Reducing apnea

When a baby has an apneic spell, we often respond by physically stimulating them. Usually they will start breathing again; but how does that work? If it is more than a coincidence (and I think it is, even though there are no randomized trials to prove that apneas are shorter when you shake them, compared to just waiting for them to start breathing again), then what is the mechanism that leads to babies restarting to breathe?

You might think that the mechanism is that they wake up, and breathe again because they are awake, but preterm babies have apneas regardless of their sleep state, in quiet or active sleep, or when they are awake. There is one study I am aware of (Thoppil CK, et al. Behavioural arousal in newborn infants and its association with termination of apnea. J Appl Physiol. 1991;70:2479.) which looked at this carefully analyzing videos of the babies, signs of arousal were only present a minority of the time when a baby terminated an apnea, and started breathing again: so arousal is not essential to restart breathing.

What else might be going on? Well the movement detectors in our muscles (proprioceptors) are known to be linked to the respiratory centers. Which is why sprinters start to increase their ventilation even before there is any detectable increase in oxygen consumption; just moving one’s limbs stimulates breathing!

Now a group has tested this by examining the effects of transcutaneous proprioception stimulation on respiratory pauses. (Kesavan K, Frank P, Cordero DM, Benharash P, Harper RM. Neuromodulation of Limb Proprioceptive Afferents Decreases Apnea of Prematurity and Accompanying Intermittent Hypoxia and Bradycardia. PLoS One. 2016;11(6):e0157349.)

The stimulation consisted of a battery driven vibrating pair of disks placed on a hand, and another on a foot. This was a short-term crossover study looking at the incidence of breathing pauses, and of longer apneas associated with hypoxia or bradycardia, using continuous recording of the signals from the bedside monitor, analyzed by an individual who was unaware of the (randomized) sequence of whether the device was switched on for 6 hours, or left off.

There were fewer pauses, fewer hypoxic spells and fewer bradycardias during the periods with the device vibrating.

Which suggests to me that when we stimulate a baby and they start breathing, they might be responding to a similar sort of pathway.

It’s also of course a potential active treatment for apnea of prematurity. Apnea is associated with worse outcomes in preterm babies, perhaps because of frequent hypoxia, and re-oxygenation (often including hyperoxia, which may be fairly prolonged).

My biggest question is whether the effect will be maintained, I can easily imagine that babies will habituate to the stimulation, and it may not have a persistent effect, but this very nicely done study could now easily be repeated with a much longer intervention period, to see if the reduction of apneas is maintained over a few days. If that does work, then wide introduction of this device could have significant benefits to our babies, and an RCT, probably as an add-on to babies already receiving caffeine, given the proven benefits of caffeine, would be important.

The device vibrates at 128 Hertz, which is about 1 octave below middle C (I think), in the future, ward rounds may be accompanied by a gentle buzzing from little discs stimulating our babies to breathe. I wonder if we tune them to different frequencies, and have a little symphony going on…

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A new publication

Janvier A, Farlow B, Barrington KJ. Parental hopes, interventions, and survival of neonates with trisomy 13 and trisomy 18. Am J Med Genet C Semin Med Genet. 2016: This new article draws on the results of the on-line survey that Annie and Barb performed with Ben Wilfond. It is an exploration of parental hopes, medical interventions, and factors associated with survival among a cohort of families who had a live-born child with trisomy 13 or trisomy 18.

We found that the hopes of parents in this group fitted a number of very frequent themes, they hoped to meet their child alive, to take them home, to be a family, and to give their child a good life.

We also found that about 100% of parents recall receiving a recommendation soon after the diagnosis to pursue comfort care, and most of those with antenatal diagnosis had a recommendation to terminate the pregnancy. Some of those recommendations were quite directive, and a few of the remarks made by medical professional that the parents quoted are shockingly inappropriate.

One of the comparisons that we made, that was quite a powerful predictor of outcomes, in fact the most powerful predictor of outcomes, was when the diagnosis was made. Babies with an antenatal diagnosis had fewer interventions, were much more likely to die on the first postnatal day (compared to almost none of the postnatal diagnoses), were much less likely to go home with their family, and had a very restricted approach to comfort care, often without oxygen or tube feeding. Those diagnosed after birth were very likely to be able to go home (87%) and had more interventions, even when the decision was made for comfort care.

