Premies with Sepsis, what is happening to the circulation?

This is  a study of the hemodynamic profile of preterm infants who have septic shock, compared to matched controls. And an analysis of changes after institution of therapy.

Saini SS, Kumar P, Kumar RM: Hemodynamic changes in preterm neonates with septic shock: a prospective observational study. Pediatric critical care medicine: 2014, 15(5):443-450.

This is, I think, almost unique data. There is a previous study of the hemodynamic profile of infants who were thought to have sepsis (from Koert de Waal and Nick Evans) but not, like this study, restricted to that group of babies that are most problematic and high-risk, those in shock.

We really need data like these in order to be able to decide which kinds of therapy to test. I was, based on guesswork rather than data, of the opinion that septic shock in the newborn was often different to the kind of urosepsis that is a common cause of (usually gram negative) septicemia and warm shock in the adult. That was largely based on animal data, particularly data based on animal modelf of GBS sepsis .

This study using mostly echocardiography, along with clincial assessment, studied 52 preterm infants with a diagnosis of septic shock, half of whom had positive cultures. There were 52 infants matched for gestational and postnatal age who served as controls.

One thing these authors did not do was to divide the cases by cause of sepsis, I think it is likely, or at least possible, that gram negative organisms and their endtoxins lead to a differnet hemodynamic profile than gram positive organisms. Certainly in the studies I mentioned in newborn animals with GBS sepsis, they usually have a low cardiac output, and cold shock, which is a bit different to what these authors show, in their preterms. Of the 26 babies with positive cultures, 18 had gram negative organisms. I guess with only 8 ‘others’ (6 gram positives, 2 fungi) an analysis by type of organism would be problematic, but on the other hand it would have helped people to have preliminary data to see if enterococcal or staphylococcal sepsis might be different.

There are some findings, though, which are difficult to understand, for example, the study reports a substantially higher left ventricular output, LVO, in the septic babies than the controls, suggesting vasodilatation as an important cause of the shock, which is understandable, but at the same time, RVO was higher than LVO in both groups, and was essentially the same in the 2 groups, meaning that in the controls RVO was very much higher than LVO, while in the septic shock babies it was only slightly higher.

To have a right ventricular output so much higher than left is quite surprising. Usually, of course, with an open PDA and a left to right shunt, the LVO is higher than the RVO. If there are no shunts at all, the 2 are obviously equivalent. If the RVO is that much higher than the LVO, then maybe the control babies had large left-to-right inter-atrial shunts, which woud be strange, or large right to left PDA shunts, which also wouldn’t make a lot of sense.

Other published data are consistent with what I am saying here, for example, this study (Sirc J, Dempsey EM, Miletin J: Diastolic ventricular function improves during the first 48-hours-of-life in infants weighting <1250 g. Acta Paediatr 2015, 104(1):e1-6.) shows LVO consistently greater than RVO and increasing over the first 48 hours of life.

Which suggests to me that maybe there is a systematic error in the measurements by this group, inflating RVO. So we should treat these data with caution, and note that they suggest that vasodilatation is common in preterm babies with gram negative sepsis, or with negative cultures and similar clinical findings. But they can’t be considered definitive.

Further studies of the hemodynamics of septic shock are need to confirm these findings in the systemic circulation and clarify what is happening in the relative outputs of the 2 ventricles, and the circulatory shunts.

When we look at the effects of therapy, the authors were able to have before and after data from 41 septic babies who receive either dopamine or dobutamine. They didn’t show much in teh way of changes, apart from some increases in heart rate, particularly with dopamine.

More data about infants with septic shock would definitely help to determine which therapies are the most appropriate to study.

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Updated Photo Page

I have just added another batch of Australian Bird Photos, and reformatted the ‘Photos’ page on this blog.

Hope you like them: if you click on one of the photos you can see a high-resolution version.

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What is the news about probiotics?

A few things have been happening recently: first of all, the big news was that Solgar recalled ABCDophilus as a result of some contamination of the product. As many of you will probably know, there was fungal contamination of the final product which was associated with a preterm infant developing intestinal mucormycosis, which was fatal.

