What Sick Babies Can Teach Us

Posted on 13 November 2024 by Keith Barrington

As usual for a TED talk this is 18 minutes long, and, in that brief time, Annie recounts her trajectory: learning from families of kids with trisomy 13 and trisomy 18; our own experience with counselling for threatened extreme preterm birth, from both sides of the conversation; and the Parents Voices Project. The only thing I don’t like about this video is the still that was chosen by their algorithm to appear with the title, which has a weird expression on Annie’s face.

The description below the video of Annie’s TEDx talk, which she presented in Fort Lauderdale in September this year, at the Delphi conference of neonatal innovation, notes:

In this heartfelt TEDx talk, Dr. Annie Janvier, Professor of Pediatrics and Clinical Ethics at the University of Montreal, shares profound insights from her work as a neonatologist and ethicist. Drawing on her personal experiences as a mother to children with healthcare needs, including one born at just 24 weeks, Dr. Janvier explores the lessons that premature and critically ill babies can teach us about resilience, life, and the complexities of healthcare. Her unique perspective sheds light on the challenges families face and the ethical questions that arise in critical care, encouraging us to view life and health through a compassionate lens. Dr Annie Janvier is a Professor of pediatrics and clinical ethics at University of Montreal. She is neonatologist and clinical ethicist at the Sainte-Justine University health center. She holds a PhD in Bioethics and co-directs the Masters and PhD programs in clinical ethics at University of Montreal. She works first hand with patients and families confronted with difficult decisions such as end-of-life issues, and decision-making in the face of uncertainty. She is also the parent of three children who had or have healthcare needs, one of which was born at 24 weeks

The most recent publications from the Parents’ Voices Project include

Pearce R, et al. Partnering With Parents to Change Measurement and Reporting of Preterm Birth Outcomes. Pediatrics. 2024;154(5).
Church PT, et al. NICU Language, Everyday Ethics, and Giving Better News: Optimizing Discussions about Disability with Families. Children (Basel). 2024;11(2).
Synnes A, et al. Redefining Neurodevelopmental Impairment: Perspectives of Very Preterm Birth Stakeholders. Children (Basel). 2023;10(5).
Thivierge E, et al. Pulmonary important outcomes after extremely preterm birth: parental perspectives. Acta Paediatr. 2023;112(5):970-6.
Janvier A, et al. Fragility and resilience: parental and family perspectives on the impacts of extreme prematurity. Arch Dis Child Fetal Neonatal Ed. 2023;108(6):575-80.

Posted in Neonatal Research | Tagged , , | 1 Comment

Surgery for NEC; enterostomy or anastomosis?

Posted on 7 November 2024 by Keith Barrington

There are only a few randomized trials in neonatal surgery, but those that exist have had a major impact. This new publication may do the same, even though the sample size is relatively modest, and there are some issues with the article. You can see some of the difficulties in doing such trials from the fact that it took 12 hospitals 9 years to recruit 80 patients, 58 of which came from only 3 of those hospitals, Sick Kids, GOSH, and University Children’s Hospital in Belgrade, the others having between 1 and 5 patients each. (Eaton S, et al. STAT trial: stoma or intestinal anastomosis for necrotizing enterocolitis: a multicentre randomized controlled trial. Pediatr Surg Int. 2024;40(1):279).

The investigators enrolled infants with NEC prior to surgery, and randomized them during the procedure if they felt that either enterostomy or primary anastomosis were both reasonable surgical options. After elimination of one subject who had been randomized twice, they had 79 patients enrolled, with 42 having a stoma and 37 a primary anastomosis. This appears to be a very reasonable trial approach, where the individual surgeon has equipoise at the moment of surgery.

The first problem with the trial is that there were 6 patients lost “to all follow up”. I don’t understand how it is possible that the authors don’t even know if they survived or not. If there were big problems with record-keeping in some centres maybe the primary outcome variable, ‘days on parenteral nutrition’ might be difficult to find years later. But this was a prospectively registered trial, so it is not clear to me how simple data, easily available during the initial hospitalisation, can be missing on 7% of the subjects.

There are other significant problems with the manuscript. The primary outcome was, as mentioned, days on TPN, but how the investigators dealt with mortality in this outcome is not at all clear, the results present the primary outcome among survivors initially, which was a median of 51 days (range 3 days to 4 babies still on TPN at the end of follow up 310 days) among the stoma babies, and 30 days (range 4-105). They then present an analysis by an adjusted Cox regression, censored for mortality. As noted, they state in the text that 4 stoma babies were still on TPN at the end of follow up, but the figure shows everyone as being off TPN before 300 days.

The survival curves are also strange. There were only 4 deaths in the primary anastomosis group, but the curve seems to show about 13 steps down in the survival curve, and both curves continue to show deaths up to 200 days, this isn’t because some patients haven’t yet reached the final follow-up as that was completed in January 2020, and there were no further losses to follow-up in the anastomosis group at 3 months or at 1 year. The curves seem to suggest that the final proportion of the stoma patients surviving was 0.8, but there were 4 deaths of 35 with known outcome, which leaves a proportion of 0.88 surviving.

While keeping all of these concerns in mind, the results do seem to show major advantages of primary anastomosis, with the duration of TPN among survivors being shorter, and there being more survivors, 8 deaths in the stoma group vs 4 after anastomosis.

It would be interesting to see whether the experience with the stoma patients in the trial is similar to other patients having a stoma outside of the trial. It seems to me that the fact that 10% of the stoma patients were still on TPN at one year of age, when they were already a selected group, who were relatively stable and with relatively restricted disease, is a surprisingly poor outcome. There were substantially more complications in the survivors in the stoma group, with more wound infections, and, of course, more stoma complications, than among the survivors in the anastomosis group.

The study report may have a lot of big problems, but it does at least suggest that immediate primary anastomosis is a very viable approach in infants who are stable enough to have it considered, and in whom the distribution of disease makes it feasible. There may well be fewer post-op complications with anastomosis, and the number of later strictures were similar between groups.

Posted in Neonatal Research | Tagged , , | 1 Comment

The nicuverse and 99NICU

Posted on 6 November 2024 by Keith Barrington

As some of you may have noticed, I left Twitter (X), apart from sending a link to each new post on this blog. I never any longer visit the website and I have deleted the App on my phone.

A great alternative is the nicuverse, nicuverse.org a Mastodon community with many similar functionalities that we could use to chat with each other, discuss research and clinical approaches. You will see also that there are links there to another on-line community 99NICU. They recently organised a conference in Portugal, much of which is available on-line, and they have a YouTube channel which has numerous videos of presentations from that conference. Several of which I have watched, and they are all of high quality.

For example, in keeping with some of my recent posts, there is a very good presentation about the use of antibiotics and the evidence-base for our current practices.

