Recently my heart betrayed me…

Recently my heart betrayed me, after more than 60 years of excellent service it decided to beat far too quickly. My atria started to beat at nearly 300 times per minute, and my ventricles, unable to beat that fast, responded to every second atrial contraction to beat at 145 per minute, this is a cardiac arrhythmia known as atrial flutter. Although I felt OK in general, I could feel my heart was beating too fast, and after waiting for 30 minutes to see if it would calm down, I decided to take myself off to a local emergency room. I didn’t feel sick enough to call an ambulance, so I called a cab and asked them to take me to the nearest Emergency Room, at the Jewish General Hospital in Montreal. When I arrived, I was seen within seconds by a nurse who triaged me as a level 2 emergency which meant an immediate admission to one of the ‘crash’ rooms. (level 1 means you are actively bleeding or in cardiac arrest!) Within about 5 minutes of my arrival ER, I was in a highly monitored bed, with my ECG displayed for the emergency room doctor to see, an I.V. in place, in a hospital gown, having my vital signs taken by an experienced nurse, who was able to tell me that I was stable and that the doctor would see me within a few minutes, which she did.

In total I was in the ER for about 8 hours, during which time I had an x-ray, 2 formal ECGs, an expensive drug that I had never heard of before, multiple disposables, and a bedside echocardiogram. The expensive drug converted my heart rhythm to normal, after about 10 minutes, and then after a few hours of monitoring, I was able to go home. I got back home in the early hours of Canada Day, the year was the 150th anniversary of the convention that created Canada. Two days later I was seen by a specialist, and had another ECG and a formal echocardiogram by an experienced technician. About 4 weeks after this (I delayed the appointment for my annual vacation)  I had a 48 hour recording of my heart activity, which showed no further evidence of atrial flutter, I was then seen by an internationally reputed expert in cardiac electrophysiology within a month, and we decided together that I should have a cardiac catheterisation and an endomyocardial ablation, which means advancing a catheter into my heart and burning the lining of the heart in a particular place to make it very unlikely that another episode would ever occur.

Three weeks after seeing the specialist in his clinic I was admitted to a day hospital, an ECG showed my heart rhythm was normal, and I was sent to the catheterisation room, one of the most advanced that exists anywhere, where under x-ray control, and with 3-dimensional mapping of my cardiac activity, the electrophysiologist burnt the inside of my heart, and interrupted the pathways that might otherwise leave me at risk of a recurrence. About 6 hours later I was allowed to go home.  

When I got home from that, I thought I had better figure out my bill to make sure I could afford it all:

Taxi to hospital for initial episode $14, taxi home from hospital $14, outpatient prescription drugs $1.84 (outpatient drugs are not completely covered for most people), parking for the first specialist appointment $12. Public transport to get to the Sub-specialist appointment $3.25

Total cost $45.09

That’s it.

Everything else was covered by the provincial healthcare system, paid for by taxes.

Tommy Douglas was a former professional boxer, who was also a baptist minister, and is the father of Canadian Medicare. He was from the Canadian Prairies, has been referred to as the ‘greatest Canadian of all time’ and worked tirelessly to start a Canadian Health Care system which provides care to all, regardless of ability to pay.

Our system (actually systems, there are significant differences between provinces that are responsible for administering health care) is far from perfect, acute and emergency care tend to be favoured, so neonatal care, for example, what I do on an a daily basis, is in a privileged position. Central management has advantages, it makes regionalisation quite effective, so we have almost no avoidable deliveries of very preterm babies in non-tertiary hospitals. Central management also creates problems, with, for example, the size of medical school intakes oscillating as the government tries to decide if we have too many physicians or too few, and keeps changing its mind.

Chronic care, and domiciliary care are the big losers in our system, as it is politically easier to cut budgets when the adverse effects are slowly cumulative rather than acutely visible. Non-urgent surgery is another place where our system does relatively poorly, so a hip replacement might be quite delayed, with consequent avoidable pain and disability. Although, in fact, some type of waiting list for non-urgent procedures his an important way of containing costs, if everyone can get a hip replacement within a few days of qualifying for one, there has to be a great deal of redundancy in the system.

One interesting comparison with the US system was made a few years ago by John Ralston Saul. The cost of US Medicare and Medicaid, divided by the entire US population, (even though those items only cover a small part of the US population) was substantially greater than the cost of Canadian Medicare, divided by the entire Canadian Population; but the Canadian system covers everybody. A system with a layer of administration dedicated to making a profit has to be more costly.

Outpatient drug costs are one area where there are substantial differences between provinces. In Quebec where I live, if your employer does not provide drug benefits there is an ‘individual mandate’ and everyone must buy their own medication insurance. This insurance has a maximum co-pay of about 1/3, but has an annual cap, which means that there is an annual maximum which any individual has to pay of 1066$ in any year. As I have now passed 65 years I am covered by the provincial medication insurance, as is anyone without a job or with a lower income.

I am certainly grateful for the Canadian health care system, both as a patient and as a part of the system, no-one find themselves in debt because of medical costs, those who pay taxes pay for the medical care of those who pay little or no taxes. In a relatively just society, that is how it should be.

I was stimulated to publish this post, which I wrote 3 years ago on hearing of the tribulations of my friend and colleague Nick Embleton, In one of his posts on his blog he mentioned his gratitude that his medical care was covered by the UK National Health Service. He referred to the care as being “free”.

But of course it is not free, the nurses and physicians and technicians and administrative personnel are all paid, the drugs are paid for, the equipment is bought, the hospitals are built and maintained (sometimes poorly!). None of that is “free”.

What actually is happening is that we, as a society have decided, that when anyone gets sick we will all pay a little bit towards their care. Anyone who pays taxes in Quebec contributed a few cents towards my care, the purchase of the 3-dimensional fluoroscopy unit, my drugs, the salary of the nurses who cared for me and my physicians fees. Even those in other provinces contributed a little, as the federal government collects money from taxes and sends then to each province in the form of equalization payments.

This is sometimes referred to as public health insurance, but it isn’t really even that. Insurance policies are paid for by the individual towards an eventual adverse occurrence, in which case their costs will be paid. Paying for health care as a collective is a way of caring for those who are sick at the moment that they need it. No-one has to worry about health care bills or becoming bankrupt. Of course, the young rich and healthy contribute towards the care of the old poor and sick more than they get back… at first. But one day we all need health care, to receive it without having to dread the bills that might arrive is a sign of a healthy society.

There have been attempts to de-fund Canadian Medicare, and the NHS, from ideologues whose idea of society is more a “sink or swim” image. But Medicare in Canada and the NHS in the UK are extremely popular, so attempts in the UK to destroy the system are usually disguised as attempts to “improve efficiency” or “decrease overheads”. Our systems, however, are already incredibly efficient, with much lower proportions of costs going to administration than happens in systems relying on profit-taking insurance companies.

I am privileged to live in a province (Quebec) where these collective principles are never under attack. None of the political parties are opposed to Medicare being funded out of the public purse (i.e. our collective contributions), even though they may have different approaches, and tend to try to re-organize the system every time there is a change in government, with resultant chaotic periods. I can rest assured that the next time I need acute care I will not end up with a bill (if I have to take an ambulance it will be even cheaper, as that is covered also) because my colleagues, my neighbours, and people in far away towns that I will never meet will pay for my costs.

Thank you Tommy Douglas, thank you Canada, thank you Quebec.

Posted in Neonatal Research | 10 Comments

How often does Whole Genome Sequencing really help the baby? Or their family?

It is a long time since I have written anything on this blog about the above issue, I have an article in submission to the real scientific literature with some illustrious co-authors, but I was prompted to write this blog post by a new publication (NICUSeq Study Group, et al. Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial. JAMA Pediatr. 2021).

One feature of the redesign of Pubmed from a couple of years ago was that the abstract view now gives a place for the conflict of interest statement, which in this case is very long. The article has 44(!) authors of whom 10 were employees of Illumina, and 4 others had some potential conflicts. The study was apparently designed by a group of people 4 of whom were Illumina employees, and the corresponding author is an Illumina employee. That really makes a mockery of the statement in the small print after the article that “Outside the sponsor employees listed as authors, the sponsor organization had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.” I have no idea what that means when company employees were intimately involved in every single stage of the trial, which was entirely funded by the company.

