Cardiovascular support in the preterm, how to determine adequate perfusion?

Posted on 17 January 2022 by Keith Barrington

As many of you will know, I have advocated for many years for evaluation and management of very preterm babies based on their tissue perfusion rather than the blood pressure. There is little or no correlation between BP and perfusion, and many of the commonest interventions, in particular dopamine, may increase BP almost exclusively by vasoconstriction, thereby worsening tissue perfusion. Such an approach, however, suffers from the difficulty in evaluating tissue perfusion in the preterm infant, clinical signs are limited, and lab tests may be misleading. Echocardiography is relatively objective, but difficult, has some inter-rater variability, and multiple repeated studies are often needed during management, leading to major disturbance of fragile babies.

A reliable continuous method with minimal invasiveness would be a major step forward. The perfusion index of some pulse oximeters excited me a few years ago, and a study that my group performed showed a useful correlation of perfusion index in limited circumstances, at 6 hours of age among babies with a low SVC flow.

A group from Saitama in Japan have been studying laser doppler skin blood flow for a few years. They have described the normal transitional changes in flow, and noted that low flow may precede later intraventricular haemorrhage. In contrast to my statement above, they looked at the impact of dopamine on skin blood flow, and showed that dopamine appeared to increase both blood pressure and skin blood flow, at least blood flow in the lower limbs (increased by 5%), blood flow to the skin and subcutaneous tissue on the forehead was not affected, despite a 10% increase in mean blood pressure; I don’t know of any other study that shows an increase in systemic perfusion with dopamine in compromised preterm babies, but even I must admit that the currently available data are poor. If mean BP increased by 10%, but perfusion locally increased by between 0 and 5% that is some evidence of vasoconstriction, but perhaps locally in some vascular beds there may be a sufficient increase in perfusion pressure to improve perfusion.

The big question with any such method, is whether using the method can improve management to the extent that outcome are better. We know that, statistically, babies with lower blood pressure have worse outcomes and that babies who receive treatment have worse outcomes than those who do not; which means that treatment is either a risk factor itself, or is a marker of increased risk. We tried to differentiate between those possibilities in the HIP trial, but were unable to enrol enough babies to find a definitive answer.

The Saitama group have just published the results of an RCT to try and answer the question, does treatment according to the results of the laser doppler device improve clinical outcomes? (Ishiguro A, et al. Randomized Trial of Perfusion-Based Circulatory Management in Very Low Birth Weight Infants. J Pediatr. 2021). They randomized VLBW infants to have one of 2 approaches, one based on normalising the blood pressure, and the other on normalising the blood flow measure.

The 440 VLBW infants were randomized to one of 2 contrasting protocols within 6 hours of birth, if they had no IVH on screening head ultrasound. Not all the infants had invasive blood pressure monitoring which is a reasonable pragmatic choice (and is, in fact, what I wanted to do for the HIP trial), but immediately introduces uncertainty, as non-invasive blood pressures are somewhat unreliable, especially in the smallest babies, and especially if the baby is hypotensive. All babies had skin blood flow measured from one foot, and were treated by the assigned protocol if the BP was below the gestational age in weeks, or if the BF (blood flow) was below 14 mL/min in the first 24 hours or 17 mL/min thereafter; depending on group. If they passed their treatment threshold then a functional echocardiogram was performed (in addition to a routine daily echo) and treatment given according to the schema above. The primary outcome was any intraventricular haemorrhage. They also evaluated how often the treatment was successful in improving the randomized parameter to above threshold within 3 hours.

The trial was a single centre study that took 7 years to complete, randomizing about 2/3 of eligible admissions. 37% of the BF group and 42% of the BP group passed their treatment threshold and had intervention. In the BF group they almost all had dobutamine, and nearly half of those also had dopamine. In the BP group about half of those with intervention received dopamine, and a similar proportion received dobutamine. In both groups 12% had a volume bolus and 6% had hydrocortisone.

I would question some of the reasoning that went into constructing these algorithms, but overall, I think they are not unreasonable. On the other hand, I find it a bit surprising that one in five VLBW infants had low blood flow with normal contractility with decreased preload indices and didn’t respond to a fluid bolus (as that is the only way a BF baby could get dopamine added to their dobutamine); which makes me wonder how well the algorithms were actually followed. Indeed I find it a bit surprising that such a high proportion of VLBW infants were considered to need cardiovascular support, they were enrolled early in life and for 40% of the babies to need some cardiovascular intervention in the first 72 hours seems aggressive. They do however have a historically low proportion of babies with IVH, in the CNN about 30% of VLBW babies have at least a grade 1 IVH, small subependymal haemorrhages being included in their outcome of IVH. Overall the outcomes are the typically very good outcomes of Japanese centres with a remarkably low mortality, with 1 death out of 440 VLBW babies within the first 7 days, and only 7 deaths prior to discharge, very low NEC and low late-onset sepsis are also evident.

The sample size was calculated based on that previous incidence of IVH of 13%, with a power to detect a reduction to 6%. I presume, though it is isn’t mentioned, that the previous IVH rate was in the context of BP-directed management of the infants. They actually showed an 11% rate of IVH in the BP group, and a 7% incidence in the BF babies. The 95% compatibility limits for the difference in IVH rate (not given in the manuscript) are a 9.4% absolute risk decrease in IVH and a 1.2% increase.

The study included some babies at relatively low risk, so the infants of 1001-1500 g birth weight only had 2% vs 3% IVH rate. It would be just about impossible to design a trial to find a reduction in an adverse outcome from 2%. Among the ELBW babies there were 18% IVH in the BP babies, and 10% with BF targeting, which give 95% compatibility limits of -17% and +0.5% absolute risk difference.

