Time to abandon the Papile classification? (part 3)

What should we do now?

I think we should stop using the Papile classification.

We should clarify that an intraventricular hemorrhage with acute hemorrhagic dilatation of the ventricle(s) is not the same pathophysiology as a hemorrhage followed by dilatation. (stage 2 followed by PHVD compared to a stage 3)

We should differentiate between an acute intra-parenchymal echodensity (which may be hemorrhagic or edematous) and PVHI, associated with intraventricular blood on the ispilateral side.

We should analyze and record the brain regions affected by the PVHI or IPE.

We should follow, and report the outcomes, of several hundreds of individuals, in order to have reliable information.

In other words, we should abandon the Papile classification, we should use descriptive terms to interpret head ultrasounds, we should use published percentiles to determine if a ventricle is dilated or not, we should record the brain regions affected on ultrasound, unilateral and bilateral, and we should work at correlating these findings with long-term outcomes.

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Time to abandon the Papile classification? (part 2)

As I mentioned in the last post, the initial report of outcomes by Bassan and others showed that the infants with severity score 0, (unilateral haemorrhage without midline shift affecting one zone) had reasonably good outcomes, 7 of 8 had cognitive scores within the normal range, 4 of 8 were without gross motor dysfunction. They also showed that having a VP shunt did not change significantly the neurological or developmental outcomes. As should therefore be obvious ‘grade 4 hemorrhages’ with these characteristics should be considered relatively benign, warranting close follow-up, and surveillance for complications such as ventricular dilatation or development of multiple cysts. Many PVHI resolve with a single porencephalic cyst in their wake, some resolve and leave findings similar to cystic PVL, that second group may well have worse motor outcomes than single porencephalic cysts, I will come back to this point later.

The Bassan study reports is obviously very small numbers, there were only 30 infants with PVHI in all (which isn’t bad for such a relatively uncommon lesion), so I asked myself if there are other similar data with larger numbers.

The largest I have found so far is a study from North Carolina (Maitre NL, et al. Neurodevelopmental Outcome of Infants With Unilateral or Bilateral Periventricular Hemorrhagic Infarction. Pediatrics. 2009;124(6):e1153-60) which has outcome data from 69 surviving infants with PVHI, 52 unilateral and 17 bilateral. The infants with bilateral PVHI were more immature than the unilateral babies, otherwise there was little difference in the early clinical course of the infants, but their outcomes at up to 36 months were very different.

Infants with unilateral PVHI had a Bayley II MDI at 18 to 36 months which averaged 82, compared to 49 with bilateral PVHI (almost all had an assigned score of 49). Cerebral palsy was much less common and much less severe with unilateral than bilateral PVHI, 15 of the 17 with bilateral PVHI had moderate or severe CP, compared to 19 of the 52 with unilateral PVHI. In concert with these findings the proportion with BayleyII scores above -2 SD on the MDI was significantly better with unilateral PVHI. In this study there is no description or analysis of the extent of the lesion on each side, or the worse side. They did report that those infants who had PVL on late ultrasounds had worse MDI, worse PDI, and more severe motor dysfunction than those who had porencephalic cysts.

Van Buuren et al (van Buuren LM, et al. Cognitive outcome in childhood after unilateral perinatal brain injury. Developmental Medicine & Child Neurology. 2013;55(10):934-40)
reported the outcomes of 21 babies who had unilateral PVHI, it is a somewhat unusual cohort in that the mean gestational age was 30 weeks, and ranged from 26 up to 41 weeks. One strength of the study is the later age IQ testing (performed, however, between 6 and 20 years of age) which showed that the children who had PVHI had full-scale IQ results which were lower than the standardizing population, but mostly within one standard deviation of that population, with a mean of 86. Verbal IQ scores were not significantly different from the theoretical norm at 96. Infants with post-hemorrhagic ventricular dilatation did worse, with a mean IQ of 80 compared to a mean of 96 for those without. The extent of the lesions is not clearly described they are noted as being frontal, fronto-parietal, or parietal and that the location had no impact on outcome, they don’t mention laterality (uni- vs bilateral); 12 of the 21 had a hemiplegia, but the severity is not described.