One might guess that this potentially leads to some bias. Over-interpretation of the value of WGS is likely in a study designed to determine whether WGS leads to clinically important changes in clinical management (COM, as they abbreviate it) if the very existence of the company funding the trial depends on clinicians believing that WGS is often beneficial.

The trial was designed in a fairly innovative way, probably as a way of trying to ensure high consent rates, they performed WGS in all of the babies and families in the trial, but told them the results at different times. Infants and families (at least one family member had to participate, so either duo, trio or more WGS was performed) were randomized to have sequencing results revealed either at 15 days after randomization or at 60 days. Infants less than 120 days of age were eligible if they had a strong clinical suspicion of a monogenic disorder. They were then followed to see if a COM occurred up to 60 days after enrolment for the primary outcome, and then up to 90 days to see what happened to the delayed reveal group.

I have a question about the ethics of this; if WGS revealed a treatable condition (for example a metabolic disorder requiring a diet change) would it be ethical to continue to hide the results for 45 days? I don’t know if there was a possibility in the protocol to do that, but I think that question does point out that it is extremely unlikely that WGS will reveal a condition that needs, and is responsive to, a specific treatment. Most such conditions will be rapidly screened out by the testing we already do in the NICU. In the ethics section of the protocol there is no mention of this as an issue.

One thing I like about this study is that they acknowledge that those other tests are going on, and therefore compare the COM in the 2 groups, but that starts to get a bit murky, what does COM mean in the delayed group? These were critically ill babies in the NICU (mostly, 7% from the PICU and 10% from cardiovascular ICU) so changes in management were happening all the time.

There is no actual calculation of sample size. They decided to enrol 300 infants and then state that this gives an 80% power to detect “a significant increase in the proportion of cases with COM on the assumption of a 20% difference in diagnostic yield between the early and delayed groups”. Which is a strange way to express it, and doesn’t state what difference in COM they are powered to detect. In the published protocol accompanying the article they state that 300 infants gives a 90% power to detect “a significant increase in proportion of cases with” COM.

I think that determining an arbitrary sample size based on resources is not unreasonable in trial design, sample size is always a compromise between the ideal and the possible, but the power should then be calculated appropriately and presented clearly.

Sample size has to be based on a clear primary outcome. I was very surprised that the protocol has no clear definition of the primary outcome. The section of the protocol on determination of test outcomes is all about the WGS results, there is no definition of what is meant by COM, and in particular what is meant by COM in the delayed group. It was apparently the site PI who decided about the presence and classification of a COM, and they were of course, not blinded, but knew what genetic results were available. In the second supplement to the publication there is a table that looks like this

This looks like a reasonable way of defining COM after genetic testing, and I will assume that this also was used to determine COM in the delayed group if they received a genetic diagnosis prior to getting the WGS results.

That being so, there were finally 354 babies randomized; why there were more than 300 is never explained. The primary outcome of the study was that, at day 60, 21% of the early WGS group had a change of management and in the delayed group 10% had a COM, which using chi-square with Yates’ correction gives a p-value of 0.011.

Because I am cynical I wonder if there are more than 300 infants in the study because after 300 it wasn’t quite significant, so they decided to enrol another 50 or so… That is probably libel to write that, and as I am against reliance on p-values in any case, I wouldn’t dream of making that statement. But to go 17% over the planned sample size is unusual.

More important than the p-values is the question of whether there was a real added value to the parents or the infant of getting early WGS results. One thing I really appreciate about this, and a few other publications about the possible value of WGS, is the individual patient data that are available (obviously without any details that could allow identification of the individual). Which means that some of the purported COM can be investigated in detail. For example subject 312, who had a diaphragmatic hernia and a secundum ASD. This patient was in the early group and is listed as having a COM type S after a non-contributory WGS. I think this is pushing it a bit, I presume the idea is that they proved the baby probably did not have a lethal genetic condition, and that was the added value of WGS. Patient 17 had a long QT interval, and the specific gene defect found was in RYR2, which apparently leads to a malignant form of recurrent ventricular tachydysrhythmias. Treatment is probably the same as other prolonged QT patients, but I can certainly go along with the evaluation that this WGS result helped the infant and their family, the standard panel for long QT apparently doesn’t pick this up.

Another infant in the trial, listed as having a COM, had a diagnosis of a hypomyelinisation myopathy, for which there is no specific therapy, did knowing the gene really help the infant? Surely the supportive care the baby needs is related to his hypotonia, feeding difficulties etc. and not to his genetic abnormality.

Another example is an infant with multiple anomalies who had a diagnosis of Cornelia de Lange syndrome after WGS, for whom the COM is noted as both M and S. However, there is no specific treatment for the syndrome, and supportive care depends on the symptomatology, not on which gene is abnormal. I’ve seen several babies with this syndrome, and not knowing which gene was abnormal did not, I think, have any impact on how we looked after them.

One thing that geneticists are all too aware of, but which seems often lacking in publications of the proposed benefits of WGS, is the problem of phenotype-genotype correlation (or the lack of correlation). It is vital to remember that exactly the same genetic defect can cause a range of phenotypic expression. In relatively common disorders, for example CHARGE there are enough cases to have publications about the issue, and there have even been cases of monozygotic twins with CHARGE who have dramatically different phenotypes. As the article I just linked to concludes, “the phenotype cannot be predicted from the genotype”.

Although I am being very critical of this article, I do think that WGS is sometimes indicated, and I do think there may sometimes be important benefits for families. Just knowing the diagnosis can be a benefit, having some idea of prognosis is important, even though it is important to always be aware of the limitations of predictions based on genotype. For genetic counselling, a diagnosis, and sometimes the identification of the gene, may be essential. And, for future possible pre-implantation diagnosis, knowing the precise genetic abnormality is essential. For some parents, however, knowing that their infant’s problems are due to genes inherited from them can cause them to feel guilty.

In a study which Annie Janvier and our genetics group at Sainte Justine did, 14% of parents, when asked about their experience with Chromosomal Micro-Array testing, expressed concern that they may be responsible for their child’s genetic condition and 12% of parents did actually feel an increase in guilt after the test. (although others, also about 10%, will feel less guilty).

The benefits of WGS testing, however, very rarely include a specific change in management. In this trial, unlike other studies, there are very few instances of COM involving palliative care or end-of-life care. Two of the cases listed as having a COM involving palliative or end-of-life care had a non-contributory WGS, so I don’t understand how that helped to make the decision. In other cases reported in other studies it seems to me that performing WGS only delayed the decision to redirect care. Often, the clinical details presented for those other cases suggest that redirection of care would have been appropriate without WGS. If parents and care teams continue intensive care in the hope that the WGS is going to produce a result which will dramatically change their infants treatment and prognosis, then that is going to be an extremely rare occurrence, and parents should know that. It may be that the most common impact of WGS testing is continuing invasive care and life support while waiting for a result, care which may be painful, stressful, and ultimately prove futile.

Informed consent for WGS testing requires that we have an honest evaluation of the potential benefits and risks. Some of the investigators who have published on the issue seem to have vested interests in proving how beneficial it is to clinical care. In my personal experience, the most common benefit of a positive WGS to the individual baby has been that we can stop searching for other diagnoses, and concentrate on their symptomatic management. The majority of WGS are non-contributory, however, and we just carry on doing what we were before. I think our group’s scepticism about the likelihood of finding a treatable diagnosis means that we have not delayed redirection of care while waiting for a WGS result.

All of our advanced diagnostic testing, from genomes to PET scans to whatever is next, needs to be accompanied by an unbiased evaluation of benefits and risks (and costs). Only then can we adequately inform parents.

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Neonatal Updates

It’s a long time since I did one of these, but there were several publications that I thought warranted a quick comment.

Abbey NV, et al. Electrocardiogram for heart rate evaluation during preterm resuscitation at birth: a randomized trial. Pediatr Res. 2021.

