More Doubts about BOOSTing saturations?

Posted on 22 February 2016 by Keith Barrington

As I just mentioned I received another thoughtful comment from Reese Clark, which I reproduce in its entirety below:

“After re-reading my post and at the risk of being a bit redundant with what Dr Barrington has already carefully presented – I offer a bit more thoughtful comment

  1. Oxygen is a toxic drug and it should be used and monitored with great caution.1-6
  2. Results of clinical trials are always important and they offer important information. The interpretation of the results can be wrong.
  3. Narrowing oxygen targets/limits increases the frequency of alarms and we begin to ignore alarms (especially the high alarms), and that is a mistake.
  4. We manage the high end; the baby more often determines the low end. We can make a baby have a 100% oxygen saturation. Providing oxygen treatment to an infant who is not breathing will not make their oxygen saturation better.
  5. Our “therapeutic response” to pulse oximeter alarms is likely to be more important than the limits/targets themselves.
  6. We may have studied the wrong thing in the wrong way. Schmidt et al7 showed “Caregivers maintained saturations at lower displayed values in the higher than in the lower target group. This differential management reduced the separation between the median true saturations in the 2 groups by approximately 3.5%”. Thus “the design of the oximeter masking algorithm may have contributed to the smaller-than-expected separation between true saturations …” If the differences in the two study groups is small, how can we attribute any outcome to one group or the other.
  7. The mortality finding is small and confounded by site of care and revision of the pulse oximeter algorithm. To reproduce the results in another prospective study would be hard. Site variation in mortality is greater than the mortality findings in any of the pulse oximeter studies.8, 9
  8. We need to see outcomes by site in order to understand the overall results. What if one or two sites drove the overall findings? For sure we can say New Zealand reports different results from the UK.
  9. A total of 2448 infants were enrolled in the three trials (973 in the United Kingdom, 1135 in Australia, and 340 in New Zealand). In combined data, there was no significant difference in rate of death in the lower-target group, as compared with the higher-target group (19.2% vs. 16.6%; relative risk, 1.16, 95% CI, 0.98 to 1.37; P = 0.09). Note that the mortality in the NZ cohort was lower and in the opposite direction of the combined data.10
  10. We now have 2 year follow-up data. Data from New Zealand11 follow up at 2 years shows death or major disability at 2 years’ is lower in the low oxygen group compared to the high oxygen group (Death or major disability 65/167 (38.9) in the lower target group; 76/168 (45.2) in the higher target group).  The relative risk of a bad outcome was higher in the high oxygen group RR=1.15 (0.90-1.47); p=0.26. Death occurred in 25 (14.7%) and 27 (15.9%) of those randomized to the lower and higher target, respectively, and blindness in 0% and 0.7%. These data do not support the concept that high oxygen saturations promote better outcomes or that low oxygen targets promote worse outcomes.
  11. But now, the data from the UK and Australia are reported and show use of an oxygen-saturation target range of 85 to 89% versus 91 to 95% resulted in nonsignificantly higher rates of death or disability at 2 years in each trial, but significantly increased risks of this combined outcome and of death alone in post hoc combined analyses.12 In post hoc combined, unadjusted analyses that included all oximeters, death or disability occurred in 492 of 1022 infants (48.1%) in the lower-target group versus 437 of 1013 infants (43.1%) in the higher-target group (relative risk, 1.11; 95% CI, 1.01 to 1.23; P=0.02). Death occurred in 222 of 1045 infants (21.2%) in the lower-target group versus 185 of 1045 infants (17.7%) in the higher-target group (relative risk, 1.20; 95% CI, 1.01 to 1.43; P=0.04).” Note the mortality rates are higher here than reported in the NZ data.
  12. Again, where a premature infant is born is as important as any specific therapy that you receive.13-15
  13. Carlo et al16 astutely pointed out that during the SUPPORT trial “The infants in both treatment groups had lower rates of death before discharge (16.2% in the higher-oxygen-saturation group and 19.9% in the lower-oxygen-saturation group), than did those who were not enrolled (24.1%) and historical controls (23.1%), and rates of blindness (even though severe ROP decreased) did not differ between the treatment groups.” Therefore, being in the study and in the lower-oxygen-saturation group was associated with improved outcomes (4.2 percent less mortality in patients in the lower-oxygen-saturation group to non-enrolled patients. There was only a 3.7% between group difference in SUPPORT study patients)
  14. STOP ROP – Use of supplemental oxygen at pulse oximetry saturations of 96% to 99% did not cause additional progression of pre-threshold ROP, but also did not significantly reduce the number of infants requiring peripheral ablative surgery. A subgroup analysis suggested a benefit of supplemental oxygen among infants who have pre-threshold ROP without plus disease, however, this finding requires additional study.  Supplemental oxygen increased the risk of adverse pulmonary events, including pneumonia and/or exacerbations of chronic lung disease and the need for oxygen, diuretics, and hospitalization at 3 months of corrected age.17
  15. If you are not confused; worry.