The intervention was not always successful at increasing the target parameter within 3 hours of initiating treatment, and a very interesting post-hoc analysis is presented, which shows that the BP and BF group babies who never received intervention had very low rates of IVH, (3% vs 6%) but those who had a successful increase in their BF did better than those who had a failed application of the protocol (i.e. BF stayed low at 3 hours of intervention) whereas the low BP babies who continued to have a BP below GA at 3 hours of age did better than those in whom BP increased.

This obviously has to be interpreted with a great deal of care, but does suggest several possible interpretations.

This study helps in calculating sample sizes for future trials, 11 of the 39 IVHs occurred in babies who had no cardiovascular intervention. I don’t have any way of calculating how many of those babies had both normal BF and normal BP throughout the trial, but a baby who stayed above both thresholds throughout 72 would have had no change in management. If we guess that about 40-50% of babies will have no cardiovascular intervention regardless of which group they are in, and perhaps 25% of IVH occurs in those babies, then that impacts the numbers of babies required for a trial to show that intervention algorithm reduces IVH frequency. It is complicated, of course, because some babies with low BP will have normal flow, and vice versa.

I think this trial is clearly not enough evidence for a universal change in practice, but it is strong evidence that we need to do more investigations of this way of managing cardiovascular support in the newborn. Refinement of the protocols, comparison with other indicators of perfusion (perhaps cerebral NIRS, perhaps perfusion index) and a larger sample size, or perhaps concentrating on the babies at highest risk, are needed to answer the vitally important questions posed by this study.

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STOP-BPD follow up study

Posted on 13 January 2022 by Keith Barrington

Does routine hydrocortisone, started at 7 to 14 days of age among infants <30 weeks GA and/or <1250g birth weight who were ventilator dependent and at increased risk for BPD, affect their long term developmental progress? (Halbmeijer NM, et al. Effect of Systemic Hydrocortisone Initiated 7 to 14 Days After Birth in Ventilated Preterm Infants on Mortality and Neurodevelopment at 2 Years’ Corrected Age: Follow-up of a Randomized Clinical Trial. JAMA. 2021;326(4):355-7).

That is the question addressed by this follow-up of babies enrolled in the STOP-BPD study. As you may remember, that study used a 22 day tapering course of hydrocortisone, starting at 5 mg/kg/d for 7 days, and had the beloved primary outcome “death or arbitrary dichotomised definition of lung injury”. The trial showed no real difference in the primary outcome 71% HC, 74% control, but mortality diverged starting at about 7 days after enrolment, and was “statistically significantly” different at 36 weeks PMA (16% vs 24%), but not quite “significant” by discharge (20% vs 28%).

As I mentioned previously, the trial included very few babies under 24 weeks, as they were not receiving active care in Holland, where the study was mostly performed, and active care was rare in the Flanders region of Belgium which accounted for most of the non-Dutch centres, Liège and Charleroi were also involved, which are in Wallonia, but I don’t know what their approach was or if they enrolled any babies <24 weeks. As I have also mentioned, and has been shown many times, centres which don’t intervene at <24 weeks, or at <25 weeks, have poor outcomes at 24, or 25, weeks compared to centres which are active at lower gestational ages. Survival for the study participants was much lower than I would expect in my centre, even taking into account the selection of a higher-risk group, ventilator dependent on oxygen at 7 to 14 days of age.

Another problem with this study, especially with regards to long-term outcomes, is the frequent treatment of control babies with steroids (principally hydrocortisone) either after the study drug period, according to protocol, if they were thought to be at high risk of dying, or outside of the protocol. 108 of the original 190 control babies received hydrocortisone during their hospitalisation.

By the 2 year follow up there were a small number of extra deaths in each group, so the mortality was now 22% (HC) vs 30% (control); 95% confidence limits for absolute difference in percentage mortality are -17% to +1%.

There were no substantial differences in any measured developmental or neurological outcome. A dichotomised “NDI”, largely driven, as usual, by scores on the Bayley Scales of Infant Development (version III), was found in 44% of hydrocortisone, vs 47% of control survivors. I presume that the total dose of HC given to the HC babies was probably higher than the total dose given to controls, so this does give some reassurance that development, including motor and cognitive development as measured by Bayley, was not adversely affected. Cerebral Palsy, blindness and deafness were all a little less common among the HC babies.

Despite the limitations, this trial does suggest that long term development is not very seriously affected by the intervention tested, a total of 72.5 mg/kg of hydrocortisone, among infants of 24 weeks and more who are considered to be at high risk of BPD at 7 to 14 days of life, at least in comparison to relatively liberal use of rescue hydrocortisone if there seems a higher risk of death.

There is a modest difference in mortality favouring the HC group, despite rescue HC among controls. Can a similar study be performed in centres with active treatment at 22 and 23 weeks? Centres which will likely already have a lower mortality than this study’s intervention group, but which probably already use some steroids in babies at high risk? (In the CNN all the centres with very immature babies have some use of steroids for BPD, but it is very variable). It would be difficult to perform such a study, and some rescue use of steroids will have to be allowed in order to make the study feasible, but I think it is essential in order to answer the questions we still have about when to give steroids for lung disease, which dose, of which molecule, for how long.

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Antenatal treatment of Diaphragmatic Hernia, indications for intervention.

Posted on 12 January 2022 by Keith Barrington

My previous post about the FETO trials noted that the published trials reported a clear benefit of antenatal treatment of the highest risk group, but the moderate risk group had an improved outcome which didn’t meet classic definitions of statistical significance. I noted then that, if the trials had been run as a single trial with 2 risk strata, the overall benefit for the entire sample would have been highly significant, and that it was likely that a test for interaction would not have shown a statistically significant difference between the risk strata.

That evaluation has been confirmed by an analysis published by the authors, (Van Calster B, et al. The randomized TOTAL-trials on fetal surgery for congenital diaphragmatic hernia: re-analysis using pooled data. Am J Obstet Gynecol. 2021), they pooled the data from the trials and found no significant difference in the benefit of FETO according to risk category. The surgical protocol for the trials included intervention and FETO at 27 to 29 weeks and 6 days in the severe group, or 30 to 31 weeks 6 days in the moderate group.