A study from Groningen (Roze E, et al. Functional Outcome at School Age of Preterm Infants With Periventricular Hemorrhagic Infarction. Pediatrics. 2009;123(6):1493-500)
followed 21 babies who had PVHI, there were 38 babies with this diagnosis in the cohort, 15 died and 2 were not included in the follow-up. They showed that only a minority had significant functional impairments, even though 9 of them had bilateral PVHI, and 5 had extensive (described as fronto-parietal-occipital) lesions. Although 16 children had Cerebral Palsy, 13 were GMFCS 1 or 2, only 3 had more severe motor problems. Most of the cognitive outcomes were normal or mildly affected with only about 10% more than 2 SD below the standardized mean at 4.4 to 12 years of age. They did not show an association between bilateral or more extensive PVHI and worse outcomes, but clearly the power is relatively low for these comparisons. Post-hemorrhagic ventricular dilatation was present in 8 infants, who had poorer scores, again the numbers are very small, but they seemed to have more cognitive difficulties.

The ELGAN cohort study included 54 babies with a diagnosis of PVHI. (O’Shea TM, et al. Neonatal cranial ultrasound lesions and developmental delays at 2 years of age among extremely low gestational age children. Pediatrics. 2008;122(3):e662-9). 44% of them had a Bayley II MDI less than 70 at 2 years of age, and 59% had a PDI under 70, there is no analysis of whether unilateral or bilateral PVHI were different, to unilateral or localised lesions.

A more complex system called the Abdi score is calculated as the square of the highest traditional IVH grade (so scoring 1, 4, 9 or 16), plus the IVH grade on the contralateral side, plus 5 for each hemisphere when more than two of its territories are involved, and plus 5 when there is a midline shift of the brain. The “territories” refers to the brain regions from the Bassan system. The score was first published in the Saudi Medical Journal and I can’t access the paper to see how it was derived, but as far as I can tell it was rather arbitrary. A recent outcome study using the Abdi scores (Al-Mouqdad M, et al. A New IVH Scoring System Based on Laterality Enhances Prediction of Neurodevelopmental Outcomes at 3 Years Age in Premature Infants. American journal of perinatology. 2016(EFirst) followed 183 very preterm babies at 3 years of age. They included 55 babies with intraparenchymal bleeds, whose Abdi scores could range from 16 (i.e. 4-squared) to 35 (4-squared plus 4 plus 5 plus 5 plus 5). The authors showed that  this score was better at predicting outcomes than simply using the Papile grade, but they did not compare to the Bassan system for PVHI. Although this score seems better for an individual patient prediction, it would be difficult I think to use it in daily practice, and the small numbers with each individual score mean that a very large database would be required to validate differences between each score

You may be asking yourself why is Keith Barrington/neonatalresearch.org going over all this older data? I was stimulated to do so by recent cases in my NICU and also by this publication from Texas (Sheehan JW, et al. Severe intraventricular hemorrhage and withdrawal of support in preterm infants. J Perinatol. 2017;37(4):441-7). The authors note that the long-term prognosis of very preterm infants with parenchymal hemorrhage has been shown to be much better than previously thought.

As you can hopefully see from this (non-exhaustive) review, the majority of infants with parenchymal bleeds (“grade 4 IVH” or PVHI) have outcomes which are within the range of healthy full term infants, only a minority have serious impairments (although, as most of the follow-up is only to 2 years of age, permanent functional impairments are impossible to quantify).  As you might expect, but with little data to support it, it seems likely that more extensive hemorrhagic lesions, and bilateral lesions have worse outcomes than limited or unilateral lesions, but there are very few patients who are informative in the published cohorts.

Sheehan’s study examined discussions and decisions regarding redirection of care among very preterm infants with a diagnosis on ultrasound of serious brain injury (“grade 3 IVH” or PVHI). They showed that the improved knowledge about the benign outcome of many of these lesions has not led to fewer decisions for comfort care. They also examined the outcomes of survivors with PVHI: 13/35 or 37% had no or mild NDI, 10 or 29% had moderate-to-severe impairment and 12 or 34% had profound impairment. Survivors with profound impairment had a median of 4 (IQR 3, 4) territories vs 2 (IQR 2, 3) territories in survivors without profound impairment.

Their data are therefore quite consistent with others, that parenchymal injury is often compatible with little or no impairment, and that the more severe the parenchymal injury the more severe the disability (although with wide confidence intervals). But this has not led necessarily to changes in decision making.

Why is this? In any other area of medicine, I suggest, if outcomes were shown to be much better (or at least, much less bad) than previous beliefs about long-term outcomes, decision-making would surely have changed, no?

I think we should reconsider our outcome data, and how good we are at predicting profoundly adverse outcomes.