Another, about what on earth should we do about the PDA? Has 3 stellar presenters rather than just one!

One of the reasons for mentioning this now, is the upcoming series of Webinars about, and by, adults born preterm. You can register for them, or, I am sure, watch them later on-line. One of them is embedded below.

Posted in Neonatal Research | 1 Comment

Making Clinical Research Oversight Fit-for-Purpose

Posted on 6 November 2024 by Keith Barrington

The title is a slightly edited copy of the title a discussion article in JAMA, that discusses some important issues in IRB oversight of clinical research. (Kass NE, et al. Making the Ethical Oversight of All Clinical Trials Fit for Purpose. JAMA. 2024), and is part of a special issue including a renewed version of the Declaration of Helsinki World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Participants. JAMA. 2024.and several other discussions.

Rethinking the definition of clinical research, and how we approach the essential protections of research subject is clearly needed.

In my NICU, if I have a 3 week old preterm baby who develops signs of septic shock with poor perfusion and a low blood pressure, in general my approach would be to give a bolus of normal saline (10 mL/kg) over a fairly short time, then to start a norepinephrine infusion, and usually start low dose steroids very early. I would start norepinephrine at about 0.1 mcg/kg/min, often the response is slow, and I may increase to as much as 0.4 mcg/kg/min before, often, being able to back off fairly quickly as the steroids and antibiotics have their effect.

How much of that approach is evidence-based? Just about none of it. I have published about the use of norepinephrine (Rizk MY, et al. Norepinephrine infusion improves haemodynamics in the preterm infants during septic shock. Acta Paediatr. 2018;107(3):408-13) and using steroids early (Altit G, et al. Corticosteroid Therapy in Neonatal Septic Shock-Do We Prevent Death? Am J Perinatol. 2018;35(2):146-51). But those small observational cohorts will never tell us if outcomes were improved or worsened by the approaches.

Were those publications “research”? We described our practice and the outcomes, in the hope that others will evaluate their own practice and compare with ours, and we had local ethics approval to go through the databases and publish our results. In another NICU, they might routinely give multiple fluid boluses, followed by dopamine, and only use steroids as a last resort. Also without a good evidence base. As each baby is so different to the last, observational studies have limited value. It is, indeed, very hard to imagine how comparing these approaches and determining best practice is possible, even with all the fancy statistical adjustment in the world, including the latest version of propensity score matching, unless large randomized trials are performed.

I can treat babies in this non-evidence-based way, and then compare with other approaches, or change my practice and then re-evaluate, with almost no oversight, and certainly no prior IRB approval. What if I wanted to do something much more scientifically valid, such as trying to standardize therapy as much as possible, then prospectively comparing the outcomes from my centre to other centres that have also tried to standardize their treatment approaches? Then, even if every baby gets exactly the same therapy as they would have done anyway, does this suddenly become a research study? The CNN, Canadian neonatal network, are actually doing such a study, in which centres who usually use norepinephrine for septic shock, and those who use dopamine try to standardize their initial treatment, and we will compare outcomes.

A much more valid study, and one which would cost much more, and be substantially more difficult to organise, gain approval, and perform, would individually randomise eligible babies to one approach or the other. An intermediate type of study, where NICU’s are randomized, has some advantages in terms of, for example, ensuring the team is familiar with the approach over time, and not requiring masked vials of study drug; but has major impacts on sample size. Either a cluster-randomized or individually randomized trial will require prior IRB approval.

One big question for an IRB is how to determine the risk of such a study. In the past, because there is a substantial risk of death, and of major complications, this should be labelled as a high risk study. The risks of a participant in the study are much greater than the risks of daily life, even of daily life of a preterm baby in the NICU. Surely, though, the risks of the research project should be a comparison of the risks of adverse outcome if you are in the trial compared to being not in the trial. What matters is whether there is additional risk over not being a study participant. Clearly, in the scenario I have described, the risks are identical to not being in the study. It should be considered as “no additional risk”.

The new Declaration of Helsinki does not go into any detail about which risks to include in evaluating a research project. It states that a project must be “preceded by careful assessment of predictable risks and burdens to the individuals and groups involved in the research in comparison with foreseeable benefits to them and to other individuals or groups affected by the condition under investigation.”

The discussion by Kass et al puts it this way: “Our specific recommendation here, with relevance for comparative effectiveness and other types of research on approved or widely used clinical approaches, is for oversight bodies to make their risk-level determinations, including whether a study qualifies as minimal risk, on the marginal or additional risks and burdens of research participation, relative to those of ordinary usual care.”

An accompanying editorial in JAMA points out how these proposals differ from current rules. According to OHRP current rules, “in general the reasonably foreseeable risks of research in a study include the already identified risks of the standards of care being evaluated as a purpose of the research when the risks being evaluated are different from the risks some of the subjects would be exposed to outside of the study”. In other words all possible risks of being a preterm baby in the NICU with septic shock undergoing intensive care are considered study risks. Which means that all possible adverse outcomes of the extremely high-risk situation are included, death, IVH, renal failure, and so on. That interpretation of the OHRP rules makes intensive care research just about impossible, as it requires the IRB to ascribe all the risks of being critically ill to the trial, even if there are no additional risks compared to not being in the study. I think that many IRBs already interpret the risks of a trial as being those additional risks, and I can only hope that this interpretation will become widespread.

Another question is about consent. Normally, I do not share with parents all the many the uncertainties regarding the best approach to septic shock, I do not ask them to make an informed choice between norepinephrine and dopamine, I don’t counsel them about the uncertain role and timing of steroids, and get them to sign a consent form. If I am planning to prospectively collect the data, with the explicit intention of comparing outcomes with dopamine centres, does that now require specific informed consent? Even though I am doing exactly what I would have done in any case? Indeed, so are my comparison centres, who use a different approach.

I think that this does not require specific informed consent, I am not even sure that we should obtain consent to contribute the baby’s data to a truly anonymous database for future comparative analysis.

What if I decide, for a while, to switch my approach to using dopamine, and collect the data, because I understand the uncertainty involved, and I think that dopamine is an equally valid choice? And my comparison centres will also switch to using norepinephrine. According to this new discussion article:

(Informed consent is required if)… the research removes from patients the ability to make a decision that may be meaningful to them—a decision that, in ordinary clinical care, they may have been invited to make.

They go on to note :some commentators support the view that consent can, ethically, be waived when risks are low and when consent is typically not sought for either approach being studied, others oppose complete waivers of consent requirements in some or all circumstances. Importantly, most of these critics of complete waivers support streamlined approaches to consent for these lower-risk, randomized studies.