In this RCT of babies of 30 weeks or less, 51 babies were randomized to either what has become standard NRP, i.e. trying to put an ECG in place as quickly as possible after the baby arrives on the resuscitation table, or doing the same thing but hiding the monitor. The study was performed 4 years ago, and the time it took to get the babies to the resusc table is said to be “22” in 1 group and “18” in the other. I have to assume that these are seconds, and I have to assume that delayed cord clamping was not being practiced at that time. The heart rate was visible at just over a minute in both groups, and about 10 seconds earlier in the ECG visible group.

There was no difference in any clinical variable, including time to get a pulse over 100, about half of the babies were bradycardic at first evaluation, and PPV was started at about “36” in each group, i.e. before the heart rate was visible on any monitor, presumably because of auscultation or palpation of a slow heart rate.

This is an OK study, but I hope it isn’t interpreted as showing that the ECG is a waste of time. For most babies, even the very preterm, you don’t need anything other suction or a few puffs of positive pressure to get them going, as in this study, so nothing we do to try and improve resuscitation will likely have much impact in a study of 50 babies. In order to demonstrate whether ECG really makes a difference among those babies who really need resuscitation, you would need a sample size of a few thousand probably. Or at least a few hundred. I don’t know whether adding ECG to our resuscitation standards is a significant improvement or not, we certainly need to be aware that it can be misleading, if there is an ECG but no output (Luong D, et al. Cardiac arrest with pulseless electrical activity rhythm in newborn infants: a case series. Arch Dis Child Fetal Neonatal Ed. 2019). On the other hand if you can have an accurate heart rate faster, I think that is self-evidently a good thing, and will probably occasionally change the resuscitation approach to a more appropriate intervention.

Gehle DB, et al. A predictive model for preterm babies born < 30 weeks gestational age who will not attain full oral feedings. J Perinatol. 2021.

Occasionally I read something, and I wonder if I am on the same neonatology planet as another group. At the University of South Carolina they send about 16% of their babies <30 gestation home with gastrostomies and tube feeding. I found this rather bizarre, I know there are pressures in the US to send babies home that I don’t have to deal with, but that doesn’t seem to be the explanation here. The G-tube babies in this study are not going home early, indeed the major risk factor for not establishing oral feeding seems to be when you first offer oral feeds, which averages 40 weeks in their G-tube babies.

This centre seems to choose gastrostomy over home NG tube feeding, which I think is questionable unless you think the tube feeds are going to last at least several weeks. But we send very few preterm babies home with any kind of tube feeding. The G-tube babies in this study had a mean birth weight of just under 700g and lots of complications, but I am still really stunned by this extremely high frequency of needing home tube feeds. We are often too slow to insert a G-tube I think, when we reach around 42 weeks and babies aren’t feeding very well, and don’t have much sign of improvement then a G-tube may be the best option. I guess without actually doing the calculations that occurs in about 4% of our babies under 28 weeks (we have about 100 a year <28 weeks), almost all of whom are 22 to 24 week babies.

I would like to see some multicentre evaluation of this phenomenon, we should aim to determine whether one can reduce the numbers of babies who need home tube feeds by uniformly introducing oral feeding at different criteria. In South Carolina apparently their “criteria for oral feeding attempts were respiratory support of ≤0.5 LPM NC and PMA of at least 31 w”. This may be part of the difference from our centre, we routinely start oral feeds between 32 and 34 weeks regardless of O2 requirements, babies on high-flow cannulae have oral feeding attempts if they are still dependent on high-flow at 35 weeks, and we have tried to orally feed a few babies who were still on CPAP. We have a standardised feeding competence scale that we developed (and which I am supposed to write up, I will get round to it soon, honestly, maybe) and have just started nutrition rounds, which are mostly oral feeding rounds, with a great team of professionals, including an OT and lactation consultant.

This is something that has a huge impact on babies and their families, and it really needs much more attention.

Takahashi T, et al. Betamethasone phosphate reduces the efficacy of antenatal steroid therapy and is associated with lower birth weights when administered to pregnant sheep in combination with betamethasone acetate. Am J Obstet Gynecol. 2021.

I had forgotten, until reading this article, that the “Celestone” that we use in Canada for antenatal lung maturation is a mixture of 2 different molecules, betamethasone phosphate and betamethasone acetate. I vaguely remember hearing about this years ago, and assumed it was unimportant. Not so. Alan Jobe has been emphasising how little we know about this treatment for years, the dose we use is the same as was originally investigated by Liggins and Howie, which was an arbitrary extrapolation from animal data. What has been shown is that the kinetics of the two molecules are quite different, with the Phosphate having a rapid distribution from IM injection to the blood stream, while the Acetate absorbs more slowly and lasts longer.

In this study, pregnant sheep were randomized in 3 groups to either get placebo, or “celestone” (a mixture of betamethasone phosphate and acetate) just like our patients in threatened preterm labour, or just betamethasone acetate. They thought the acetate alone would give a good response as they have previously shown that prolonged low serum concentrations of betamethasone were effective. The total betamethasone dose was twice as large in the combination group as in the acetate alone group.

Efficacy was similar in terms of induction of surfactant synthesis, but the clinical response rate (determined by CO2 levels after 30 minutes of ventilation) was better with the acetate alone. Lung compliance was better and the pressure volume loops more normal with the acetate alone, the lambs were also smaller after the combination drug. There were much higher serum concentrations in the sheep and fetal lamb with the combination, and evidence of pituitary suppression with the combination compared to the acetate alone.

I think we are rapidly approaching having enough data to perform a clinical trial comparing celestone to the acetate alone.

Rakshasbhuvankar AA, et al. Vitamin A supplementation in very-preterm or very-low-birth-weight infants to prevent morbidity and mortality: a systematic review and meta-analysis of randomized trials. Am J Clin Nutr. 2021.

I have always been a bit sheepish about not giving vitamin A to my very preterm babies, with the data showing a reduction in BPD with routine intramuscular injections. The evidence-based approach should be, I believed, to routinely offer vitamin A. My reticence was based on not knowing what the background vitamin A status of mothers in my region, and not wanting to give multiple intramuscular injections for what seemed to be about a 10% reduction in BPD. Vitamin A in TPN is degraded, and very little gets to the baby, although you might be able to improve that by protecting it from light and giving it separately, or mixing it in with the lipid, as is often done in Europe.

This new SR and meta-analysis confirms that vitamin A is probably effective, with a relative reduction in BPD of about 17%, but if you divide up the studies according to background vitamin A intake, those who had a higher enteral intake in the controls (>1500 units/kg/d) didn’t seem to have a benefit. Although the studies with the higher background intake were quite small with a total of 500 babies in a total of 5 trials, this makes me think that we should be making certain that enteral vitamin A intakes are adequate, and if that is difficult then consider parenteral supplementation.

Singh N, Gray JE. Antibiotic stewardship in NICU: De-implementing routine CRP to reduce antibiotic usage in neonates at risk for early-onset sepsis. J Perinatol. 2021;41(10):2488-94.

The CRP does not adequately differentiate between infected and non-infected babies. We should stop doing them. If you stop measuring CRP them you no longer have to treat raised CRP with antibiotics. This study showed that was true for early onset sepsis, there was a 30% reduction in antibiotic usage for early onset sepsis without any downside. If you do the same thing for Late-onset sepsis, where the data about the uselessness of CRP are equally strong, I am sure you would find the same thing. Less antibiotic use, no downside.

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Delivering better CPAP in the delivery room, can we avoid intubation in the most immature babies?

Randomized trials have shown that trying to prevent intubation in the DR leads to less severe lung injury. The Cochrane review of prophylactic CPAP compared to immediate intubation included 3 trials (SUPPORT, COIN and DR Management study), that review found less BPD, and less “BPD or death” among very preterm infants who were randomized to CPAP rather than immediate intubation. The control group frequency of BPD was somewhat different between the studies, due to differences in entry criteria (about 25% in DRM, 33% in COIN, and nearly 50% in SUPPORT) but all showed less BPD with a similar relative risk reduction, which overall was 0.89.

Many of us have found it difficult to avoid intubation in the most immature babies, even though there are reports from centres like Koln, who are able to deliver surfactant without intubation to infants as early as 22 and 23 weeks gestation. Our centre hasn’t been able to avoid DR intubation in 23 weeks or less. I assumed this was a problem with the babies not havign sufficient resiratory drive and stability, but maybe a better CPAP system could improve the chances of keeping the extremely preterm baby extubated.

