Caffeine protects the lungs

From the CAP trial we know that caffeine administration leads to less bronchopulmonary dysplasia. The question is how? The mechanism could help to design other studies, or help in a decision about clinical use where the question hasn’t been directly answered by CAP. One possibility is just that improving respiratory drive allows earlier more successful extubation, and less exposure to positive pressures; I think this is likely to be part of the mechanism. On the other hand there is now evidence of direct effects of caffeine on inflammation, which are mostly anti-inflammatory, and on apoptosis. This new study in neonatal rabbits (Nagatomo T, et al. Caffeine Prevents Hyperoxia-Induced Functional and Structural Lung Damage in Preterm Rabbits. Neonatology. 2016;109(4):274-81) exposed preterm cesarean delivered rabbits to 95% oxygen, and randomly divided into groups receiving either caffeine or control. Without going into all the methodologic details of this excellent study, the authors found that caffeine was highly protective against the reductions in lung function caused by hyperoxia. Caffeine use also reduced the size of the alveoli, but prevented the reduction in alveolar numbers caused by hyperoxia.

With other data this suggest that caffeine helps to protect immature lungs from the effects of too much oxygen. The impact of caffeine on bronchopulmonary dysplasia could be partly as a result of this effect.

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Tattoos, Beer and Bow-ties, a worthy follow up to “Pepperoni Pizza and sex”

Annie Janvier has just had another article published on-line, in JAMAPediatrics. The full title is “Tattoos, Beer, and Bow Ties: The Limits of Professionalism in Medicine” 

It tells of a day when she met a patient’s father for the first time who had seen her out in her running gear previously, and noticed her tattoos. It describes the evolution of their relationship during the medical course of Émile, the baby. A relationship in which she broke several of the rules of “professionalism”.

All of Annie’s narratives are like this one, perceptive, thought-provoking, and often moving. In this one she talks about how medical professionals are being given simplistic rules about use of social media, sharing email addresses, and the way they interact with patients and parents, simplistic rules which sometimes interfere with humane, compassionate professional practice; and all in the name of professionalism.

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Meta-analysis of the oxygen trials, including the long term outcomes

This new publication is not a complete systematic review, but is a review of the history, design and outcomes of the oxygen saturation targeting trials, and of the early stopping of 2 trials. Stenson BJ. Oxygen Saturation Targets for Extremely Preterm Infants after the NeOProM Trials. Neonatology. 2016;109(4):352-8. It includes a meta-analysis of the primary outcomes of the trials, including mortality, disability, and certain of the components of those outcomes. The only difference between the groups was in mortality, which led to a significant difference in the combined primary outcome, of death or disability at 18 to 24  months. In case you can’t get access to the full text, here are 2 small parts of the publication, the mortality data, showing a 16% increase in mortality with lower saturations, and no heterogeneity between trials:

Stenson mortality

Ben Stenson discusses the impacts of the changes in oximeter calibration algorithm, and shows the before and after mortality data for those studies where the algorithm was changed part way through :

Stenson mort software

Perhaps because the separation between the saturation ranges was a little greater after the change, that is where the mortality difference is seen, in all the 3 trials where it was changed.  There is also an increase in NEC (relative risk of 1.25), which is at least one of the causes of death that seems to have increased with the lower saturations.

One  might ask why the SUPPORT trial, with only the old algorithm, showed a difference in mortality. I think it is possible that that was because of the antenatal consent and enrollment at birth, it may be that aiming for lower saturations is even more hazardous if you start the lower saturations immediately during the transition period.

Nevertheless the first graph shows that all of the data together, including both algorithms and all the trials, there is an increase in mortality.

The final conclusion is:

In trials conducted in a developed world setting with continuous SpO2 monitoring and protocols for screening for and treating ROP, targeting SpO2 below 90% in extremely preterm infants increased mortality and did not reduce the risk of blindness or other disabilities and cannot be recommended.

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New Pages on the blog

I am in the process of re-organizing the “Important Neonatal Publications” page, into a number of sub-pages with topics. It was getting a bit long and hard to find anything you are particularly interested in. I will be adding more sub-pages as I get a chance over the next few weeks. The original idea was for this to be a reading list for our fellows, to give a good grounding in evidence based neonatology. I hope others find it useful. If you hover over the “Important Neonatal Publications” item in the menu above you will see a list of topics.

Also new pages of bird photographs, one from the UK, another from Florida. The pictures from the UK with the Coot family including the still-bald babies I quite like.