Quality control and highly reliable products are essential for preterm infants. Complications, expected (at least in retrospect) and unexpected, have been frequent in the brief history of neonatology. I am on record as having suggested that ABCDophilus might be an appropriate preparation for use in the NICU, it certainly appears to be effective, it was the preparation used in the Australian Pro-Prems trial. Solgar, the company that supplies ABCDophilus, do not I think, produce the organisms themselves, they appear to be responsble for the final compounding, which is the stage that seems to have been contaminated. This case emphasizes how essential good quality control is. In order to ensure that the benefits of probiotics are maximized, we have to avoid such risks.

As most things in medicine and in neonatology, an intervention should be used based on the balance of risks and benefits, and how those risks and benefits are valued by the patient or their family. Avoidable risks such as this one should of course be avoided. It would be a great mistake to suggest that this is a valid reason to avoid introducing probiotics. Previous problems in manufacture of medical devices or medications have led to withdrawal, correction, and re-introduction. We need reliable and safe products for preterm infants, the one we use in Montreal certainly seems to fit those criteria.

In other news, the Pips trial has been presented, although not yet published. This large high quality multi-center trial from the UK randomized 1000 babies to placebo or to a single species probiotic (a Bifidobacterium Breve). The primary outcome variable was survival without NEC or late onset sepsis. NEC stage 2 or worse occurred in 10% of controls and 9.4 % of treated babies. In isolation such a small change could easily be due to random chance alone.

Why the benefits of probiotics in this trial should be less (or absent) is not immediately clear. Among the possibilities, this study avoided biases that exaggerated the benefits in other studies: this study suffered from biases that reduced the benefits: the organism chosen was less effective for this purpose (or less effective at colonizing the infants’ intestines): random variation in efficacy across numerous studies.

The 95% CI of the relative risk from this individual trial are from 0.68 to 1.27. Which means that although this was a high quality trial, it cannot with confidence exclude a substantial benefit (or indeed harm) or probiotics.

Two other trials have also recently been published. Sanjay Patole and colleagues performed a small study with the primary objective of ensuring that their preparation and strain of B breve succesfully colonized their babies, without adverse effects. They had about 80 babies per group (with or without probiotics) and had only one case of NEC, in the placebo group.

In another trial, this time from Turkey, probiotics were administered to 2 of their 4 groups, either with or without inulin, a prebiotic molecule. The other two groups were either control, or received only inulin. The 400 babies were eligible if they were under 32 weeks, and less than 1500 grams, and fed before 7 days  of age. The controls had an 18% incidence of NEC, which was a little lower in the prebiotic group (12%), and much lower in the probiotic group (2%) and combined group (4%). The probiotic organism they used was a Bifidobacterium Lactis.

I haven’t seen any other RCTs, so if we add all these data, Pips and the other studies, to the meta-analysis we get a Forest plot which looks like this: (I must emphasize that this is not the same as an updated systematic review: much more methodologic rigour is required, but I think it gives an indication how the data currently stand).:

Forest plot

What I think this means is that we now sorely need comparative trials. We have to find out if the differences in efficacy are due to random variation, or is there a real difference in the efficacy of the organisms used.

I think it might well turn out that some probiotic organisms, perhaps because of differences in their utilisation of prebiotic molecules (I will come back to this) are less effective at preventing NEC. The only way we will know is if we perform very large comparative trials. NEC is such a devastating disease, with long-term consequences, that we have to find out.

Finally, the other news is that a case series of bifidobacterial bacteremias has been published. Two of the 3 cases were transient bacteremias requiring no therapy, the third was an infant who develoepd NEC despite prophylaxis and grew B longum which is the strain found in Infloran, which all 3 affected infants were being given.

In contrast to the avoidable contamination of ABCDophilus with a fungus, this complication is, I would think, an unavoidable cost of using probiotics. At some point, after treatment of many thousands of infants with probiotics, it was inevitable that this type of complication would arise. This is not to say that we should ignore this risk, but it must be weighed against the enormous proven benefits.

