Neonatal Updates

Posted on 22 May 2014 by Keith Barrington

Dardas M, Gill SR, Grier A, Pryhuber GS, Gill AL, Lee Y-H, et al. The Impact of Postnatal Antibiotics on the Preterm Intestinal Microbiome. Pediatr Res. 2014. It will be no surprise to readers of this blog that antibiotics are bad for your bugs, and not just the ones that you don’t want. This study of postnatal development of the intestinal microbiome took samples at 10 days and 30 days in very preterm infants. They show that babies that received more than 7 days of antibiotics, compared to those who received only 2 days, had reduced diversity in their intestinal flora. Reduced diversity has been linked to the development of NEC in some studies.

Victor S, McKeering CM, Roberts SA, Fullwood C, Gaydecki PA. Effect of permissive hypercapnia on background cerebral electrical activity in premature babies. Pediatr Res. 2014. Higher CO2 had little effect on EEG activity in this study, there may have been an increase in delta activity with higher CO2, but as the authors tested many correlations of different aspects of the EEG, his may have been spurious, as they acknowledge.

Czaba-Hnizdo C, Olischar M, Rona Z, Weninger M, Berger A, Klebermass-Schrehof K. Amplitude-integrated electroencephalography shows that doxapram influences the brain activity of preterm infants. Acta Paediatrica. 2014. As I started my research career studying doxapram I have stayed interested, even though it is no longer available in Canada. The results of this study are quite are concerning, an increase in continuous background activity, and a major increase in seizure like episodes was seen on aEEG monitoring of preterm babies receiving doxapram. Both compared to the same babies when not receiving doxapram, and compared to similar control babies. At first I wondered if they had used a high dose, as we used to think that low doses affect the peripheral chemoreceptor and higher doses had a direct CNS stimulant effect, but the dose they used, of 0.5 to 1 mg/kg/h was what we devised from pharmacokinetic studies years ago. So it doesn’t seem too high. The electrical seizure like activity disappeared after the doxapram was stopped. You can’t be 100% definite about seizures from an aEEG it is possible, I guess, that doxapram induces EEG changes that look like seizures on the EEG but are really some other phenomenon, but maybe its a good thing that I can’t prescribe it any more!

Vendettuoli V, Bellù R, Zanini R, Mosca F, Gagliardi L, Italian Neonatal Network. Changes in ventilator strategies and outcomes in preterm infants. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014. This study of data from the Italian database compared interventions and outcomes in 2006 and 2010. Despite similar babies, fewer babies had invasive ventilation, more received non-invasive ventilation, and the outcomes of mortality and combined mortality and BPD were reduced.

Chollat C, Enser M, Houivet E, Provost D, Bénichou J, Marpeau L, et al. School-Age Outcomes following a Randomized Controlled Trial of Magnesium Sulfate for Neuroprotection of Preterm Infants. The Journal of pediatrics. 2014. Follow up to an average of 11 years of children who had been enrolled in the French antenatal magnesium for neuroprotection study. About 73% of the surviving subjects were seen in follow-up, n=431. Most of the outcomes were a little better in the magnesium exposed group, although there was nothing that could not easily have been due to chance. I think this is re-assuring.

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All trials reported, all results available

Posted on 20 May 2014 by Keith Barrington

The ‘All trials’ campaign is picking up steam, a new video is embedded below. I think the inclusion of a patient volunteer was a great idea, the altruistic aspect of consent for clinical trials, and the betrayal of that altruism when a trial is not published, are so important in this campaign. All those parents who consented for their children, thinking that medical science would be advanced by their participation are being betrayed.

Please follow the link and sign the petition.

 

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Probiotics in preterm infants: not just for NEC prevention any more

Posted on 20 May 2014 by Keith Barrington

A new RCT in more mature preterm infants 32 to 37 weeks compared the incidence of viral respiratory infections during the first year of life between infants who received prebiotics (galacto-oligosaccharide and polydextrose) probiotics (lactobacillus rhamnosus) or placebo between the 3rd and the 60th days of life.  Luoto R, Ruuskanen O, Waris M, Kalliomaki M, Salminen S, Isolauri E. Prebiotic and probiotic supplementation prevents rhinovirus infections in preterm infants: a randomized, placebo-controlled trial. The Journal of allergy and clinical immunology. 2014;133(2):405-13.

