Better research, for better care

Posted on 28 April 2014 by Keith Barrington

I hope this commentary in JAMA receives a lot of ‘likes’!

Eapen ZJ, Lauer MS, Temple RJ. The imperative of overcoming barriers to the conduct of large, simple trials. JAMA. 2014;311(14):1397-8.

The commentary includes a report of a conference about the issues outlined in the title, a conference which reached 3 conclusions with which it is hard to disagree.

First, trials determining the risk-benefit balance of therapies must be larger. Improvements in existing standards of care are likely to be incremental (10%-25% relative reduction in events), and large studies with numerous events are needed to identify moderate treatment effects. It is important that these trials use clinical, not surrogate, end points.

Second, trials must be simpler. The cost of large, complex trials—often hundreds of millions of dollars—is a significant hurdle, in both initially bringing a treatment to market and subsequently conducting comparative studies. Moreover, restrictive inclusion criteria and excessive exclusion criteria often limit clinicians’ abilities to extrapolate findings to a broader, heterogeneous population. Data collection during the trial may also be excessive, and this too adds to the cost. According to the Tufts Center for the Study of Drug Development, the typical clinical trial in 2012 involved 13 end points, 169 case report form pages, and 175 days of on-site monitoring.1

Third, for most therapies, studies must be randomized. Estimates of effect size in large observational studies may be precise but remain fundamentally hampered by bias and confounding that can be controlled only through random allocation.

Simplifying approval processes, reducing the burden of data collection, using existing registries for data collection, and at the same time maintaining protection of subjects are top priorities for the future.

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Retraction of a systematic review

Posted on 28 April 2014 by Keith Barrington

Exactly when should an article be retracted? That is not so easy a question to answer, fraud and significant data or image manipulation are one fairly obvious group of reasons. Making errors and/or poor research design are more tricky. When the errors are such that the major results are unreliable, then retraction should be considered.

Retractions have been very few in neonatology, but one recent example, is an article that I blogged about previously, a systematic review of NIDCAP from a French group. The retraction notice states that the authors had included some data twice, which I hadn’t realized. Some of (or at least 2 of ) the articles that they included in fact were reporting data from the same infants.

The retraction notice also notes that there were errors in the description of the outcome variable. As far as I can see this is because some of the scores that were included were actually from the 1st version of the Bayley scales, but in the systematic review it was stated that they were from the 2nd edition. I already noted that it really isn’t appropriate to mix Bayley scores at different ages, especially very early scores at 9 months of age, mixing version 1 and version 2 scores makes that error worse. In fact the second edition of the Bayley became available in 1993, so all the babies in the first NIDCAP trial were examined with the first edition. These babies were also re-reported in the paper in 2009 by McAnulty, at which time some of them were 25 years old. So I think it is the duplicated publication of data in McAnulty 2009 which is the culprit.

I think the right decision has been made here, once those data points are subtracted, and once the Bayley 1 are evaluated separately to Bayley 2, then it seems unlikely that there will be any difference between NIDCAP and control. So the results were unreliable and the literature is better with a retraction.

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Neonatal Updates

Posted on 27 April 2014 by Keith Barrington

Corvaglia L, Martini S, Battistini B, Rucci P, Aceti A, Faldella G. Bolus versus continuous feeding: effects on splanchnic and cerebral tissue oxygenation in healthy preterm infants. Pediatr Res. 2014. During a 6 hour period, preterm infants had either a bolus feed an a 3 hour infusion of milk. Bolus feeding led to an increase in the intestinal NIRS signal.  A 3 hour infusion led to a decrease. I’m not sure what this means, Randomized comparisons of clinical outcomes generally show now substantial difference between bolus and continuous feeding. So if the oxygenation is lower but the clinical function is OK, do we need to worry?

Fox LM, Choo P, Rogerson SR, Spittle AJ, Anderson PJ, Doyle L, et al. The relationship between ventricular size at 1 month and outcome at 2 years in infants less than 30 weeks’ gestation. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014;99(3):F209-F14. If you have bigger ventricles, and therefore, on average, less brain, your outcome is worse. That is a facetious comment on an interesting paper, which confirms that one of the better predictors of outcome is ventricular enlargement.

Wang D, Aubertin C, Barrowman N, Moreau K, Dunn S, Harrold J. Examining the effects of a targeted noise reduction program in a neonatal intensive care unit. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014;99(3):F203-F8. The NICU is a noisy place, especially if you have fragile preterm baby ears. Reducing noise intensity is not very easy, and may even have contrary effects to those that you desire.

Emond A, Ingram J, Johnson D, Blair P, Whitelaw A, Copeland M, et al. Randomised controlled trial of early frenotomy in breastfed infants with mild–moderate tongue-tie. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014;99(3):F189-F95. Tongue-tie has always been rather controversial, but I think overall the evidence shows that cutting a severe tongue-tie has short term benefits in breast feeding success. This new RCT investigated immediate frenotomy in moderate cases compared to breast feeding support. The primary outcome was the LATCH score of breast-feeding efficacy at 5 days of age, and it was not different between groups: but the proportions of mothers who gave up breast-feeding (a secondary outcome) was substantially lower in the frenotomy group than in the controls. There were no adverse effects noted. So with the usual proviso about secondary outcomes, this appears modestly successful.