In this situation, parents would not ordinarily be asked whether they prefer norepinephrine or dopamine, so the first criterion does not apply. However, my initial intervention choices are being determined by a written protocol, I think this should require that I tell the parents that their infant is getting a therapy determined by a protocol, a therapy which is, nevertheless, within the usual range of good clinical practice.

I don’t think it is appropriate to perform prospective comparative research, even with zero additional risk, without informing the parents. It seems to me to be hiding important information from the parents, and that is likely to create distrust.

I propose for such a study that consent should be altered to focus on informing parents of the important details of the study, and giving them an opportunity to opt-out of data collection. A 2017 article refers to this as “targeted consent”, whereby patients who are individually randomized to one of two reasonable, clinically appropriate treatments have a verbal information sharing session, and a brief targeted consent form outlining the patient’s rights. I don’t think that a cluster-randomized trial should be considered to be morally different, if all patients admitted in January have one approach, then in February we switch to another approach, from the patient’s point of view this is identical. Or if NICU A is randomized to dopamine, and NICU B is randomized to norepinephrine, and then switched over after 6 months. In each situation we are performing pre-planned research, and parents should know about it, and have the chance to opt-out of information collection, and even from non-essential aspects of the care protocol if there are any.

Of course, as always, if I have a valid reason to believe that this particular patient would benefit from norepinephrine, then I am morally obligated to do so, and treat them as a protocol violation, or a non-enrolled subject.

If I was to introduce levosimendan, however, a drug with almost zero use in the NICU, and no experience in the preterm infant with septic shock, then there would be a possibility of a major impact on important clinical outcomes, and the study should have completely different, and more extensive requirements and consent process.

After the dopamine and norepinephrine study finishes, it may be found that mortality is higher in one group or the other, or the incidence of a major complication differs between groups. I don’t think we can then, in retrospect, suggest that the risk of the trial changes.

This is what happened with the SUPPORT trial, where the 2 oxygen saturation target ranges, both considered to be acceptable within usual clinical practice were prospectively randomly compared. Outside of the trial and infant could have been treated with either of the 2 approaches, so, according to the standards that I am promoting here, this would be considered a trial with no additional risk. In fact, as we all know, we found a higher mortality with the lower target range, which created a storm, and was largely responsible for the OHRP guidance which I quoted above.

But, if it turns out that norepinephrine babies have a lower mortality in our study, even after correcting for every baseline imbalance possible, that does not change the a priori risk assessment of the study. To think otherwise requires some sort of magical thinking, that things which are unknowable because such a trial has never been done, should have been known before the facts existed.

Building cluster randomized comparative effectiveness trials on top of existing databases, such as the CNN, will allow us to improve therapy for future babies, with no additional risk to our current patients, and the chance of major benefits for the next cohort.

Posted in Neonatal Research | Tagged , , | Leave a comment

Badly performed, badly presented, unethical published research; what to do?

Posted on 29 October 2024 by Keith Barrington

Since at least 2013 the World Medical Association Declaration of Helsinki has mandated registration of clinical trials prior to enrolment of the first subject. Since 2005 the International Committee of Medical Journal Editors has required trial registration as a condition of publication, before the onset of patient enrolment.

This principle is reiterated in the new version of the declaration of Helsinki, just published and discussed in many places, including JAMA.

Nonetheless, retrospectively registered trials are still being accepted by journals, most of whom should know better, as well as publications with no mention of registration at all. It has been a recurrent problem in some neonatal studies, and some large recent neonatal trials were retrospectively registered after being completed, and after all the data were collected. The fact that prominent journals will still sometimes accept such research gives the publications a credibility which is not deserved.

This has a significant impact on how we analyse the literature and make therapeutic decisions. To take one example, the use of Erythropoietin in preterm infants. Let’s analyse the literature to determine if Epo prophylaxis decreases NEC, a major health issue in these babies. A recent high-quality systematic review was published by Ananthan et al, Ananthan A, et al. Early erythropoietin for preventing necrotizing enterocolitis in preterm neonates – an updated meta-analysis. Eur J Pediatr. 2022;181(5):1821-33. This SR found 22 studies with over 5000 patients enrolled, and a clinically significant reduction in “definite” NEC, RR 0.77 0.61-0.98. However, of the 4 largest trials in that review 2 were registered after completion of enrolment (Song 2016, n=743, Wang 2020, n=1285), one was registered in 2006, shortly after the first patients were enrolled in 2005 but prior to completion (Natalucci 2016, n=365) and one was registered prospectively (Juul 2020, n=936). If we re-analyze the data excluding the retrospectively registered data, and the older non-registered trials, the effect of Epo on NEC no longer reaches classical statistical significance

It does still look like there might be an effect, doesn’t it? Adding Natalucci back in (the absolute requirement for prior registration dates to around the time the study was started, so it is much less of an issue) makes little difference, as they had only 3 cases with Epo and 4 in the controls. Which points out how desperately important this is. Are we failing to provide an effective therapy for our babies? Are we at risk of dosing thousands of babies with a prophylactic intervention which is ineffective?

One characteristic of many of these retrospectively registered trials is they are not published in the typical neonatal/pediatric literature, Wang 2020, for example was published in the Journal of Translation Research. Song 2016 was published in Annals of Neurology, which claims to follow the ICMJE guidelines and the declaration of Helsinki, but clearly failed to do so for this article.

I’m not sure what to do about this on-going problem. If it was bench research we could just refuse to publish, but when babies have been subjected to research procedures and parents to the stress of having a baby in an NICU and in a trial, it seems unfair to those research subjects to categorically refuse to publish. But, unless there is some sort of sanction, this will continue, and indeed it does continue. Perhaps there should be a separate journal: “The Journal of Unregistered Research”, or a separate section in some journals: “Unreliable Information”. We can’t ascribe ignorance to the authors, Song et al, who retrospectively registered the first trial in 2016 are the same authors as Wang et al, who retrospectively registered that later trial in 2020! There are numerous other problems with these 2 projects, they were unmasked trials but the controls still received placebo injections, why on earth would you do that?

The importance of trial registration is discussed in many different places, including by the WHO, one thing that the WHO don’t discuss, but which is vitally important, is that prior trial registration makes it clear if primary outcomes have been changed, or if outcome definitions have been “adjusted”. Even better is full publication of the trial protocol, in addition to registration, which makes those things even clearer, and less liable to fudging the results.