What I suggest is the follows:

  1. The construction of robust large databases which relate head ultrasound findings to long-term, functional, outcomes. With enough detail to be able to relate a particular constellation of findings to a range of probable outcomes. Such databases will need to take into account mortality, but that must be predicated on whether care was re-directed or not. Withdrawal of life-sustaining interventions as a result of head ultrasound (or other considerations of long-term outcomes) must be factored into such databases.
  2. Development of tools to teach neonatal and perinatal trainees (and established caregivers) how to counsel parents regarding the results which would be routinely available from 1.

We must move on from a discussion focussed on “your baby has a grade 4 hemorrhage” and “life therefore is no longer worth living” (often implying, or overtly saying, that the long-term outcome will be “terrible”). To “your baby has these findings on imaging” which means that she (or he) will most likely be within the following range of outcomes, the majority of which are associated with an entirely acceptable quality of life.

 

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The end of the Papile classification? (part 1)

In 1978 Lu-Ann Papile published a landmark article detailing the incidence of intraventricular hemorrhage (IVH) in 46 VLBW preterm infants using CT scanning, describing the differing extent of hemorrhage that may be seen, and developing a grading system (there are over 3,000 citations to this article!). To recap, for those who don’t know, a grade 1 ‘IVH’ actually does not have blood in the ventricles, but rather in the germinal matrix region, also known as a GMH or an SEH (sub-ependymal hemorrhage). A grade 2 hemorrhage is bleeding into the ventricles without dilatation, a grade 3 is hemorrhage distending the ventricles, and a grade 4 is bleeding into the substance of the brain (with or without blood in the ventricles).

With the advent of head ultrasound more frequent and less invasive imaging became possible, and most centers adopted the Papile classification for grading hemorrhages seen on ultrasound.

There are several problems with this system, one is the definition of a grade 3 hemorrhage, as many people seem to think that a grade 2 hemorrhage which is followed by early post-hemorrhagic dilatation becomes a grade 3 hemorrhage. It is clear to me from the original description that a grade 3 hemorrhage is one where the ventricles are acutely dilated by the hemorrhage, even though in the original article this is called “intraventricular hemorrhage with dilatation”, the image shown is one of acute hemorrhagic dilatation of the ventricle. The early studies by Joseph Volpe’s group made this clearer by referring to grade 3 hemorrhages as those where “IVH completely filled and distended at least one lateral ventricle” (their articles don’t use a grade 4, more below).

This makes it very difficult to interpret and compare studies which include ‘grade 3’ bleeds, as it is sometimes unclear whether the hemorrhages are grade 3 as I understand them, or whether they are grade 2 hemorrhages followed by ventricular dilatation, which is often transient.

A bigger problem is the use of the term ‘grade 4 IVH’. Parenchymal echodensities without intraventricular blood are often not actually bleeds, and frequently resolve completely, there being a high degree of inter-rater variability in their diagnosis and interpretation. Many intraparenchymal bleeds in the preterm are associated with an ispilateral intraventricular hemorrhage, and have a somewhat heterogeneous appearance on ultrasound.  Such hemorrhages are often called Peri-Ventricular Hemorrhagic Infarction (PVHI) and they are not all equal, they may be small or enormous, unilateral or bilateral, and should not be lumped together in outcome studies. A classification scheme was developed in 2006 (also from Volpe’s Harvard group) to address the severity of the lesions. Bassan H, et al. Ultrasonographic features and severity scoring of periventricular hemorrhagic infarction in relation to risk factors and outcome. Pediatrics. 2006;117(6):2111-8. This classifies PVHI into 4 grades, depending on whether it is bilateral or unilateral, the extent on the worst side, and whether there is a midline shift of the brain. Extent is graded by dividing the brain into 5 zones by drawing lines around the thalamus.

This figure is from the article referred to above and shows the percentage of PVHI affecting each zone, the numbers add up to more than 100% because a PVHI may, of course, affect more than one zone.

In this scoring scheme, if the PVHI involves just one zone it scores 0, if more than one zone it scores 1 (if bilateral it scores 0 or 1 according to the extent on the worst side). The same goes for the other features, scoring 0 or 1 depending on whether the feature is present or not (bilateral, and midline shift, earning a 1 each). The severity score can therefore range from 0 to 3. It is a slightly confusing system as a unilateral PVHI without midline shift affecting one zone is referred to as a PVHI severity 0. In most scoring systems for other diseases a grade 0 means that the disease is absent. In this system a severity score of 0 does not mean that, so you have to remember this feature of the score. In the original report about 3/4 of the PVHI were unilateral, and about half of the unilateral PVHI affected one region only. In the original report the long-term outcomes reported were death, Ventriculo-peritoneal shunt, seizures (during the NICU stay or in the first 5 days after the PVHI), microcephaly, and neuromotor signs at follow-up at more than 12 months of age. Early seizures, death, and neuromotor abnormalities were all more common as the score increased, but those with more severe scores were more likely to have a redirection of care, and most of the deaths were associated with provision of comfort care. 8 of the 12 infants with a PVHI which scored 0 had a normal motor examination at 12 months.

