Supporting oxygen limits

Posted on 19 January 2013 by Keith Barrington

The initial results of the SUPPORT trial examining the effects of different oxygen limits stopped a lot of us in our tracks. We started these trials because most of us thought that aiming for lower oxygen saturation targets would reduce eye disease, would reduce chronic lung disease and would be safe. We were uncertain enough however to put together randomized trials to scientifically compare the effects of choosing 2 different oxygen targets, to make sure that what we thought we were seeing from observational studies was in fact true.

We confirmed that less oxygen meant less retinal disease, including more retinal disease severe enough to need surgery, there wasn’t really any effect on chronic lung disease (a probably chance reduction from 39.7 to 37%) but there was an increase in mortality. More babies died in the lower oxygen group than the higher group.

The newly published results (Vaucher YE, Peralta-Carcelen M, Finer NN, Carlo WA, Gantz MG, Walsh MC, Laptook AR, Yoder BA, Faix RG, Das A et al: Neurodevelopmental outcomes in the early cpap and pulse oximetry trial. The New England journal of medicine 2012, 367(26):2495-2504) from the 20 month follow up confirm that the difference in survival persists, and now shows that all the actual outcomes on visual function were not different, neither blindness, severe visual impairments nor squint. Even though there were twice as many infants who had eye surgery in the high saturation group as the low sat group.

In addition the neurological and developmental outcomes (at least as measured by the Bayley score) were not different. Significant cerebral palsy was 5% in each group, and a Bayley score less than 70 was about 7.5% in each group.

With the interim analysis that stopped the BOOST2 trials in the UK and Australia also showing an increased mortality, it certainly looks like we should avoid the lower saturation range of 85 to 89% that was targeted in each of the low groups of the oxygen trials. This evidence is also enough I think to encourage us to do further trials examining other targets, as well as looking for other ways of avoiding hyperoxia. If we are to target 90 to 95% saturation, then the risk of episodic hyperoxia will be increased, maybe automated FiO2 controllers, adaptive alarms and other interventions can help us make the higher limits safer to the eyes.

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Transplanting Poo

Posted on 18 January 2013 by Keith Barrington

That’s right, Poo not Pooh; this post is not an AA Milne tribute.

The smallest trial in a while at the PNEJM (van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JFWM, Tijssen JGP et al: Duodenal infusion of donor feces for recurrent clostridium difficile. Prestigious New England Journal of Medicine 2013) only 42 patients were in the trial when it was stopped, they were planning 120. The patients were all adults with C difficile diarrhoea that had relapsed after treatment. They were randomized to either get Vancomycin, Vancomycin plus bowel washout with 4 litres of a special solution, or a short vancomycin treatment followed by the bowel washout followed by the infusion of donor feces into the duodenum. They created a pool of donors who had acceptable feces (they were healthy, had stool cultures screened for all sorts of bad stuff and were able to poo on demand (I added that last bit)) and on the day they had an eligible patient they provided a sample which was immediately transported to the hospital, diluted down and then infused into the patients duodenum through a tube.

This has actually been done many times, without controls but with good apparent success rates. So this study from the Netherlands was designed to answer an important question; recurrent C diff is really bad news; difficult to treat and with many complications. The study was stopped because almost all the poo recipients had a cure immediately, and 2 of the 3 failures responded to a second treatment (with another donors feces).

I think it is clear that this treatment is aimed at restoring a normal microbiome in patients in whom the microbiome was very disturbed. An accompanying editorial in the PNEJM does in fact refer to this as a microbiome transplant. And discusses why it has not become more widespread. He notes that it is aesthetically unappealing… what I would call an understatement!

Probiotics are of course attempting to do the same thing, with a less disturbing aesthetic! A recent editorial points this out, the wonderfully titled ‘The power of poop‘ (Floch MH: The power of poop: Probiotics and fecal microbial transplant. Journal of Clinical Gastroenterology 2012, 46(8):625-626.)

So normalizing the intestinal microbiome benefits not just preterm babies but clostridium difficile as well.

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Testing treatments

Posted on 14 January 2013 by Keith Barrington

Imogen Evans, Hazel Thornton, Iain Chalmers, and Paul Glasziou have written a great book about why we need to do clinical trials, with introductory chapters about how they should be done. The second edition of their book is available free as a pdf. It has actually been available for a while, but I only just became aware of a web-site that has all the same information, the website has the text of the book, and a number of open educational resources, Including for example a you-tube video featuring a poem about regression to the mean.  If you’ve been visiting this blog for a while you will know I have written about this myself.

There is also a link to a satirical video from the Onion, that I really enjoyed. And the website of testing treatments has a link to download the whole book for free.