In this re-analysis the authors looked at the GA of intervention and conclude that FETO leads to improved survival in both the severe and the moderate groups, indeed overall there was no impact of severity (O:E LHR) on effectiveness of the procedure, rather it seemed that earlier treatment was associated with greater improvements in survival, but also greater increases in prematurity.

These 2 figures show the survival advantage of having FETO as compared to usual treatment based on the O:E LHR, even with the lowest risk babies in the trial, FETO is advantageous, as shown by the blue line and the blue shaded area representing the confidence limits of the benefit. The dotted lines are what the predicted survival benefits would have been if the babies had FETO at different GA, not allowed by the protocol, suggesting an even greater survival benefit for the moderate babies if they had FETO earlier.

Of course this analysis is confounded by the correlation between severity and timing of intervention, as by design more severe lesions were treated earlier.

The next challenge will be to find ways of preventing membrane rupture and preterm labour after fetoscopic intervention, if we can do that, then the benefit of FETO for improving survival will likely be even greater. I think this analysis confirms, that, if it is available, FETO should be discussed with mothers carrying fetuses at moderate risk, not just the most severely affected.

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Ethically acceptable pain research

Posted on 12 January 2022 by Keith Barrington

Just imagine for a moment that you are the parent of Jo, who is 4 years old, Jo has a sudden onset of breathlessness and the investigations in the Emergency Room show a spontaneous pneumothorax, that needs a drain. You are approached to participate in a research trial of a new anaesthetic spray, shown to be effective in animals, to be given prior to the intercostal incision between Jo’s ribs for chest drain insertion. The control group will have a placebo spray with no active ingredients. The study is a standard, high-quality placebo-controlled trial with masked randomization, and masked intervention. Sounds great, right? You are informed that the local ethics committee approved the trial, which has been registered on a public database.

I think any parent agreeing to potentially have a chest drain inserted in their child without local anaesthesia would be failing in their duty of care to that infant; any researcher designing, performing, or interpreting such a study is unethically assuring that half of the research subjects will feel avoidable pain; and any journal publishing the results is complicit in promoting such unethical practices. The approval of such a trial by an ethics committee does not absolve anyone of their responsibility for their participation.

Why is it different for newborn infants?

Pain from heel-stick procedures is often severe, as shown by frequent elevations of pain scores to the moderate to severe pain range (Bellieni CV, et al. How painful is a heelprick or a venipuncture in a newborn? J Matern Fetal Neonatal Med. 2016;29(2):202-6.). Such pain can be dramatically reduced by concentrated sucrose solutions with non-nutritive sucking, or kangaroo care especially combined with breast feeding. These links are all to Cochrane reviews which are several years old.

There is no excuse for designing or performing or publishing a study where any of the infants are assigned to have pain. Just as there would be no excuse for those involved in Jo’s care allowing or participating in a trial where half of the children have a chest drain inserted with no analgesia.

How should we perform research to advance the care of newborn infants who need painful procedures?

The only reason for performing clinical research is to improve care. So trials showing that a new intervention is better at controlling pain than no analgesia are useless. The only justification for such a trial would be if analgesic interventions currently known to be effective were unavailable or toxic. Neither is true. Skin-to-skin care may not always be possible prior to a heel-stick, for example, if it is needed urgently, or the parents are absent, or the baby is too unstable to move in a hurry. In those cases giving a dose of sucrose and a soother can easily be done. If you don’t have licensed preparations of sucrose then concentrated sterile glucose can be given orally, overall I think it is a little less effective, but still causes a beneficial reduction in pain.

Any new intervention should be initially studied in combination with a proven effective approach, randomly compared with the proven effective approach alone. Perhaps an exception could be made for an intervention shown to be dramatically effective in animal models, where a direct comparison with optimal pain control could be envisaged, but without an untreated control group in either type of study. Studies comparing interventions already known to be effective are clearly OK, such as this one for example (Sen E, Manav G. Effect of Kangaroo Care and Oral Sucrose on Pain in Premature Infants: A Randomized Controlled Trial. Pain Manag Nurs. 2020;21(6):556-64) a well-performed randomized trial showing an advantage of kangaroo care compared to sucrose, or this one (Lago P, et al. Repeating a dose of sucrose for heel prick procedure in preterms is not effective in reducing pain: a randomised controlled trial. Eur J Pediatr. 2020;179(2):293-301), where babies in both groups received sucrose prior to the procedure, and the intervention group received a second dose 30 seconds afterward, showing no additional benefit, or this one (Bresesti I, et al. New perspective for pain control in neonates: a comparative effectiveness research. J Perinatol. 2021;41(9):2298-303) which randomized babies to either breastfeeding or sucrose gel with non-nutritive sucking, or sucrose liquid with non-nutritive sucking, suggesting that the gel is a little better than the liquid and approximately as effective as breast-feeding, or again this one (Nimbalkar S, et al. Blinded randomized crossover trial: Skin-to-skin care vs. sucrose for preterm neonatal pain. J Perinatol. 2020;40(6):896-901) randomly comparing kangaroo care to sucrose showed similar efficacy of the 2 interventions.

Clinically useful, ethically acceptable pain research is not difficult to perform in newborn infants, these above examples are from around the world, and I have found examples from countries with good resources, and from countries with very limited resources. As has been noted, (Harrison D, et al. Sweet Solutions to Reduce Procedural Pain in Neonates: A Meta-analysis. Pediatrics. 2017;139(1):e20160955.) the effectiveness of sweet solutions has been known since the very first trial, and since their effectiveness became incontrovertible, more than 800 babies have been assigned to groups who are intended to experience avoidable pain. Since that analysis was published in 2017, there have been many more.