Which suggests a number of things, first of all, many children with these diagnoses survive to discharge if they have some medical interventions immediately after birth; there appears to be decreased respiratory drive after birth that tends to resolve quickly if they get a little support, so CPAP, non-invasive ventilation, or invasive ventilation may be an approach that gets the babies through the first couple of days; caffeine might also help to shorten or avoid mechanical respiratory support.

Secondly, palliative care means a lot of different things, so much that maybe it has become a term that means nothing, some children in palliative care mode had cardiac surgery, presumably with the idea that they would be more comfortable afterward, which I think may well be the right thing for those babies, but is it really palliative care? Or is it just good medicine?

Many children who received comfort care survived to discharge, mostly those who had a postnatal diagnosis, but also some of those also who had a prenatal diagnosis. Part of our planning with these families, even when comfort care is decided, should be to consider how to facilitate a discharge home.

This study adds the decision-making part of the picture that you can’t get from registry or population based studies. Although this is a self-selected group the results overall for survival don’t look that much different from the population based study I posted about recently, with much longer survival among those who opt for some active medical intervention than we are used to seeing in the older literature. Most children who have surgery will be able to be discharged home.


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Preterm babies have fixed dilated pupils

There is a reason we don’t perform pupillary reactions to light in preterm babies, and that is that they don’t react. They also tend to be large. This post is in response to my trying to find out what had been published about this phenomenon, when a case in our NICU raised a teaching point. I decided to go back through the literature to find out what was actually documented in peer-reviewed publications, and found, for a change, some good quality data.

The first of these, chronologically, is from 1989 Isenberg SJ, et al. The pupils of term and preterm infants. Am J Ophthalmol. 1989;108(1):75-9. This group from UCLA studied prospectively pupils of 100 babies from 26 weeks through to 46 weeks, with a standardized methodology; pupils were larger in mm for more immature infants, even though their eyes are a bit smaller. Pupillary light responses were usually absent before 30 weeks PMA, and only reliable after 32 weeks.

Robinson J, Fielder AR. Pupillary diameter and reaction to light in preterm neonates. Arch Dis Child. 1990;65(1 Spec No):35-8. A similar study from Birmingham, England followed 50 babies, and found similar things, the few babies who responded before 31 weeks all had a slow reaction.

Isenberg SJ, et al. The fixed and dilated pupils of premature neonates. Am J Ophthalmol. 1990;110(2):168-71. The UCLA group again, this time with a cohort of 30 babies who were examined every week, they were all less than 31 weeks at the first examination and none of them reacted at that time. The proportion having a detectable response to light increased, and most were reacting by 32 weeks.

Isenberg SJ, Vazquez M. Are the pupils of premature infants affected by intraventricular hemorrhage? J Child Neurol. 1994;9(4):440-2. The answer to the question in the title is no. The pupils of babies with any grade of hemorrhage (1 to 4) are not larger and do not have different reactions to light than those without hemorrhage.

There are a couple of more recent publications, but they don’t really add anything. Until the baby has passed 32 weeks post-menstrual age, there is no point looking for pupillary light reflexes, and the pupils will look fixed and dilated.

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Hey, doctor, leave those guts alone!

Intestinal function is often sluggish after preterm delivery. Establishing early enteral nutrition, the goal of all of us, is interrupted often by repeated regurgitation, or large residuals (if you measure them) or abdominal distension. There are also reported correlations between delayed meconium passage and the later development of NEC.

This has led many clinicians and investigators to look at the use of various methods to stimulate gut function, hopefully with the goal of reducing time on intravenous nutrition, and maybe even reducing NEC.

If we look at the downstream result of those methods, that is, methods to improve evacuation, do they actually promote earlier stooling, or feeding tolerance?