And of note,  Iain Chalmers has also just published an editorial in the BMJ. “All trials must be registered and the results published”  It is a scandal that we still have trials performed that do not get fully published, and people or companies hanging on to the data that should be considered to belong to the whole community and the trial participants, not to the investigators. As many as half of all the trials performed never get published. This means that many treatments that are being prescribed currently have already been shown to be ineffective, and many others are not used as they should be. Please sign the petition. http://www.alltrials.net/

One example that Iain Chalmers mentions, that brings this home, was a high quality trial looking at whether you should do an adenoidectomy in addition to tympanostomy drainage for persistent otitis media with effusion. The study was not published for 10 years after being completed. So for 10 years all the ENT surgeons and parents in the world have been making decisions about what to do for these children without evidence that should have been easily available.

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Weekly Updates #20

Posted on 11 January 2013 by Keith Barrington

My endnote database got corrupted partway through the week, I nearly had a “crise de nerfs” and it took most of a day to put right… the final solution wasn’t that difficult, but I tried about 15 other things first. I think having a huge database and a synchronisation program between 3 different computers may be the problem. All of this to say that when the database was fixed the last few additions were out of order, so I might have missed some good stuff this week.

Bekhof J, Reitsma JB, Kok JH, Van Straaten IH: Clinical signs to identify late-onset sepsis in preterm infants. Eur J Pediatr 2012:1-8. The authors studied 187 episodes of possible sepsis, and evaluated 21 clinical signs.   They then went back to see which kids actually were septic (including some culture-negative sepsis) and compared the signs between septic and non-septic babies.   Increased respiratory support, capillary refill, grey skin and central venous catheter were the most important signs associated with sepsis. Clinical signs that were too non-specific to be useful were temperature instability, apnoea, tachycardia, dyspnoea, hyper- and hypothermia, feeding difficulties and irritability. They produce an algorithm that allows you to calculate the possibility of sepsis. There are not many good studies that have done anything like this before.

Ceelie I, de Wildt SN, van Dijk M, van den Berg MM, van den Bosch GE, Duivenvoorden HJ, de Leeuw TG, Mathot R, Knibbe CA, Tibboel D: Effect of intravenous paracetamol on postoperative morphine requirements in neonates and infants undergoing major noncardiac surgery: A randomized controlled trial. JAMA 2013, 309(2):149-154. Babies randomized to intravenous paracetamol (that’s acetaminophen to the N Americans) needed a lot less morphine that the controls, about 1/3 as much. we need a preparation available in Canada.

Moran PM, Hawkes CP, Dempsey EM, Ryan CA: T-piece gas flow palpation as a clinical indicator of endotracheal intubation in neonates. Eur J Pediatr 2012:1-4. The neonatal group in Cork keep doing very interesting studies which may change how we do resuscitations, (conflict of interest alert, 2 of the authors are my very good friends!) in this study they showed that when there is a tidal volume of 5 mL or more, just by holding you wrist next the exhalation flow of the Neopuff you can usually tell if there is a breath, and it is more obvious at 10 mL, so one way to tell if you think the baby is intubated in the right place.

Romero R, Korzeniewski SJ: Is there a long-term price to pay for infants not exposed to the stress of labor? How the microbiome and the immune system can affect our lives. Am J Obstet Gynecol 2012(0). This is an editorial accompanying a review article Cho CE, Norman M: Cesarean section and development of the immune system in the offspring. American Journal of Obstetrics and Gynecology 2012 (0). which both suggest that being born by C section isn’t so benign after all. It may increase the risk of developing immune diseases such as asthma, allergies, type 1 diabetes, and celiac disease. Some of this may be due to abnormal neonatal microbiome development. Maybe all babies born by C-section should get probiotics too!

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Let it flow?

Posted on 10 January 2013 by Keith Barrington

There are now accumulating a few trials of the use of high flow nasal cannulae (HFNC) as a means of respiratory support in the newborn Collins CL, Holberton JR, Barfield C, Davis PG: A randomized controlled trial to compare heated humidified high-flow nasal cannulae with nasal continuous positive airway pressure postextubation in premature infants. J Pediatr 2012. . This new trial is an RCT of 132 infants under 32 weeks gestation who were enrolled when they were extubated, and given either CPAP or HFNC. They had objective criteria for extubation failure, which occurred in 15 (22%) of the HFNC group compared with 22 (34%) of the NCPAP babies. Which was consistent with a chance effect, but they did have much lower nasal trauma score 3.1 (SD 7.2) with HFNC compared to NCPAP 11.8 (SD 10.7), P < .001. The study was designed to show if HFNC were better than NCPAP, and it seems to show that there probably wasn’t a real difference. This study used the Vapotherm system, starting at 8 litres per minute or CPAP at either 7 or 8 depending on the FIO2.