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Seizures are bad for you

Fox CK, et al. Neonatal seizures triple the risk of a remote seizure after perinatal ischemic stroke. Neurology. 2016. This analysis of a Kaiser Permanente database had 87 children with perinatal strokes. Those who had seizures during the neonatal period had far higher risk of later epilepsy, including refractory epilepsy requiring multiple medications.  Of the whole sample more than half had at least one seizure in later life, and half of those had refractory epilepsy. The risk of both was about twice as high if you had neonatal seizures.

Hart AR, et al. Neonatal seizures—part 1: Not everything that jerks, stiffens and shakes is a fit. Archives of disease in childhood – Education & practice edition. 2015;100(4):170-5. As this review article notes, diagnosing seizures is difficult. Previous evidence has shown that about half of what we think are “fits” (in the good old English terminology) are not, and we only recognize about half of actual seizures as diagnosed by routine clinical monitoring. Some studies show we are even worse than that.

Glass HC, et al. Contemporary Profile of Seizures in Neonates: A Prospective Cohort Study. The Journal of pediatrics. 2016. This was a prospective multi-center cohort study, with newborns who were considered at risk for convulsions all being monitored by continuous video EEG. Most of the 426 included babies had HIE, or strokes, or intracranial hemorrhages. Many of the babies had large numbers of seizures and 16% had status epilepticus. Half of the survivors still had abnormal clinical signs at discharge, with another 17% dying. Those that had the most seizures were more likely to die or be abnormal at discharge.

Continuous video-EEG is clearly now an essential tool in any tertiary NICU, and we need to find ways to recognize the seizures faster, and treat them more effectively.


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Give poor pregnant women cash

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

Prenatal care is supplied to everyone, in every province, and leads to us having perinatal outcomes which are excellent. There are still disparities, however, and poor women have a number of outcomes which are worse than women with more resources.

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

Chronic care, and domiciliary care are the big losers in our system, as it is politically easier to cut budgets when the adverse effects are slowly cumulative rather than acutely visible. Non-urgent surgery is another place where our system does poorly, so a hip replacement might be quite delayed, with consequent avoidable pain and disability. One interesting comparison with the US system was made a few years ago by John Ralston Saul. The cost of US Medicare divided by the entire US population, (even though it only covers a small part of the US population) was greater than the cost  of Canadian Medicare, divided by the entire Canadian Population, but the Canadian system covers everybody.

In Manitoba (one of the Canadian Provinces, total population just over a million) they introduced a program in 2001 where any pregnant woman with an annual income under $32000 was eligible to receive an income supplement, as long as she applied for it, the income supplement was up to $81.41 a month,and was accompanied by written information about prenatal care, breastfeeding, etc.

In this new study the authors examined the outcomes of the nearly 11,000 pregnancies where the woman claimed and received the supplement, to those of eligible women who did not (nearly 4,000). After matching for propensity scores, those who got the extra cash had less low birth weight, less small for gestational age, more breast-feeding initiation, and more large for gestational age babies.

The average annual income of the mothers who received the supplement was less than $10,000, so the supplement, which doesn’t sound like much to a Canadian doctor like me, was actually a nearly 10% increase in their monthly income.

The authors of this remarkable work contrast their results with those of other countries (mostly in Latin America) who have introduced income supplements, but only for mothers who attend antenatal care, or who satisfy other conditions.

They note that when the program was introduced in Manitoba there were questions:

As a society, we tend to assume that poor people cannot be trusted to make good choices. Indeed, when HBPB (the income supplement program) was first introduced in Manitoba, concerns were expressed about introducing a program for low-income women without conditions or accountability.  Although information about prenatal and infant health is included with the monthly payment, the Manitoba HBPB program trusts low-income women to make good choices regarding their pregnancies.

For a small cost, just giving poor pregnant women a small amount of money every month during their second and third trimesters, improves pregnancy outcomes. There was also a decrease in length of stay after delivery, so it probably saved money as well.

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Outcomes of babies with surgical anomalies

Neonatologists basically invented the field of outcomes research; many of my colleagues from around the world have closely examined the outcomes of very premature and extremely premature infants for many years: well before people in other fields were doing so. Outcome research for other babies that we look after has been more recently performed; here are a few recent studies about surgical congenital anomalies.