Reference List

  1. Gandhi B, Rich W, Finer N. Achieving Targeted Pulse Oximetry Values in Preterm Infants in the Delivery Room. J Pediatr 2013;(13):10.
  2. Dawson JA, Vento M, Finer NN et al. Managing oxygen therapy during delivery room stabilization of preterm infants. J Pediatr 2012;160(1):158-161.
  3. Vaucher YE, Peralta-Carcelen M, Finer NN et al. Neurodevelopmental outcomes in the early CPAP and pulse oximetry trial. N Engl J Med 2012;367(26):2495-2504.
  4. Dawson JA, Vento M, Finer NN et al. Managing Oxygen Therapy during Delivery Room Stabilization of Preterm Infants. J Pediatr 2011.
  5. Vento M, Saugstad OD. Oxygen supplementation in the delivery room: updated information. J Pediatr 2011;158(2 Suppl):e5-e7.
  6. Vento M. Tailoring oxygen needs of extremely low birth weight infants in the delivery room. Neonatology 2011;99(4):342-348.
  7. Schmidt B, Roberts RS, Whyte RK et al. Impact of study oximeter masking algorithm on titration of oxygen therapy in the canadian oxygen trial. J Pediatr 2014;165(4):666-671.
  8. Smith PB, Ambalavanan N, Li L et al. Approach to Infants Born at 22 to 24 Weeks Gestation: Relationship to Outcomes of More-Mature Infants. Pediatrics 2012.
  9. Alleman BW, Bell EF, Li L et al. Individual and center-level factors affecting mortality among extremely low birth weight infants. Pediatrics 2013;132(1):e175-e184.
  10. The BOOST II United Kingdom AaNZCG. Oxygen Saturation and Outcomes in Preterm Infants. New England Journal of Medicine 2013.
  11. Darlow BA, Marschner SL, Donoghoe M et al. Randomized Controlled Trial of Oxygen Saturation Targets in Very Preterm Infants: Two Year Outcomes. The Journal of pediatrics . 2-21-2014.
  12. Manley BJ, Kuschel CA, Elder JE, Doyle LW, Davis PG. Higher Rates of Retinopathy of Prematurity after Increasing Oxygen Saturation Targets for Very Preterm Infants: Experience in a Single Center. J Pediatr 2016;168:242-244.
  13. Rysavy MA, Li L, Bell EF et al. Between-hospital variation in treatment and outcomes in extremely preterm infants. N Engl J Med 2015;372(19):1801-1811.
  14. Alleman BW, Bell EF, Li L et al. Individual and center-level factors affecting mortality among extremely low birth weight infants. Pediatrics 2013;132(1):e175-e184.
  15. Smith PB, Ambalavanan N, Li L et al. Approach to infants born at 22 to 24 weeks’ gestation: relationship to outcomes of more-mature infants. Pediatrics 2012;129(6):e1508-e1516.
  16. Carlo WA, Bell EF, Walsh MC. Oxygen-saturation targets in extremely preterm infants. N Engl J Med 2013;368(20):1949-1950.
  17. The STOP-ROP Multicenter Study Group. Supplemental Therapeutic Oxygen for Prethreshold Retinopathy Of Prematurity (STOP-ROP), a randomized, controlled trial. I: primary outcomes. Pediatrics 2000;105(2):295-310.”

