Pain, still bad for you

Posted on 24 February 2014 by Keith Barrington

Roofthooft DWE, Simons SHP, Anand KJS, Tibboel D, van Dijk M: Eight years later, are we still hurting newborn infants. Neonatology 2014, 105(3):218-226. The answer is yes, but much less! In this study from a single hospital in Rotterdam with a focus on pain research, there were many fewer painful procedures performed than in the previous study, using a similar methodology, and more sucrose and kangaroo care and other interventions were used for the procedures that were still required. But we can still do better!

One thing the authors noted was that as the number of procedures has decreased, the percentage of unsuccessful procedures has increased. So peripheral arterial lines (which have a high failure rate as the catheters are often around the same size as the artery being cannulated) were unsuccessful 38% of the time in 2001 and 63% of the time in the new cohort. There were a lot fewer of them, so I think this shows that, as we are doing better at being less-invasive, then, when we really need to be invasive, we don’t have the same skills anymore. In our group one or two of us are recognized as having a higher success rate at peripheral lines, so they tend to get asked to do them, and maintain a reasonable success rate, which I think is best for the babies, but when they are not available, what then?

For a much more frequent procedure, peripheral intravenous catheter insertion, success rate dropped from 69% to 62%. So a large number of potentially painful procedures are performed for no benefit. A failed procedure also affects the use of analgesia for the subsequent procedure. If I have put EMLA for a procedure and then fail, re-application may not be possible as time is passing, and I may start to be concerned about toxicity, even sucrose may be less effective if you have to give it multiple times to get a single i.v.

We must find ways of improving success, with new technologies, simulation training etc. I think the next big step forward in neonatal pain control could well be finding ways to reduce unsuccessful procedures.

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Stop the Antibiotics!

Posted on 21 February 2014 by Keith Barrington

We know that prolonged antibiotic use in preterm babies increase their chance of later developing NEC. The assumption being that the disturbance of the intestinal flora leads to the increase in susceptibility. Here is some more direct evidence to support that assumption.

Greenwood C, Morrow AL, Lagomarcino AJ, Altaye M, Taft DH, Yu Z, Newburg DS, Ward DV, Schibler KR: Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of enterobacter. The Journal of pediatrics 2014(0).

There were 74 babies under 33 weeks studied, who had their microbiomic analysis performed weekly, 3 times. They divided the babies into those who had antibiotics for 0 days, 1-4 days, or 5-7 days.

All of the antibiotic use was empiric, defined as treatment based solely on clinical suspicion of infection without a positive culture result.

RESULTS: Infants who received 5-7 days of empiric antimicrobial agents in the first week had increased relative abundance of Enterobacter (P = .016) and lower bacterial diversity in the second and third weeks of life. Infants receiving early antibiotics also experienced more cases of necrotizing enterocolitis, sepsis, or death than those not exposed to antibiotics.

The table 2 in that article requires a bit of explanation, it took me  a while to realize that the row labelled ‘cases’ means those babies who had the combined outcome of death, NEC or sepsis.

The message to me is clear, prematurity is not in itself a septic event. You don’t have to have antibiotics just because you are admitted to an NICU! If you do have an indication for expectant antibiotic therapy, they should be stopped if the cultures are negative unless you have a very good reason.

Of course the other method is that all babies develop a microbiome, we can wreck it by giving antibiotics, and we can nudge it in the right direction by administering probiotics.

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Does being ventilated hurt? It depends who you ask

Posted on 21 February 2014 by Keith Barrington

Ruth Guinsburg is a neonatologist in Sao Paulo who has been super-productive, especially in the area of pain control in the newborn. Her latest is an interesting comparison of how caregivers and parents rate pain in infants on ventilators.

Elias L, dos Santos A, Guinsburg R: Perception of pain and distress in intubated and mechanically ventilated newborn infants by parents and health professionals. BMC Pediatrics 2014, 14(1):44. (Open Access).