The problem is not, it seems, going away. Which may, in part, be because of the proliferation of biomedical journals, some of which have very loose standards it seems. The journal “Biotechnology and Genetic Engineering Reviews” of the Taylor and Francis group, has just published what appears to be a clinical trial of caffeine in preterm infants. (I won’t add to the hit count of the journal by providing a direct link, but the article is listed on PubMed if you want to read the abstract: Jiang Q, Wu X. Effect of early preventive use of caffeine citrate on prevention together with treatment of BPD within premature infants and its influence on inflammatory factors. Biotechnol Genet Eng Rev. 2024;40(3):2730-44). A clinical trial in newborn infants is way outside of the apparent aims of the journal, which you can read on the website. I wonder if the journal was picked at random, or because it was known to have lax editorial standards, and/or if the article was refused in other places first. None of the named editorial board members has a medical background, (it also takes on average 209 days from submission to first decision, so stay away!) As it is not a medical journal, there is no mention of the ICMJE in the descriptions I found. It is an open-access, pay to publish journal, maybe it was cheaper than other alternatives.

Not only is this the wrong place to have published this article, it is written in very bizarre English, and has very questionable features to its design. Infants were “chosen and segregated within control and observation groups through random number table protocol” which led to two groups with “no significant difference in perioperative data” and then received caffeine by “intravenous pumping” or saline.

According to the methods, apparently “Doctors and nurses should show enough patience and love in the face of children, speak gently, smile and communicate with children, try to calm the children’s mood, so that the treatment can proceed smoothly”. Who can disagree with that?!

There is no mention of ethical review board approval.

The study was apparently performed without any funding, even though there was blood work, lab analyses, respiratory mechanics equipment and procedures, and repeated neurodevelopment testing. Several inflammatory markers (MMP-9, TNF-alpha, TLR-4) were measured prior to and after therapy. TLR-4 is of course a transmembrane receptor, so I have no idea if measuring circulating concentrations is of any interest, and the results they report are 10 fold higher than any others I have found in the literature. Also it required multiple blood samples, with the pain involved.

The authors give data for respiratory mechanics, which are almost certainly fictional, as they describe no methodology for measuring mechanics (resistance, compliance and work of breathing), which is extremely difficult in any case in spontaneously breathing newborn infants. The company that they claim made the equipment they used for lung mechanics lists no such equipment on their website.

Even more bizarrely, they report the neurodevelopment of the babies which was “evaluated by Child Development Center of China (CDCC), including Psychomotor development index (PDI) and Mental development index (MDI), with scorings ranging across 0–100 points for each part”. They give results at baseline before treatment as well as after treatment (age not specified). No actual results are given, just a p-value claiming that the caffeine group had better MDI and PDI after therapy, but not the controls. The figure of these results, figure 3, is actually the same as the figure for growth, figure 4, and shows length, head circumference and weight gain.

The desperately bad research described here makes me hope it is actually a work of fantasy, as the idea of subjecting real babies to such an awful protocol horrifies me.

A huge concern is how an apparently legitimate publisher and the editorial board of this journal can allow this garbage to pollute the medical literature. I have written to the company, Taylor and Francis, (there is apparently not currently a chief editor of the journal) and left a comment on PubPeer. If any of my gentle readers have a link with Taylor and Francis, maybe you could try to trigger a response, and hopefully a retraction, before these data get incorporated into Systematic Reviews.

I started writing this post because I wanted to discuss the new version of the Declaration of Helsinki. You will have to wait for the next issue!

Posted in Neonatal Research | Tagged , , , | 4 Comments

Too much antibiotics, part 2

Posted on 28 October 2024 by Keith Barrington

The multicentre project, that I started the last post with, has just published a new important article, which addresses the duration of antibiotic treatment (Dimopoulou V, et al. Antibiotic exposure for culture-negative early-onset sepsis in late-preterm and term newborns: an international study. Pediatr Res. 2024) and is particularly focused on those babies with negative blood and/or CSF cultures. They divided the babies who received antibiotics without ever having a positive culture into those which were treated for less than 5 days, or for at least 5 days.

I think that 4 days of treatment, for a well baby with risk factors who has negative cultures, is already far too long, the optimal duration for such a baby would be 0 days! But, given that there was enough concern to perform a blood culture, then antibiotics can be stopped after 36 hours, with only a tiny possibility that a true-positive blood culture will become positive after 48 hours, and then very rarely for organisms treated with our usual empiric antibiotics.

But what about those babies who are thought to have “culture-negative sepsis”? In this new study, babies treated with antibiotics for 5 days or more, one extant definition among many, were 20 times more frequent than true EOS. There were 8000 babies with negative cultures who received treatment for >4 days, compared to 375 with a proven EOS.

What are we treating, when we continue antibiotics despite negative cultures? I well remember some twins (more than 1 pair) where one twin was sick with sepsis and positive cultures, and the other was similarly sick, but with negative cultures. To me, those cases have been the best proof that culture-negative sepsis does indeed exist. But what is it? Many such infants do not have an active bacterial infection. Many have circulatory and respiratory illness caused by the inflammatory cascade following a bacterial infection. Some cytokines have been shown to cross the placenta, such as IL6, for example, so the infant could become passively ill as a result. In other cases the infection may already have been effectively treated, such as when a mother had chorioamnionitis, and has received antibiotics. In such a case the infant is affected by the cytokines and other inflammatory mediators released by the mother or by the infant themselves. In the example I gave at the beginning of this paragraph it may be that a truly infected co-twin sets up enough of an inflammatory response that their sibling is symptomatic.

In such an infant, blood cultures will be negative, but also they will not benefit from antibiotics. The sensitivity of current culture techniques are such that, down to about 1 CFU/m, over 98% of cultures are positive, and any concentration of bugs higher than this will rapidly make the culture machine alarm ring.

For a more complete discussion of the issues in “culture-negative sepsis” you could do no better than to read Joseph Cantey’s article from the Journal of Pediatrics in 2022. I can’t tell if it is open access, but if you have difficulty getting it, I am sure we could find a way to get a copy to you.

I mentioned, in the part 1 post, another recent publication, with probably some overlap in the data, from a national Swedish database (Gyllensvard J, et al. Antibiotic Use in Late Preterm and Full-Term Newborns. JAMA Netw Open. 2024;7(3):e243362). In that publication the incidence of EOS had fallen over time up to 2020, and treatment of culture negative infants had decreased also, but the gap had actually widened. Also, in that study, the median duration of antibiotic treatment among all infants with negative cultures was 5 days, IQR 3-8 d, 97% of infants who received antibiotics had negative cultures. It is clear that not all infants who have a culture taken and are started on antibiotics have sepsis, culture-positive or -negative. Although there do not appear to be national Swedish guidelines for when to screen for and treat neonatal sepsis, there are guidelines about when to stop them (again translated by Microsoft Word)

Full-term child with suspected early onset sepsis (illness before 72h): discontinue antibiotics after 48-72h and do not diagnose as neonatal infection:
• Never required ventilator care or had septic shock
• Mother not diagnosed with obstetric infection
• Blood culture negative, growth of contamination or not yet responded to
• Well-being at 48-72h age
• CRP peaks below 60 mg/L, and CRP decreases during antibiotic withdrawal
• CRP peak between 60-100 mg/L, and CRP in decreasing consider discontinuing antibiotics