It is reassuring that there certainly did not seem to be a substantially worse outcome with the HFNC. Despite the fact that, as reviewed by Carlo Dani and his associates, HFNC deliver “continuous distending pressure (CDP) in patients with closed mouth, whose value is proportional to the delivered flow only in smaller infants; the CDP delivered by HFNC is unpredictable and present large inter-patient and intra-patient variability” so maybe as long as there is some CPAP after extubation it doesn’t matter very much how high the pressure is, or maybe the improved comfort outweighs the fact that some babies might have lower pressures delivered.

The only previous RCT post-extubation that I am aware of showed higher extubation failure with the HFNC, but that was a non-heated system, used at flow rates between 1.4 and 1.7 litres a minute, with a sample size of only 30 babies.

The evidence is still not very strong to use HFNC post-extubation, but it does seem that it may turn out to be a reasonable alternative, but you probably need a heated system with very high flows.

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How do Probiotics and Breast Milk prevent NEC?

Posted on 10 January 2013 by Keith Barrington

The question of the mechanism of action of probiotics and the manner in which breast milk reduces the incidence of NEC are important if we are to figure out for the future how to advance.

There are specific components of breast milk that can be considered to be part of an innate immune system in human milk, which protects the infant by inhibiting the binding of certain organisms and thus reducing infection. These oligosaccharides have been studied for a few years now, and as well as inhibiting the attachment of mucosal pathogens they promote the growth of probiotic organisms such as bifidobacteria even when added to artificial formulas. This has been shown in preterm infants also.

Lactoferrin is also a component of breast milk, largely absent in commercial formulae; lactoferrin is an important antibacterial agent in breast milk, and may have a role in the prevention of NEC.

A new publication seems to show that when breast milk is partially digested in vitro, the resulting mixtures are much less toxic to neutrophils than when the same procedure is performed using formula. The same was true of intestinal epithelial cells also, which may be more relevant to NEC.

Breast milk also promotes the growth of probiotic organisms and in fact breast milk often contains bifidobacteria, which are probiotics.

Another new publication suggests that probiotics may in part reduce NEC by effect on the expression of genes in the enterocytes that regulate inflammation. Other studies have shown that bifidobacteria when grown with prebiotic oligosaccharides affect intestinal epithelial function.

We still don’t have all the answers, but there is an accumulating evidence base which explains the actions of breast milk and of probiotics, which seem to overlap, and probably re-inforce each other.

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Using YouTube to save babies’ lives

Posted on 8 January 2013 by Keith Barrington

A great series of videos produced by the global health media project are designed to help health care workers diagnose and treat neonatal health problems. I haven’t yet watched them all, but the evaluation of respiratory problems video, and the how to insert an IV video are well done, simple and clear. I just hope they will be able to provide narration in multiple languages.

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Weekly Updates #19

Posted on 4 January 2013 by Keith Barrington

Scattolin S, Gaio P, Betto M, Palatron S, De Terlizzi F, Intini F, Visintin G, Verlato G: Parenteral amino acid intakes: Possible influences of higher intakes on growth and bone status in preterm infants. J Perinatol 2013, 33(1):33-39. This was an RCT in 115 babies less than 1250 grams birth weight enrolled in the 1st 3 days of life to receive a standard of 3 g/kg compared to 4 g/kg per day. There was no overall difference in non-protein energy intake, the actual eventual intakes were quite a bit lower than the 3 or 4 grams planned. Even so the high protein group had more weight gain, grew more in length and had better bone mineralization. This is more evidence that we are not giving enough protein to our preterm infants (see previous blog post here ), and that giving more protein might be a safe way to improve growth outcomes.

Thankavel PP, Rosenfeld CR, Christie L, Ramaciotti C: Early echocardiographic prediction of ductal closure in neonates <30 weeks gestation. J Perinatol 2013, 33(1):45-51. This seems sort of self-evident, but its nice to have some actual figures to confirm. Bigger PDAs are less likely to close than smaller ones. The way the authors evaluated size is not, I think, standard, but makes a lot of sense, rather than a measure in millimeters, they compared the size of the PDA to the Left pulmonary artery.  So if you are less than 28 weeks and the PDA is more than half the size of the LPA, only 9% are closed without therapy at 10 days. Now we could do with an RCT in this high risk group to see if earlier attempted closure with ibuprofen improves any clinical outcomes.

Le Compte AJ, Lynn AM, Lin J, Pretty CG, Shaw GM, Chase JG: Pilot study of a model-based approach to blood glucose control in very-low-birthweight neonates. BMC Pediatr 2012, 12(1):117. I was thinking of doing this myself, so it must have been a good idea. There are data in older ICU kids that using a computer algorithm to decide on changes in insulin therapy for hyperglycemia can be safer and lead to more normal sugar values (I have blogged about this before) This new publication shows that after introducing a computer based algorithm for extremely immature babies with hyperglycemia, there was no hypoglycemia, and more nomoglycemia.