Comparison of Respiratory Support After Delivery in Infants Born Before 28 Weeks’ Gestational Age

Donaldsson S, et al. Comparison of Respiratory Support After Delivery in Infants Born Before 28 Weeks’ Gestational Age: The CORSAD Randomized Clinical Trial. JAMA Pediatr. 2021;175(9):911-8. This multicentre trial enrolled babies under 28 weeks gestation (although the figure above notes < or = 28 weeks), with antenatal consent to have assisted ventilation and CPAP using either a new system or a usual care group of T-piece resuscitator with face mask.

The visual abstract above just shows the patient interface, but there was also a difference in the pressure generation circuit, as shown below.

In this system the inspiratory gas flow arrives in the small tube with the green arrow (with a bias flow in the larger tube) and the baby receives positive pressure and breathes spontaneously exhaling through the outlet A. In order to deliver positive pressure breaths the outlet is occluded.

The idea behind this circuit is to reduce the imposed work of breathing, and in their published bench testing the iWOB was indeed dramatically less than with a standard neonatal T-piece reuscitator; but how much this matters in clinical practice is unclear to me. Does it really matter if the extra work of breathing imposed by the system is 1 mJ/breath rather than 8 mJ/breath? The authors state that it has “been suggested” that a high iWOB might contribute to treatment failure, (they give a reference from 1979), but I’m not sure if it really is of clinical importance.

Just like the T-piece resuscitators this is not really a constant pressure system (bubble CPAP gives a constant pressure equivalent to the height of the water column), it is a constant flow system, which will need flow and/or resistance adjustments to achieve the pressure desired. In the model system, there wasn’t any difference of importance between the iWOB with facemask compared to short binasal prongs.

In the CORSAD trial babies either were assisted at birth with the new circuit and close fitting short binasal prongs, or with a standard T-piece and a round face mask. Respiratory support protocols were otherwise identical in the 2 groups. Randomisation was masked, but the intervention, for obvious reasons, was not.

The intervention group resuscitators chose prongs which were tight fitting, and gently held the mouth shut with a finger. Controls used a standard face mask covering the nose and mouth.

The primary outcome variable was “death or intubation” in the delivery room, mortality was expected to be very low, I suspect, so the study was really designed to see if intubation could be avoided with the new system. “Criteria for DR intubation were no or inadequate response to PPV and CPAP defined by one of the following: (1) bradycardia heart rate less than 100 beats per minute despite 60 seconds of effective PPV, (2) persistent apnea, (3) poor respiratory effort during the intervention, and (4) inadequate oxygenation and respiratory distress”. Of course, the decision to intubate, even if protocolized, will always be a bit subjective, and you can see in this list of criteria, there is some subjectivity. In a non-masked trial that potentially introduces bias, but I think that is unavoidable in a pragmatic trial.

Secondary outcomes included need for assisted ventilation in the first 72 hours in the NICU, airleaks, IVH surfactant use, etc. But not survival to discharge or BPD, which I think should have been reported, even if the authors thought BPD unlikely to have been improved. Fewer babies in the intervention group were intubated within the first 72 hours of life, 56% vs 69%, which I think is a large enough difference, in what is probably a critical period in postnatal pulmonary adaptation, to improve lung injury. Now it may be that the difference in intubation is mostly among more mature babies, of 26 and 27 weeks gestation with a much lower risk of BPD, but I don’t see that information in the publication or in the supplementary data.

Summarizing, this looks promising as a way of improving the success of keeping extremely preterm babies from being intubated in the DR. I don’t know whether the circuit or the interface is more important, however. Other studies (there are 4 references below if you are interested) have suggested that nasal masks are preferable to short binasal prongs for delivery of CPAP in the NICU, they seem to be associated with less nasal trauma, and perhaps less CPAP failure. Nasal masks and face-masks are of course quite different. I would like to see more studies like CORSAD, isolating the effects of nasal prongs vs face mask, the new circuit vs a standard T-piece. For now, the improvement in success rate of avoiding intubation is a good start, but I don’t know if I should think of changing my interfaces, or wait for commercialisation of the new system and then buy new resuscitation machines. Might a nasal mask be even better in the DR than either a face mask or short binasal prongs?

Bashir T, et al. ‘Nasal mask’ in comparison with ‘nasal prongs’ or ‘rotation of nasal mask with nasal prongs’ reduce the incidence of nasal injury in preterm neonates supported on nasal continuous positive airway pressure (nCPAP): A randomized controlled trial. PLoS One. 2019;14(1):e0211476.
Say B, et al. Binasal Prong versus Nasal Mask for Applying CPAP to Preterm Infants: A Randomized Controlled Trial. Neonatology. 2016;109(4):258-64.
Chandrasekaran A, et al. Nasal masks or binasal prongs for delivering continuous positive airway pressure in preterm neonates-a randomised trial. Eur J Pediatr. 2017;176(3):379-86.7.
McCarthy LK, et al. A Randomized Trial of Nasal Prong or Face Mask for Respiratory Support for Preterm Newborns. Pediatrics. 2013;132(2):e389-e95.
Yong S-C, et al. Incidence of nasal trauma associated with nasal prong versus nasal mask during continuous positive airway pressure treatment in very low birthweight infants: a randomised control study. Arch Dis Child Fetal Neonatal Ed. 2005;90(6):F480-3.

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Babies feel pain, and they remember it!

I usually don’t post about studies of painful procedures where there was no analgesic prophylaxis in some of the the subjects, except to criticize them, and if they are recent, to call for their retraction. So when I first saw this study, which recorded pain responses to arterial punctures in newborns, I was going to file it in the recycle bin. However, after reading the methods, I found that they did have a protocol to use 25% glucose and facilitated tucking during the arterial punctures. The article doesn’t say that the protocol was actually followed, which is a problem in many NICUs; despite good intentions, pain is often not adequately prevented. So let’s assume for this article that the protocol was followed, not a bad protocol, but not optimal. Sucrose is probably preferable to glucose as it tastes sweeter, and the initial analgesic effect is probably due to the intensity of the taste, with a sort of distraction effect, later effects, by about 2 minutes are probably related to endorphin release. Also sucrose is more effective if combined with a soother/pacifier/dummy or whatever the local term is. (Alberice RMC, et al. Assessment of newborn pain during arterial puncture: an observational analytical study. Rev Bras Ter Intensiva. 2021).

The article, as I read it, is a translation of an article in Portuguese, I love the translation of what I suppose is cleaning the skin with antiseptic as “degermation”.

No surprise; aterial punctures hurt!

If we give the authors the benefit of the doubt, and assume that all the babies received the glucose/swaddling intervention, pain was between minimal and severe, with nearly 50% reaching a PIPP score of 12 or more, despite a reasonable analgesic approach.

The NICU that this was from seems to do an awful lot of arterial punctures, they were actually performed by their lab techs! The messages of the article are: don’t do blood work unless you need to; if you need to then capillary sampling can be performed with much lower PIPP scores than the scores reported here when using a combination of sucrose, soother, and swaddling, or skin to skin care. If you do need to do an arterial puncture then consider EMLA or liposomal lidocaine in addition.

In a previous study of infants who had previously had multiple blood sampling (infants of diabetic mothers) it was shown that they start to have adverse responses when someone comes the next day to prepare them for another heel prick, Taddio A, et al. Conditioning and Hyperalgesia in Newborns Exposed to Repeated Heel Lances. JAMA. 2002;288(7):857-61, during the degermation phase the infants were able to anticipate that something bad was about to happen.

In this newer study, (Mehler K, et al. Pain response to vaccination in newborn infants of diabetic mothers. Early Hum Dev. 2020;149:105139) in infants of diabetic mothers who were about to have their 2 month vaccination, all the babies received 20% glucose with a soother prior to the 2 IM injections that the German standards required. Control infants were from a previous study that the authors published, which is one weakness of this study. The controls had a median of 1 heel stick as neonates (maximum 3) while the infants of diabetic mothers had suffered between 4 and 19, median 5.

The IDM babies had a greater increase in their heart rate, and took longer to recover than the controls.

They also had greater increases in their salivary cortisol after the vaccine.