The way I understand it, you need all of those in order to stop the antibiotics; thus, ongoing treatment of increased CRP concentration without other signs of infection is recommended by this guide, a practice which has no evidence-base, and leads to major over-treatment of uninfected babies. Previous publications have shown that you can stop measuring CRP, and routine CBCs, without any adverse impact, only a reduction in unnecessary antibiotics. Although the Swedes are doing much better than most of us in reducing the number of antibiotic courses administered, they are still treating 50 babies with antibiotics for every truly infected infant, and as noted, they treat for a median of 5 days. If they just stopped doing CRPs, but still used the other criteria in that national standard, they could do even better, and there is no evidence that there would be any risk involved. It is well known that CRP concentrations increase several hours after the initiation of inflammation, so they are usually ignored if they are low during the initial sepsis evaluation. They also increase easily and are very non-specific, so they should also be ignored in later analysis of whether an infant has “culture-negative sepsis” or not.

There has been a lot of woolly thinking about this. Infants are defined as having “culture-negative sepsis” if they are treated with 5 days or more of antibiotics. Studies have then shown that infants with “culture-negative sepsis” have higher CRP concentrations, and this is published as evidence that CRP concentrations are useful in the diagnosis of the phenomenon. But, it is often the high CRP which leads to the prolonged antibiotic use. Circular reasoning anyone?

One early study of the neonatal use of CRP, for example, showed that 9% of the babies who were considered “definitely not infected” had raised CRP. Infants delivered vaginally have higher CRP than those delivered by Cesarean, especially CS without labour. Infants with a final diagnosis of TTN have higher CRP, as do those with Meconium Aspiration, who are often treated with prolonged antibiotics in the absence of other risk factors for sepsis. In part, this is probably because CRP increases to a mean of over 40 at 48 h in such babies, despite negative cultures and no evidence of any benefit from antibiotic use.

As this figure from the new article shows, the babies who clearly do need antibiotics, in red, are vastly outnumbered by the others, both the group with <5 days antibiotics, and those with 5 or more days. And there is enormous variation between networks.

Routine stopping orders for antibiotics after 36 hours, and requiring a conscious decision to continue if cultures are negative, could immediately have a big impact on exposure. A re-evaluation of each case, and a thoughtful answer to the questions “does this baby really have “culture-negative” sepsis?” and, “is this baby likely to benefit from continued antibiotic therapy?”, which are linked but not identical questions, could further reduce the unnecessary overuse of antibiotics. It would help to preserve their usefulness for the future, as well as reducing adverse impacts on that individual.

Posted in Neonatal Research | Tagged , | 3 Comments

Too much antibiotics, part 1.

Posted on 25 October 2024 by Keith Barrington

An important multi-centre observational study examines how many newborn infants, term or late-preterm are receiving antibiotics, for how long, and the responses to negative cultures. Centres from Europe, Australia and North America are represented. Data collection differs between the participants which are all regional networks (or in the case of Norway, national), but all provided data on babies who received antibiotics for any reason within the first week of life.

The first publication from the study (Giannoni E, et al. Analysis of Antibiotic Exposure and Early-Onset Neonatal Sepsis in Europe, North America, and Australia. JAMA Netw Open. 2022;5(11):e2243691) showed that 2.86% of the babies in the networks (total births over 750,000) received antibiotics, but the variability was enormous between networks, from 1.18% to over 12%.

The overall incidence of culture positive sepsis was less than 0.05%, if the coagulase negative staph are eliminated (they were not automatically considered to be contaminants in this study, but I think it is very rare that EOS in term and late preterm infants is really caused by CoNS) the incidence was 0.041%.

One thing I really appreciated in this publication is the openness of the investigators to identify themselves. As you can see below, the centre with the highest exposure of babies to antibiotics was Perth. As you can also see, from panel B, they, and Rhode Island, are the sites with the shortest duration of treatment of culture negative babies. As you can also see, panel D, Perth dramatically reduced antibiotic exposure between 2014 to 2018.

Figure 3 in that publication shows a vague correlation between actual sepsis incidence and antibiotic use. In the supplement there is a version without CoNS

I find it hard to believe that individual decision making about sepsis evaluations and antibiotic treatment are affected by a difference in true EOS rate between just over 1 per 1000 compared to 0.3 per 1000. But, perhaps, the local choice of which guidelines to follow is affected by sepsis rates?

In terms of the consequences of sepsis, EOS mortality was very low, at 3.2% of the true EOS cases, or 12 deaths among 750,000 babies. As you can see from the figures, Stockholm county has an average incidence of EOS, but consistently has the lowest rate of antibiotic treatment. They do this, it appears, by not using the Kaiser Permanente sepsis calculator. That calculator has reduced antibiotic use in centres where it has been introduced, but the lowest antibiotic use reported after introduction of the sepsis calculator is 3%. In Stockholm the rate is less than half of that. How do they do it, without an increase in sepsis mortality? As far as I can tell, there are no published guidelines in Sweden regarding when to screen and/or treat the term and late preterm infant for sepsis. I downloaded and translated the national recommendations, but they only discuss the antibiotics available, the importance of blood cultures, a statement that culture negative sepsis is a possibility, and a vague discussion of epidemiology. This is the automated translation (Microsoft Word) of the section about screening and diagnosis:

Underdiagnosis of severe neonatal infection can quickly lead to a worsening situation of septic shock and even death, while overdiagnosis can lead to unnecessary antibiotic use. Fatigue, poor skin color, episodes of apnea, and bradycardia are common symptoms of sepsis.

Using hands, eyes, ears and stethoscopes to examine the patient and interpret these symptoms is and remains the basis of all diagnostics. In addition to this, the doctor has a number of diagnostic methods available, each with its different strengths and weaknesses (Table III). There is currently no method that has optimal speed, sensitivity and specificity. CRP is the most commonly used diagnostic test.

Another recent publication of national data from Sweden, which includes over 1 million babies and extends until 2020, shows a continuing low frequency of antibiotic exposure, with a decreasing incidence of EOS. Again, in that publication there is no mention of any general guidelines for when to screen and treat for suspected sepsis.