The first priority must always be to put the baby and their family first, and treat them as you would wish Jo to be treated, if you had to go with Jo to the Emergency Room. Ensuring that your child had adequate pain protection for a planned painful procedure should definitely be your goal, the same thing applies for our patients.

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Unethical pain research in the newborn. A list of shame.

Posted on 11 January 2022 by Keith Barrington

Unethical pain studies are still being published, in journals which include several from mainstream publishing houses.

In these studies published recently and appearing on-line in recent weeks, newborn infants were assigned by the researchers to experience pain. The reviewers of the articles accepted that the research subject babies had pain imposed by the investigstors. The editors of the journals involved are also complicit by agreeing to publish articles whose research required that babies experienced avoidable pain.

This must stop.

It is unacceptable to inflict pain on babies in order to complete a research project.

Please inform the editorial board of the following journals of your concerns. The chief editor’s professional email is provided, or an email address associated with the publication if I can find one.

I will repost this page with new articles whenever I spot them.

The Effect of Maternal Voice on Venipuncture Induced Pain in Neonates: A Randomized Study. Chen Y, Li Y, Sun J, Han D, Feng S, Zhang X. Pain Manag Nurs. 2021 Oct;22(5):668-673. doi: 10.1016/j.pmn.2021.01.002. Epub 2021 Mar 2. PMID: 33674242. The trial randomized 58 babies undergoing venepuncture to have a recording of their mother’s voice, or to have the painful procedure without analgesia. Editor-in-Chief: Dr Elaine Miller, MILLEREL@ucmail.uc.edu

Effect of White Noise and Lullabies on Pain and Vital Signs in Invasive Interventions Applied to Premature Babies. Döra Ö, Büyük ET. Pain Manag Nurs. 2021 Dec;22(6):724-729. doi: 10.1016/j.pmn.2021.05.005. Epub 2021 Jun 28. PMID: 34210600. In this trial 66 babies (which was either randomized, according to the text, or non-randomized, according to the figure) were assigned to either have a lullaby, or white noise, or to have no intervention, prior to the pain of a “blood collection” (not further specified). Editor-in-Chief: of Pain Management Nursing, Dr Elaine Miller, MILLEREL@ucmail.uc.edu

Gao H, Xu G, Li F, Lv H, Rong H, Mi Y, Li M. Effect of combined pharmacological, behavioral, and physical interventions for procedural pain on salivary cortisol and neurobehavioral development in preterm infants: a randomized controlled trial. Pain. 2021 Jan;162(1):253-262. doi: 10.1097/j.pain.0000000000002015. PMID: 32773596. In this trial, 38 preterm infants were randomized within 7 2hours of birth to have all of their painful procedures during hospitalisation untreated, they were allowed to get a soother when they cried! In the combined interventions group, preterm infants received sucrose, massage, music, non-nutritive sucking, and gentle human touch. I think this is the worst of all the trials I have seen recently, the control babies had repeated evaluations of PIPP score during painful procedures, and continued to have multiple experiences of moderate to severe pain, with average PIPP scores of over 12. How can the reviewers and editors possibly have thought this was OK? Editor-in-Chief: Dr Francis Keefe keefe003@mc.duke.edu

Here is some suggested text you can cut and paste into an email if you wish.

The article “XXXXX” published in your journal, describes research which is clearly unethical and should not have been published.
In this study, newborn babies were assigned to a group designed to experience pain. Effective methods to prevent pain caused by skin breaking procedures are well known, easily available, and cheap or free. Those methods include kangaroo care/skin-to-skin contact, oral sucrose or glucose solutions, especially when combined with non-nutritive sucking, and breastfeeding. There is no valid reason for denying such pain reduction methods to research subjects. Publication in a high-quality journal such as the one you edit gives credibility to the research and suggests that it is acceptable to inflict pain on babies in order to complete a research project.
Research which compares an analgesic intervention for a painful procedure in newborn infants to an untreated control group is useless in improving care. As effective pain measures are already well known, the only research which could possibly improve care is that which compares different analgesic interventions, or examines the addition of measures to those already known to be effective.
The most effective way your journal could improve pain control in newborn infants would be to cease publishing research which unethically randomizes babies to have avoidable pain. All future trials in newborn infants undergoing planned painful procedures that the journal publishes should ensure that research subjects in all groups receive proven effective methods of pain control.
I urge you to retract this article and to establish editorial standards which prohibit the publication of research in which avoidable pain is imposed on newborn infants. Pain inflicted on babies in order to perform research should be an immediate criterion for rejection of a manuscript.

Posted in Neonatal Research | Tagged , , , | 3 Comments

How do we make decisions for the most immature babies, with their families?

Posted on 10 January 2022 by Keith Barrington

Although babies under 25 weeks account for a tiny proportion of births, and a small proportion of NICU admissions, the importance of the question asked in the title can be seen by the ongoing number of publications, below are just a few of recent relevant publications of interest.

Wood K, et al. Individualised decision making: interpretation of risk for extremely preterm infants-a survey of UK neonatal professionals. Arch Dis Child Fetal Neonatal Ed. 2021.
Di Stefano LM, et al. Viability and thresholds for treatment of extremely preterm infants: survey of UK neonatal professionals. Arch Dis Child Fetal Neonatal Ed. 2021;106(6):596-602.

These first 2 are results from a on-line survey study in the UK. The 336 respondents were 50% neonatologists, but, as an on-line study it is hard to know how representative the responses are. Nevertheless it really suggests a shift in attitudes, with respondents more likely than in previous years to accept active intervention at 22 weeks, and to take into account other risk factors than just gestational age. A major concern I have with these types of decisions is that they are often based on risk of mortality, and also on risk of “major impairment”. Although what this means is discussed in the “framework” document, and is generally intended to mean a severe intellectual impairment (IQ <55), disabling CP, blindness or profound hearing impairment, I don’t think that the implications of that label are necessarily always explicit. Especially in an online survey, which didn’t, as far as I can see from the supplement, re-iterate the criteria for a definition of major impairment.

