Treating pneumothoraces? Either a tube or leave them alone.

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

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

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

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!

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?

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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Neonatal Updates: more nutrition

It is not surprising when I write a blog post about nutrition in the preterm neonate to find that at least one, and on this occasion two, of the articles are from the productive pen of Johannes van Goudoever.

Vlaardingerbroek H, Vermeulen MJ, Carnielli VP, Vaz FM, van den Akker CHP, van Goudoever JB: Growth and fatty acid profiles of vlbw infants receiving a multicomponent lipid emulsion from birth. Journal of Pediatric Gastroenterology & Nutrition 2014, 58(4):417-427.

SMOFLipid is a new-ish lipid emulsion which is made from several different sources, and as as result contains omega-3 fatty acids, as well as omega-6. It has been approved in Canada for TPN in adults, and has been approved in Europe also for neonates. Which I find a bit surprising as we had a recent presentation from our pharmacy, and the total published data from several small trials came to about 100 treated preterm babies, and 100 controls.

The NICU team in Rotterdam now add to that data, they have performed a clinical RCT comparing clinical outcomes among infants randomized to either SMOFLipid or Intralipid. 96 VLBW babies were randomized within 6 hours of birth, starting at 2 g/kg/d on day 1, and 3 g/kg/d on day 2.

The growth on SMOFLipid was improved, and the fatty acid profile was also improved with the DHA and EPA levels being maintained and significantly higher than the controls. There were no adverse effects noted. There were fewer cases of late onset sepsis, 27% rather than 40% had this complication. This is not individually significant, but some of the same authors have previously published a meta-analysis, which showed a 25% reduction in LOS based on 2 small trials and barely significant. If you add the new numbers to the data already in the literature, which which they do in their discussion, you now have a reduction in sepsis of 28% and the upper limit of the 95% CI is 0.94. So a very interesting finding, for which there is some theoretical/basic science support, which needs to be replicated in further larger trials.

I think there is good theoretical justification for using an emulsion which includes omega-3 fatty acids, and if we were to design the first ever intravenous lipid for a trial today we would probably have something like SMOFLipid in mind. However, I think we really should demand robust efficacy and safety data in comparison to the current standard before changing over. Even with the knowledge that when intralipid was introduced for preterm babies there was really no good controlled evaluation. I don’t think there is a single RCT against placebo of intralipid as a component of TPN in preterm infants, which is not that unusual for things that were introduced in the 50′s and 60′s. What to do about that is not entirely clear to me, but I don’t think the answer is to switch to a newer therapy after a few very small RCT’s. I think the time is now to ensure that we have big simple RCTs comparing current usual care to any innovation, even is the current usual care is based on very little, or almost no, data.

Olsen IE, Harris CL, Lawson ML, Berseth CL: Higher protein intake improves length, not weight, z scores in preterm infants. Journal of Pediatric Gastroenterology & Nutrition 2014, 58(4):409-416.This secondary analysis of data from a trial of a concentrated liquid human milk fortifier shows that there was a correlation between higher protein intakes and better length at 28 days.

Christmann V, de Grauw AM, Visser R, Matthijsse RP, van Goudoever JB, van Heijst AFJ: Early postnatal calcium and phosphorus metabolism in preterm infants. Journal of Pediatric Gastroenterology & Nutrition 2014, 58(4):398-403. How much calcium and phosphorus should we supply, and what should be the ratio between them? The answers to these questions are still not entirely clear to me. Avoiding early hypocalcemia, and/or hypophosphatemia, and then ensuring later good bone mineralisation may need different answers to those questions. The data in this study supports the idea that you need a lower calcium/phosphate ratio in the first couple of days, and that gradually changes afterward.

An accompanying editorial gives some guidance, much of which needs confirmation in other studies.

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