At least that is the conclusion of a systematic review of 5 RCTs and a couple or observational studies. Kamphorst K, et al. Enemas, suppositories and rectal stimulation are not effective in accelerating enteral feeding or meconium evacuation in low birth weight infants: A systematic review. Acta Paediatrica. 2016. To prove no effect, of course, is just about impossible, but we can have reasonable confidence that there is not a clinically important effect on accelerating enteral feeding, and does not speed up the evacuation of meconium.

And there is no evidence that these interventions achieve any of the laudable goals of reducing TPN duration or reducing NEC incidence. A systematic review published last year suggested the opposite, a risk of increased NEC.

I think the best we can do improve feeding tolerance at present is the early introduction of breast milk, as periods of being npo slow down gut recovery (Maybe I should say ‘probably’, there as the evidence is limited).

And the use of probiotics. When reported as an outcome variable, probiotics have almost always improved feeding tolerance, and decreased time on TPN, which was certainly the case in our study, and is confirmed in the latest version of the Cochrane review.

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We found more bad things, that must be a good thing

Frequent readers of this blog will know that I have been critical of the promotion of pre-discharge MRI as a universal screening standard for very preterm babies. The positive predictive value of most findings on MRI at term-equivalent age is low, especially when you take into account that most significant findings will already be seen on prior head ultrasound. The PPV in particular of white matter abnormalities is well below 50% in almost all studies. Nevertheless, people like to look, and try to convince themselves that seeing more bad things in the brain of a very preterm baby must be a good thing to do. Hence we get articles like this one : Melbourne L, et al. Clinical impact of term-equivalent magnetic resonance imaging in extremely low-birth-weight infants at a regional NICU. J Perinatol. 2016.

The authors report results from 103 term equivalent cerebral MRIs in infants with birth weight less than 1000g. They report that they found new abnormalities in about half of the MRIs, not seen or suspected on serial head ultrasounds. Where the paper gets weird is that they asked a pediatric neurologist to look at the scans (US and MRI) and predict what the prognosis would be, and they then use this prediction as an outcome variable, even performing a statistical test to show that “simulated prognosis” was worse when you looked at the MRI.

Only 26 of the babies actually had a follow-up assessment, so it’s not really even worth talking about that part, except to say that they note there were a lot of “false positives”. The authors note that based on the MRI 14% of those 26 babies (that is, 3.6 of them(?)) were predicted to have cortical blindness, and none of them did. The one baby with cortical blindness was not predicted by the MRI.

How on earth a pediatric neurologist can give a  prognosis of the degree of developmental delay based on an MRI is beyond me. There is so little correlation between MRI findings for an individual baby and Bayley scores, (or between head ultrasound findings and Bayley scores for that matter) that to predict that an individual will have moderate delay, or mild delay or severe delay is impossible. To use that prediction as the outcome variable for this study is bizarre. Of the very few babies with follow-up there were 9 who had a Bayley (version 2) MDI more than 2 SD below the mean, of whom 4 were predicted from the MRI, and 12% of the babies (3, I presume) were predicted to have that low an MDI and were false positives. Which is pretty useless.

The authors end the abstract with this statement:

TE-MRI detects new abnormalities and impacts developmental prognosis in the extremely low birth weight, which supports its use despite the added financial cost.

and end the entire article with a similar conclusion.

There is no data about how the parents felt about the new abnormal findings of doubtful prognostic interest.

The MRI cost $1600, which is a large additional cost at the end of already costly hospitalizations. They note that this cost “is not negligible and should not be incorporated into practice without measurable advantages to providers, patients and/or families.” I agree with the patients and/or families part of that sentence; I don’t think we should be doing things to babies that cost money and disturb them and their families because of benefit to providers, though. They certainly have not demonstrated any benefit to anyone of routine MRI.

Basically the authors are saying we found more bad things, so that must be a good thing. I would say that they discovered imaging findings of uncertain significance, and low prognostic value, and that might equally be a bad thing.