Other jurisdictions have adopted the “Serial Physical Examination” approach, but the details of such an approach vary, it generally requires hourly structured physical examination by a nurse, following a written and agreed protocol, of at-risk infants. This article from Stavanger, Norway, for example, (Vatne A, et al. Reduced Antibiotic Exposure by Serial Physical Examinations in Term Neonates at Risk of Early-onset Sepsis. Pediatr Infect Dis J. 2020;39(5):438-43) is rather vague on which infants qualified as “at-risk”; it seems to be any infants born after chorioamnionitis (undefined) or with a previous sibling with GBS, and “neonates who during the first 72 hours of life developed clinical symptoms indicating a possible sepsis”. All such babies were admitted to the NICU for an hourly structured physical exam.

we accepted mild symptoms (heart rate >160/min, grunting or respiratory rate >60/min, poor feeding and decreased activity) of <2–4 hours duration. We only started antibiotics if these mild symptoms persisted (>2–4 hours) despite corrective actions, if additional alarming symptoms occurred (Table 1) or if the neonate became clinically ill as judged by the attending neonatologist.

This is the Table 1 referred to:

That study was limited to babies of at least 37 weeks, and was able to decrease antibiotic exposure from about 3% to about 1.3%; the incidence of “culture-negative sepsis” also declined dramatically, but remained, supposedly, 50 times more frequent than culture-positive sepsis.

One factor which has probably reduced the incidence of “culture-negative sepsis” is the reduction in CRP measurements! As you will see in part 2, many babies receive prolonged antibiotics to treat their CRPs.

Antibiotic treatment rates much lower than those which follow use of the current EOS calculators can be achieved without any increase in sepsis mortality. Of course the consequences of EOS are not just mortality, untreated, or late-treated EOS may lead to more severe acute illness and long term disability. Such outcomes are very difficult to capture in studies such as these, all-cause mortality is one outcome to be followed, in case babies present with severe illness not recognized as being sepsis, and, in these studies, lower antibiotic use is not associated with increased all-cause mortality.

Decreasing antibiotic exposure in uninfected infants is an issue which is important individually, as it leads to major disturbances of the intestinal microbiome, which are very prolonged, pain caused by IV access, cost, interference with parent-infant interaction, vulnerable child syndrome, and perhaps long term health impacts such as obesity, allergic predisposition, asthma, diabetes, juvenile idiopathic arthritis, celiac and inflammatory bowel disease. To the health care system as a whole, the exposure of a significant proportion of the population to antibiotics must contribute to antibiotic resistance.

Posted in Neonatal Research | Tagged , , | 2 Comments

Does preterm formula cause NEC?

Posted on 23 October 2024 by Keith Barrington

The question in the title was recently adjudicated in US courtrooms, with an enormous award of damages to the family of a premature infant who developed Necrotising Enterocolitis, and survived, but has, apparently, major neurodevelopmental issues. In July, the jury awarded the infant’s mother $95 million in compensatory damages and another $400 million in punitive damages against Abbott who produce the preterm formula that the baby had received. A previous case against Mead-Johnson (the only other preterm formula producing company in the US) was also decided against that company in favour of a family whose baby died of NEC, they were awarded $60 million. As far as I can tell, the basis for the awards is that the companies failed to warn the families of the risks of their formulas. I don’t know how the companies are supposed to warn the families, or how neonatal programs across the USA are responding to this situation, but there are apparently hundreds of other lawsuits that have been, or are in the process of being, launched.

I just did a Google search for Necrotizing Enterocolitis, lawsuit, and breast milk, 15 of the first 16 results were web pages of US law firms touting for business, some of them being hidden as pretend legal news sites. The sites rapidly open active chat windows, trying to get you to communicate with them to find out how much money you could win. The other one was a real US news station.

No company could possibly run the risk that each baby who receives their formula and then develops NEC will cost them millions of dollars. There is a real chance that the 2 companies that currently make artificial formula for preterm infants will pull out of the market, and what then?

There are also apparently parents in NICUs (in the USA) currently who are refusing preterm formula, as they have heard about these lawsuits, or have heard from lawyers that preterm formulas are dangerous, and cause NEC. Fortunately, this has not yet arrived in Canada, but such things have a tendency to osmotically pass through the semi-permeable membrane which is the longest border in the world separating us from the madness.

Without the preterm formulas, when feeding preterms with artificial formula we would have to return to supplementing term formula with additional protein, calories (probably mostly fat) and minerals (especially phosphorus, but also calcium and others). With no reason to think that this would be preferable in terms of NEC risk, indeed almost certainly this would not reduce NEC, but would introduce other risks: of errors, of contamination, or of excessive osmolarity.

The courts are clearly not the best place to determine scientific causality. So what does the science say? There are no RCTs comparing mother’s own milk (MoM) to artificial formula, for reasons which I hope are obvious, nor are there any trials comparing MoM to donor human milk (DHM) for the same reasons.

There appear to be 12 RCTs which have compared artificial formulas, all of those tested being based on cows’ milk, to DHM for preterm infants. As the most recent Cochrane review notes, there are multiple differences between the trials

The 4 oldest trials, published 1976 to 1983 used standard term formula, and only one of them (Gross 1983) reported NEC, which was nearly 5 times more frequent with term formula than with DHM! However, the trial was small and the numbers with NEC were tiny; so the difference in incidence of NEC, 3/26 babies receiving term formula compared to only 1/41 who got DHM, is not statistically significant (RR 4.73 95%CI 0.52-43.09). I don’t think statistical significance matters to law courts, however, so maybe that finding could be used in court to show that term formula is associated with the same risks of NEC as preterm formula.

In some ways, this is a philosophical question of the meaning of causation. NEC is more common in very preterm babies receiving artificial formula than in those receiving MoM, with an intermediate risk with DHM. Does that mean that MoM is protective, or does this mean that DHM causes NEC? And that formula is even more dangerous?

Or does it mean that the pathogenesis of NEC is very complex, that there are some components of human milk that are protective, and that there is an advantage of MoM over DHM. The advantage of MoM over DHM is, I think, in part because it is not pasteurized, and perhaps also because there are some differences in the composition of the milk of mothers who deliver preterm. Also, babies getting MoM are more likely to get maternal colostrum, which is not available from milk banks, and may be especially protective, perhaps maternal colostrum is part of the explanation why babies receiving MoM have lower NEC rates than DHM.

Preterm milk composition differences from term milk, which is the majority of what is supplied by almost all milk banks in the world, include higher concentrations of protein and some minerals. There is also probably some impact of PT birth on the oligosaccharide composition of milk (Human Milk Oligosaccharides HMOs). Bifidobacteria and Lactobacilli are present in most unpasteurized human milk, and are able to metabolise HMOs, which humans are not able to digest. Preterm milk has higher concentrations of HMOs, but they apparently are less diverse. I have previously posted about the potential role of DSLNT Di-Sialyl-Lacto-N-Tetraose (a specifically human HMO), which has now been shown in 4 studies to be present in lower concentrations in the breast milk of mothers whose babies develop NEC despite receiving MoM, Autran, Hassinger, Masi, Van Niekerk. It also protects against NEC in Lars Bode’s rat model. Apparently it is difficult to synthesize, but hopefully we will eventually get trials to see if NEC can be prevented by adding DSLNT to MoM, DHM or preterm formula.

