous.

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Resuscitation before clamping the cord, some physiologic considerations

Posted on 30 August 2022 by Keith Barrington

Delaying cord clamping until respiration is well established is a physiologically pleasing approach, and avoids the dramatic decrease in left ventricular preload, simultaneously with an increase in afterload that occurs with early clamping. But does delaying clamping during positive pressure ventilation have the same physiologic benefits? I had previously thought that the decrease in intra-thoracic pressure associated with an inspiratory effort might increase placental venous return, and that therefore positive pressure ventilation with the cord intact might not have the same benefits. That is probably wrong, although the differential effects of delayed cord clamping with spontaneous respiration and assisted ventilation are not clear to me.

What is clear is that positive pressure ventilation decreases pulmonary vascular resistance, although surprisingly, we don’t really understand the mechanism. Stuart Hooper’s group has done much of this work and in one fascinating study (Lang JA, et al. Increase in pulmonary blood flow at birth: role of oxygen and lung aeration. J Physiol. 2016;594(5):1389-98), they showed that positive pressure ventilation of one lung with nitrogen, causes improved lung perfusion, of BOTH lungs. This was a study in near term fetal rabbits who were instrumented during partial cesarean delivery with the cord intact, but the actual procedures and images were taken after cutting the cord. So it tell us about the physiology of PVR reduction during positive pressure ventilation, but not about other aspects of delayed clamping and ventilation.

The fetal rabbit kits were ventilated unilaterally in the right lung with nitrogen or air or oxygen, then unilaterally with air (1LV2) then the tube was pulled back to ventilate both lungs with air. This is one selected image from the publication, showing the number of vessels that were seen in each lung, and that ventilating the right lung increased perfusion of both lungs, ventilating the right lung with oxygen increased perfusion further, especially of the right lung.

When you are doing physiologic studies in animals it is difficult to ensure that the animals make respiratory efforts reliably at the right moment, so most studies are about positive pressure ventilation. I guess in some ways it is less important for the future of delayed cord clamping what happens during spontaneous respiration, as it has become the standard of care to clamp the cord after at least one minute, if the baby is breathing. The responses to clamping before or after initiating PPV are of more relevance for the decision that we are still considering, whether we should routinely initiate PPV prior to cord clamping in depressed babies. The recent studies have not suggested any reason to me why we should clamp before PPV, if that is technically, logistically possible. In cases of an increased risk of needing PPV, I think the recent trial from Melbourne shows that it is not too difficult to get organized to do this. See the comment on my previous post from Doug Blank. (I’ve never linked to a comment before, hope that works).

I was thinking, based on the physiology, and the BabyDUCC trial, that we should all prepare to perform the initial steps of resuscitation during “natural cord management”. But hang on, what about an alternative… cord milking? (see next post!)

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Is glucose gel safe? Is it necessary?

Posted on 25 August 2022 by Keith Barrington

The Auckland group has been studying the treatment and implications of neonatal hypoglycaemia for many years now, with unique high quality studies. Two of their recent publications have addressed the safety of glucose gel for hypoglycaemia, the first (St Clair SL, et al. Effect of prophylactic dextrose gel on the neonatal gut microbiome. Arch Dis Child Fetal Neonatal Ed. 2022;107(5):501-7) was a substudy of the hPOD trial of prophylactic glucose gel in at-risk babies. If you remember, the original trial enrolled late preterm babies and term babies who were Infants of Diabetic Mothers, or small or large for GA. The trial showed a reduction in the number of babies with hypoglycaemia (<2.6 mmol/L) from 42 to 37%, but no difference in NICU admission (which was the primary outcome). Long term follow up of the hPOD trial, which I already blogged about, showed no major difference in neurosensory outcomes, except for an increase in motor delay in the active treatment group. This substudy examined the impact of glucose gel on the development of the intestinal microbiome, and showed no real difference in bacterial diversity between gel-treated, placebo-treated, and untreated non-randomized controls over the first 4 weeks of life. They did show the expected differences between vaginally delivered and cesarean delivered babies, and despite the tiny numbers of mothers not breast feeding, they showed impacts of milk source on the microbiome also. This is reassuring data that the intervention does not impact gut colonization.