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Pulse Oximetry Screening : It’s About Time

Posted on 27 April 2014 by Keith Barrington

It is about time! Timely diagnosis, and timely intervention for children with potentially lethal cardiac defects make an enormous individual difference to their survival and other outcomes.

A new enormous study in the lancet from China (over 120,000 babies screened) has similar findings to the previous studies, showing good sensitivity, low false positives and overall acceptability of pulse oximetry screening of apparently healthy newborns.

The study is accompanied by one of the best editorials that I have read, measured, reasonable, evidence based, and clearly written (Ewer AK. Pulse oximetry screening: do we have enough evidence now? The Lancet). As he notes, the added value of pulse oximetry screening will depend upon the background rate of detection of critical heart disease in your health care system: but all of the studies show some added value. False positives are much less frequent with pulse oximetry screening than with physical exam, so the added burden to your health care system is likely to be quite small, and in developed economies, minimal.

I certainly think it is time that Canada had a national policy, and that we introduced routine universal pulse oximetry screening for our babies.

 

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Treating pneumothoraces? Either a tube or leave them alone.

Posted on 21 April 2014 by Keith Barrington

I never understood why it was recommended to give 100% oxygen to treat a pneumothorax. I think the idea was that the gas in the pneumothorax could be replaced by oxygen which would then be reabsorbed more quickly if we gave oxygen rather than air or another mixture with lower oxygen content and more nitrogen. But that would only work if the pneumothorax was being ventilated, and there was an open bronchopleural fistula, which is not usually the case. so we needed someone to examine the data.

This retrospective study shows absolutely no sign of an effect of giving 100% oxygen. Clark SD, Saker F, Schneeberger MT, Park E, Sutton DW, Littner Y. Administration of 100% oxygen does not hasten resolution of symptomatic spontaneous pneumothorax in neonates. J Perinatol. 2014.

Another therapy to consign to the garbage can of history.

Oxygen is toxic. Oxygen is life saving. Give only as much as you need to maintain ‘adequate saturations’ : whatever they are.

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Something else that doesn’t work in sepsis; albumin

Posted on 21 April 2014 by Keith Barrington

Another multi-center RCT in adults with severe sepsis or septic shock with a negative result. This time 1800 adults in 100 ICUs in Italy were randomized. Fluid boluses were either crystalloid or 20% albumin and crystalloid. Blood pressure was somewhat higher in the albumin group (by a massive 2 mmHg in the mean BP on day 1 and 1 mmHg on day 2), and they had a better short term fluid balance. There were no differences in any clinically important outcome, including the primary outcome of mortality.

The study confirms once more that severe sepsis is bad for you, mortality in both groups was around 40%.

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Bloody Placentas

Posted on 21 April 2014 by Keith Barrington

No, literally.

There is now quite good evidence of the advantages of delayed cord clamping in the term infant, with most particularly an improvement in iron stores in the baby that has lasting effects during the first year of life. The current recommendation is to hold the baby at the level of the vaginal introitus. But it is also recommended to place the baby directly on the mother’s abdomen, and then to encourage immediate skin to skin contact.

So you can’t do both. Keeping the baby at the level of the vagina is recommended in order to encourage the transfusion of placental blood, but it may not be necessary. Gravity may not be that important, as the forces of uterine contraction can probably easily overcome the weight of a few centimeters of a column of blood.

Nestor Vain and colleagues from Argentina have just published a trial in term delivered mother infant pairs where they randomized to either keeping the baby down low, or lifting the baby onto the mother’s abdomen. They weighed the baby as quickly after birth as possible (usually within 15 seconds), and the again after 2 minutes, which is when the cord was clamped and cut.

In both groups the weight  of the baby increased by about 50g, there were no differences by group assignment, and no apparent effect of the position of the mother’s body. There were about 270 babies in each group, with about 80 exclusions in each group, for quite appropriate reasons (c-section, need for resuscitation, cord around the neck etc).

I congratulate Nestor and his colleagues for this study, I would never have thought of doing this, but it is very useful information for obstetricians everywhere, you can deliver the baby onto the mother’s abdomen and delay clamping the cord for 2 minutes; getting the benefits of both early skin to skin contact and placental transfusion.

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Resuscitating preterm infants: how many O’s

Posted on 21 April 2014 by Keith Barrington

Very often in neonatology (and in life) we have to make a decision based on inadequate data. For example, when resuscitating a very preterm baby you have to decide where to set the starting FiO2, even if there are no data at all (as was the case a few years ago, and we ‘all’ started with 100%).