Thanks very much for this Reese. I think you make some important points, I’ll be posting another response very soon!

 

 

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Doubts about BOOSTING saturations?

Posted on 22 February 2016 by Keith Barrington

I received a very thoughtful comment from Reese Clark, who many of you will know as a leader in neonatology whose many years of experience and important scientific contributions to neonatology make him someone worth listening to.

He has doubts about the reliability of the BOOSTII results, and therefore about the oxygen saturation target ranges that should be used. He notes 2 things, that mortality was getting better during the period that lower saturations were being introduced, and he refers to the meta-analysis by Manja et al. (Manja V, et al. Oxygen saturation target range for extremely preterm infants: A systematic review and meta-analysis. JAMA Pediatrics. 2015;169(4):332-40.)

I will refer to the systematic review first, because I didn’t comment on it when it was first published:

The systematic review by Manja, in fact, showed that death before hospital discharge was significantly increased by targeting low oxygen saturations, and that necrotizing enterocolitis was also increased. They downgraded the quality of evidence using, they stated, the GRADE criteria. But some of their reasons given for downgrading the evidence are bizarre, and not consistent with those guidelines at all.

For each of the outcomes they give these two reasons for downgrading them:

c. The pulse oximeter algorithm was modified midway through the study owing to a calibration correction, and this caused a deviation from SpO2 values.

d. The separation of SpO2 values obtained was not as planned in the study design/protocol. The median SpO2 value in the restricted arm (planned SpO2 of 85%-89%) was higher than 90% in some studies (Figure 1).

c. I don’t see how the change in the calibration would lead to downgrading the evidence, the trials were carried out as designed, and, when the calibration error was discovered, this was noted so that the analyses could take this into account if need be. It also is not entirely true. There was no oximeter calibration change in SUPPORT or in BOOSTII-NZ.

d. This is just not true. The separation of SpO2 values actually obtained was not part of the study protocol. The protocol was to compare the saturation target ranges, not the saturations actually achieved. This is like saying a trial of an anti-hypertension drug is lower quality because the blood pressure was not lowered as much as expected. IF you still see a significant difference in outcomes, despite the intervention being less successful than planned, isn’t that a major red flag?

Two other reasons for downgrading the evidence for the outcome “death before hospital discharge” are given as:

e. This was not a prespecified outcome in the Benefits of Oxygen Saturation Targeting II trial, which was prematurely stopped because of this outcome.

f. Only 4 of the 5 eligible trials reported on the outcome of death before hospital discharge (the Canadian Oxygen Trial group did not).

e. This is evidence of good research practice. If children are dying more in one arm of a trial than another, by a highly statistically significant (more than 3 standard deviations) degree, then to wait another 2 years, allowing continued enrollment, would be a criminally unethical thing to do. I addition there are very few deaths between discharge and two years, so the difference is likely to remain.

f. Why should this lead to downgrading the evidence? It is the quality of the included trials for each outcome that is important, not whether all trials reported the outcome.

At the time the Manja paper was published there were data regarding mortality at 24 months from 3 of the trials (SUPPORT, COT and BOOST-NZ). Mortality was increased by 16%, or in absolute terms, by 27 per 1000 infants, with the lower saturation target. This was not statistically significant (but not far off, 95% confidence intervals from 0.98-1.37), this evidence was downgraded to “moderate” quality for reasons c and d above. The new results from the BOOST-II studies show a relative increase in mortality of 20%, and an absolute risk difference of 35 per 1000 infants (all oximeters combined). Which is remarkably close to the pooled results from the previous studies.

To return to the first issue in the new comment, i.e. the fact that survival was improving during the period that lower saturations were being sporadically and inconsistently introduced. I think this is really questionable as evidence of the impact of lower saturation targets. It may be that survival was improving despite the lowering of saturation targets; in fact I think that a lot of the improved survival was due to changes in obstetrical attitudes and interventions, extremely preterm babies are often delivered in much better condition these days than they used to be. The only way to answer reliably the question of the impact of saturation targeting practices is to perform the kind of large RCTs that we have performed.