The group asked the participants to observe different babies who were 24 to 96 hours old, in an incubator on a conventional ventilator, who had a gastric tube and and IV, During the one minute of observation they were not handled and had no procedures.

The participants were in 3 groups, pediatricians, nurse technicians (who seem to be nursing auxiliary types who work under the supervision of RNs) and parents. There were enormous discrepancies between the observers regarding whether they thought the babies were in pain, or distressed. Which makes it really difficult to treat or prevent such pain and distress. I think that many preterm babies who are intubated and ventilated seem very calm in between interventions, and have little evidence of pain or distress, which is probably why there is little evident benefit of routine analgesic (or sedative) infusions during assisted ventilation. Some babies, especially I think, the more mature infants do seem somewhat distressed and may benefit from maneuvers to decreases this.

It is of interest then that the very long term follow up of one of the trials of continuous morphine infusion during assisted ventilation has now been published. (de Graaf J, van Lingen RA, Valkenburg AJ, Weisglas-Kuperus N, Groot Jebbink L, Wijnberg-Williams B, Anand KJS, Tibboel D, van Dijk M: Does neonatal morphine use affect neuropsychological outcomes at 8 to 9 years of age? Pain 2013, 154(3):449-458).  There were 132 survivors of the original trial, of whom 89 were seen at 8 to 9 years. Reassuringly there were no adverse effects of the morphine detected, and there was even a tendency for executive functions to be better in the morphine group. With all the concerns about such agents potential effects on brain development and increase in apoptosis, it is comforting that very little was found.

 

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Yet more probiotic stuff

Posted on 14 February 2014 by Keith Barrington

Here is the other study of saccharomyces that I mentioned previously on this blog (Demirel G, Erdeve O, Celik IH, Dilmen U: Saccharomyces boulardii for prevention of necrotizing enterocolitis in preterm infants: A randomized, controlled study. Acta Paediatrica 2013) recently published on-line 271 VLBW babies were randomized to receive the probiotic yeast or control. Infants were enrolled when they were ready to start enteral feeds. There was no effect on NEC. Secondary outcomes showed that feeding intolerance might have been reduced, and clinical sepsis, but not definite culture proven sepsis.

They had no invasive fungal sepsis in either group. A reduction of which might be one reason for including saccharomyces in future multi-species probiotic mixtures. But further work will be required before doing that.

The same group has already published a randomized comparison of the same fungus to Demirel G, et al: Prophylactic saccharomyces boulardii versus nystatin for the prevention of fungal colonization and invasive fungal infection in premature infants. Eur J Pediatr 2013:1-6. This was a comparative RCT in 181 VLBW infants who received either Saccharomyces or Nystatin to prevent colonization and infection with Candida. Infants were randomized at 72 hours of age. There were no significant differences between the groups’ outcomes, 2 nystatin and 0 probiotic babies developed invasive candida.

Both of these studies have the same important error, which probably doesn’t affect the conclusions but should have been picked up by the referees: several infants died after enrollment in the trial, and they are then eliminated from the data, as if they had been ineligible. They are not even included in the numbers of deaths. This means that it is not an intention to treat analysis, any event occurring after enrollment must be included, 9 deaths among 190 subjects is a lot of deaths, and if unevenly distributed might mean that there is a difference between the groups. No justification is given for eliminating these babies from analysis. It is certainly possible that probiotics might have effects within a few hours of being given (positive or negative) so all babies randomized must be included.

There is also something strange though that I cannot understand. Both of these studies were performed in the same mega-hospital, which has an enormous NICU and 4000 admissions per year. The first was performed between March and November 2011 during which time they had a total of 365 VLBW infants admitted, 86 were excluded and the remainder were randomly assigned to saccharomyces or control. The second study was performed between May 2011 and November 2011, there were 240 admissions of VLBW infants, and 50 were excluded, leaving the 190 who were randomized, 9 of whom died later and were excluded.