Do we really think that an increased risk of blindness is a good reason for denying intensive care to babies? Or disabling motor dysfunction with a normal intellect? I think in reality that it is the risk of severe intellectual impairment which drives all of our concerns about “severe impairment”, and that we should acknowledge that. To take this further, if a baby was born needing resuscitation at term, with known congenital blindness, would it be ethically acceptable to deny that baby intervention because of known (rather than a predicted statistically increased chance of) blindness? We could ask the same thing for congenital deafness, and for GMFCS of 3 or 4 (level 3 meaning able to walk with a hand-held mobility device, and level 4 meaning self-mobility is limited, may need a wheelchair, but usually with head and trunk control), if we had a definite diagnosis of those impairments prior to birth would it be justifiable to withhold intensive care? I think we should focus on the outcomes we really worry about the most, level V GMFCS, and very severe intellectual impairment. They are outcomes which are relatively uncommon, even at the most extreme gestational ages.

In addition, in this study, the respondents were asked to estimate the probability of death and severe impairment, and the responses were extremely variable. This figure shows the range of opinions about potential survival and proportion of “severe disability”, each dot represents one response, the horizontal lines are medians and IQRs, and the asterisks are estimates from the on-line NICHD risk calculator. However, the NICHD calculator now gives a range of outcomes, rather than a point estimate, and the definitions of profound impairment, etc. are not the same as the BAPM definitions. The data do show major variability in estimates of survival and long term outcomes.

LoRe D, et al. Physician Perceptions on Quality of Life and Resuscitation Preferences for Extremely Early Newborns. Am J Perinatol. 2021(EFirst).

This survey study asked physicians involved in perinatal care what makes an acceptable quality of life, and what proportion of infants born at various extreme gestational ages would be likely to have an acceptable QoL, and then what their own resuscitation preferences were. One notable finding is that very few respondents had any encounters with former very preterm children, and those with the fewest encounters, in particular obstetricians, had the most negative views of quality of life outcomes.

There was a close correlation between having a negative opinion of the QoL of extremely preterm infants, and not wishing to actively intervene. This has been shown before; the over-estimation of serious adverse outcomes drives an unwillingness to actively intervene.

The belief that there is a dramatic reduction in the proportion of survivors with an “acceptable quality of life” as GA gets lower is a common prejudice that is not based on any data. As you can see from this graphic from a systematic review of long term outcome studies (Ding S, et al. A meta-analysis of neurodevelopmental outcomes at 4-10 years in children born at 22-25 weeks gestation. Acta Paediatr. 2019;108(7):1237-44), there is very little difference in “severe disability” between 22, 23, and 24 weeks, with a trend to more moderate disability.

Of course, an unacceptable quality of life is by no means equivalent to severe disability, the large majority of disabled children have a good quality of life, there is nothing in the literature to support the prejudice against extremely immature babies, that supposes that they have a high probability of an unacceptable quality of life.

One other disturbing result of the LoRe study was the belief that having an extremely preterm baby would have a negative impact on the family as a whole, a belief held by 73% of the respondents. There is absolutely no data to support this, the large majority of families report both positive and negative impacts of very preterm delivery. Of course there are challenges, sometimes major challenges, but living with a former extremely preterm infant does not have an overall negative impact on families.

Geurtzen R, et al. Decision-making in imminent extreme premature births: perceived shared decision-making, parental decisional conflict and decision regret. J Perinatol. 2021;41(9):2201-7.

In this study parents were counselled about threatened extreme preterm delivery at between 23 weeks 0 days and 24 weeks 6 days, they and their physicians then completed questionnaires about shared decision making, and they were later followed up to see if they experienced decisional regret. This study took place in the Netherlands, where active care is generally not offered at 23 weeks gestation, and, in fact, the mothers included in this study all delivered at 24 weeks (n=3) or later. To be brutal, shared decision-making does not occur in the Netherlands for babies born at <24 weeks gestation. Parents are given no share in that decision. Four of the 22 counselling sessions resulted in a decision for perinatal palliative care, there were low scores for decisional conflict, and, from the few surveys returned 1 month later, little decisional regret. I can’t tell from the publication if any babies actually died after receiving perinatal palliative care or not, which is an important limitation. Decisional regret is relatively uncommon after many different decisions in life, we all tend to believe in retrospect that we probably made the right decision. Decisions which lead to a child dying may be different, especially if you later discover that your baby had a greater chance of survival, and of survival with a good QoL, than you were informed. Another study by this group showed no significant difference in decisional regret according to the decision taken, but there were only 4 who had a decision for palliative care, and 2 of those 4 had high scores for decisional regret.

De Proost L, et al. On the limits of viability: toward an individualized prognosis-based approach. J Perinatol. 2020;40(12):1736-8. This article is a commentary, the authors of which include the first author of the previous article, pleading for a revision of the Dutch guidelines to take into account other factors than gestational age, and against a rigid guideline based on GA alone. Indeed, I think it is about time; survival of babies in Holland at 24 weeks is substantially lower than many other jurisdictions, and survival of babies at 23 weeks gestation is 0. This is despite a high quality health care system, dedicated staff, good regionalisation, excellent training, all the things that are needed to have excellent results. I think Dutch families deserve better.

Overall, I think these articles give me some hope that things are changing in the right direction, caregivers are more willing to intervene for more immature babies, and some prominent physicians are working to promote individualized decision making, rather than blanket denials of active care. There is a still a crying need for education, otherwise couples with threatened extremely preterm delivery are being given information which is biased and inaccurate.