The same authors provided more detailed developmental outcome data in what appear to be the 30 survivors of the same babies, in a 2007 article. The babies were examined between 12 and 66 months of age. There was a progressively increasing proportion of the survivors with abnormal scores  (<-2SD) on the various subscales of the Mullen scales of early learning with increasing scores on early ultrasounds. Most of the babies with a severity score of 0 did not have abnormal results on any of the scales, apart from gross motor where the proportion was 50%.

I think this should have led us to abandon the Papile classification, which was an important advance when it was described, but was a descriptive scale  and was not related to any long-term data. It is clear that there is a huge range of different severities of imaging abnormalities which are hidden by the use of the term “grade 4 hemorrhage”. We should be referring to intraparenchymal echodensities for those cases where they are not clearly PVHI, in particular those echodensities without intraventricular or at least subependymal blood. When a PVHI is present a scoring scheme such as the Bassan scheme should be used. Much larger studies could then give us a better idea of what the true range of outcomes is likely to be for each early appearance of the brain, whether having 3 zones affected is worse than 2, whether the volume of brain affected might be better than just dividing into zones (as a small hemorrhage which crosses zone lines might be less problematic than a large hemorrhage confined to one zone) and so on.

In the next post I will try and review the literature to see how much data of that sort is available.

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Ethical conflicts and moral distress in the NICU, are they all bad?

The term “moral distress” was coined by nursing researchers who were, generally, referring to situations in which nurses were constrained to act in opposition to their ethical beliefs, usually by having to follow medical orders that they disagreed with. More recently the term has been applied to a wider range of issues that incorporate ethical conflicts.

A new publication from Melbourne (including my wife, Annie Janvier, as a senior author) questioned staff in two NICUs, both physicians and nurses, about their understanding of moral distress, whether they experienced it, and how often, and what could be done about it. (Prentice TM, et al. Always a burden? Healthcare providers’ perspectives on moral distress. Archives of disease in childhood Fetal and neonatal edition. 2017).

Nurses and Physicians experienced moral distress equally frequently, and those who looked after the sickest babies experienced it more frequently. However, they did not generally  consider it to be avoidable, nor to be always an adverse phenomenon. Indeed the majority didn’t even want to try to eliminate it completely.

The same 4 authors have followed this up with a review article.  They argue that since the term “moral distress” was developed, the decision-making landscape as changed. The nursing investigators who first created the term studied nurses who sometimes felt that they were forced into doing things that were against their moral beliefs about what was in the best interests of infants. In the newly emphasized “shared decision making” where decisions are made in a much more open way, and where parents are encouraged to participate in all the major decisions regarding the care of their infants, we often find a range of opinions about a treatment course, and a decision that therefore does not satisfy everybody.

Sometimes I myself feel that a patient that I am treating is not receiving care which is in their best interests, but the parents do feel that. We always try to avoid over-riding the parents wishes, working on compromises that are acceptable to the team, leading to days, or sometimes weeks, where many members of the team feel morally distressed. Unlike the caricature of the paternalistic over-invasive doctor imposing harmful treatments on a poor baby, by far the most common disagreements involve parents wanting to proceed with intensive care options that we feel are unlikely to succeed, or sometimes it is because of a different definition of “success”.

The authors of this review (Prentice TM, et al. The use and misuse of moral distress in neonatology. Seminars in fetal & neonatal medicine. 2017) encourage a process of self-reflection which can be used to build a type of moral resilience, to allow an appreciation of the complexities we deal with, prevent burnout, and encourage ongoing involvement, with a sort of moral courage.

After doing this for almost 40 years, I do not think that ethical conflicts are avoidable in neonatology, or in other critical care areas. I don’t actually they are any more or less frequent than in the past; we can do more, we are more able to support babies at more extreme degrees of illness, we also know much more about the long-term futures of our babies, when studied as groups of infants, but at the same time I am much less definite about my ability to predict what the future of an individual child will hold.