Bissuel M, Deguines C, Tourneux P: [a national survey on pain management before tracheal intubation in neonates in french type iii maternity units.]. Arch Pediatr 2012(0). Thsi survey shows that many units in France are still not premedicating before routine endotracheal intubations, and even those that are are largely using medications that have either never been studied, have been inadequately studied, or are ineffective! (sufentanil, ketamine, midazolam, and propofol). A few years the French were ahead of other countries in premedication practice, but the situation appears to have stagnated.

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Donor Breast Milk Banking, and the effects on maternal milk use and production

Posted on 3 January 2013 by Keith Barrington

Human breast milk is the best food for human babies. Although the evidence for some of the benefits is not as sound as I would like, I think it is clear that the benefits for preterm infants are substantial. Hence the growth in human milk banks, which are now supposed to be run according to standards which are similar to those for blood product banking (which makes the milk much more expensive than in the olden days). One possible risk of having such banks is that it might reduce the use of mothers own milk.

Two recent publications are reassuring; (Delfosse NM, Ward L, Lagomarcino AJ, Auer C, Smith C, Meinzen-Derr J, Valentine C, Schibler KR, Morrow AL: Donor human milk largely replaces formula-feeding of preterm infants in two urban hospitals. J Perinatol 2012.)  2 Hospitals in Cincinnati introduced a program to supply donor milk in 206, and progressively over the subsequent years, as donor milk increased, there was much less formula used, but no apparent effect on breast milk use.

The other is an observational study from a number of Italian NICUs, some of them had Human milk banks, and others did not; (Arslanoglu S, Moro GE, Bellu R, Turoli D, De Nisi G, Tonetto P, Bertino E: Presence of human milk bank is associated with elevated rate of exclusive breastfeeding in vlbw infants. J Perinat Med 2012:1-3). . Exclusive breastfeeding rate at discharge of very low birth weight infants was significantly higher in NICUs with a milk bank than in NICUs without (29.6% vs. 16.0%, respectively). Any breastfeeding at discharge was 60.4% vs. 52.8%, P=0.09. These are not very impressive rates, but they at least don’t suggest an adverse influence of having a breast milk bank.

 

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The Eyes have it! Retinopathy of Prematurity updates

Posted on 1 January 2013 by Keith Barrington

A review article in the PNEJM introducing the basic concepts in the pathophysiology and treatment of retinopathy of prematurity (Hartnett ME, Penn JS: Mechanisms and management of retinopathy of prematurity. Prestigious New England Journal of Medicine 2012, 367(26):2515-2526). I think it would be a really good article for a first-year fellow. As usual in the PNEJM review articles, the llustrations are excellent.

Another interesting article is a secondary analysis of data from the multicenter superoxide dismutase trial, in which the principal investigator was Jonathan Davis, you may remember that the original trial (an RCT of intra-tracheal recombinant human SOD in about 300 babies less than 1200 g birth weight) was negative in terms of reducing the risk of bronchopulmonary dysplasia or death, which was the primary outcome variable, although there were some signs of potential beneficial effects on the severity of the disease at 1 year follow up. This new secondary analysis examines the possible effects of superoxide dismutase on retinopathy of prematurity. Overall there was a small reduction in retinopathy but when the highest risk groups were examined, in particular those under 25 weeks, there seems to be a substantial reduction in retinopathy in the patients who received active treatment. As always you have to be super-careful with secondary analyses and in particular careful with those that were not planned at the time of the initial study design; but this is suggestive and biologically plausible. It probably means we need another larger RCT to examine effects on RoP, but recombinant human SOD is probably very expensive, as most thing are that start with ‘recombinant’, maybe another look at bovine SOD would be worthwhile.

Finally a new version of the AAP guideline on screening for RoP, and the timing of repeat eye exams depending on the initial or subsequent findings. A very clearly written guideline in general. However the section on reducing pain during screening is, how shall I put this, pathetic.   I quote ‘Effort may be made to minimize the discomfort and systemic effect of this examination by pretreatment of the eyes with a topical anesthetic agent such as proparacaine; consideration also may be given to the use of pacifiers, oral sucrose, and so forth.’    So forth!  I notice that the authors of this guideline do not include the committee on fetus and newborn. Which I find a bit strange, and probably the reason the authors say that you ‘may’ make an effort to reduce pain (which they try to minimize I think by calling it discomfort), and you might use ‘so forth’. I think the neonatologists on the committee on fetus and newborn would have had more to say about this, and would have requested the evidence base to be reviewed. Each of the individual methods the authors of this guideline suggest have very limited efficacy. Combined methods, using sucrose, swaddling, soothers and local anesthetics are effective, but not 100%, and should be the routine for retinal examinations.

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