In particular we need further exploration of which outcomes parents in general find unacceptable (other than death), and also how to elicit individual parental preferences within the antenatal decision making framework. One recent publication asked mothers and their partners with threatened delivery between 22 weeks and 24 weeks 6 days about their attitudes to outcomes, including various impairments, (Tucker Edmonds B, et al. Values clarification: Eliciting the values that inform and influence parents’ treatment decisions for periviable birth. Paediatr Perinat Epidemiol. 2020;34(5):556-64). This is one table from this fascinating study from Indianapolis

Among the participants of this study, “the majority described a good QoL in terms of emotional well-being (eg “loved”, “happy”, “supported”), whereas a poor QoL was described in terms of functionality (eg “dependent” and “confined”)”. They were a mix of different ethnic, religious, educational and financial backgrounds, but the sample is too small to analyze whether those factors were important in their attitudes.

It has been shown several times that healthcare workers attitudes differ from the rest of the population, I think probably rather more than 54% of caregivers would agree that “some disabilities are worse than death”, certainly that is the implication from the study by LoRe et al, but this study from Indianapolis had a substantial number of respondents who disagreed with that statement.

Update: Jan 10 2022; I slightly changed the title of this post, from “how do we make decisions for the most immature babies, and their families” to “how do we make decisions for the most immature babies, with their families” as I think that better reflects the subject matter (about shared decision-making) and my feelings of how we should partner with families to make the best decisions for our patients.

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Should we treat electrographic seizures?

Posted on 6 January 2022 by Keith Barrington
Effect of Treatment of Clinical vs Electrographic Seizures in Full-Term and Near-Term Neonates

In order to answer the question posed in the title you would need to take babies at risk of seizures, but not yet having clinically diagnosed convulsions, randomize them to have routine continuous EEG monitoring or not and then treat according to the EEG results or according to whether they had clinical seizures. In order to know what was happening in the controls, they should have continuous EEG monitoring as well. Then you would follow the babies up to an age where clinically important differences can be reliably determined.

The study that this post is about did just that, (Hunt RW, et al. Effect of Treatment of Clinical Seizures vs Electrographic Seizures in Full-Term and Near-Term Neonates: A Randomized Clinical Trial. JAMA Netw Open. 2021;4(12):e2139604), with the difference that infants who were referred to a study centre who already had suspected seizures would be eligible if they were diagnosed as having clinical seizures by the attending physician. Presumably all such babies would have received an immediate loading dose of phenobarbitone.

That study design ignores the fact that we don’t even really know whether treatment of clinical seizures improves long term outcomes, compared to just ignoring them. I am not suggesting we should ignore them, just that we have no proof that anticonvulsant treatment of seizures improves long term outcomes. Many neonates have a few seizures during a relatively short period of their life, and it si possible that treating them doesn’t do much to protect their brain. It is however, the standard of care to treat recurrent clinical seizures in the newborn, and current evidence suggests that phenobarbitone is the preferable first line treatment.

NEST (Newborn Electrographic Seizure Trial) was designed to enrol 520 babies in 2 groups, with amplitude integrated EEG either masked or unmasked. However, slow enrolment and loss of equipoise led to termination of the trial after 212 babies were randomized, and 20 in each arm were lost to outcome assessment, leaving 86 babies in each group.

As the visual abstract above shows, in terms of outcomes there were small differences in “survival without disability” which favoured the treatment of clinical seizures alone group. As this table shows all of the electrographic seizure treatment babies and all but 3 CSG (clinical seizure treatment alone) babies did indeed have seizures on the EEG, and babies in the ESG (electrographic seizure treatment group) received more anticonvulsants; most babies in both groups received the maximum 40 mg/kg of phenobarb that was allowed but more ESG babies received phenytoin and 3rd or 4th medications.

Seizure Burden and Anticonvulsant Use by Randomized Group

What isn’t discussed very much is that the ESG babies had a greater seizure burden, especially between 12 and 72 hours, where the seizure burden was about double. So, despite randomization, seizure burden was higher in the group that eventually did worse. Also, it is not clear why there were 78 babies in the CSG group with seizures, but only 64 of them received phenobarb, whilst the treatment algorithm suggests that any baby with a single seizure should receive at least one loading dose of 20 mg/kg of phenobarb. Perhaps they had just a single seizure and the attending physician decided not to follow the protocol, suggesting that they were less seriously affected infants.

Unfortunately the early termination of this trial and the difference in seizure burden despite randomization makes it difficult to conclude one way or the other regarding treatment of non-clinical seizures. But the small difference in the results favouring clinical seizure treatment alone will allow future investigators to design and perform another trial. The actual differences in medications administered were relatively small, there were 14 in the clinical group who received no anticonvulsants, and 16 who received more than one anticonvulsant, compared to 0 and 26 in the electrographic group. Suggesting that only 24 babies in the trial had their management affected, which makes the trial, the largest yet conducted of the issue, severely under-powered. What I mean is that even if the underlying reason for treating was different in the two groups, the majority of infants in both groups received 40 mg/kg of phenobarb and nothing else, and you wouldn’t expect much difference in outcome in those infants, even though perhaps the ESG babies received their second phenobarb load earlier.

A future trial will have to be significantly larger than this one, large enough to ensure that randomization leads to a seizure burden which is similar between groups, and large enough to ensure a significant difference in anticonvulsant receipt. I think conventional EEG is probably preferable, although many centres cannot easily install cEEG in the middle of the night, so starting with aEEG and switching to cEEG when possible would be a pragmatic design reflecting reasonable current practice.

Based on this trial and the rest of the literature, I still have concerns that multiple electrographic seizures are associated with, and may worsen, brain injury. I certainly don’t think this means that we should ignore the frequent “non-convulsive” seizures that are seen in asphyxia, especially after initial doses of anticonvulsants, but perhaps we can be less aggressive at treating occasional electrographic seizures. In contrast, I have seen babies with electrographic status epilepticus lasting hours, with no clinically evident convulsive movements, and I am sure that can’t be good for your brain. I think it is likely that phenobarb treatment of such babies is the right thing to do, as brain protection by phenobarb has been shown in a number of models, and in one human infant RCT. What the second line treatment should be, I am completely in the dark; bumetanide, or perhaps just more phenobarb?