It looks like from these publications that the studies were performed at the same time in the same NICU, but the total numbers don’t add up, as there aren’t enough total babies to give the numbers in the CONSORT flow diagrams. Is it possible that there were babies in both studies? If so the controls in the first study were actually getting nystatin, and their data have been duplicated. If not there seems to be another error of some sort.

Finally a study of a lactobacillus: Oncel MY, Sari FN, Arayici S, Guzoglu N, Erdeve O, Uras N, Oguz SS, Dilmen U: Lactobacillus reuteri for the prevention of necrotising enterocolitis in very low birthweight infants: A randomised controlled trial. Archives of Disease in Childhood – Fetal and Neonatal Edition 2014, 99(2):F110-F115. This is again from the same 150 bed NICU, but from a different time period. 424 VLBW infants were randomized if they survived to start enteral feeds, to either Lactobacillus reuteri or placebo. Unfortunately the authors do the same thing with the early deaths in this study as well, infants who died within the first week of life were eliminated post-enrollment. 16 deaths are therefore not analyzed (7 probiotic vs 9 placebo). Unlike the majority of other studies, the authors showed no effect on NEC, which was 5% among placebo babies, and 4% with probiotics. Nor on teh combined outcome of survival without NEC, which was 90% with probiotics and 97% with placebo (to invert their numbers).

Even if you add back in the babies eliminated from consideration as they died too soon, (which I have done) the chi-square is nowhere near significance, p=0.37 with Yates correction. So this is a negative study, is it the wrong probiotic? The wrong dose? Inactive organisms? Just the expected random variation?

This particular organism, (it seems to be exactly the same, with the same DSM number) has been used before, in a retrospective cohort study fewer of the 79 babies under 1 kg who received L reuteri developed NEC than those admitted before routine use. This was a much higher risk group, with a much higher rate of NEC before initiation of probiotic prophylaxis than the control group rate in the new study. Maybe that is the difference, a lack of power of the new study, which was prospective and randomized. Oncel et al did have fewer episodes of sepsis, and like most of the studies that have reported their findings, less feeding intolerance, and shorter duration of TPN as a result.

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Your mother is the source of your microbiome

Posted on 12 February 2014 by Keith Barrington

An interesting review article from last year (free access) which discusses information from many different species, several non-mammalian, that show that, not too surprisingly, our mothers are the source of our microbiome. They speculate that the bacterial contamination of breast milk with probiotic organisms, one of the sources of that microbiome, may actually be due to the presence of an entero-mammary pathway, so the good bugs may be actual transported in lymph to the breast. There doesn’t seem much evidence for that, but it is an interesting idea: colostrum which has been collected as aseptically as possible is colonized.

I found that article following a link from a blog post by the excellent Ed Yong, he writes about other ways in which breast milk affects the microbiome, including new data which suggest that the secretory IgA in breast milk (the actual initial research article was about mice). The results of the series of projects where mice were engineered to produce breast milk without IgA showed :

Early exposure to maternal SIgA prevented the translocation of aerobic bacteria from the neonatal gut into draining lymph nodes, including the opportunistic pathogen Ochrobactrum anthropi. By the age of weaning, mice that received maternal SIgA in breast milk had a significantly different gut microbiota from mice that did not receive SIgA, and these differences were magnified when the mice reached adulthood. Early exposure to SIgA in breast milk resulted in a pattern of intestinal epithelial cell gene expression in adult mice that differed from that of mice that were not exposed to passive SIgA, (Rogier EW, et al: Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression. PNAS 2014.)

So the effects of breast milk derived IgA on the intestinal microbiome persisted into adulthood.

Another article by Ed Yong recounts the investigation of microbiomes from isolated, indigenous peoples, and shows that they seem to have much more microbial diversity and some very different patterns to what he refers to as WEIRD people, (Western Educated Industrialized Rich and Democratic) from which almost all the published data have been derived so far. So that means that almost everyone I know is weird, I thought so! Plus they got their microbiomes from their mothers, so we have something else to blame our Mums for.