I don’t see any other way of interpreting these data than to admit that lower saturation targets lead to higher mortality from a variety of causes, as well as an increase in necrotizing enterocolitis. We might not like it (I don’t like it) but I can’t see any other valid explanation of this weight of evidence from high quality trials enrolling 5000 infants.

Reese Clark has now sent me some more interesting comments which I will put in the next post, and then discuss, probably in a third post.

 

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Do Clinical Guidelines make a difference?

Posted on 17 February 2016 by Keith Barrington

The question in the title is hard to answer, without a randomized controlled trial of some kind where the guidelines are followed in one group, and not in another. The whole point of most guidelines, though, is to put the best available evidence into a clinical pathway to be followed, so an RCT would have to randomize half the patients to not follow best practice, which would be ethically questionable.

Another way of evaluating their impact is to perform other types of studies, less scientifically convincing, but often the best that can feasibly be done.

In 2007, while I was chair of the Fetus and Newborn Committee, we produced a guideline on screening and management of hyperbilirubinemia.  As most readers will know, jaundice in newborns is very frequent, almost always short-lived and benign, and frequently treated with phototherapy. Severe hyperbilirubinemia leading to neurological damage is very rare, but potentially avoidable. In 2006 Micheal Sgro and colleagues published data from the Canadian Paediatric Surveillance System (babies born in 2002-2004) that 1 infant per 2480 births developed severe jaundice (peak bili more than 425  micromol/L or an exchange transfusion); they also showed that 12% if them had acute neurological findings. From a different project investigating cases born in 2007 and 2008 they estimated that 1 in 44,000 births the baby had developed chronic bilirubin encephalopathy.

They have now repeated the earlier CPSP study: Sgro M, et al. Severe Neonatal Hyperbilirubinemia Decreased after the 2007 Canadian Guidelines. The Journal of pediatrics. 2016.  In the new report there were 91 cases of severe hyperbilirubinemia country-wide, for a calculated incidence of 1 in 8600. One third of the previous incidence. This good news may, I would like to think, be at least partly due to the guidelines. Our guidelines recommended universal measurement of bilirubin, within the first 72 hours of life; they were based on the best available evidence, showing that visual inspection is unreliable, that many babies with severe hyperbilirubinemia had been discharged without having a measurement of bilirubin, and that a single measurement could predict with some accuracy which babies would become severely jaundiced.

The actual highest bilirubin in the 2 studies was almost identical at about 480, which hopefully means that the proportion of babies who develop chronic neurological problems will also decline by two thirds.

This has been achieved at, probably, very low cost. I say “probably” because the impacts on the use of phototherapy and duration of hospitalization are not consistent among studies examining the effects of introducing similar guidelines. Some have shown a small decrease in resource utilization, others a small, or not so small, increase in phototherapy and hospital stay. The guidelines were designed to limit phototherapy to those that really “needed” it (recognizing that very few would ever develop long-term harm), but then to do it properly and intensively. One of the studies showing an increase in phototherapy after guideline introduction in the USA noted that only half of the babies who received phototherapy actually should have had it, if the guidelines were really being followed.

Did the guideline make a difference? I like to think so, and I like to think that the difference was mostly a positive one. At least we seem to have moved in the right direction.

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BOOST-II long term outcomes

Posted on 16 February 2016 by Keith Barrington

The long-running epic of the oxygen saturation targeting trials is nearing completion. This publication of the joint results of the Australia and UK trials now includes the primary outcome for the trials, the combined rate of death or “disability”. Australia Boost-II and United Kingdom Collaborative Group. Outcomes of Two Trials of Oxygen-Saturation Targets in Preterm Infants. The New England journal of medicine. 2016. Disability is defined as being a cognitive or language score on the Bayley-3 of less than 85, severe visual loss, or disabling CP (GNFCS of 2 or more). I will avoid (for a change) ranting about the inappropriateness of referring to a Bayley cognitive or language score of less than 85 as a “disability”.