There were only just over 20 in each group that completed the follow up period, but there was a significant reduction in total respiratory infections, and particularly in rhinovirus infections. The prebiotic group did better than the probiotic group, but both had a significant reduction in rhinovirus and overall respiratory infections than the controls, over the first year of life.

The authors include a systematic review of previous studies in the discussion, of either prebiotics or probiotics or both: of the 7 previous studies (in full term infants) 5 have shown a reduction in respiratory infections, for some reason 3 of the previous studies were from Finland, including the largest which had 1000 babies enrolled (and showed a reduction in respiratory infections).

Maybe we shouldn’t be limiting our probiotics to just the early preterms, the late preterms may have advantages too!

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Hero: Not just for infections any more

Posted on 15 May 2014 by Keith Barrington

Sullivan BA, Grice SM, Lake DE, Moorman JR, Fairchild KD. Infection and Other Clinical Correlates of Abnormal Heart Rate Characteristics in Preterm Infants. The Journal of pediatrics. 2014. Monitoring for abnormal heart rate characteristics has previously been shown in a randomized trial to reduce mortality. Infants who are developing sepsis have a reduced baseline heart rate variability with more episodic decelerations, leading to earlier detection and treatment.  This new study looked at other clinical complications which were associated with an increase in the score that the monitor calculates. A spike in the score to more than 3 above the previous 5 days average was associated with  noted. The score relates to the relative risk of developing sepsis in the next 24 hours. In addition to sepsis, increases in the score were seen within 24 hours of sepsis, with urinary tract infections, with necrotising enterocolitis, and with respiratory deteriorations (a 50% increase in apneas, O2 needs and/or ventilatory requirements). They also increased after surgery.

So if (or when) you have this technology, you can be a bit skeptical if the baby just had surgery, and make sure you evaluate for NEC and UTI as well as sepsis.

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Poietins for the brain?

Posted on 14 May 2014 by Keith Barrington

Ohls RK, Kamath-Rayne BD, Christensen RD, Wiedmeier SE, Rosenberg A, Fuller J, et al. Cognitive Outcomes of Preterm Infants Randomized to Darbepoetin, Erythropoietin, or Placebo. Pediatrics. 2014. I’ve written about this trial before, a smallish 3 arm trial of erythropoietin, darbepoietin and placebo. About 100 babies 500 to 1250 g birth weight were randomized before 48 h of age. Eighty were followed up at 18 to 22 months, with Bayley 3 evaluations and neurological exams. The Bayley cognitive scores were higher, and the language scores a bit higher , and there were fewer babies with cerebral palsy in the 2 poietin groups compared to placebo.

If you remember from the original publication there were fewer transfusions in the poeitin groups, as you might expect, and fewer donor exposures per patient. Darbepoietin being longer acting, could be given less frequently, so the babies had fewer injections.

This new trial doesn’t show any increase in the risk of retinopathy with either of these therapies, but it is of course quite underpowered for that outcome.

The 3 Cochrane Reviews authored by Arne Ohlsson and Sanjay Aher (Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane database of systematic reviews (Online). Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane database of systematic reviews (Online); Aher SM, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane database of systematic reviews (Online).) divided the trials into those that started in the first week, and those that started later. They have very recently been updated (in April).

As noted in the discussion of this new trial, the updated Cochrane Review of the early use studies no longer show a statistically significant effect on serious RoP, typical RR 1.37, 95% CI 0.87 to 2.17; I2 = 0%; typical RD 0.03, 95% CI -0.01 to 0.06; I2 = 29%; 7 studies, 801 infants. (the previous version of the review did suggest an increase). But when they put all the trials together (early and late) there was a statistically significant increase. 

A post hoc analysis including all studies that reported on ROP stage ≥ 3, regardless of the age of the infant when EPO treatment was started, showed a significantly increased typical RR of 1.48 (95% CI 1.02 to 2.13; P = 0.04; I2 = 0%) and typical RD of 0.03 (95% CI 0.00 to 0.06; P = 0.03; I2 = 50%; 10 studies, 1303 infants) with a number needed to treat to harm (NNTH) of 33 (95% CI 17 to infinity)

This may be unreliable information, not all the studies reported stage 3 RoP, not all the studies were masked, and multiple small studies can sometimes be misleading (the average sample size as you can see is only 130 babies per study). But it is a risk that needs to be fully evaluated.