Although there is some overlap in the results, the authors also examined a more direct measure of pain sensistivity, using the Frey filaments, where you poke the baby with progressively stiffer filaments to see at what threshold they have a withdrawal response. This suggested that the IDM babies had hyperalgesia, responding at a lower threshold than the previous control group.

Of course, the difference in responses my not be because of a “memory” of the painful experiences as a neonate, and may be due to other factors, such as epigenetic changes associated with maternal diabetes. But one possible explanation is that repeated painful experiences as a newborn may have long term consequences in pain reactions at 2 months of age.

Yet another reason, as if we needed more, that pre-emptive analgesia, prior to planned painful procedures, is important.

Indeed, it is a moral imperative.

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Intestinal perforation in the very preterm, what causes it, and what to do about it.

There are 2 main causes of intestinal perforation in the very preterm, Necrotising Enterocolitis and Spontaneous Perforation. NEC, as I have previously discussed, may be a convenient name for a few different conditions which present in a similar fashion. In particular NEC in infants with congenital heart disease, in infants with Hirschsprung disease, and in infants with gastroschisis, may all have differing pathophysiology, and methods to prevent and treat them may also differ. For the moment, very preterm infants without those conditions who develop NEC are considered to have a single disease, but it may be that more than one pathophysiologic process can lead to what we call NEC. After we introduced probiotics in our nursery the incidence of NEC fell, but also the average age of the infants who presented with NEC was substantially younger, making me wonder if the balance of different aetiologic factors is different in younger versus older cases.

Most database publications have noted that NEC overall is quite a lot more frequent than Spontaneous Intestinal Perforation (SIP) and even the NEC infants requiring surgery (mostly for perforation, but not all) are a larger group than SIP.

The Canadian Neonatal Network, for example, reported that among 2,019 infants <28 weeks gestation, 39 (1.9%) had spontaneous intestinal perforation, 61 (3%) had perforated necrotizing enterocolitis, and 115 (5.7%) had non-perforated necrotizing enterocolitis.

The German Neonatal Network reported, among 8,022 babies under 1500g birth weight (and <37 weeks gestation), 177 cases of surgical NEC and 123 with SIP.

Which makes the distribution of cases in this newly published trial somewhat surprising, with rather more SIP than surgical NEC. Blakely ML, et al. Initial Laparotomy Versus Peritoneal Drainage in Extremely Low Birthweight Infants With Surgical Necrotizing Enterocolitis or Isolated Intestinal Perforation: A Multicenter Randomized Clinical Trial. Ann Surg. 2021;274(4):e370-e80.

In this trial, babies of <1001 g birth weight, and less than 8 weeks postnatal age with either NEC or SIP, for whom a decision to perform surgery had been made, were randomized. They either were directed towards initial laparotomy or initial peritoneal drainage in the NICU under local anaesthesia. Planned sample size was 150 per group in order to have an 80% power of detecting a 15% absolute improvement in the primary outcome, which unfortunately was “death or NDI”. For this trial “NDI” was cerebral palsy with a GMFCS of 2 or more, a Bayley III cognitive composite score of <85, or blindness or deafness, at 18 to 22 months corrected age.

This trial is a perfect example of why we should abandon this outcome. Death is common in this group of babies, neurodevelopmental problems are also common among survivors. But this definition of NDI, which is given the same weight in the outcome as being dead, includes infants who will mostly be ambulant but walk with some difficulty, i.e. they will limp. A Bayley cognitive score of <85 has very little correlation with functional capacities or outcomes. Ask a parent of a deaf or blind child if that outcome is equivalent to them being dead; or ask them themselves when they are old enough! There is also no good reason for supposing that mortality and neurological impairment or developmental delay will change in the same direction with these interventions. This would have been a perfect trial for a “win-ratio” approach, with a substantial risk of death, and a major risk of long term difficulties among survivors. What I want to know, in order to make the best decision for my patients, is whether mortality will be affected, and if not then is the long term outcome better or worse? If mortality is better with one approach rather than another, are all the extra survivors profoundly impaired? (That would be a unique result in neonatology if it happened, but I guess it is possible). Becaue if not, then mortlaity trumps all the other outcomes.

The authors achieved a very high follow up of 96%, but the difficulties on doing such a trial are illustrated by the fact that enrollment took 10 years!

They did indeed finally enrol 300 babies, but as mentioned, somewhat surprisingly, there were 95 with NEC and 213 with SIP. This immediately makes me concerned about some sort of selection bias in the enrolment process. It may be that infants with what was thought to be definite NEC were less likely to be approached for consent, I would guess that for many of those babies the care team thought that going straight to laparotomy was appropriate, but potential randomisation to bedside drainage was not. Among the NEC babies enrolled nearly half were on vasopressors at enrollment, suggesting that babies who were more unstable, and therefore thought potentially worth consideration of peritoneal drainage, were more likely to be enrolled.

With those provisos, lets look at the results. In a strictly trial design sense, there was a nul result. No difference between the 2 approaches for the primary outcome, 69% death or NDI with laparotomy, and 70% with peritoneal drainage. About half of the drainage babies went on to have a later laparotomy, about 1 in 5 of the laparotomy babies needed another laparotomy later on. Mortality for the 2 randomized groups was similar, 29% vs 30%.

Mortality, however, was quite different among those babies who the Surgeon thought, pre-op, were NEC rather than SIP, (there were 7% of the laparotomy babies who actually had neither NEC nor SIP, but another diagnosis including volvulus and gastric perforation). Among the “thought to be NEC” babies, mortality was 40% with laparotomy and 51% with initial drainage, the “thought to be SIP” babies mortalities were 23% (laparotomy) vs 19% (drainage).

Although neither of these differences is “statistically significant”, the authors performed a Bayesian analysis of the results (Jon Tyson is the second author!), which showed that initial laparotomy is much more likely to lead to a reduction in “death or NDI” in the NEC babies with a probability of 97%, and is somewhat less likely to be beneficial in the SIP babies, only 18% chance of being better, compared to 82% chance of being worse.

I think these Bayesian analyses are a reasonable attempt to explain the implications of the data, when, despite the enormous efforts involved in a trial lasting 10 years, final sample sizes are modest. Obviously not as good as having a trial with 1000 babies per group, but it does suggest that such a large trial would be very unlikely to show a benefit of intial drainage among bbies with surgical NEC.

Among babies with a pre-op diagnosis of NEC, there were 25 long-term survivors after laparotomy (of 42 infants), and 26 survivors of the 52 who had initial drainage, of whom 25 were followed up. Of the laparotomy babies, 13 of the 25 survivors had no “NDI”; among the drainage babies 9 of the 25 had no “NDI”. The fairly small numbers lead to low confidence in the results, but all the differences in long term outcomes in these babies favour intial laparotomy. Among the SIP babies there are fewer babies with CP (GMFCS 2 or more) after initial laparotomy, but somewhat more babies with lowish Bayley scores. Here are the details of the “NDI” outcome, from the supplemental materials:

As an article I just published with Elliott Weiss and Stephanie Kukora (Weiss EM, et al. Use of composite NICU research outcomes for goals of care counselling creates ethical challenges. Acta Paediatr. 2021) discusses, not only are such composite outcomes a problem for clinical trial design and interpretation, they make counselling of families more difficult, what are we to say to families when trying to decide which approach to take for an infant with NEC who needs surgery? This trial shows, strictly, no difference between the two approaches. But I think it is much more helpful to parents to be able to say, for a baby with a diagnosis of NEC and an indication for surgery, that mortality is lower with immediate laparotomy, and in the long term, despite significant risks with either approach, outcomes seem to better with immediate surgery (48% “NDI” among survivors with laparotomy and 68% “NDI” among survivors after initial drainage, in this trial).