Because of what happened during the trials the analysis can seem quite complex. But the overall message is that the adverse outcome was increased in the low saturation group when the two trials are combined, however you slice the data.

In case there are any readers who don’t know, a calibration artefact was discovered during the trials, which was corrected, leading to each of these trials, and the COT trial, to have babies with oximeters from a before-correction group and an after-correction group. In the two trials, the difference in mortality only occurred after the change in oximeter algorithm, whereas the smaller NZ trial used only the original algorithm and didn’t find an effect on mortality (or on long term outcome) and SUPPORT, with somewhat different entry criteria, did show a difference in mortality despite using only the original oximeters. The Canadian Oxygen Trial also showed a higher mortality in the low saturation group after the oximeter adjustment, but it didn’t reach statistical significance.

The new publication shows no effect of the trial on “disability”, but the analysis of the primary outcome “death or disability” was significant for the pooled data. What gets complicated is that the UK group changed their primary outcome during the trial to be the rate of death or disability with the revised oximeters, whereas the Australians kept this as the whole group. In the UK the oximeters were changed after roughly ¼ of the babes were enrolled, while in Australia 3/5 of the babies were studied with the original devices.

So the primary outcome analysis of the original trials presented doesn’t include some of the randomized babies (in the UK trial), which bothers me a bit, but their data are presented and analyzed. And then there is quite a lot of detail in one of the tables. The combined outcome of death or disability was significant for the pooled data which included all of the randomized babies (48% vs 43%) and not far from significant for the revised oximeters (49% vs 44%, RR 1.12, 95% CI 0.99-1.27). As I mentioned above, there isn’t any sign of an effect on disability, the difference is all in mortality, now updated to mortality before 2 years of age, most dramatically when the analysis is restricted to the revised oximeters. For the revised oximeters alone the relative risk of death in the low saturation target group was 1.45, (95% CI 1.16 to 1.82).

As everyone now who has Masimo oximeters, they use the new algorithm, and other oximeters were never affected, this is the part of the results which is now most relevant, and I think needs to be taken very seriously.

One comment I would like to make is that the primary analysis for the trials is described as “pre-specified”. But how can the analysis by oximeter algorithm be pre-specified if the problem was discovered during the trial? Pre-specified is supposed to mean, “determined before the trial started”. I think the analysis is just fine, the dilemma about what to do when this was discovered part way through a trial is not easily resolved, and the different choices of the 2 trials can both be justified. It is the use of the word “pre-specified” that I think is incorrect. Also the definition of disability was changed after the study commenced as they (quite appropriately) changed from the Bayley version 2 to the Bayley version 3. The authors describe these events quite clearly in the text, but as they were changed after the trial started they shouldn’t be referred to as pre-specified. the authors are using the term to mean specified before the analysis was started, which  is of course essential and very important, to avoid picking data that look interesting after they have been collected.

To end the saga that I mentioned at the beginning now only needs the NeoPROM collaborative to analyze the individual patient data. It’s hard to think that this will give any result other than an increase in mortality with the lower oxygen target.

One other outcome of interest is that in this trial, as in all the others, there was no increase in blindness. This despite an increase in retinopathy requiring treatment. This was also seen in the SUPPORT trial, but there was no increase in retinopathy in COT. I think this means we can be a bit re-assured that the use of carefully targeted saturations in the low 90’s will not lead to a new epidemic in blindness; but should not be sanguine about the risks of targeting the higher saturation group, treatment of retinopathy is not, by any means, without consequences, even if we can usually prevent blindness, very severe myopia, loss of peripheral vision, and poor cosmetic results are common.

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Antenatal Steroids at 36 weeks?

Posted on 11 February 2016 by Keith Barrington

Most of the studies of antenatal steroids for lung maturation included mothers at less than 34 weeks. Most babies at 34 to 36 weeks do fine, although there is a growing realization of their increased long term risks. Even the proportion who develop respiratory disease usually have relatively short-lived disease, and rarely get very sick, although that can happen. Therefore, to show the efficacy and safety of steroids at later preterm gestational ages you would need to perform a very large study.