So the new trial is very interesting for long term outcomes, but it too may be misleading, with only 24 controls it could just be chance that they had a mean Bayley3 cognitive score of 88, and 5 cases of CP. If these effects are real, this has the potential to really improve outcomes of small preterms: a much larger trial is needed.

 

 

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Funny shaped heads? You can take the helmet off now.

Posted on 13 May 2014 by Keith Barrington

I often see kids around my hospital wearing orthotic helmets, designed to make their heads more round (some of them ex-preterms), and I often wondered if they really work. A new RCT from the Netherlands shows no effect . Renske MvW, Leo AvV, Catharina GMG-O, Catharina PBVdP, Maarten JI, Magda MB-B. Helmet therapy in infants with positional skull deformation: randomised controlled trial. BMJ. 2014;348. A multicenter RCT randomized 84 infants to helmet or no helmet. No differences in the outcomes were found at 24 months of age on a blinded evaluation. The improvement scores in the 2 groups were identical and about 1/4 of infants had ‘complete recovery’ in each group.

The inimitable Richard Lehmann discusses the article on his blog; as he notes :

 The investigators argue that this shows that helmets are a useless encumbrance. They cannot be the “helmet of salvation” famously alluded to by St Paul the Apostle. Ah, but not so fast, reply the advocates of baby headwear in the Rapid Responses. Can you guess their arguments? Yes, that this study proves that skull deformities persist, so more not fewer treatments are need. Parents should flock to clinics like their own to be assured of better fitting-helmets. And the helmets need to be fitted in the first weeks of life. You have this on the authority of (inter alia) Timothy R Littlefield , MSEng, Vice President, Research and Regulatory Affairs, Cranial Technologies, Inc., Tempe, Arizona, USA.

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Neonatal Updates

Posted on 12 May 2014 by Keith Barrington

Lipstein EA, Dodds CM, Britto MT. Real Life Clinic Visits Do Not Match the Ideals of Shared Decision Making. The Journal of pediatrics. 2014. The investigators video-taped discussion of higher risk interventions for chronic conditions (juvenile rheumatoid arthritis and inflammatory bowel disease). The ideals of shared decision making were rarely explicitly achieved.

 Detailed information was typically given about the provider’s preferred option with less information about other options. There was minimal elicitation of preferences, treatment goals, or prior knowledge. Few parents or patients spontaneously stated their preferences or concerns. An implicit or explicit treatment recommendation was given in nearly all visits, although rarely requested. In approximately one-third of the visits, the treatment decision was never made explicit, yet steps were taken to implement the provider’s preferred treatment

There certainly were several limitations in the way the interactions took place, the preferences of the families were never explored, and there was almost no real evaluation of the family’s understanding. We are maybe fortunate, when we are taking life and death decisions about newborn babies, that we are usually able to make time to explore the desires and values of parents. I like to think that the decision which is taken is truly a shared decision, where we work together to find the best option for the particular situation; but I don’t know if a video-tape analysis would always give me high scores!

Schneider LA, Burns NR, Giles LC, Higgins RD, Nettelbeck TJ, Ridding MC, et al. Cognitive Abilities in Preterm and Term-Born Adolescents. The Journal of Pediatrics. 2014. In addition to neuropsych testing these adolescents had transcranial stimulation to measure the excitability of their brains. There were only minor differences between preterm and term born adolescents. ‘Corticomotor excitability explained a higher proportion of the variance in cognitive outcome than GA. But the strongest predictors of cognitive outcome were combinations of prenatal and postnatal factors, particularly degree of social disadvantage at the time of birth, birthweight percentile, and height at assessment.’

Saleemi MS, El-Khuffash A, Franklin O, Corcoran JD. Serial changes in myocardial function in preterm infants over a four week period: the effect of gestational age at birth. Early Hum Dev. 2014.

Eriksen BH, Nestaas E, Hole T, Liestol K, Stoylen A, Fugelseth D. Myocardial function in term and preterm infants. Influence of heart size, gestational age and postnatal maturation. Early Hum Dev. 2014. Two very nice studies with repeated measures on echo of myocardial function that show the effects of maturation and postnatal age.