There are 2 previous trials with similarities to this one. A European trial of 69 babies with perforation, including NEC and SIP babies (Rees CM, et al. Peritoneal drainage or laparotomy for neonatal bowel perforation? A randomized controlled trial. Ann Surg. 2008;248(1):44-51) showed somewhat lower mortality with laparotomy, 33% vs 40%. In that trial over 60% of the babies had NEC confirmed if they had surgery. A previous North American trial of 117 infants (Moss RL, et al. Laparotomy versus peritoneal drainage for necrotizing enterocolitis and perforation. NEJM 2006;354(21):2225-34), was supposedly limited to infants with NEC, but the entry criteria as described in the article would have included SIP “preterm infants (birth weight, <1500 g; gestational age, <34 weeks) with evidence of intestinal perforation, including free intraperitoneal air on an abdominal radiograph (96 infants); stool, bile, or pus found at paracentesis; or clinical evidence of perforation in the joint opinion of the attending surgeon and the neonatologist. This definition included both infants with extensive disease and others with focal perforation”. 60% of their subjects did not have pneumatosis on abdominal x-ray. In that study mortality was 35% in each group.

If I try and put all of this together, it looks to me that infants with perforated NEC should probably be directed, if possible, to immediate laparotomy. There is no advantage to initial drainage, and some evidence of lower mortality, and perhaps better long term neurologic and developmental outcomes, with immediate laparotomy. Also, 7% of the infants may turn out to have another diagnosis, which probably mostly require surgery also.

In infants with probable SIP the question is more difficult, but there doesn’t appear to be a clear advantage to delaying laparotomy, there may be a slightly higher survival with initial drainage, but in the long term outcomes seem rather balanced; with the highly problematic outcome, of uncertain real importance, that a cognitive Bayley composite <85 was a little more frequent after laparotomy than after drainage.

Makes me wonder, yet again, how we got to the point where a Bayley cognitive composite of 86 is fine, but a Bayley cognitive composite score of 84 is a disaster, an impairment, equivalent to death! Dichotomizing human development into normal and subnormal is an affront to me, and I think to most of those who actually do follow up.

This review points out a number of problems with NEC research, one is the lack of good definitions. A recent publication by Janet Berrington and Nick Embleton (Berrington J, Embleton ND. Discriminating necrotising enterocolitis and focal intestinal perforation. Arch Dis Child Fetal Neonatal Ed. 2021) has illustrated some of the difficulties: reviewing a large cohort, many cases that had been classified as NEC were found after extensive review to more likely be SIP. Some of the babies satisfied published diagnostic criteria for one disease, but after review, including surgical histopathology, they had the other. I am rather sceptical in general about the usefulness of many published biomarkers, which often seem to be a way of increasing numbers of publications rather than helping clinical practice, but here is one situation where a good discriminating biomarker might really help to differentiate these conditions, and also point, perhaps to other diagnoses. This study shows clearly, yet again, that CRP is of no use (not always being elevated with either diagnosis), and most of the articles that I have looked at don’t seem to have tried to differentiate NEC and SIP using their biomarker.

Surgical NEC has a very high mortality in all of these studies, and the mortality of SIP is not negligible. Neurological impairments and developmental delay are frequent with surgical NEC, medical NEC, and probably following SIP also. The fight to reduce these diseases has to intensify, we have made relatively little progress in recent years. Mother’s milk, and donated human milk when mother’s milk is not available are interventions that reduce NEC compared to formula feeding, but we have known that for years. Finding ways to normalise the intestinal microbiome are are potential part of the solution, but administration of current probiotics is only partly successful, both in normalising the microbiome and in reducing NEC. Avoiding antibiotics whenever you can, and having a feeding protocol are both helpful, but neither can eliminate NEC, and probably have no impact on SIP.

I have seen too many babies die of NEC in my career, I sincerely hope that, during the careers of my trainees, we will be able to stop these scourges.

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Extreme preterm survival and outcomes

There are frequently publications about the outcomes of extreme preterm infants; as a community I think we should be proud of our investment in outcome research. Indeed, neonatologists invented the entire field of outcomes research (Barrington KJ, Saigal S. Long-term caring for neonates. Paediatr Child Health. 2006;11(5):265-6). When very preterm babies started surviving, the obvious question was: how will they do in the long term? With the survival of extremely preterm (24-28 weeks) and now profoundly preterm (<24 weeks) infants the questions continue.

Multiple cohorts have been extremely informative, and give an opportunity to perform comparisons between those cohorts. A new publication comparing babies from France, Canada, and New Zealand has just been published. (Chevallier M, et al. Mortality and significant neurosensory impairment in preterm infants: an international comparison. Arch Dis Child Fetal Neonatal Ed. 2021). As a disclosure, the first author, Marie Chevallier, was one of the excellent fellows in our programme, and has gone on to be a neonatologist and researcher in Grenoble; the last author, Thuy Mai Luu, is a colleague and friend from my hospital.

They and an international groupd of researchers compared outcomes from 3 cohorts born in 2011. The Canadian cohort have their data collected in CNN, with standardized examinations and data collection in the Canadian Neonatal Follow-Up Network (CNFUN) at 18 – 21 months corrected age. The Australian and New Zealand Network is a similar prospective database with outcome data also being collected at 2 to 3 years, but without the same structured follow-up and data collection. The data from France are derived from EPIPAGE-2, with outcomes at 2 years corrected age derived from questionnaires.

The authors have focussed survival and on long term neurosensory impairments, which I think was wise, given the differences in ages and methodologies. Disabling cerebral palsy, blindness and deafness and relatively stable outcomes, and probably less affected by methods of data collection than, for example, developmental delay.

There are 3 findings of note, I think. One of which is not discussed in the article, that being the proportion of babies by completed week of gestational age, which was much lower at 24 weeks in France than the other 2 cohorts.

Birth and antenatal characteristicsANZNNCNNEPIPAGE-2P value
Gestational age, mean (SD), weeks25.7 (1.1)25.8 (1.1)25.9 (1.0)<0.01
 24 weeks, n (%)182 (19.0)159 (15.6)102 (9.5)<0.01
 25 weeks, n (%)218 (22.7)235 (23.1)258 (24.0)0.78
 26 weeks, n (%)254 (26.5)314 (30.8)361 (33.6)<0.01
 27 weeks, n (%)306 (31.8)311 (30.5)355 (33.0)0.48
Birth weight, mean (SD), g856 (201)864 (216)843 (172)0.05
Male sex, n (%)519 (54.1)537 (52.8)557 (51.8)0.58
Maternal age, mean (SD), years29.3 (6.5)30.7 (5.8)29.4 (5.9)<0.01
Complete course of antenatal steroids, n (%)601 (63.1)692 (70.0)622 (60.2)<0.01

I don’t think there is any biological reason why French women would have fewer deliveries at 24 weeks, this difference is probably because of a relatively lower willingness to provide active obstetrical and neonatal care to babies born at this gestation.

Keeping in mind that there are somewhat fewer of the highest risk babies in France, the outcomes, the primary and the various parts of the primary are here:

OutcomesANZNN, n/N (%)CNN/CNFUN, n/N (%)EPIPAGE-2, n/N (%)P value
Mortality or sNSI204/960 (21.3)210/1019 (20.6)305/1076 (28.4)<0.01
Mortality179/960 (18.7)177/1019 (17.4)283/1076 (26.3)<0.01
Any sNSI among survivors25/578 (4.3)33/621 (5.3)22/659 (3.3)0.22
Cerebral palsy with GMFCS >214/565 (2.5)14/610 (2.3)15/659 (2.3)0.97
Disabling hearing loss12/568 (2.1)14/607 (2.3)7/641 (1.1)0.23
Visual impairment4/570 (0.7)12/562 (2.1)2/623 (0.3)0.01

Mortality is substantially higher in France, but impairments are very similar; apart from more visual impairment in Canada. (But remember that the CNN/CNFUN have formal visual testing, which was not the case in France or in the ANZNN, so this may not be directly comparable).

One general implication of these results is that having a less “aggressive” intervention policy does not select babies who are more likely to have unimpaired outcomes. It just leads to fewer survivors.

These data are, of course, from babies born 10 years ago. Even though neonatal clinical science has not changed that much, attitudes can change much more quickly! In Canada in 2012 about 9% of babies delivering alive at 24weeks gestation had palliative care instituted at birth, in 2019 that was 6%. The CNN doesn’t detail why such babies did not receive active intensive care, but many would have been because of serious congential anomalies or severe growth restriction. It has become quite unusual in Canada for an infant born at 24 weeks gestation to not be admitted for active NICU care in the absence of such additional complications. (CNN annual reports available here, and the CNFUN annual reports here)

From what I have seen, the attitudes in France have also changed, and many more babies born at 24 weeks or profoundly preterm (using the Barrington classification above) now receive active intensive care. These data suggest that such “interventionism” should lead to more survivors, with a similar proportion of survivors having neurosensory impairments.