When I feel constrained to provide care that no longer seems in the child’s best interest (usually because of parental desires) it can create distress. Fortunately I work in an NICU where we frequently have open and wide-ranging multidisciplinary discussions about such cases. These really help the team to realize the diversity of opinions about the best course of action, that no-one is blind to the multiple potential courses of action, but are thoughtfully trying to seek what is optimal for the baby and family. We also often acknowledge the difficulty it may pose to the bedside nurse who spends many hours a day with a baby who is not being treated according to their own opinion of the right thing to do. I think this really helps to avoid statements such as “she’s always pro-life” or “he’s often ready to stop before anyone else”, but to, rather, appreciate the struggle we all go through to make the best decisions for our babies.

I think this approach in our unit (we are unique, I think in having three neonatologists who are also PhDs in clinical ethics!) reflects many of the suggestions of this review article as ways to reduce the impacts of moral distress; and, in fact, reflects much of what I have read about the so-called “Schwartz rounds”, an article about which has just appeared, promoting such rounds as a way of encouraging compassionate care in children’s hospital. That proposal irritates me a bit, as I have never noted a lack of compassion in children’s hospitals, or in general hospitals either! On the other hand, I do think that transparent, inclusive, multidisciplinary discussions about our most problematic cases can make a big difference to the emotional state of the caregivers.

Moral distress, and the ethical conflicts underlying such distress, help us to push past our preconceptions, to realize that caregivers and parents may have varying opinions while all still wishing to find the best decision for the baby under our care. I think that not having such distress, such emotionally charged conflicts, would mean that we thought we knew all the answers. I think this is why many people in the article that stimulated this post did not think that we should even try to completely eliminate moral distress. We should, instead seek ways to reduce and control and use it to advance our care for the newborn.

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Recent publications

Even though the blog has been quiet recently, other academic output has continued…

In the NICU we are often faced with babies with late- or early- onset sepsis. The worst cases develop shock, which carries a significant mortality; they may survive if they receive intensive treatment. We have no idea really which treatments are helpful, and which are harmful. We try to follow physiologic principles but without much confidence that we are doing the right thing; we have been analyzing our treatments to try and figure out which interventions are helpful, and which might not work.

What often happens is that babies have standard interventions, (antibiotics, fluid boluses, dopamine or epinephrine infusions…) and when things are not going well we introduce other therapies, such as steroids or norepinephrine.

The first of these two studies looked at steroids: Altit G, et al. Corticosteroid Therapy in Neonatal Septic Shock-Do We Prevent Death? American journal of perinatology. 2017. We examined the responses to steroid, almost always hydrocortisone, therapy for babies in septic shock (i.e. hypotensive and not responding to first line inotropes). As this was not a research protocol, but just desperately trying to save babies who were in dire straits, the use of steroids was variable. But usually was after their response to either dopamine or epinephrine was inadequate. After starting hydrocortisone we were able, almost always, to reduce the doses of, or stop, other catecholamines. As time has progressed we have tended to use steroids earlier, sometimes before getting to high doses of catecholamines…

We compared episodes of septic shock among preterm babies who received steroids in addition to their inotrope, to those who did not receive hydrocortisone. We would expect the babies who received steroids to be more sick, and indeed their inotrope use index was higher, and they received inotropes for longer than the comparison group. Babies in both groups almost always had cultures that were positive, apart from a few cases of severe NEC with negative cultures. The babies receiving steroids were more immature. Mortality was significant 22% of those who did not get steroids, and 40% among those who did, reflecting their increased severity of illness (the difference may have been a chance difference by statistical testing). There were further deaths in both groups prior to discharge, and among survivors severe BPD was frequent. Because of the severe BPD we examined survival to follow-up at one year corrected age, in fact there were no more deaths after discharge. When we statistically corrected for gestational age and duration of inotrope use, there were more deaths among the babies who received hydrocortisone than those that did not.

We looked at the hemodynamic responses to the hydrocortisone and found a rapid improvement in blood pressure, starting within 6 hours, this was followed by a progressive reduction in inotrope requirements, mostly after the first 6 hours, and an improvement in urine output, starting after the blood pressure had increased. As you can see in table 4, these babies, who had a GA at birth on average of 26 weeks, and were about 2 weeks old, on average had mean blood pressures when we started the steroids of only 28 mmHg.

The second study examined our use of norepinephrine in another group of babies with septic shock. Before moving to Sainte Justine I don’t think I had ever used norepinephrine in a newborn infant, but the experience in adults, which shows a better hemodynamic profile in sepsis with norepinephrine compared to other catechols, led us to use norepinephrine in septic shock, mostly late-onset septic shock or NEC with shock.