Remember that if you use unpasteurized breast milk in your infants, you are already giving them bifidobacteria, of varying species and strains. B breve, B longum and B bifidum have all been found in breast milk, and probably others also. We do not have the choice to leave an infants gut sterile, in any case it would not be a good idea! Giving a nudge in the right direction with a reliable probiotic preparation is about the best we can do at present.

As a post-script I learnt in Australia that Koalas transfer their microbiome as they start to wean their infants. The mother Koala produces a special stool (pap) that is eaten by the baby. Which is just another excuse for a photo.  This little guy came into the garden of the house we rented near Apollo Bay in Victoria. Eucalyptus leaves are a poor nutritional source, and toxic for most mammals, so Koalas need their intestinal microbiome in order to thrive.1-1D8A1343

 

 

 

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Not neonatology : the Antipodes, Farewell New Zealand

Saying goodbye to New Zealand was tough. The amazing scenery, spectacular geothermal region, and unique wildlife, although expected, exceeded all my expectations. What was a bit unexpected was the sincere, open, friendliness of the people, we never met anyone who was not helpful and generous.  I don’t think that was just because we were foreigners, as we experienced the same attitude whether people knew we were visitors, or not. I don’t think I could manage to be so unfailingly good-natured, so maybe I wouldn’t fit in here.

I was also very impressed by the approach to environmental protection, which seems to be a priority for every decision that is made. Good luck to them, they have a great deal which is unique, and sorely needs protection. Half of the bird species that were endemic when the Maoris arrived are already extinct; most of those in the last few decades.

Which is an excuse for another series of photos:

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Not neonatology : the antipodes, week 6. Lake Tekapo and Christchurch

Week 6 was, too quickly, our final week in New Zealand, and we moved back to the interior of the North Island. Lake Tekapo is a Glacial Lake which gives it a milky turquoise colour. It is also in a Night sky reserve, where nocturnal lighting is very limited, and the views of the night sky are very clear, as clear as they used to be everywhere, I guess, until the invention of electric lighting. I don’t believe I have ever seen the Milky Way so clearly, most nights it is not visible at all in Montreal. I think the kids were surprised that there are so many stars. The second night there we had a guided description of the sky by an astronomer, who pointed out features using a laser pointer, surprisingly this worked very well for the whole group. The next day we walked up to the Observatory on Mount John (which is the reason for the night sky reserve) where at one point we could see lake Tekapo, and Lake Alexandra right next to it, which is not filled by glacial run-off, and so has a completely different colour, a dark green as a result of the algal growth. I haven’t adjusted the colours on this photo taken near the peak of Mount John, with Lake Tekapo on the right, and Lake Alexandria on the left, in person the contrast is even more striking.

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The mountain range behind includes Aoraki, Mount Cook. The highest mountain in New Zealand, and one that has 2 names. There is no record that James Cook ever saw, and he certainly never visited, the mountain that carries his name, so recently the old Maori name was given back to it, and the Europeans’ name kept for historical and guide book reasons. Our first view of the mountain was unusually clear over a lake. The Maori name may (or may not) mean something like Cloud Piercer, which, even if it isn’t true, would be appropriate as the summit is almost always hidden by clouds. So this view is rare.

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The walk to the glacial terminal lake was not very taxing, but well worth it, with many striking views.

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Our trip to New Zealand ended in Christchurch, a city in the middle of reconstruction after the devastation of the 2010, 2011 earthquakes. I was stunned by the extent of the destruction, remembering the images after the earthquakes I had not expected whole city blocks to be empty, but many buildings which were still standing after the quake had to be demolished as a result of structural damage, and it will take many more years (15 by some estimates) to rebuild. This is what remains of the Cathedral.

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Some businesses have set up in containers, placed in front of their damaged former premises while they wait to be rebuilt.

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Despite this, Christchurch is, like all of New Zealand in a gorgeous region; we had a walk in the hills around, and another in the estuary where there were thousands of Banded Godwits, Stilts, Gulls and Oystercatchers in the early evening, in this estuary very close to the center of town.