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Opioid infusions for ventilated preterm babies

Many practices in neonatology are variable between NICUs, and many vary from year to year; without any good scientific data practices become fashionable or routine or ingrained without necessarily having an evidence base to support them.

One such practice is that mentioned in the title, a few years ago it was rare for me to see babies with opioid infusions, but it seems to have become more common, despite the lack of a good rationale.

Infants who are unquestionably in pain, such as in the post-operative period, are excluded from this discussion; pain control after surgery is unquestionably necessary,(although there are serious questions about agents, route, and dosage, etc). I am referring to the use of opioid infusions (most commonly either morphine or fentanyl) for infants who are receiving routine care during assisted ventilation, which includes some potentially painful interventions, blood sampling and endotracheal suctining being the most common.

I think one of the first considerations is that the procedure of being intubated is very painful and should always be premedicated with analgesics, potent opioids with a rapid onset of action are needed (fentanyl or analogues; not morphine).

But I question whether being ventilated is painful. Earlier in my career I worked in the PICU, where it was not unusual to have chldren who were intubated (usually nasotracheally) and on assisted ventilation who needed no analgesia or sedation, I have played with intubated children and seen them reading and listening to music with no need for opiates!

Many babies can spend days or weeks ventilated, during which they can sleep for over 20 hours a day, without routine sedation or analgesia.

There are several considerations that should enter into our decision of whether to use opioids for a ventilated preterm baby. One of which is the lack of evidence from randomized trials of benefit. Indeed the latest version of the Cochrane review was recently published, Bellù R, et al. Opioids for newborn infants receiving mechanical ventilation. Cochrane Database Syst Rev. 2021 Mar 17;3(3):CD013732. doi: 10.1002/14651858.CD013732.pub2. As always you can access for free via the VON website, That review found 23 relevant trials, 15 of which compared routine opioid use to control (although, in all of them where I can see the information, opioids were permitted in the controls). They found no evidence of benefit, in the short or the long term. Of particular importance, there was little evidence of a reduction in pain scores, the best and easily the largest trial (NEOPAIN) showed, after the first few hours of infusion, a trivially lower PIPP score among the opioid group than the controls; 8 vs 8.7. For each of the long term outcome measures, only a single small study was available, therefore showing little difference, and with very little confidence.

We can learn, I think, from the recent evolution of practice in adult ICUs where light or no sedation has become routine. Trials have shown that routine heavy sedation prolongs assisted ventilation in adults. There are, as a result, a number of studies of patient experiences of being ventilated, many of which have addressed pain, as well as other parts of the patient experience of awake assisted ventilation. (Baumgarten M, Poulsen I. Patients’ experiences of being mechanically ventilated in an ICU: a qualitative metasynthesis. Scand J Caring Sci. 2015;29(2):205-14). In general, pain is not a major part of the reported experience of ventilated adults. They do, however, concur that being suctioned is very painful and unpleasant, although they often report feeling better after the suctioning, as the airway secretions are cleared.

Volume Controlled Ventilation in Adults works differently to volume “guarantee” ventilation in babies, with the presence of a background bias flow babies can take larger breaths if they wish, one of the complaints reported by adults during awake assisted ventilatoin was that they could not take a larger breath when they wanted, which should be less of a problem with our systems.

Also of note, many of these neonatal studies were performed in order to get babies to be better synchronised with the ventilator, at a time when non-synchronized assisted ventilation was the norm in the NICU. With the development of synchronous modes, which are now universal, that is no longer an issue, in general as long as the ventilator is set correctly.

With these considerations in mind, these are the major issues for deciding whether to give analgesia or sedation to a ventilated preterm baby, in particular morphine infusions:

  1. Being ventilated is not, by itself, usually painful. It is stressful for adults, but it doesn’t hurt. Non-pharmacological calming procedures help adults (in particular communication, less relevant for the newborn but calming sounds, voice, touch, swaddling, and gentle interventions are likely to be helpful).
  2. Opiod infusions are ineffective for preventing pain from blood sampling procedures;
    1. sucrose, skin to skin care, in combination and with the addition of non-nutritive sucking, can dramatically decrease pain from blood sampling.
    2. These interventions are still required even in a baby on an opioid infusion!
  3. More invasive skin-breaking procedures, such as lumbar puncture or chest drain insertion, benefit from local anaesthesia as well as sucrose etc. Lidocaine should always be administered for lumbar punctures and chest drain insertion.
  4. Endotracheal suctioning is unpleasant and painful but pain responses are not improved by any currently investigated modality. In particular opioids are ineffective.
  5. Retrospective and observational studies have shown more IVH, more death, and more NEC among preterm infants who receive opioid infusions.
  6. The prospective trials, in particular NEOPAIN, showed a very small increase in mortality and IVH (with 95% confidence intervals which included no difference), but did not report NEC.
  7. Morphine infusions often cause hypotension.
  8. Morphine infusions do not improve short or long term outcomes, additional doses are associated with worse pulmonary outcomes.
  9. Fentanyl is an unreliable sedative, but an excellent analgesic, as a relatively selective mu-opioid receptor agonist it is a poor choice when sedation is the goal.

There are some recent PK studies that I think are very relevant. The most immature babies risk major accumulation of morphine and its metabolites. There is a dramatic accumulation of morphine-3-glucuronide during morphine infusions in the very immature infant. It is a metabolite which is an opioid antagonist. In other words it prevents the analgesic effects of morphine, and interferes with the sedative effects also. This may be why morphine is not a very effective sedative in the most immature infants. Very immature babies accumulate M3G and have enormously high concentrations after a few hours of infusion.

There is a meta-model of neonatal morphine pharmacokinetics published a couple of years ago (Knosgaard KR, et al. Pharmacokinetic models of morphine and its metabolites in neonates:: Systematic comparisons of models from the literature, and development of a new meta-model. Eur J Pharm Sci. 2016;92:117-30) which paper has a link to this app . Play around with it for a while and you will see that the most immature babies risk having extremely high morphine and M-3-G concentrations after standard doses of morphine.

This is an example of predicted morphine and morphine metabolite concentrations for a 24 week 600g 1-day old baby who receives a 100 mcg/kg bolus and a 10 mcg/kg/h infusion, with the 95% confidence limits.

And here for clarity without the confidence limits

There are also huge variations in kinetics, one study showing a 40-fold variation in clearance! That variability can be reduced by taking into account gestational and postnatal age.

How about the long term? Well as mentioned there is very little information from randomized trials, so little confidence in the impact. However, there are observational studies, in particular a worrying series from Vancouver (Zwicker JG, et al. Smaller Cerebellar Growth and Poorer Neurodevelopmental Outcomes in Very Preterm Infants Exposed to Neonatal Morphine. J Pediatr. 2016;172:81-7 e2. Ranger M, et al. Internalizing behaviours in school-age children born very preterm are predicted by neonatal pain and morphine exposure. Eur J Pain. 2014;18(6):844-52) which show that the more morphine the babies received, the smaller were their cerebella (cerebellums?), and the more behaviour problems they had at long term.

They have recently followed this up to show that differences in morphine kinetics, or at least differences in the genes which metabolized morphine, were correlated with those behaviour problems. (Chau CMY, et al. Morphine biotransformation genes and neonatal clinical factors predicted behaviour problems in very preterm children at 18months. EBioMedicine. 2019;40:655-62), the exact meaning of which isn’t clear yet, but continues to make me anxious about the use of morphine for babies who are not clearly in pain.

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Drug use and abuse in the NICU

The title does not refer to”drugs of abuse” but rather to how we use and choose medications for use in newborns, particularly the very immature. A new publication has just appeared on-line which focuses of medication use in the NICU, and the changes over an 8 year period. (Stark A, et al. Medication Use in the Neonatal Intensive Care Unit and Changes from 2010-2018. The Journal of Pediatrics. 2021).

The enormous database of the Pediatrix medical group has been trawled to find medication exposure data for nearly 800,000 newborns.