So here it is…

Gyamfi-Bannerman C, et al. Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. The New England journal of medicine. 2016; 2800 mothers at risk for preterm delivery at 34 weeks 0 days up to 36 weeks and 5 days were randomized to IM betamethasone or IM placebo. Mothers were not eligible if they were expected to deliver in less than 24 hours, in order to try and get enough time for the steroids to have optimal effect. In fact the median time from starting the intervention until they did indeed deliver was about 30 hours, with interquartile range from 14 to 110 hours.

The primary outcome was a composite made up of signs of respiratory failure, including needing CPAP (or high flow cannulae) for more than 2 hours, or needing more than 30% oxygen for over 4 hours, or being ventilated. That outcome was decreased from 14.4% (placebo) to 11.6% (betamethasone). Among other secondary outcomes, there was also a reduction in the “need for resuscitation at birth” which was defined as : any intervention in the first 30 minutes other than blow-by oxygen, This dropped from 18.7% to 4.5%

Which all sounds great.

BUT.

The incidence of hypoglycemia (blood sugar under 2.2 mmol/L, that’s 40 mg/dl for the Americans) was greatly increased, from 15% to 24% in the steroid group. There were no other safety issues identified, maternal adverse effects were similar in the 2 groups, and there was no increase in infection (maternal or neonatal). I can’t tell from the data presented how many of the babies needed invasive treatment for their hypoglycemia, or how many had more severe hypoglycemia.

If that is a real effect of the antenatal steroids, I am not sure what the mechanism would be, I wouldn’t have thought that 30 hours of antenatal steroids would be enough to induce hyperinsulinism in the babies, but I do think this is a serious potential hazard of the steroids in this group. Almost all of the control babies recovered from their respiratory distress without a significant complication, so if the hypoglycemia had long-term consequences in some babies then the balance of benefits and adverse effects might not be positive.

For now this seems hopeful that antenatal betamethasone at 34 to 36 weeks could lead to an absolute risk reduction of 3% in the development of respiratory failure, a 0.7% decrease in the use of assisted ventilation. But unfortunately a 9% increase in hypoglycemia, most of which was presumably mild and of short duration. I am not sure that this should become routine therapy unless we can get some long term follow up. I for one hope the MFM units network of the NICHD will fund such a follow up to this study, at least to 3 years of age.

 

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Preventing and Treating Sepsis in Preterm Babies

Posted on 10 February 2016 by Keith Barrington

These two studies are both issues that I am involved with, Theresa Ochoa’s study I was aware of, and was waiting for the full publication, the other, from Egypt, I didn’t know about but should have done, but it confirms the need for a large RCT.

Ochoa TJ, et al. Randomized Controlled Trial of Lactoferrin for Prevention of Sepsis in Peruvian Neonates Less than 2500 g. Pediatric Infectious Disease Journal. 2015;34(6):571-6.

This study enrolled just under 200 babies and randomized them to lactoferrin or placebo in three NICUs in Lima, Peru. It showed that routine lactoferrin prophylaxis reduced clinically diagnosed sepsis episodes in low birth weight infants, a reduction which was not quite significant on the primary statistical analysis, but if you are only interested in culture positive, “definite” sepsis, then there was no difference. The authors note that in low and middle income countries lab facilities may be limited, so a clear definition of clinical sepsis, might be the best that can be done. The study included babies up to 2.5 kg, and used a body weight adjusted dose of lactoferrin. In my pilot study (accepted for publication in the Journal of Perinatology), we also did not show a difference in sepsis, but our study was even smaller than this one (with 79 infants enrolled) so we knew we were underpowered for sepsis, but we did work out many of the mechanics of performing a masked RCT of lactoferrin.

Which means that we need other, larger, better powered studies. Hello ELFIN and LIFT, and hopefully soon LIFT-CAN!