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Was OPTIMIST too optimistic?

Posted on 5 January 2022 by Keith Barrington

One of the trials we have been waiting for has just been published Dargaville PA, et al. Effect of Minimally Invasive Surfactant Therapy vs Sham Treatment on Death or Bronchopulmonary Dysplasia in Preterm Infants With Respiratory Distress Syndrome: The OPTIMIST-A Randomized Clinical Trial. JAMA. 2021;326(24):2478-87. As you can see above, there was “no significant difference” in the primary outcome of death or BPD, as defined by needing more than 30% O2, or being on respiratory support, or having <30% oxygen and failing a room air challenge, all at 36 weeks. I have ranted often enough about this outcome that I won’t repeat it here. I will say that I think OPTIMIST is the second best trial name ever in neonatology (after ELVIS), but maybe it was too OPTIMISTIC to think that there would be a large reduction in BPD in the most immature infants who were stable enough to be eligible for this study. To be eligible the baby had to be breathing sponatneously on CPAP in the NICU, so many of the sickest babies, would already be intubated, and infants thought to be in need of immediate intubation were also excluded. Those are quite appropriate exclusions, but it means that the remaining babies were relatively lower risk infants.

I’m trying out a new format with a sort of home-made visual summary of the article that you can see above, but it’s quite a lot of extra work, so I don’t know if I’ll continue. Anyway, my bottom line is that MIST looks positive for the 27 and 28 week infants, but the unexpected increase in mortality at 25-26 weeks gives me pause. Apparently the causes of mortality were distributed among all the usual causes, which is a bit strange as all the usual adverse outcomes were slightly less common with MIST, late onset sepsis, NEC, spontaneous perforation and IVH.

As usual, I hate to say it, but I think we need another study. A trial with even earlier surfactant, perhaps prophylactic MIST or at 25 % oxygen, and concentrating on the more immature infants, perhaps combined with a higher dose of caffeine.

I think if such a trial could show the pulmonary benefits, in particular the reduction in home oxygen therapy, without a mortality effect, then MIST/LISA could become routine for the very immature, 25 to 26 week infant. Until then, I think that an overall benefit in those babies is not proven.

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Caring for the most profoundly immature babies; what works?

Posted on 4 January 2022 by Keith Barrington

The upcoming issue of “Seminars in Perinatology” is about the controversies in caring for the babies <25 weeks gestation. Babies born at 24, 23, 22 or even now 21 weeks gestation are so physiologically immature that we can’t just assume that something that works at 28 weeks will also be beneficial for that sub-group. My contribution to the collection of articles (Barrington KJ. The most immature infants: Is evidence-based practice possible? Semin Perinatol. 2021:151543) was an attempt to find data about the most immature babies from recent large RCTs, the kind of evidence base that is reliable for determining treatment options. I searched large multi-centre RCTs from the last 5 years, and found 30 trials enrolling a total of over 25,000 very preterm infants. Many trials excluded the most immature babies, either formally by setting a lower limit for gestational age, or by being performed in countries (France and Holland) where active treatment at 22 and 23 weeks is absent or rare, and even at 24 weeks is (or was) quite limited. I could finally find only 3 babies of 22 weeks whose data were presented in those studies, and very few who were clearly of 23 weeks gestation. There were three trials that reported results by GA strata that included a stratum <25 weeks, and those trials, in total, included 711 babies.

Our entire evidence-base for therapies in the most immature babies is thus extremely limited, and most things that we have questions about are uncertain for those babies. That uncertainty can be seen in other articles of the series, such as this one (Sindelar R, et al. Respiratory management for extremely premature infants born at 22 to 23 weeks of gestation in proactive centers in Sweden, Japan, and USA. Semin Perinatol. 2021:151540) in which Richard Sindelar and his co-authors describe how different centers use assisted ventilation for the profoundly immature. In Uppsala, Sweden they start the babies on “conventional” ventilation with volume guarantee, and are able to maintain the majority of their babies like this, in Iowa, USA they start the infants on high-frequency jet ventilation and extubate at 850 grams minimum, in Kanagawa, Japan they start on conventional ventilation but change to high-frequency oscillation early if cardiac function is good. The authors describe a few points in common in their approaches, and one that is not mentioned. They have in common the use of 2.0 mm ETT for the 22 weeks infants, a focus on preventing over-distension, especially with the oversight of experienced clinicians, minimal handling, not trying to extubate too early, and giving surfactant very early. What they don’t mention is probably the most important factor; a belief that good survival is possible, that good long term outcomes are usual, and that it really is worth it.

To follow on from my previous post, there is also an article from Thuy Mai-Luu who runs our follow-up program at Sainte Justine, and Rebecca Pearce, an ex-NICU parent. They discuss how to improve neonatal follow-up to make it more relevant to parents, they include the following table:

The focus on examining the strengths, rather than just the weaknesses, of former preterm infants, and avoiding simplistic dichotomised outcomes in favour of a broader, more balanced portrait of functions, are approaches that I absolutely agree with.

There are several other articles in this issue that should have a major impact on how we practice, including a pro-active integrated approach to the mother with her fetus, the nursing approach to these babies and their parents, and many others, all of which I would recommend. Given the possibility of more than 50% survival at 22 weeks gestation, shown by several groups, it is no longer ethically justifiable to universally deny intervention to such infants. But as we plan our intervention strategies for such babies we should all be listening to the experts and learn from how they have been able to get such good results.

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Outcomes of very preterm infants: what matters to parents?