The longer term outcomes of the “Sugar Babies”, randomized treatment trial at 4.5 years have also just been published (Harris DL, et al. Outcome at 4.5 years after dextrose gel treatment of hypoglycaemia: follow-up of the Sugar Babies randomised trial. Arch Dis Child Fetal Neonatal Ed. 2022:fetalneonatal-2022-324148). A very high proportion were evaluated, 78%, and there were very minor differences in background characteristics between groups. Overall there were no real differences in the primary outcome between groups, that is “neurosensory impairment” defined as : one or more of cerebral palsy; visual or hearing impairment; full-scale intelligence quotient (IQ) or Visual Motor Integration score >1 SD below the test mean; Movement Assessment Battery for Children-2 total score <15th centile; motion coherence threshold or executive function score worse than 1.5 SDs from the CHYLD (Children with Hypoglycaemia and their Later Development) cohort means.

The primary outcome occurred in about 38% of each group. Which seems like a lot! There are in particular many infants with MABC scores below the 15th centile, 25% vs 34% in the gel and placebo groups respectively. There are also many actively treated babies with VMI scores below 85, which is a standard deviation beneath the standardized mean, 24% glucose vs 15% placebo. There were a very large number of comparisons, so to find one that was “statistically significant” is hardly a surprise, but it does suggest that there is a need for further studies and further evaluation to see if the difference between groups in VMI scores is reproducible. The high rate of “neurosensory impairment” warrants evaluation, is that similar to other New Zealand infants at this age? I would have expected about 15% below -1 SD for each test, with a lot of overlap, so it is hard to guess how many in the general population would satisfy that definition of “NSI”. It makes me think that infants eligible for the study, and at risk for neonatal hypoglycaemia, are also at increased risk for these outcomes, regardless of how they are treated; which is consistent with other data I have discussed before.

Being maximally critical you could say that there are some minor indications of a possible adverse effect of oral dextrose gel, with a hint of a possible adverse effect on visual motor integration. Could this possibly be related to the effect that the same group reported a few years ago, infants with hypoglycaemia who had glucose therapy and had a more rapid rise in their glucose levels appeared to have an increase in risk of neurosensory impairment (RR 1.8)? This certainly isn’t an argument against glucose therapy, nor against glucose gel therapy, which I think is an advance that can spare many babies from intravenous infusions, but perhaps the first approach should be feeding with breast milk rather than glucose, at least for the majority of babies who have lowish blood sugars, above the threshold that HypoEXIT suggests is safe (2.0 mmol/L). It looks possible that a too rapid increase in blood sugar might have some minor adverse effects. Trying to balance this against the adverse effects of severe hypoglycaemia, and the apparent association of hypoglycaemia risk factors with poorer outcomes is a hugely complex undertaking.

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Anti VEGF treatment of retinopathy: and the long term?

Posted on 9 August 2022 by Keith Barrington

There remains some doubt about the impacts on cerebral development, and thus on developmental progress of anti-VEGF treated babies. It is possible that there are cerebral effects of VEGF inhibition (or interception) and it isn’t clear what the exposure of the brain really is. In this new trial (Stahl et al, that I just posted about), most babies had undetectable serum aflibercept concentrations throughout the study, which is reassuring. Data from other observational cohort studies has shown some association between anti-VEGF “-mab” administration, and poorer outcomes. In this study from the NICHD network, which Roger Soll refers to in his editorial accompanying the FIREFLEYE trial publication, their long term primary outcome, “death or severe NDI” was not much different between bevacizumab and surgery treated babies (adjusted Odds Ratio was 1.42; with 95% CI 0.94 to 2.14). However, mortality was somewhat higher (most of the deaths, and the difference in deaths, was prior to hospital discharge; 9% of the treated babies vs 3.5%), and Bayley III cognitive composite scores were shifted lower by a mean of 3 points, so somewhat more babies were under 85 (aOR 1.78 [95% CI 1.09 to 2.91]). The motor scores were slightly lower in the bevacizumab group, and the language scores were almost identical. The babies in the bevacizumab group also had longer assisted ventilation, oxygen therapy, and hospitalisation, so perhaps they had more severe BPD.