Shabaan AE, et al. Pentoxifylline Therapy for Late-Onset Sepsis in Preterm Infants: A Randomized Controlled Trial. Pediatric Infectious Disease Journal. 2015;34(6):e143-e8. Pentoxifylline has many different actions, in particular it inhibits transcription of tumour necrosis factor-alpha, which might be a good thing in sepsis; also, according to the authors of this study, it

preserves microvascular blood flow, prevents circulatory failure and intestinal vasoconstriction and has beneficial effects on endothelial cell function and coagulation in sepsis.

This study randomized 120 newborn preterm babies with clinical signs of sepsis to get either pentoxifylline or placebo, starting with the first dose of antibiotics, and continuing for 6 days. The babies in the pentoxifylline group had inotropic support less frequently, and less intravascular coagulation and thrombocytopenia. There was a minor benefit in mortality with the treatment (10% vs 17%), and other differences between groups favoured the pentoxifylline babies.

The latest version of the Cochrane review of pentoxifylline notes that the data are currently inadequate to be sure that this is a good thing to do, but they are all, so far, positive. It concludes

Low-quality evidence from six small studies suggests that pentoxifylline therapy as an adjunct to antibiotics in neonatal sepsis decreases mortality without any adverse effects. We encourage researchers to undertake large, well-designed multicentre trials to confirm or refute the effectiveness of pentoxifylline in reducing mortality and morbidity in neonates with sepsis or NEC.

The NHMRC in Australia has just funded such a trial! I am privileged to be one of the investigators, for an international trial of 900 very preterm babies with sepsis or NEC who will get either pentoxifylline or placebo. Pentoxifylline is already licensed in many countries, for other indications, and is actually fairly cheap. So if this works in a well-performed trial then there is a real chance of doing good things for preterms around the world.

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Good Advice

Posted on 9 February 2016 by Keith Barrington

Sometime you can find things on the Internet that are better than many medical help sites. Here is advice that can apply to almost anyone with a newborn baby who has a life-changing diagnosis, almost anytime.

Always remember this: “A diagnosis defines a lot of things, but it doesn’t define love”

Diagnosed

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Enhanced Nutrition

Posted on 9 February 2016 by Keith Barrington

Strømmen K, et al. Enhanced Nutrient Supply to Very Low Birth Weight Infants is Associated with Improved White Matter Maturation and Head Growth. Neonatology. 2015;107(1):68-75. This is a report of a secondary outcome of a small RCT, there were only 50 babies in total (the study  was stopped early because of an increase in sepsis in the high nutrition group) and only 25 of them had the MR imaging; VLBW infants were randomized to standard nutrition, or an enhanced protocol which started IV amino acids at 3.5 g/kg/d increasing to 4.4.

Lipids were increased from 0.5 to 7 g/kg/day by day 10 in the control group and from 2.0 to 8.8 g/kg/day in the intervention group. The control group received the lipid emulsion ClinOleic ® (Baxter, Norway), whereas the intervention group received SMOFlipid ® (Fresenius Kabi, Norway) to ensure a higher supply of the essential fatty acids docosahexaenoic and arachidonic acid. The supply of proteins and lipids was gradually increased in both groups, mostly by increasing the enteral supply of human milk. Fortification was initiated when 110 ml/kg/day of human milk was tolerated with a gradual increase to 4.2 g Nutriprem /100 ml human milk. The intervention group received an additional enteral supply of amino acids (0.6 g Complete Amino Acid Mix)/100 ml human milk,

They also got additional docosahexaenoic acid and arachidonic acid.

Now I am all for enhanced nutrition, but that sounds really really enhanced, I don’t think I have ever given any where near that much lipid to a baby. The intervention group received a very high calorie intake, 166 kcal/kg/d, but even the controls got a lot of energy, 146 kcal. There was an even bigger difference in protein intake, 4.4 g/kg/d compared to 3.6 g. I have mentioned this study previously I think. it is a shame they stopped the study for a marginally significant finding on a secondary outcome, but I can certainly understand it, I don’t know if I would have had the guts, or the ruthlessly scientific approach, to continue a study when 61% of the intervention group have sepsis compared to 29% in the controls.