1-IMG_5058And this white-faced Heron, caught in the evening glow of the setting sun.

White-faced Heron

 

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Getting Better

Brett Manley, and a group of the CAP investigators, including yours truly, have just published an article about the long term cognitive testing results of the trial subjects. (Manley BJ, Roberts RS, Doyle LW, Schmidt B, Anderson PJ, Barrington KJ, Bohm B, Golan A, van Wassenaer-Leemhuis AG, Davis PG et al: Social Variables Predict Gains in Cognitive Scores across the Preschool Years in Children with Birth Weights 500 to 1250 Grams. The Journal of pediatrics 2015). The 5 year outcomes of the CAP trial, if you remember, were interesting in showing that only 18% of the babies who had a Bayley 2 score at 18 months corrected age which had been below 70 still had cognitive testing scores (on the WISC-R) less than 70 at 5 years of age. The babies who had the lowest scores on the Bayley had, overall, the greatest “improvement” in their scores at 5 years of age.

You may also remember that the primary outcome was no longer different between the caffeine and control groups at 5 years, although there were some differences between the groups, which still favoured the caffeine exposed infants. The average IQ score of the whole group of infants at 5 years of age was 98.9, almost identical to the population standardised mean.

We thought that the changes in scores, and the lack of difference between the groups when they reached 5 years, was probably evidence of the variable influences of environmental factors, which become much more important as babies age, so we used those social variables that we had collected in the CAP data set to see if they were associated with the changes in cognitive scores.

Obviously the tests that were used were not the same at 2 years and at 5 years, a developmental evaluation at 2 years, and a more formal test of “intelligence” at 5 years, but, with that proviso, we were able to show that much of the difference in test scores was explained by the contribution of a number of social variables, which actually all had additive effects. The most important social variables were paternal education, maternal education and parental employment. Having two parents in the home was important on individual analysis, but dropped out when combined with the other factors in the model.

Our data confirmed that developmental testing at 18-20 months is very poorly predictive for cognitive abilities at 5 years, among very preterm infants. Which is entirely consistent with other published data.

One important implication of this is that we need to be very circumspect making treatment decisions or therapeutic choices based on predictions of 18-20 month developmental outcomes.

It also strongly suggests that we should focus programs to try and improve the long term function of very preterm infants on those with more social limitations. Consistent with this suggestion is the recognition among several results of trials of early intervention programs that benefits are difficult to demonstrate, except among those with more social disadvantages. Presumably, families with more resources (of all kinds) may well already be able to provide the kind of environment which aids the very preterm infant to achieve their potential, those with more difficulties need more assistance to end up in the same place.

I think in the future we should find ways to screen families in neonatal follow-up to identify those that will most benefit from intervention aimed at improving outcomes, the families most likely to benefit are likely to be those who have more limited resources.

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Back to Blogging

Hello everyone, as we return slowly to Montréal, with a little stop-off on the way for an excellent conference in San Diego (Cool Topics in Neonatology, organised by my good friend Yvonne Vaucher), I am starting to see time and opportunities and topics for blogging.

While I was away the number of page views of this blog clicked over the 250,000 mark since inception. I have also met many individuals who claimed to read the blog and told me they found it useful. The feedback is much appreciated and helps me to be motivated to keep going.

Over the next few days I will be posting about some recent publications I have been involved with, about what is happening with probiotics, about suctioning for meconium, and other selected issues.

I will also post a steady stream of ‘not neonatology’ posts about my travels, with associated Photos.

In addition I have added a Photos page which you can reach from the top menu, with a few of my bird and wildlife photos, and occasionally others that I think are OK. When I post new photos on that page I will probably give a heads-up on the main page. Here, as a little taster is a photo of an Australian Parrot called a Galah. (To be more precise, as a budding ornithologist, I guess I should say that the Galah is a member of the Cockatoo family, the Cacatuidae. Species name is Eolophus roseicapilla). GalahOne of the things which struck me in Australia was the variety of the birds that could be seen easily with little effort, many which were strikingly attractive.

I hope you will enjoy them as much as I have.

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