This graphic is from a recent Chinese study (Zhang W, et al. Causative role of mast cell and mast cell-regulatory function of disialyllacto-N-tetraose in necrotizing enterocolitis. Int Immunopharmacol. 2021;96:107597), which examined the role of DSLNT in a rat model of NEC, which reproduced the protective effect in rats. It also showed that human intestinal specimens from NEC resections demonstrated Mast Cell activation compared to specimens without NEC, and also that an enzyme (chymase) produced by Mast Cells caused epithelial loss; and that in a human foreskin cell model DSLNT protected against this. Which is apparently a new potential mechanism for the beneficial effects of DSLNT.

In the current climate I cannot imagine any business putting money into trying to develop a preterm formula with DSLNT to try to reduce NEC risks, however. I suppose it will be up to public funding agencies to do so, and then hopefully for public organisations to profit, if it can be shown to be protective.

For the present, all very preterm babies at increased risk of NEC should have access to DHM when mother is unable or does not wish to provide enough MoM, which means all babies born at less than 33 weeks. From 33 weeks onward, the risk of NEC appears to be, currently, very close to the baseline risk in term babies, although very good recent data are difficult to find.

All of the discussion in this post has made some very questionable assumptions, which include (1. that NEC can be diagnosed reliably, and (2. that NEC is a single disease in the very preterm. I know that neither point #1, nor point #2 are actually reliably true. But I also know that NEC can be a devastating disease, with a high mortality and long term consequences, despite these considerations.

NEC in full term infants, including those with cardiac malformations, post-asphyxia, and after gastroschisis repair, is probably even more pathophysiologically variable, and not clearly impacted by breast milk use. Among late preterm infants the protective impact of breast milk is also unclear, they have been excluded from most trials. One of the earliest trials to show a benefit of breast milk in prevention of NEC, by Lucas and Cole, included babies of under 1850g birth weight, some of whom were over 32 weeks. They had 4 cases of NEC among 34 to 36 week infants who only received formula, compared to 0 in the breast milk groups. One very interesting finding in that early study was that babies who received breast milk AND formula had the same risk of NEC as those who received 100% human milk. Here is the table of results from that study including all gestational age groups:

Which, if I was a lawyer/expert witness, I would quote as good evidence that it is not formula that causes NEC, but breast milk that is protective.

Posted in Neonatal Research | 4 Comments

Long-term outcomes after preterm birth; the next step

Posted on 9 October 2024 by Keith Barrington

I usually try to avoid buzz-words and phrases like “paradigm shift” but it applies well, I think, to what is happening in the world of neonatal follow-up, and more broadly, I hope, to neonatal research as a whole.

Neonatologists were pioneers in the development of outcome research (Barrington KJ, Saigal S. Long-term caring for neonates. Paediatr Child Health. 2006;11(5):265-6), when we started saving babies who would have universally died in the past, we wanted to know how they would turn out, and what kinds of lives they would have. Follow-up clinics developed with a dual mandate, to ensure that ex-preterm infants were evaluated and to co-ordinate any care they required, and to measure and collate their outcomes for quality control and research.

We used measures that were available, and we have gradually developed an almost universal approach, focusing primarily on brain injury, with standardized screening for developmental problems, neurologic exams to identify motor dysfunction, and hearing and vision screening. Other domains which have an impact on families after discharge have been less well evaluated, such as behaviour, feeding issues, sleep, pulmonary symptoms.

Developmental screening tests of various types have been used, and in, most of the world, the Bayley Scales of Infant Development (BSID) have become the default developmental screening exam. Despite what you might think, if you have read these blogs for a while, I actually think that developmental screening is a good thing! Some sort of universal screening for developmental issues is important to identify infants having difficulties, and ensure that they can receive any intervention that they need. What I am very opposed to is the simplistic dichotomising of outcomes into “impaired” if the score is less than 85 (and severely impaired if it is less than 70), and “non-impaired” if the infant gets 85 or more! Even worse is compounding low developmental screening test results with death, to give the dichotomous outcome of “death or NDI”.

I am now not even sure what to call a low BSID score. I have frequently referred to this as “developmental delay”, however, I have heard that some parents dislike this term as it implies that the infant will catch up. While this is true for large numbers of infants, it is not universally the case. We showed in the CAP cohort that only 18% of babies with a 2 years BSID score more than 2 SD below the mean had a 5 year IQ >2 SD below the mean. (Schmidt B, et al. Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity. JAMA. 2012;307(3):275-82.Manley BJ, et al. Social variables predict gains in cognitive scores across the preschool years in children with birth weights 500 to 1250 grams. J Pediatr. 2015;166(4):870-6 e1-2).

This figure is from the first of those publications, with the red parallelogram I added to include all the babies who had an 18 month BSID <70, but had a 5 year IQ >70, the differences between the 2 scores we referred to as “cognitive gain”. As you can see, many babies with BSID version2 MDI scores considered to be impaired had normal IQ, or even above average IQ, once they reached 5 years. Only the few beneath the red shape still had IQ >2SD below the mean. Perhaps we should just call a low BSID, or other similar test, score “LDSTS” a low developmental screening test score, that, I think would emphasize the ridiculousness of equating death with low BSID scores, and cerebral palsy and visual or hearing problems. It doesn’t lend itself to a snappy acronym however, “NILDSTS” (neurological impairment or low score on developmental screening test) hardly trips off the tongue.

When I review the literature about the predictive ability of the BSID (whichever version) for later outcomes, many publications have reported that the BSID have a statistically significant correlation with later outcomes, but few have really evaluated the predictive value of the BSID for later outcomes. It is hardly surprising that a screen for developmental problems will be statistically correlated with later IQ tests. But whether the developmental screen is individually useful as a predictor of the likelihood of intellectual impairment is a totally different question! Publications often include statements such as, in this interesting publication among preterm infants, “there was a highly significant correlation between language scores at 2 years and later literacy skills”, but they usually do not continue with what this study showed “language development at 2 years explained 14% to 28% of the variance in literacy skills 5 years later”.

To make sure that is clear, there was a significant correlation between scores on the developmental screening test and later abilities, but that correlation explained only a very small part of the later outcome. The same has been shown with other domains of the screening tests, especially cognitive. Motor development scores tend to be more predictive of later motor outcomes.