The point of this post though is that they did show that

1. Head circumference was closer to normal in the enhanced group

2. MRI Diffusion Tract Imaging (DTI) were much closer to normal in the enhanced nutrition group.

If the effect on sepsis is a real effect of the increased nutrition, then that outcome has to be balanced against the improved head growth and brain structure. Other studies, such as ours (which was not a randomized trial) did not show any increase in sepsis with increased nutrition, but we didn’t go near to their intakes. Is there a limit to calorie or fat or protein intakes that impairs white cell function? It certainly is possible, so we really need…. guess what? Randomized controlled trials, that’s what (suprise, surprise).

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Neonatal Updates

Posted on 9 February 2016 by Keith Barrington

Glasson EJ, et al. Improved Survival in Down Syndrome over the Last 60 Years and the Impact of Perinatal Factors in Recent Decades. The Journal of pediatrics. 2016;169:214-20.e1. This is a fascinating study, showing dramatic improvements in the survival of persons born with Down syndrome (trisomy 21) over the last 60 years with data from a linked western Australia database. Infants with Down syndrome are much more likely to be born preterm, and the survival disadvantage of having T21 is much greater for very premature babies with the diagnosis. Although the survival disadvantage of Down syndrome has diminished over the years, such that they know are 93% as likely to survive to 30 years of age as the general population, the same is not true of premature babies with T21, who still have a major survival disadvantage. Of course this kind of study can’t say why that is, are premature babies with T21 more fragile? Do they have more serious complications of prematurity? Or are attitudes still a problem, with less intensive care given to these babies, with a greater willingness to limit care?

Schwarz CE, et al. Repeatability of echocardiographic parameters to evaluate the hemodynamic relevance of patent ductus arteriosus in preterm infants: a prospective observational study. BMC Pediatrics. 2016;16(1):1-5. This also I found a little surprising, but maybe I shouldn’t have, measuring things with ultrasound in tiny preterm babies often approaches the limits of resolution of the technology. For example a study which tells you that the diameter of the PDA is 1.8 mm, if your cutoff for treatment is 1.6mm, should probably be repeated, by another person, who doesn’t know the results of the first study. The second study might give you such a different answer that you would change your treatment decision, and the same is true for all the indices of whether a PDA is significant or not.

Baxter B, et al. Neonatal lumbar puncture: are clinical landmarks accurate? Archives of Disease in Childhood – Fetal and Neonatal Edition. 2016. This study also makes me question what I do, the usual landmark for doing an LP, the line between the 2 iliac crests, is a very poor indicator of the lumbar segment, and a worryingly poor indicator of the end of the spinal cord. Makes me wonder if we should find another anatomic landmark, or whether we should routinely do a spinal ultrasound to find the right point.

Shetty S, et al. Work of breathing during CPAP and heated humidified high-flow nasal cannula. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2016. High flow cannulae at 8 litres per minute, or 6 litres for babies less than 1 kg, were compared with CPAP at 6 cmH2O. There were no differences in calculated work of breathing, or in thoracic/abdominal asynchrony, or in saturations.

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Interesting comments

Posted on 9 February 2016 by Keith Barrington

I get a small number of comments on the blog, almost always interesting, depending on how you view the content you may not have noticed them.

Three of my recent posts have stimulated some comments that are worthwhile: If you click on the links below, it should open an individual page with the comments at the bottom, and my replies if there are any.

Please feel free to leave comments on my posts, your first comment will have to be approved by me, in order to avoid spam. WordPress filters out a lot of spam (hundreds and hundreds of comments that come from weird people who have invented automated comment posts for blogs from places such as lasixwithoutprescription.com and onlinepokerfrommalaysia.net) but there are still a few that get through that I have to delete manually. I will approve any comment that is from a real person, relevant to the purposes of the blog, and is not abusive. Even if I disagree with you!

ventilating-infants-with-diaphragmatic-hernia

The death knell for Xenon?

How-frequent-is-acute-kidney-injury-in-the-NICU? Not-as-frequent-as-some-publications-would-have-you-believe

And here is one comment from a parent

A new publication

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