Published follow up of the CNN and CNFUN Canadian cohort also shows lower scores among the bevacizumab treated babies compared to laser surgery, but the pattern is different, cognitive scores were identical between groups, but language and motor scores were worse. There were very few deaths between treatment and discharge. The CNN bevacizumab babies also seem to have been a bit sicker in terms of their lung disease than the laser treated infants. The difference in severity of lung disease is understandable, as bevacizumab was emerging as a treatment during these periods, we tended to use it for babies who we were most worried about deteriorating during surgery, so the simplicity of bedside intravitreal injections made us prefer it among the babies with the most unstable pulmonary status.

The real impacts at long term will require follow up of randomized trials, at present the observational data are conflicting and confusing, in addition to the two large multicentre cohorts discussed above, there are several others, and a systematic review in 2020 that found a total of 8 studies, actually showed no overall difference in outcomes. Another systematic review, (Kaushal et al) also published in 2020 included data from 13 studies. There are however, errors in their meta-analysis which I have just noted as I was reviewing it now. They calculated the mean and SD of the data from the CNN, estimating them from the median and IQR which were published. But the SDs they calculated are tiny, and are, I think, incorrect, using the method they claim to have used (I checked with an online calculator which is supposed to be based on the method the authors used, but gives SDs which are larger and more reasonable). As a result the CNN data are given huge weight compared to the other studies, which means that their calculations for the continuous outcomes are in error, I think.

The Cochrane review of this intervention doesn’t include any long term follow-up, but there are now some data available from comparative trials, or at least from the RAINBOW trial. (Marlow N, et al. 2-year outcomes of ranibizumab versus laser therapy for the treatment of very low birthweight infants with retinopathy of prematurity (RAINBOW extension study): prospective follow-up of an open label, randomised controlled trial. The Lancet Child & Adolescent Health. 2021;5(10):698-707)

A caution about the introduction to the trial, as you can see from the conflicts of interest statement, there was heavy involvement of Novartis in the trial. Novartis markets both bevacizumab (Avastin) and ranibizumab (Lucentis), which are derived from the same antibody. Novartis, however, want everyone to use ranibizumab for eye injection because they charge many times as much for it, they prepare it in the small doses needed for eye injections, and, according to them, it is less likely to cause systemic effects. The molecules are very different in size, with ranibizumab being a much smaller molecule which is probably cleared from the circulation much faster, which might possibly make it safer. Comparative trials in adults, however, haven’t shown much difference in either efficacy or complications. Bevacizumab is in fact “non-inferior” to ranibizumab in adult wet macular degeneration efficacy. (Moreno TA, Kim SJ. Ranibizumab (Lucentis) versus Bevacizumab (Avastin) for the Treatment of Age-Related Macular Degeneration: An Economic Disparity of Eye Health. Semin Ophthalmol. 2016;31(4):378-84).

All that being said, the first author is Neil Marlow, and I am sure he wouldn’t have written this unless he was sure about the data. These long term outcomes show equivalent development in almost all domains, but ranibizumab led to much less high myopia, and less ocular structural abnormalities than laser. There is very little follow up of the bevacizumab, trials, the BEAT-ROP trial only reported follow up from 16 infants from one centre, and therefore no power to show anything. Kennedy KA, et al. Medical and developmental outcomes of bevacizumab versus laser for retinopathy of prematurity. J AAPOS. 2018;22(1):61-5 e1. Even though cognitive scores were 20 points higher among those who received bevacizumab rather than laser there was such a wide range, and small numbers, that this might well have been a chance difference.

The long term, therefore, must be classified as uncertain, with some concerns from observational studies, and some reassurance from the little data available from RCTs. Which is a very unsatisfactory state of affairs when trying to counsel parents.

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