Posted on 3 January 2022 by Keith Barrington

Neonatologists can be said to have invented “Outcomes Research”, the systematic evaluation of patients after an acute-care event. It is a field of research which has now been extended from early infancy into the adult period and provided enormous insights into what happens to babies who are born very preterm. When the field was developing there were concerns about how our patients would fare when their brain development had been interrupted by preterm delivery, often accompanied by serious illness, and sometimes major complications, surgery, and brain injuries seen on CT scan or ultrasound. As a result much work has concentrated on neurological examinations and developmental screening tests, partly to evaluate and describe outcomes, but also to ensure that chlidren received any interventions they might need with minimal delay.

The major question that we need to ask now is: what outcomes are most important to parents? One serious problem with our outcome research had been the attempt to categorize infants into “normal” and “abnormal”. This has been driven by the appropriate concern that our NICUs should be aiming for not just improved survival, but for improved “intact survival”. That is a term that I have heard many times, but it requires some thought; what do we mean by intact? And who decides what is an acceptable outcome?

I have written many times on this blog about the problems that arise when we decide that a Bayley score at 18 to 24 months of age below 2 SD below the mean is an adverse outcome, whereas a score of 1.9 SD below the mean is a good outcome, even when the child has a serious behaviour disorder. This arbitrary and artificial dichotomising of the whole of child development skews the literature, and has impacts on how we care for babies.

What we measure matters also because we use the results of outcome studies in our counselling of parents regarding the institution and continuing of active NICU care. (Weiss EM, Kukora S, Barrington KJ. Use of composite NICU research outcomes for goals of care counselling creates ethical challenges. Acta Paediatr. 2021) Data which are collected in order to describe outcomes are then used to determine whether babies should be allowed to die without active intervention.

In this post I will not be concentrating much on how the artificial dichotomising of child development skews research design, even though that is a major problem. Because it is easier to design studies with a dichotomous composite, where death and “NDI” are given equal weight, and the answer to whether a treatment is better than another is supposed to them be yes or no, based on the impact on that composite outcome.

In everyday clinical practice we (as health care professionals) really want to know whether treatment A decreases death compared to treatment B, and if not, what are the relative impacts on developmental progress, pulmonary development, neurologic impairment, etc. But what do parents want to know? I think we can be sure that parents would want to know if one treatment compared to another affected mortality, but beyond that, what outcomes are really important to parents? What are their relative importance? What kind of adverse outcome would be enough to outweigh an improvement in survival?

Personally, I would be surprised if a group of parents cared whether their babies’ Bayley scores were more likely to be above or below 70.

A group of collaborators from my hospital have just published an article reporting a study (which is part of the Parent Voices Project) where parents were asked their opinions about the progress of their extremely preterm infants. Jaworski M, et al. Parental perspective on important health outcomes of extremely preterm infants. Arch Dis Child Fetal Neonatal Ed. 2021:fetalneonatal-2021-322711. This was a group of parents with 213 children aged from 18 months to 7 years of age, less than 29 weeks gestational age. Children are routinely followed until 36 months corrected age, and then some are discharged if they are doing well with normal developmental progress and the parents have no behavioural concerns, which means that the older children in the cohort tend to be those where there are some issues that need following. Overall there were 55% of parents who had some concerns about their infants developmental progress, including an 18% who had concerns about behavioural and emotional issues. Parents of the 53 infants identified as having “severe NDI” (defined as a motor, language, or cognitive composite score <70 on the Bayley3, or cerebral palsy with a GMFCS of 3,4, or 5, or needing amplification or being visually impaired in both eyes), were only slightly more likely to have concerns about the development of their infant than the 82 without “NDI”. Growth, feeding and respiratory concerns were similarly represented among the subgroups. Mothers and Fathers had similar concerns and there were no substantial differences by gestational age group.

Of the issues that matter to parents, the quotes suggest that it is really the child’s functioning that they worry about (‘I wish she would express herself more clearly’), whereas scores on standardised tests were never mentioned! Of course, if those scores help to identify infants who would benefit from intervention, then they may be of value to the individual. If they, overall, reflect the function of the group then they could be a reasonable way of summarizing outcomes. But behavioural/emotional development is very rarely mentioned in outcome studies, despite the major importance to many parents, nor are feeding and growth commonly reported.

This project says to me that we should systematically describe and report behavioural, emotional, feeding and growth outcomes in our follow-up studies, and in the follow-up of our RCTs in extremely preterm infants. Those things concern parents just as much as developmental delay, and have impacts on the families similar to other things that we describe routinely.

As a parent myself of an extremely preterm infant, perhaps I can allow myself, for this first post of the new year, to give my opinion of what outcomes matter. My daughter indeed had her standardized tests, administered by a friend and colleague in the McGill University follow up system (Dr Elise Couture). I was rather uninterested in the results of those tests, I don’t even remember if she “passed” or not. I knew she was progressing, was learning new skills, and had behavioural issues that were not out of the ordinary. She had feeding issues that were more disruptive than any problems with cognitive development, and when she got to school had some issues with her learning style, of an executive function type. With the dedication of her mother, in particular, she was able to progress through school, and is very soon to graduate from high school, at which she works extremely hard. For me the most important features of follow-up were to know whether there were any specific therapies that could help to make her life easier: Did she need physio? Would speech therapy help? How could we best assist her learning pattern? Her ENT problems and pulmonary development were also of major interest, and fortunately she didn’t have any major hearing or vision problems needing intervention, other than spectacles. I try to imagine what my attitude would have been if she had turned out to have a Bayley MDI (she did the version 2) score <70. I can’t imagine Annie or I would have treated her any differently, and the idea that having a low Bayley score would have been the same outcome as her being dead, I find offensive.

On the other hand, evaluating, and finding a way to summarize, the developmental progress of our patients is worthwhile, having a more robust development, more similar to babies born at term would be a good thing. A more detailed description of outcomes, including average scores and the spread of scores, on standardized screening tests, would give a more useful picture of the outcomes of our patients than just the proportion of babies below various thresholds. More information about what outcomes matter to parents should help us to design follow up programs that respond to their needs.

Posted in Neonatal Research | 5 Comments