At least now there are some data, and Ola Saugstad and colleagues have just published a systematic review of the studies that are available. They limited the review to randomized trials of resuscitation of infants less than 33 weeks gestation where a starting FiO2 of 21 to 30% was compared with a starting FiO2 of 60 to 100%.

They found 10 studies with a total of around 650 babies included. A lot of them were relatively low risk babies, and the total mortality was below 10%. Nevertheless the mortality was lower in the low FiO2 groups, 6.5% compared to 9.8% with higher FiO2. This gives a relative risk for death of 0.62, i.e. a 38% reduction in mortality. Now this isn’t statistically significant by usual thresholds, with the upper 95% CI being 1.04. The absolute risk reduction is not that great (as these were on average relatively low risk babies), being 3.4%. The other outcomes that the authors analyzed, bronchopulmonary dysplasia and intraventricular hemorrhage, showed no evidence of being different between groups.

Also, as I’ve mentioned before on this blog, meta-analyses based on several small trials often over-estimate the effectiveness of an intervention, so the issue is far from proven, and we certainly need a larger definitive trial.

In the meantime, the next time I go to the delivery room, I will have to decide where to set the starting FiO2, and, based on this analysis, I’ll continue to start with a lowish FiO2 of probably 30%, and hope that we have more definitive data in the near future.

 

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More from SUPPORT, not research governance and consent this time!

Posted on 21 April 2014 by Keith Barrington

One of the difficulties in performing neonatal research is how to determine the most clinically appropriate outcomes. Bronchopulmonary dysplasia is often used as a dichotomous outcome variable, partly to facilitate the design of research, including combining it with other competing outcomes, such as death. If you die before 36 weeks you don’t have BPD, so that death would be counted as a good pulmonary outcome unless the 2 are combined in some way. Death is a truly dichotomous outcome (as long as zombies don’t really exist) so using ‘death or BPD’ as an outcome makes some sense as long as it is understood that this doesn’t mean they are considered equivalent!

The big downside of this is that lung injury is not a yes or no phenomenon. Lung injury in the preterm is a continuum, and deciding that a good outcome is stopping oxygen 1 day before the baby reaches 36 weeks, and a bad outcome is stopping oxygen 1 day later is patently too simplistic.  Defining different severities of BPD is useful clinically, but needs also to be considered in study design, and is still too restrictive, with just 3 categories in the Jobe and Bancalari definitions.

Longer term follow up with evaluation of the functional effects of lung injury needs to be part of trials which address respiratory interventions.

A new report of respiratory outcomes of infants in the SUPPORT trial (Stevens TP, Finer NN, Carlo WA, Szilagyi PG, Phelps DL, Walsh MC, Gantz MG, Laptook AR, Yoder BA, Faix RG et al: Respiratory outcomes of the surfactant positive pressure and oximetry randomized trial (SUPPORT). The Journal of pediatrics) has 36 authors reporting on behalf of the trial study group. The collaborating centers followed up babies at 6 monthly intervals for 2 years, data were collected by asking the parents how the infant was doing, in terms of wheezing episodes, cough, re-hospitalization and so on, using a validated questionnaire. They found that :

patients in the CPAP group had lower rates of several important respiratory morbidities at 18-22 months CA, including respiratory illnesses diagnosed by a doctor, treatment with oxygen or diuretics at home, and a trend toward a lower rate of overnight hospitalization for breathing problems.

They also saw a lot of respiratory morbidity among the SUPPORT babies who did not have a diagnosis of BPD (including 7% of them who had home oxygen, which surprised me).

This is consistent with some of the data from the COIN trial which also seemed to show that clinically important longer term pulmonary outcomes in the babies who had CPAP and attempted avoidance of intubation were improved.

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Probiotics: what do parents want?

Posted on 10 April 2014 by Keith Barrington

Some day, I might slow down with the probiotics posts, but not right now!

A letter published in Archives reports the results of a parent survey. In the 3 NICUs implicated probiotics are given with parental information and an ‘opt-out’ approach, where probiotic administration is routine, but parents can refuse if they wish.

Parents of babies recently in these NICUs were surveyed,

the vast majority of respondents (51/53; 96%) considered that parents of high-risk premature babies born at other units that do not yet offer probiotics should have the right to be informed of the evidence of their potential benefits. Most (34/53; 64%) also felt that, given the current evidence on risk reduction for NEC or death, other parents deserved the right to be informed of the data and the option of probiotic treatment for their babies.

They also note

 Only 7/58 (12%) units gave probiotics to preterm/VLBW babies; 11/58 (19%) units stated they were considering whether to introduce probiotics and 22/58 (38%) units reported that they were awaiting results of the Probiotic in Preterm babies Study.

and not surprisingly

We find that parents focus on the short-term outcomes of survival and avoiding NEC rather than on any theoretical longer-term effects such as on immune function or metabolism. While doctors debate and deliberate, parents would appear to prefer probiotic proactivity.

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