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Neonatal Updates

Posted on 12 February 2014 by Keith Barrington

Hyland R, Komlósi K, Alleman B, Tolnai M, Wood L, Bell E, Ertl T: Infantile hemangiomas and retinopathy of prematurity: Clues to the regulation of vasculogenesis. Eur J Pediatr 2013, 172(6):803-809. This observational study in 3 different NICUs shows that if a preterm infant has a hemangioma, their risk of retinopathy is much higher. I’m not sure what this means, but maybe it shows differing regulation of vascular development in those babies (which I guess is exactly what the 2nd part of the title says!)

Hayakawa M, Ito M, Hattori T, Kanamori Y, Okuyama H, Inamura N, Takahashi S, Nagata K, Taguchi T, Usui N et al: Effect of hospital volume on the mortality of congenital diaphragmatic hernia in japan. Pediatrics International 2013, 55(2):190-196. Hospitals with higher volumes of diaphragmatic hernia cases have lower mortality. Regionalisation!

Vinall J, Grunau RE: Impact of repeated procedural pain-related stress in infants born very preterm. Pediatric Res 2014. Fairly brief review article about the long term effects of pain in preterm infants. Well worth the read, it hits the high points.

Bates ML, Farrell ET, Eldridge MW: Abnormal ventilatory responses in adults born prematurely. Prestigious New England Journal of Medicine 2014, 370(6):584-585. I don’t usually bother with letters, but this is actually a brief report of a research study, and it is very interesting, especially to someone with a history of doing respiratory control research. 13 VLBW newborns who were now about 21 years of age and had normal respiratory function at rest had hypoxic and hyperoxic challenges. 12 control adults born at full term were compared. The preterm born adults had very reduced hypoxic responses, some even had paradoxical respiratory depression, they also had reduced effects of hyperoxia, with smaller decreases in ventilation. The letter could have done with a bit of editing though, in the first section they talk about ‘preterm infants being treated with hyperoxia’! which is a strange thing to write. I think what they mean is that for several weeks of their early postnatal life preterm infants have much higher arterial PO2 than a fetus at the same post-menstrual age. That looks like it has a very long-lasting effect on respiratory regulation.

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Talk to me!

Posted on 12 February 2014 by Keith Barrington

A new review article and a new research publication address the same issues, the first is a thoughtful review article: (Rand K, Lahav A. Impact of the NICU environment on language deprivation in preterm infants. Acta Paediatrica. 2014;103(3):243-8.), the authors propose that one of the reasons that preterm infants have language delays is the effect of the NICU environment. Language deprivation leads to language delay. This idea is eminently reasonable, and leads to potential interventions, which have no real cost but may well have benefits.

A new article which supports this viewpoint is : Caskey M, Stephens B, Tucker R, Vohr B. Adult Talk in the NICU With Preterm Infants and Developmental Outcomes. Pediatrics. 2014. I would be the first to say (and the authors also, Betty Vohr being one of the most brilliant neonatal scientists in history) that this is far from being definitive, but it is certainly very suggestive. Preterm infants in the NICU who were exposed to more language had better language development. There are multiple possible explanations for this, but one explanation, which is consistent with the review article above, is that language exposure affects the development of language.

The implications of these findings are important because they are inexpensive and potentially dramatic. I know from personal experience that when you visit a baby in the NICU, the idea that you should talk to your baby, a little scrap of humanity that obviously doesn’t have any idea what you are saying or what your voice might convey to them, such an idea seems bizarre.

So: talk to your baby in the NICU, and when you can’t be there, let your baby listen to a recording of your voice.

When parents come into the NICU to see their critically ill babies, encouraging them to talk to their infants, whenever they are present, and leaving a recording of their voice when they are not able to be present, might have major effects on their long term language abilities. It certainly isn’t a bad idea, and might well have very long term benefits.