Rizk MY, et al. Norepinephrine infusion improves haemodynamics in the preterm infants during septic shock. Acta Paediatr. 2017. We looked though our pharmacy database to find preterm babies who had received norepinephrine, all of whom were considered to be in septic shock. The 30 babies were already receiving either epinephrine or dopamine before we started norepinephrine, and nevertheless were very hypotensive, they were on average 26 weeks gestation, and 18 days old, but had a mean blood pressure of just over 20. We started the norepinephrine almost always at 0.1 microg/kg/min, and increased progressively, most babies not needing more than 0.2 microg/kg/min, but occasionally we went as high as 0.6. On average it took about 6 hours to achieve blood pressure and urine output within the normal range for each baby; they were oliguric when norepinephrine was started (mean urine output less than 2 mL/kg/h). We were able to commence reducing the other inotropes at that point, with all but 2 babies having reversal of their shock. Those 2 died, and one other for whom palliative care was started, for a mortality of 10% during the shock episode.  There were 7 other deaths before discharge for an overall mortality of 33%. Long term outcomes were poor, with frequent disabling cerebral palsy and low Bayley scores.

Both of these studies have serious limitations of course, we don’t know if these babies would have done as well, or better, without these interventions, but there are very few studies examining therapies in septic shock, so we thought it worthwhile to examine our practice, to see how we can study this phenomenon for the future. A previous study on norepinephrine  in preterm babies, who were mostly septic, showed a more rapid reversal of shock than our study, but started at a much higher dose (0.4 microg/kg/min) and took 24 hours to see improvement of oliguria. Their infants were also a little more mature (27 weeks), and had younger postnatal age (mean 1.5 days of age) and were sometimes being treated for PPHN, rather than sepsis.

What does this mean overall?

We desperately need prospectively controlled trials in infants with sepsis and hemodynamic compromise. In the meantime, use of steroids and/or use of norepinephrine are usually followed by hemodynamic improvement in babies who remain in hypotensive shock despite a single inotrope. That, I think is about all we can say, from these studies and others. Are such interventions much better than waiting or increasing the doses of the primary inotropes? Do they improve survival or other important outcomes?

As mortality is very high in these babies, RCTs of interventions would not need to be huge in order to have power to detect a clinically important difference in mortality; long-term adverse outcomes are also common, and moderately sized trials could also be informative for those outcomes.

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What to do with mild encephalopathy?

Therapeutic hypothermia improves the chances of babies with moderate or severe hypothermia of surviving without serious disability; referrals for evaluation for therapeutic hypothermia have exploded in our center, and many others, now that this advance is widely acknowledged. Many of the babies referred had a difficult start in life, needing resuscitation and having low umbilical cord blood pH, but have only mild encephalopathy, often with a combination of signs of Sarnat stage 1 and 2.

I actually think it is a mistake to believe that we can clearly classify infants into stage 1, 2 or 3 encephalopathy, although it is a very useful classification there are many babies that have some features of stage 2 and some of stage 3, or some of stage 1 and some of stage 2. We have developed a local evaluation system that will often give babies a stage of “1.7” for example, and then are not sure whether we should cool them or not. Are they a “mild” or a “moderate”?

In general, as the randomized trials show very little adverse effect, and the benefits are clear for moderate encephalopathy, we tend to cool babies who are possibly eligible. Occasionally a decision in the other direction has come back to haunt us, when a baby who seemed to just have classical stage 1 encephalopathy then has a convulsion at 12 hours of age (for example) and we have missed the boat.

One thing that has recently given me pause is the idea that induced hypothermia in non-asphyxiated animal models might have adverse effects on cerebral development. There is at least one study (in neonatal rats) showing a decrease in hippocampal cell proliferation following therapeutic hypothermia in non-asphyxiated animals. (I thought there was another study in piglets also, but I can’t find it right now (please send it to me if you find such an article)). If that is also the case in human babies, and there are adverse CNS effects in the non-asphyxiated, but beneficial effects in the asphyxiated, then there may be babies that we are currently treating with hypothermia who are not having a benefit, but may, rather, be having a negative effect.

But also, it may well be that mild encephalopathy is not as benign as we used to think. I was taught, based on good data (published by my mentor and great friend Neil Finer), that stage 1 encephalopathy did not increase impairment, stage 3 babies were all either dead or seriously impaired at 1 year of age, and stage 2 babies were in between (about 40% serious impairment). If stage 1, mild encephalopathy babies all do well, then we should spare them the rigours of therapeutic hypothermia, and the possible theoretical risks: is this true?