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Long term survival in trisomy 13 and 18

After my previous post on this topic, John Lantos wrote a comment pointing out this recent publication, Nelson KE, et al. Survival and Surgical Interventions for Children With Trisomy 13 and 18. JAMA. 2016;316(4):420-8. It is a large regional cohort, identified from hospital records and linked death data. Included patients were those with a hospital discharge diagnosis during the first year of life including trisomy 13 and 18, which could possibly be incomplete, and/or include patients with other disorders, but I think it’s probably as good, or better than many other methods. It also includes some children with mosaicism or translocations. 428 children were included in the study who were born between 1991 and 2012 in the province of Ontario, with these results for 1 year and 15 year survival:survival t13 and 18

As you can see survival to 1 year and to 15 years was not that unusual, as the results show

One-year survival was 19.8% (95% CI, 14.2%-26.1%) for children with trisomy 13, and 12.6% (95% CI, 8.9%-17.1%) for children with trisomy 18. At 10 years, 12.9% (95% CI, 8.4%-18.5% [n = 13]) of the trisomy 13 cohort was alive, and 9.8% (95% CI, 6.4%-14.0% [n = 16]) of the trisomy 18 cohort was alive.

They also investigated survival after surgery, 76 of the children had a surgical procedure, with a big variety of procedures, and most of them were in older infants, over 6 months of age, with the exception of the first cardiac or GI procedure among trisomy 18 infants. Most of the babies (about 70%) survived for at least a year after surgery.

Survival curves are presented in the supplementary appendix in a different way, they show for example that for trisomy 13, if the baby is alive at 1 week of age then survival to 1 month was 75% (95% CI 65-83%) survival to 1 year was 36% (CI 26-45%), to 5 years was 27% (CI 19-36%) and to 10 years was 23% (CI 15-32%). The corresponding figures for trisomy 18 are 67% (58-74%), 25% (17-32%), 22% (15-30%), and 19% (13-26%).

Because of the nature of these data there is, of course, no information about decision-making, which clearly has a large effect in this condition, as I noted in the previous post, death in the first day of life is almost completely confined to infants with a decision for comfort care only.

Dr Lantos writes the accompanying editorial, in which he discusses the decision-making ethics. He has the following to say:

The concept of quality of life is too vague and subjective to be helpful as a criterion for deciding about the appropriateness of treatment. No one can know with certainty what any infant is thinking, feeling, or experiencing, but what is observed can be interpreted. Children with trisomy 13 and 18 smile and laugh. They are not in pain. They give and receive love. These factors suggest that their subjective quality of life is not so poor that life-prolonging treatment should not be offered. Generally, the phrase quality of life is misused as a synonym for physical or neurological impairment. But if impairment is to be discussed, accurate terminology should be used. Some infants and children can have severe impairments and still have an excellent quality of life.

I’m not sure that I agree that Quality of Life is not helpful as a criterion, it seems that Dr Lantos isn’t sure either, as he states that subjective quality of life is “not so poor that life-prolonging treatment should not be offered” which seems to me to contradict the first sentence. I do agree though, that we shouldn’t just say that quality of life is OK, and then not take anything else into account, I don’t think it should be the only criterion. I think the insight about the misuse of the terminology is spot-on though, there are many health-care workers who don’t think that an impaired, or severely impaired child can have a good quality of life. John kindly references a publication I co-authored for that last statement (Payot A, Barrington KJ. The Quality of Life of Young Children and Infants with Chronic Medical Problems: Review of the Literature. Current Problems in Pediatric and Adolescent Health Care. 2011;41(4):91-101), I would have phrased that a little differently, and noted rather that there is little or no correlation between severity of impairments and quality of life. If we recall from one of Dr Saroj Saigal’s studies, the only participant who scored their quality of life lower than zero (worse than being dead) was one of the controls. Presumably a depressed adolescent who I hope got a psych referral.

John Lantos’s editorial is perceptive and clear, and I certainly agree with his conclusions; which are basically that the diagnosis is not by itself enough to deny active medical intervention for children with these conditions, that a complete evaluation of the baby (or fetus) should lead to decision-making driven by parental values.