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Probiotics : Time for Action

Posted on 10 February 2014 by Keith Barrington

As I have noted before on this blog, our article showing the effects of the introduction of routine probiotics in our NICU has been published on-line. The Journal of Pediatrics decided to accompany it with an editorial by William Tarnow-Mordi and Roger Soll. As some of you may be aware, these 2 individuals previously wrote editorials with differing points of view about this issue, but they now both feel that routine probiotic supplementation should be instituted in at-risk infants.

I want to emphasize one point, the choice we have is not between administering exogenous organisms to high risk babies on the one hand, and leaving their intestines sterile on the other hand. The choice we have is between giving probiotics or allowing pathogen-based intestinal colonization with the flora of the NICU and then wrecking even that abnormal flora with antibiotics. Many of the criticisms of routine use of probiotics seem to assume that if we don’t give them then the gut stays in a pristine state, but we know that is not true, I am just trying to make colonization more normal.

However, there are still many unanswered questions about probiotics as prophylaxis against NEC, which need to be addressed even as we go forward:

1. It seems that lactobacilli and bifidobacteria, and various species within these genera, are effective, is there a species or mixture that is more effective than others?

2. A formulation specifically designed in single dose sachets for the NICU would be an improvement, and prevent risks of cross-contamination, is there a supplier who will produce such a formulation?

3. NEC still occurs, and can still be devastating. How can we further reduce the risks?

4. If we give antibiotics should we give booster doses of probiotics to counter the adverse effects? Indeed, is there a dose effect?

5. Should we start probiotics on day one, even if the baby is nil by mouth?

6. What are the long term effects of probiotic supplementation, compared to the usual pathogen based colonization of the bowel in unsupplemented preterm infants? The effects on asthma, colic, and the intestinal microbiome in the long term?

There is accumulating evidence about the importance of the microbiome in the adult, for example in the pathophysiology of obesity; earlier normalization of the microbiome in the very preterm infant may have effects on the development of the metabolic syndrome and other potential effects that would be really important to know, but will be extremely difficult to discover.

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Neonatal Updates

Posted on 5 February 2014 by Keith Barrington

Alderliesten T, Lemmers PMA, van Haastert IC, de Vries LS, Bonestroo HJC, Baerts W, van Bel F: Hypotension in Preterm Neonates: Low Blood Pressure Alone Does Not Affect Neurodevelopmental Outcome. The Journal of pediatrics 2014. In this observational study of very preterm infants who had recording of blood pressure and of cerebral oxygenation by NIRS, having a low BP was not related to poorer long term outcome, but having a reduced cerebral oxygenation was, regardless of the blood pressure. Should NIRS be routine in the NICU? Perhaps we should have a prospective randomized trial (Gorn Griesen has already suggested this), the big problem is, when the cerebral oxygenation is low, what should we do about it? Do we have an intervention that will reliably increase cerebral oxygen delivery?

Peterson C, Ailes E, Riehle-Colarusso T, et al.: Late detection of critical congenital heart disease among us infants: Estimation of the potential impact of proposed universal screening using pulse oximetry. JAMA Pediatrics 2014. This study estimates the number of babies that are diagnosed with critical congenital heart disease after 3 days of age, and therefore potentially could have earlier diagnosis from universal screening. Using data from the National Birth Defects Prevention Study database, they found that about 30% of such babies are not diagnosed before 3 days, in the USA.

Aliaga S, Clark RH, Laughon M, Walsh TJ, Hope WW, Benjamin DK, Kaufman D, Arrieta A, Benjamin DK, Smith PB: Changes in the Incidence of Candidiasis in Neonatal Intensive Care Units. Pediatrics 2014, 133(2):236-242. Invasive Candidiasis appears to be getting less frequent in the Pediatrix NICUs. The reason may be related to their other findings, the increased use of fluconazole prophylaxis, and the reduced use of broad spectrum antibiotics in at risk patients.