I think of this as a similar issue to the value of pre-discharge MRI in preterm infants. Overall, in large groups of babies, more MRI-visible brain injury is correlated with poorer developmental and later intellectual outcomes. Which is not the same thing as showing that a pre-discharge MRI is of value to the individual. The individual predictive ability of almost any finding on an imaging study (MRI or ultrasound) for the outcomes we usually measure is between low and very low. Of course, there are exceptions, extensive bilateral cystic PVL is very highly predictive of Cerebral Palsy, for example, but most other findings have very limited predictive value. (Chevallier M, et al. Decision-making for extremely preterm infants with severe hemorrhages on head ultrasound: Science, values, and communication skills. Semin Fetal Neonatal Med. 2023;28(3):101444).

To get back to the “Paradigm Shift” I mentioned, all of the previous discussion in this post has been about outcomes that we currently measure, BSID, Cerebral Palsy, etc. which, as the Parents’ Voice Project has shown are of limited interest to parents (Jaworski M, et al. Parental perspective on important health outcomes of extremely preterm infants. Arch Dis Child Fetal Neonatal Ed. 2022;107(5):495-500). We are shifting, perhaps all too slowly, to a new paradigm, an emphasis on outcomes that are of importance to families.

A national group of investigators and parents have been working together in Canada to develop both a catalogue of outcomes that are important to parents, and to decide how best to measure and collect the data. That process is described in a new article just published in Pediatrics, with a parent and a physician investigator as co-first authors! Pearce R, et al. Partnering With Parents to Change Measurement and Reporting of Preterm Birth Outcomes. Pediatrics. 2024. (Although I was not an author of this article, you will see I am named as a member of the Network).

The publication is a clear description of the needs, and challenges, in preterm follow up, and how the network is addressing them. We really need better data about outcomes of preterm infants, measuring things that matter to families, in order to be able to intervene, research, and counsel parents.

Let’s shift that paradigm!

Posted in Neonatal Research | Tagged , | Leave a comment

What should saturation targets be in established chronic lung disease with pulmonary hypertension?

Posted on 4 October 2024 by Keith Barrington

This question has been puzzling me recently, as we are trying to evaluate our current approach, and whether it needs to be changed.

My bias has been that oxygen is toxic, and we should only give the minimum needed to maintain adequate saturation. But that, of course, begs the question “what is adequate saturation”? I take my approach partly from the results of BOOST, this was the trial with which Lisa Askie burst onto the scene of neonatal clinical research, (Askie LM, et al. Oxygen-saturation targets and outcomes in extremely preterm infants. N Engl J Med. 2003;349(10):959-67) with a multi-centre trial in 350-odd babies (<30 weeks GA) who were still needing oxygen at 32 weeks. They were randomized to have SpO2 targets of 91-94% or 95-98%. There were no advantages shown of higher saturations, but far more high sat group babies needed oxygen at home, 30% vs 17%, and more babies died of pulmonary causes (6 vs 1, p=NS).

The STOP-ROP trial was also cautionary. In that trial, very preterm infants with pre-threshold RoP, who needed O2 to keep their saturation >94%, were randomized (average PMA 35.4 weeks) to a target of 91-94% or 96-99%. There was no difference in terms of progression of their eye disease, but the higher saturation target group had “increased risk of adverse pulmonary events including pneumonia and/or exacerbations of chronic lung disease and the need for oxygen, diuretics, and hospitalization at 3 months of corrected age“.

I haven’t found any study directly addressing the clinical outcomes of different saturation targets specifically for the group of preterm infants with BPD who also have proven pulmonary hypertension.

The AHA/ATS guidelines state “Supplemental oxygen therapy is reasonable to avoid episodic or sustained hypoxemia and with the goal of maintaining O2 saturations between 92% and 95% in patients with established BPD and PH (Class IIa; Level of Evidence C)” Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015 Nov 24;132(21):2037-99.

Similarly the PPHNnet guidelines have :”Supplemental oxygen therapy should be used to avoid episodic or sustained hypoxemia and with the goal of maintaining oxygen (O2) saturations between 92%-95% in patients with established BPD and PH. (class 1, LOE B)” Pediatric Pulmonary Hypertension Network (PPHNet). Evaluation and Management of Pulmonary Hypertension in Children with Bronchopulmonary Dysplasia. J Pediatr. 2017 Sep;188:24-34.e1

Indeed there are experimental data that show that once adequate saturation has been obtained, further increases in FiO2 do not decrease pulmonary vascular resistance, in normal lungs or those with PPHN.This graphic for example, from one of Satyan Lakshminrusimha’s animal studies, shows a decrease in PVR with increasing PO2 with a maximal effect at either 50 (control) or 60 (PPHN). Further increases in FiO2 had no significant impact on PVR, but do generate oxygen free radicals, and impede NO-dependent arteriolar vasodilatation.

The same group, in another model, showed that the minimal PVR was achieved with an SpO2 of 93-97%, which in this model required an FiO2 of 50%. Further increasing the FiO2 led to much higher PaO2, and SpO2 of 98-100%, but increased the PVR.

Given this, I found it strange to note that a publication supposedly presenting the European guidelines from the EPPVD (Hansmann G, et al. Pulmonary hypertension in bronchopulmonary dysplasia. Pediatr Res. 2021;89(3):446-55) suggests an SpO2 target of >95%, with no high limit. I tried to find the source of the data from this recommendation, and the only reference they give is to the 2019 consensus statement, which doesn’t actually recommend such high targets. Indeed that statement just states “The term or preterm newborn infant should receive oxygen, ventilatory support and/or surfactant if needed to achieve a pre-ductal SpO2 between 91% and 95% when PH is suspected or established. It is useful to avoid lung hyperinflation and atelectasis, or lung collapse and intermittent desaturations below 85%, or hyperoxia with pre-ductal SpO2 above 97%. (S9-1)—(S9-3)“, the SP-1 etc seem to refer to publications which aren’t actually very relevant. There are no other SpO2 recommendations in that statement. There don’t seem to be any data to support the recommendation of >95%.

In other words, despite a major lack of good quality data to show that different SpO2 targets in infants with chronic lung disease and pulmonary hypertension have an effect on important clinical outcomes, the consensus seems to be that 92-95% is probably best. Higher targets have no known benefits, and may increase pulmonary toxicity and adverse outcomes.

Avoiding intermittent hypoxia is probably important, for which prolonged caffeine therapy appears to be effective. The ICAF trial, presented at PAS this year, but not yet published, showed much less intermittent hypoxaemia in convalescing very preterm infants who were randomized to caffeine or placebo after about 34 weeks (about 80 per group). Of course these were not babies with BPD-PH, but if the same reduction in intermittent hypoxia occurs in that subgroup, which I have no reason to doubt, then there could also be an impact on pulmonary vascular resistance.

Infants with chronic lung injury and pulmonary hypertension are a very high risk group, good quality trials to inform the best therapy for them are urgently needed.

Posted in Neonatal Research | Tagged , , , , | 1 Comment