Di Tommaso M, Seravalli V, Martini I, La Torre P, Dani C. Blood gas values in clamped and unclamped umbilical cord at birth. Early Hum Dev. 2014. Going towards delayed cord clamping raises a number of questions, such as what to do about cord blood gases? This study suggests that gases taken from unclamped cords are very similar to measures taken after clamping, but they didn’t have many that were very abnormal, the results all being within a narrow range.

Broom M, Ying L, Wright A, Stewart A, Abdel-Latif ME, Shadbolt B, et al. CeasIng Cpap At standarD criteriA (CICADA): impact on weight gain, time to full feeds and caffeine use. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014. You may remember this randomized controlled trial comparing ways of stopping CPAP, just stopping it compared to stopping and restarting again at intervals that get longer. This secondary analysis of some data from the trial shows that the babies tolerated their feeds equally in the 3 groups in the trial, had similar weight gain, and the babies who were in the immediate stopping group came off their caffeine earlier.

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Prophylactic fluconazole works; but we shouldn’t use it?

Posted on 6 May 2014 by Keith Barrington

A new high quality multicenter RCT examined the effects of fluconazole prophylaxis in about 360 very tiny babies (VTB), that is they weighed less than 750g at birth. They were enrolled in the first 5 days of life to fluconazole prophylaxis or placebo. It was given iv or po twice a week until 42 days of age. Primary outcome was death or invasive candidiasis, with definitions given for definite and probable disease, which look very appropriate, which is as I would expect given that the PI of the study is Danny Benjamin, the authority on neonatal candidiasis, (Benjamin DK, , et al. Effect of Fluconazole Prophylaxis on Candidiasis and Mortality in Premature Infants. JAMA. 2014;311(17):1742).

The study primary outcome was less frequent in the active treatment group, but the difference could have been due to chance (p=0.24), 21% placebo and 16% fluconazole. Invasive candidiasis was reduced from 9% to 3% during the treatment period and from 11% to 4% prior to discharge, both of which reductions are unlikely to be due to chance (p < 0.02). There were no appreciable toxicities.

So what should be the conclusion? I would suggest that the conclusion as it is published is scientifically accurate, but only partially true.

Fluconazole ‘did not result in a lower incidence of the composite of death or invasive candidiasis.’

The conclusion does not state, as I think it should, fluconazole greatly reduces the incidence of invasive candidiasis, but this reduction did not lead to a reduction in mortality. (Which was 14% in each group, confidence intervals for death between -7% and +7%).

I think this wording difference could be important, and I will try and explain why.

Control group mortality was 14%, with an incidence of invasive Candida of 9%. Let’s assume that during planning of the study these numbers in these 32 NICUs were similar, and that fluconazole was expected to reduce invasive candidiasis by 2/3, without adverse effects on other serious outcomes that would increase mortality. Previous data show a mortality among VTBs who develop Candidiasis of around 30%. So we can calculate that among infants without candidiasis the mortality is 12%, to give an overall mortality of 14%. If the only effect of fluconazole is the reduction in candidiasis, then we might expect the intervention group mortality to be reduced to 12.5%.

The combined outcome of death and invasive candidiasis would then be expected to fall from 20% to 15%. (Which is in fact almost exactly what the study actually showed!) That would be: 11 deaths in the 91 of the 100 enrolled control infants who did not get candida plus 9 cases of candida, compared to 12 deaths in the 97 per 100 enrolled fluconazole infants who did not get candidiasis plus 3 cases of candida.

Which means that the study was actually quite underpowered, for that combined outcome, if the only expected result was a reduction in candidiasis and its associated mortality.

A really important feature of this study was a high quality follow up component. There was no real difference in any 18 to 22 month outcomes, either in neurological outcomes or Bayley 3 scores.

If you were to do the same exercise for these long term outcomes as for the ‘death or candidiasis’ outcome, it would also show that the study was underpowered to test the hypothesis that the only effect of fluconazole was to reduce candidiasis and the neurodevelopmental impairment that goes with it.

That certainly does not mean that these results aren’t important. We did need to know that fluconazole doesn’t have serious adverse effects, or have adverse effects on long term neurologic or developmental outcomes. We can now be reasonably confident that that is the case.