There are a number of striking findings, in particular the amazing relative growth of the use of dexmedetomidine. Practically speaking use was 0 in 2010, now 5 per 1000 NICU patients are exposed to it, and 23 per 1000 extremely low birth weight infants.

Dexmedetomidine is routinely touted as being “neuro-protective”, but that assertion is based on questionably relevant animal models, some of which show reduced neuronal apoptosis. I don’t believe there is any long term human outcome data with which to make the assertion that dexmedetomidine is neuro-protective in humans. But of course we don’t have much similar data for any of the sedative/analgesic medications that we use. Morphine probably being the only exception, but the data for morphine are not very robust or very reassuring.

One recent animal study showed that adding dexmedetomidine to a reduced concentration of sevoflurane reduced apoptosis, but if enough dexmedetomidine was given to achieve the same level of anaesthesia as the higher concentration of sevoflurane, then the neuronal apoptosis was identical. (Lee JR, et al. Effect of dexmedetomidine on sevoflurane-induced neurodegeneration in neonatal rats. Br J Anaesth. 2021;126(5):1009-21). So, in this model at least, dexmedetomidine was not neuro-protective. In contrast, this review article found several animal studies that did seem to show neuro-protection (van Hoorn CE, et al. A systematic review and narrative synthesis on the histological and neurobehavioral long-term effects of dexmedetomidine. Paediatr Anaesth. 2019;29(2):125-36) but it was not universal, the details of the animal models and experimental procedures vary greatly. How relevant each one is to the sick newborn is very uncertain.

Multiple use, prolonged infusions, and use in the most fragile babies are all things which need to be better investigated for dexmedetomidine, and for our other sedative/analgesia drugs.

In contrast the same article showed the reduction in use of other medications. Three of them because they are no longer available, (at least in the USA) THAM, chloral hydrate, and ranitidine. No great loss to neonatology, I think. I was pleased to see a dramatic reduction in metoclopramide use, for which I think there is no indication in neonatology. Also, and a little more surprising to me, a marked reduction in lansoprazole use. Again I don’t think that there is much role for the medication; treatment for babies with reflux by prescibing lansoproazole ignores the fact that 50% of reflux in the preterm is non-acid, and the clinical signs attributed to reflux are both non-specific for reflux, and not necessarily caused by acid. Also gastric acid is an important barrier to GI colonisation, helps to prevent respiratory infections, and is probably important for absorption of iron and calcium.

Although it hasn’t changed much over this period, there is still a lot of midazolam being used, being the 9th most frequently prescribed medication overall, and the 13th most frequent in the ELBW. I can’t remember the last time I prescibed midazolam, other than a case of status epilepticus unresponsive to 3 other anticonvulsants in a baby at term. 21% of ELBW babies were exposed to this drug, with a total of 3,700 days of use per 1,000 patients. My comments about sedative/analgeisc medications apply here. What little data we have for long term effects of midazolam are worrying.

The study points out how much we still need to know about the common medications that we use, the majority of which are not specifically licensed for the newborn.

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Pain studies with untreated control groups in babies are unethical.

If you are performing a study of pain control in the newborn and you assign babies to untreated controls, you are creating unnecessary avoidable pain in the control patients. That is true for any patient who is incompetent, obviously including newborns, but also older children and adults unable to give consent for themselves. I guess you could allow competent adults to consent to be randomised to control and have painful procedures without analgesia, but good luck enrolling subjects!

There is no way this is ethical, and it should never be done, and should never be allowed by ethics review boards. (Bellieni CV, et al. Should an IRB approve a placebo-controlled randomized trial of analgesia for procedural pain in neonates? Pediatrics. 2012;130(3):550-3). There is no benefit to anyone, especially not the babies, but not to medical knowledge either. We already know that sticking needles into babies causes pain, and that there are many ways to reduce that pain. Why on earth would you perform a study comparing different methods of reducing pain for blood sampling, and include an untreated control group?

Unfortunately, it still goes on. (Bellieni CV, Johnston CC. Analgesia, nil or placebo to babies, in trials that test new analgesic treatments for procedural pain. Acta Paediatr. 2016;105(2):129-36). I was stimulated to write this post after my weekly trawl through the literature found 2 such studies. I hesitate to give them any credence by referencing them, but maybe naming and shaming is the way to go.

The first is from Stanford, of all places, by a group of people that should know better (Chang J, Filoteo L, Nasr AS. Comparing the Analgesic Effects of 4 Nonpharmacologic Interventions on Term Newborns Undergoing Heel Lance: A Randomized Controlled Trial. J Perinat Neonatal Nurs. 2020 Oct/Dec;34(4):338-345). The study design is also poor, it seems that the control group was enrolled and assigned to have pain without being randomized, but the other 4 interventions were randomized. At first the authors (and apparently the IRB) didn’t think this was research, even though they were prospectively randomizing babies to different interventions and recording responses! The study clearly satisfies every possible definition of clinical research, and, if the researchers and the IRB can’t recognize that, it bodes poorly indeed. The study was therefore started without IRB approval, which means it should never have been performed and clearly should never have been published. They recruited newborns from the postpartum wards, who they say were identified by “medical record review”, which makes no sense, presumably there were individuals screening admitted babies at some point.

It was also retrospectively registered, which means that the authors don’t understand the basics of doing clinical research.

Not surprisingly, the group of 50 babies assigned to having more pain had more pain.

I think the researchers, and the IRB, and Stanford Lucile Packard Children’s Hospital owe an apology to these infants and to their parents.

The second study (Cakirli M, Acikgoz A. A Randomized Controlled Trial: The Effect of Own Mother’s Breast Milk Odor and Another Mother’s Breast Milk Odor on Pain Level of Newborn Infants. Breastfeed Med. 2021 Jan;16(1):75-81) randomized babies into 3 groups, one of which was an untreated control group. The study is behind a paywall, and I am certainly not going to pay to get it, so I don’t know the numerical results, but the abstract notes that the group randomized to having more pain had more pain.

As I performed a quick recent literature search, what is clear is that many of recent articles of painful procedures in the newborn with untreated control groups appear in specialist pain journals, where surely the reviewers should know how unethical it is to deny analgesia to babies having planned painful procedures. Other articles I have seen recently compared skin to skin contact with control (it is already clear that skin to skin contact is effective) another using a vibrating device compared to control (why not give both groups sucrose and see if the device has additional benefit?) and another with combined sucrose, music, non-nutritive sucking and massage compared to untreated controls, (completely useless as an addition to the literature, no idea whether any of the interventions was a useful addition to the others).

Other recent articles have shown how you can do such studies without assigning babies to have more pain, for example this one (Benoit B, et al. The influence of breastfeeding on cortical and bio-behavioural indicators of procedural pain in newborns: Findings of a randomized controlled trial. Early Hum Dev. 2021;154:105308) which randomized babies to either breastfeeding or oral sucrose prior to blood sampling, so all received an effective intervention, they showed no susbtantial difference in pain scores between the gorups. Or this one (Hoarau K, et al. “Holding-Cuddling” and Sucrose for Pain Relief During Venepuncture in Newborn Infants: A Randomized, Controlled Trial (CASA). Front Pediatr. 2020;8:607900.) in which all received sucrose and non-nutritive suckling, but one group also were cuddled during the procedure. Adding a new or additional intervention to previously proven analgesic intervention is ethically acceptable, if it is not already known that the combination of interventions is substantially superior; this study showed no difference in mean pain scores, but fewer babies exceeded a pain score threshold with the combined intervention compared to sucrose alone.

These two studies are a useful addition to the literature, showing that breast-feeding or sucrose are both reasonable alternatives for blood sampling analgesia, and that cuddling a baby in addition to sucrose and NNS has some benefit at the higher end of the pain scores.

Researchers want to perform studies showing differences between groups, it is easier to get them published, which helps to advance your career. But no study with an untreated control group has any scientific value, we already know effective ways of reducing pain. Subjecting babies to painful procdures to improve your CV is unconscionable.

My plea is that if you are asked to be a reviewer for an article for publication which includes babies prospectively assigned to be untreated during a painful procedure, you reject the article with a clear note to the editor that the study was unethical.

If you sit on an IRB, please reject any study which assigns newborn infants, or any incompetent participant, to have avoidable pain.

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