My concerns about this situation are obviously shared by others, there is an explosion of articles about babies with mild encephalopathy recently.

Murray DM, et al. Early EEG Grade and Outcome at 5 Years After Mild Neonatal Hypoxic Ischemic Encephalopathy. Pediatrics. 2016. This well-done study (from the great group in Cork) compared outcomes among 22 babies with mild encephalopathy who were evaluated at 5 years of age to 30 controls. The mild encephalopathy group had significantly lower IQ scores (99 on average) compared to the controls (mean=117, smart kids, the Irish!), the mean IQs for the moderate encephalopathy group were similar to the mild infants, but they had a range of other problems, so fewer of them were considered “non-impaired” at 5 years. The EEG at 24 hours (but not so much at 6 hours) helped to predict the full scale IQ at 5 years.

Gagne-Loranger M, et al. Newborns Referred for Therapeutic Hypothermia: Association between Initial Degree of Encephalopathy and Severity of Brain Injury (What About the Newborns with Mild Encephalopathy on Admission?). American journal of perinatology. 2016;33(2):195-202. This study from Pia Wintermark and the group at McGill (the second best group in Montreal ;-)), showed that, of the babies referred for possible hypothermia, there were 50 who had mild encephalopathy at admission who had an MRI, 20 of them had MRI abnormalities and 5 of those had very severe abnormalities. In the figure below BG/W score is a score for MRI abnormalities in the basal ganglia and white matter.

The authors note that many of the mild encephalopathy babies worsened clinically during the first hours of life.

Walsh BH, et al. The Frequency and Severity of Magnetic Resonance Imaging Abnormalities in Infants with Mild Neonatal Encephalopathy. The Journal of pediatrics. 2017. This study from Terrie Inder’s group in Boston examined the prevalence of MRI abnormalities among babies who were cooled; they had 48 babies with mild encephalopathy, more than half of whom had an MRI abnormality during the first week. They were just as likely to have watershed injuries as babies with more severe encephalopathy, but less likely to have basal ganglia injuries.

One thing that happens when you cool babies with mild encephalopathy is that they often appear uncomfortable, they are irritable and cry a great deal, and may seem to need sedation. We sometimes, therefore, consider interrupting the cooling, or add potentially toxic sedatives to their therapy. Sometimes the babies improve so much that they don’t have many signs of encephalopathy, and we think they no longer qualify for hypothermia. Although we don’t know for sure what to do for such babies, this study is informative. Lally PJ, et al. Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy. Archives of disease in childhood Fetal and neonatal edition. 2017. This article reports 10 babies in whom hypothermia was discontinued early, in each case because they had improved so much they no longer seemed eligible for the treatment. Half of them nevertheless had MRI abnormalities, and 20% had abnormal long-term outcomes at 2 years of age.

Prempunpong C, et al. Prospective research on infants with mild encephalopathy: the PRIME study. J Perinatol. 2017. This is a prospective multi-center cohort of babies with mild encephalopathy who were not treated with hypothermia, led by my friend and former fellow Guilherme Sant’anna. Their definition of an adverse neurological outcome was an abnormal aEEG within the first 9 hours of life, an abnormal MRI, or an abnormal neurological exam at discharge. Of the 54 babies with adequate data, just over half, (n=28) had abnormalities.

I am still not sure how to put all this together. The studies used for my own training, when you examine the data more closely, do show, even 40 years ago, a small signal suggesting worse outcomes for babies who had mild, Sarnat stage 1, HIE.

This now seems to be confirmed. Mild encephalopathy following perinatal adverse events is probably not benign; even serious outcomes may sometimes follow. For the moment, I think if I am unsure about whether to cool a baby, and they have clear signs of being at least a Sarnat stage 1 HIE, then I will start therapeutic hypothermia, and try to continue for 72 hours. What to do for the babies that are very uncomfortable and seem to need sedation isn’t clear to me, I think a morphine infusion is probably the least toxic alternative, but I am not at all sure about that.

But…. the studies showing the greatest proportion of adversely affected infants after mild HIE are those of babies who were treated with hypothermia, when you compare them to studies of mild HIE babies who were not cooled.

One interpretation of this could be that hypothermia worsens the outcomes of mild HIE. Another might well be that we are good at selecting the babies, among the mildly affected, who are more severely impacted, and that we don’t cool the babies at lowest risk. This is always a problem with observational studies, causation is impossible to ascribe.

There is really only one way to answer these unknowns.