Tracy MB, Shah D, Hinder M, Klimek J, Marceau J, Wright A: Mask leak increases and minute ventilation decreases when chest compressions are added to bag ventilation in a neonatal manikin model. Acta Paediatrica 2014 It is difficult to maintain adequate ventilation by face mask once you start doing cardiac massage. Facemask leaks increase and ventilation falls substantially. What to do? Maybe we should always intubate if we do cardiac massage, or find other ways to maintain ventilation.

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If massage is so good, how come the research is so bad?

Posted on 5 February 2014 by Keith Barrington

I think its likely that massage therapy for the preterm infant has some benefits, unfortunately much of the research is under-powered, badly designed, inappropriately analyzed and overinterpreted.

A case in point is a new study in Early Human Development, which is rapidly becoming the neonatology journal with the worst editorial standards. After previously publishing an article where infants were enrolled and received their intervention before they could be eligible (see below), and more recently publishing extensive corrections that should have been picked up before publication, they now have an article that doesn’t understand the difference between calorie intake and calorie consumption, that has no proper control group, and that shows no understanding regarding normal growth curves in preterm infants. It even manages to present the correlation coefficient between percentage daily weight gain, and actual daily weight gain (surprisingly it was 0.99!! Which was significant!! More than one exclamation mark usually means I am being sarcastic.)

In this study 30 babies were randomized to either get massage therapy or ‘exercise’ that is passive flexion and extension of the limbs. After a 2 day baseline observation period the infants had 5 days of the assigned therapy. Subjects were 28 to 32 weeks, more than 15 days old, were medically stable and were all getting infant formula. As you can see at baseline the infants were not getting enough calories (only about 110 kcal/kg/day on average) and were as a consequence growing poorly (about 11 g/kg/day). The babies actually enrolled were on average 29 weeks at birth and about 30 days old. So according to Fenton’s revised charts they should have been gaining about 37 g a day, or round about 20 g/kg/d, and the actual weight gain at that postnatal age should be slightly increasing every day, so a study without controls would be expected to show an increase in weight gain over a few days.

This study showed that both groups increased their weight gain from before the intervention to the followup, and there was no difference between the groups. So in other words, there is no evidence of any effect of either intervention. Only if there had been a 3rd group, with no extra intervention and only if the nutritional intake was regulated by the study, could you say if there was an effect of one intervention or the other on weight gain. You must also not confuse calorie intake with calorie consumption. The investigators calculated calorie intake, but did nothing to measure consumption (bomb calorimetry on the stools, oxygen consumption, stable isotope techniques etc) which doesn’t stop them making dumb comments about how massage might affect calorie consumption. Of course babies like the ones they studied don’t even regulate their own calorie intake, the medical and nursing staff decide how much milk they will get, and therefore their calorie intake.

Their title ‘Preterm infant weight gain is increased by massage therapy and exercise via different underlying mechanisms’ shows how badly they have misinterpreted their results, and how poor a job the referees have done on this article. The title could have been ‘no evidence of effect of either massage therapy or exercise on weight gain’. The ‘mechanism’ that they refer to is derived from an analysis of the ECG which the authors state showed evidence of an increase in vagal activity.

Now it is possible that massage therapy does indeed have some benefits, but studies like this one give us no evidence of that.

Any attentive readers may remember the study that I mention at the beginning of this post which I wrote about in a post nearly a year ago, that article was so badly written, and poorly refereed that it made absolutely no sense. Infants were randomized at 34.5 weeks, but were only eligible if they were off oxygen by 36 weeks and discharged before 42 weeks, BPD was used as an outcome measure, but was also an exclusion criterion, and so on. I wrote to the editor of my concerns, and received an email back, not from the editor but from the publishers who asked me to submit a letter on their website. I did so, and the letter is, at last check, still with the editors. No response, of any kind, from the editor or from the authors. I presume this means that someone is too embarrassed to reply, but I think the readers of that journal deserve a response.

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