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Sustained inflation during neonatal resuscitation? Not so fast…

A sustained inflation at birth of an asphyxiated lamb which lasts 30 seconds leads to much more rapid restoration of heart rate and blood pressure than either conventional ventilation or a series of shorter sustained inflations of 5 seconds each. This new study from the same group (Sobotka KS, et al. Single Sustained Inflation followed by Ventilation Leads to Rapid Cardiorespiratory Recovery but Causes Cerebral Vascular Leakage in Asphyxiated Near-Term Lambs. PLoS One. 2016;11(1):e0146574) shows that cardiac contractility, carotid artery flow and cerebral oxygen delivery also increase much more rapidly.

But, wait a minute, is that necessarily a good thing? What is important is the eventual re-establishment of a stable circulation, and a reduction in cerebral injury, and injury to other organs. One of the reasons we have switched to room air resuscitation (at least for full term infants) is that re-oxygenation injury is reduced compared to 100% oxygen resuscitation, maybe increasing cerebral perfusion and oxygen delivery very quickly might also have some harmful effects.

In this new study the authors also performed brain histopathology  of the lambs after resuscitation, mostly looking at how many blood vessels in each of 3 sections of the brain were surrounded by extravasated serum. There were significantly more disrupted blood vessels and extravasations in the  sub-cortical white matter of the single prolonged inflation lambs than the other 2 groups, and slightly more in the gray matter and the periventricular white matter also. Exactly why this occurs, what the potential impacts are and whether it might also occur in babies exposed to different kinds of sustained inflations is unknown, but will need to be investigated.

Two fairly recent randomized trials have concentrated on pulmonary outcomes:

In the first, nearly 300 infants from 25 to 29 weeks gestation were randomized, Lista G, et al. Sustained Lung Inflation at Birth for Preterm Infants: A Randomized Clinical Trial. Pediatrics. 2015;135(2):e457-e64. They either were placed on CPAP, or had a sustained lung inflation (25 cmH2O for 5 seconds) followed by CPAP. The SLI group were more likely to avoid mechanical ventilation during the first 72 hours of life, but the number ever intubated, the proportion who developed BPD and survival were not different. As the babies were not necessarily asphyxiated, this was really a trial of SLI as a lung protective strategy, which did not really show any benefit; other complications of prematurity, including IVH and PVL, were not different between groups.

The second study enrolled nearly 200 infants of 34 to 36 weeks gestation, Mercadante D, et al. Sustained lung inflation in late preterm infants: a randomized controlled trial. J Perinatol. 2016;36(6):443-7. They described the intervention as follows :

after oropharyngeal and nasal suctioning, a prophylactic pressure-controlled (25 cmH2O) inflation was sustained for 15 s using a neonatal mask and a T-piece ventilator, followed by the delivery of 5 cmH2O CPAP. In the following 6 to 10 s, CPAP was discontinued in the absence of signs of inadequate respiratory effort (that is, apnea or gasping) or heart rate 4100 beats per min (b.p.m.). In the presence of signs of inadequate respiratory effort and/or whenever the heart rate was between 60 and 100 b.p.m. despite CPAP, a SLI maneuver with the same parameters was repeated. If the heart rate was <100 b.p.m. after the second SLI maneuver, the infant was resuscitated according to the recommendations of the American Academy of Pediatrics (AAP).

This study showed no benefit of the procedure, and 3 babies in the SLI group, but none of the controls, developed a pneumothorax.

It seems to me we should be being very careful with this intervention, and I say this as someone who has done it intermittently for many years. I think I’ve mentioned before on this blog that Anthony Milner showed years ago in depressed full-term babies who were intubated before their first breath, that a prolonged (5 seconds) slow-rise inflation pressure, up to 30 cmH20 eliminated the apparent opening pressure of the lungs and led to rapid establishment of an FRC. My anecdotal experience is that sometimes when I take over ventilating a baby who the junior staff is having difficulty with, and I apply that kind of a long inflation, often the lungs will be easy to inflate, and then assisted ventilation is much easier, often with a recovery of other clinical signs.

I’m somewhat less convinced of the value of SLI as a lung-protective strategy for preterm infants, and certainly the clinical data so far do not support it. As a part of a resuscitative strategy for depressed babies, I think there is more promise; but it now looks like we will have to carefully examine potential neurologic compromise.


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