You probably don’t need to guess…

A large multi-center RCT of therapeutic hypothermia is essential; criteria for cooling in such a trial need to be exquisitely clearly defined, so that they can be applied prospectively for future generations.

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The last word on delayed cord clamping in the preterm? part 3.

Lo and behold. Fogarty M, et al. Delayed Versus Early Umbilical Cord Clamping for Preterm Infants: A Systematic Review and Meta-Analysis. Am J Obstet Gynecol. 2017.

Some of the authors of the APTS trial have performed an updated systematic review, to put into context the results of their trial, which is exactly what should be done in such a circumstance. Their review includes the data from the trial I discussed in part 2, as they were available already (in the figure below they are listed as Duley 2016).

This review found 27 trials of delayed clamping that enrolled babies of less than 37 weeks gestation; most, as mentioned before, were tiny. When looking at the effects on mortality (for which there were 19 trials that reported the outcome) the results of the APTS trial were in fact not significant (at conventional levels of statistical significance) for death before discharge; which seems different to the published results, but the published results were for death before 36 weeks. As you can see from the figure below, death before discharge was 58 vs 79, rather than the 50 vs 70 for death before 36 weeks in the publication from the FPNEJM (the Formerly Prestigious New England Journal of Medicine); death before discharge had a relative risk of 0.73 95% CI 0.53 to 1.01.

There was little heterogeneity in the results,  and, as you can see here, the mortality results depend largely on the latest 2 trials, which together contribute 77% of the weight for the meta-analysis.

So where does this leave us? There is certainly no good evidence of a disadvantage of planning delayed clamping, compared to immediate clamping. Other outcomes: any IVH, severe IVH, PVL, a combination of serious persistent CNS abnormalities on ultrasound, late onset sepsis, NEC, RoP, were not different between early and late clamping. Hematocrit is increased by about 2.7%, and about 20% fewer babies receive a blood transfusion after delayed clamping. There are more babies with a hematocrit over 65% after delayed clamping, but no increase in partial exchange transfusions to treat them. Peak bilirubin levels are slightly higher after delayed clamping.

I remain a little sceptical about the advantages of delayed clamping beyond reducing transfusion requirements, the impact on mortality is basically from one trial (APTS) with an effect on mortality which might have been due to chance (p=0.07 from the Yates corrected chi-square), with a contribution from the Duley trial, with an individual p value of 0.12. I am should also sceptical about the relevance to my practice of a study such as Ranjit 2015, who only enrolled infants between 30 and 36+6/7 gestation who did not need resuscitation, but had a 10% mortality in the early clamping group.

For relatively uncommon events we often have to rely on systematic review to be confident about the impact of an intervention, but meta-analysis of multiple very small trials is known to be problematic, and often inflates the apparent impact of an intervention. I think though it is unlikely we will have more large trials of planned delayed clamping in the very preterm compared to early clamping. I did a quick search of clinicaltrials.gov and couldn’t find such a trial, there are, in contrast, trials comparing cord milking to delayed clamping.

Reassuring is the subgroup analysis of babies of less than 28 weeks gestation, which also showed a decrease in mortality (RR=0.7, 95% CI 0.51, 0.95), but that includes only 996 babies from 3 trials, (871 of whom were from APTS).

Why might delayed clamping reduce mortality without reducing individually any of the primary causes of mortality? It is possible that an improved perinatal adaptation could lead to more stable babies in the first hours of life that decreases a whole spectrum of later causes of death, but it is hard to understand why deaths from late onset sepsis would be reduced, for example.

In my opinion, if we take into account all the limitations in these data I am not absolutely convinced that delayed clamping leads to decreased mortality, but I think that, on balance, it probably does.

My take home message is that planned delayed cord clamping should now be the standard for the preterm infant. The benefits on reduction of transfusion without any harm detected for the baby or the mother, and a probable reduction in mortality, are important, and there is no signal for an adverse impact.

What next? The Duley trial was, of course, quite different to APTS, examining resuscitation with an intact placental circulation. The extra organization and equipment required for this approach should be justified, I believe, by a trial comparing A. planned delayed clamping at 1 minute but with clamping as soon as the baby is thought to need active resuscitation to B. planned delayed clamping at 2 minutes (or more) with active intervention as soon as thought necessary, the cord only being clamped early if there are technical obstacles.

I don’t think you should, ethically, randomize preterm babies to planned immediate clamping. The alternative would be to only randomize infants who were thought to need immediate intervention, and to compare immediate clamping to resuscitation with an intact cord, but that I think would be technically more difficult to do, and would probably require a waiver of consent.

 

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