The final sentence of the abstract, states ‘These findings do not support the universal use of prophylactic fluconazole in extremely low-birth-weight infants.’ Again I am not sure that I agree entirely with that: if ‘universal’ use of prophylactic fluconazole reduces invasive candidiasis without harm, why not?

The article also suggests that fluconazole could perhaps be considered in NICUs with a high incidence. But why not, rather, in infants with risk factors that lead to a high incidence?

This is a significant issue in therapies used as prophylaxis of a complication which is relatively uncommon, if there is a small risk of harm, then patients who receive the prophylaxis who would not have developed the complication only have potential for risk and not benefit, and patients who would have developed the complication may have major benefit. But if we cannot identify those who are at risk, then we have to determine overall whether the prophylactic treatment is worthwhile.

One thing I would like to see from this study is an analysis of risk factors, in this same cohort, and also the timing of those risk factors and the onset of candidiasis. I think based on all the data that we have, that a reasonable approach would be to use prophylaxis for VTBs at increased risk, perhaps limited to those periods of high risk, such as when on broad spectrum antibiotics, when central lines and TPN are being used, and/or when on steroids.

That to me would be more rational than using prophylaxis in all infants in high incidence units, and not in low risk units, to use it during periods of high risk, and not during periods of low risk.

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High Frequency Ventilation and long term pulmonary outcomes

Posted on 6 May 2014 by Keith Barrington

The UK Oscillation study (UKOS) was a large multicenter trial in the UK of high-frequency compared to conventional ventilation; 800 babies <29 weeks gestation were randomized, if they were intubated from birth and were less than 1 hour old, to HFO or conventional ventilation. The study basically showed no differences in anything in terms of clinical outcomes. Mortality and BPD were almost identical in the 2 groups, sub-groups were the same, and secondary outcomes were also not different. Six hundred babies survived, and most were followed up for some short/moderate term outcomes, which were also not different.

A new publication from the group reports the very long term pulmonary outcomes of 320 of those (nearly 600) survivors, who were seen at 11 to 14 years of age. 240 of them had pulmonary function testing. Many aspects of pulmonary function were better in the HFO group compared to the conventional group; including the FEF50, The FEV, the PEF, the DLco, and the lung resistance. Functional/educational outcomes were mostly the same between groups with none being worse with HFO.

The major limitation of the study is, obviously, the losses to follow up, relatively small advantages of conventional ventilation among the infants not followed would completely wipe out these differences, so we need to be very careful in interpreting these results. However, it certainly suggests that very long term pulmonary outcomes from the 2 types of ventilator approaches show no major disadvantage of high frequency, and it may have an advantage.

How could long term outcome be better if there wasn’t any improvement in BPD? I think the answer to this question, in part, has to do with diagnostic categories, and how we define outcomes. Lung injuries in preterm babies are a continuum, from none to profound: division into BPD/Not BPD is entirely arbitrary as far as clinical outcomes in the long term are concerned. 36 weeks of oxygen requirement was chosen as a cut-off in Andy Shennan’s cohort, because it was more closely associated with having adverse respiratory outcomes (which included symptoms at discharge, O2 at term, readmission for respiratory problems etc) than did O2 need at 28 days. The definition was not intended to predict extremely long term outcomes; and even though we now also have the refinement suggested by Bancalari and Jobe, that is into categories of mild, moderate, and severe, there is still no good data about whether the division into moderate or severe is a better discriminant of very long term pulmonary outcomes.

Certainly this study (with the limitations of possible bias introduced by ‘low’ follow up percentage) suggests that HFO might reduce lung injury, even though there was no effect on which babies are classified as being BPD (compared to being Not BPD). I think, however, that it is not surprising that that permanent structural/vascular impacts on the very preterm lung are not accurately predicted by something as simplistic as oxygen requirements at 36 weeks. Other indices of lung injury might be much more useful than just deciding yes/no on the diagnosis of BPD, based on need for oxygen.

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Annual PAS meeting

Posted on 6 May 2014 by Keith Barrington

Just home after an extremely busy, as usual, PAS meeting In Vancouver.

Please sir, can I be excused, my brain is full.

I will blog a bit about it in the next few days, in the mean time, I will post a few things that I have been slowly developing during the meeting and on the way home.

Coal Harbour is a beautiful spot, or at least it used to be, the unfettered construction of condos and high rises have made it into something much less than it was.

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