Bojanic K, et al. Cardiopulmonary exercise performance is reduced in congenital diaphragmatic hernia survivors. Pediatr Pulmonol. 2016. In this study performed at 5 to 20 years of age, among 27 the survivors of CDH repair, reduced exercise tolerance and other respiratory symptoms were present in about half. VO2 max was much lower but equally variable (which means in relative terms, more variable) than a control group. The results are not too surprising for a condition which is nearly universally lethal without intervention, but the implication is that testing like this could lead to an intervention (that is, exercise training) that might improve outcomes in some individuals. Of course, exercise is good for everyone who can do it. I wonder if it is possible that part of the effect is due to over-protection of children with “weak lungs” and whether one intervention should be just to re-assure parents that exercise is good, and getting tired after exercise is normal.

Calzolari F, et al. Outcome of infants operated on for congenital pulmonary malformations. Pediatr Pulmonol. 2016. In this study the authors looked at outcomes of children who had had congenital cystic adenomatoid malformations (apparently they are now called congenital pulmonary airway malformations CPAM; but it seems a bit redundant to put pulmonary and airway in the same acronym) or sequestrations (which they call broncho-pulmonary sequestrations BPS) or congenital lobar emphysema (which they now call congenital alveolar overdistension CAO). These patients biggest problem in follow up is that nobody knows what problem they had because the acronyms have all changed! There is a lot of uncertainty about what to do with children who have these lesions but who do not have symptoms. Apparently, in the Ospedale Bambino Gésu (I just wanted to type that mellifluous name) in Rome, they operate on all diagnosed cases, which may or may not be the right thing to do, or at least that is what they say in the methods, in the results, they note that there were 8 non-operated infants, who were excluded from the study. They finished with 68 patients aged 4 to 9 years, and compared them to a group of kids who had inguinal hernia surgery. 40% of the patients and 12% of controls had recurrent wheezing, and needed inhaled bronchodilators. There were only 5 patients with congenital lobar emphysema, but they all had recurrent wheeze, the other 2 groups were similar to each other. Many of the patients (20%) had had respiratory tract infections, and none of the controls. The patients who had a lobectomy were more at risk, and babies who needed post-operative assisted ventilation. As they got older the symptoms improved.

Roberts K, et al. Outcomes of oesophageal atresia and tracheo-oesophageal fistula repair. J Paediatr Child Health. 2016. A review article examining the long-term impacts of the conditions in the title. The long-term function of the oesophagus is impaired, with frequent reflux and prolonged, even life-long dysphagia. 50% to 90% of adolescents and adults have at least occasional dysphagia, with many avoiding certain foods, and up to 20% have daily symptoms. Recurrent wheeze is common, many have restrictive defects on lung function testing, but most adults have normal exercise tolerance. Developmental testing has been less frequent, but there do seem to be developmental delays, especially in the language scores of the Bayley scales, version 2, the delays seem to be greater among infants with malnutrition during infancy, underweight being common in the first year, usually improving afterward. Quality of life scores overall are similar to the general population, but Health related quality of life is reduced, mostly because of dysphagia and reflux. A very complete, and clearly written review.

Giudici L, et al. Babies born with gastroschisis and followed up to the age of six years faced long-term morbidity and impairments. Acta Paediatr. 2016;105(6):e275-80. This study from Buenos Aires followed 54 survivors of gastroschisis at 1 year, 34 at 3 years and 117 at 6 years. I don’t recognize the tests that were used to evaluate neurological and developmental progress, but there were frequent delays, with only 64 babies in the normal range at 1 year, 50% at 3 years and 35% at 6 years. Language delays were frequent, but that tended to improve with time, and intervention. 20% of the infants had growth below the 10th percentile, throughout the study.

Sterken C, et al. Neurocognitive Development After Pediatric Heart Surgery. Pediatrics. 2016;137(6). This study followed 107 infants who had cardiac surgery in early life, they were eligible for the study if they surgery at less than a year of age, many were newborns, and the median age of having surgery was 2 months. They then tested 100 of the children again 3 years later, as well as most of the controls. The heart surgery patients had IQ scores that were about 12 points lower than controls at 4 years of age, and 7 points lower at 7 years of age. They also had deficits in visuo-motor integration, alertness, motor coordination, and psychosocial functioning, and these deficits also stayed stable.

Now that we are getting much better information about the long-term problems that these children may have. We need to do the next thing, and study how to help them improve. Whether or not the same strategies will be effective for children in each of these diagnostic groups is uncertain.

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