Preventing and Treating Sepsis in Preterm Babies

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

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

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

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

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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Ventilating infants with Diaphragmatic Hernia

Snoek KG, et al. Conventional Mechanical Ventilation Versus High-frequency Oscillatory Ventilation for Congenital Diaphragmatic Hernia: A Randomized Clinical Trial (The VICI-trial). Ann Surg. 2015.

There a few few remarkable things about this study; the first is part of the preamble:

Since 2008, all CDH patients born in European countries represented in the CDH EURO consortium have been treated according to a standardized neonatal treatment protocol that was developed at a consensus meeting. After implementation of this protocol, mortality decreased from 33% to 12%. This decrease in mortality rate should be interpreted against of the year upon year variability in mortality rates. Nevertheless, standardization of care is an ideal backcloth to undertake multicenter randomized controlled trials (RCTs).

In this study full term babies with an antenatal diagnosis of CDH were randomized to start on either conventional ventilation (Initial settings were a positive inspiratory pressure (PIP) of 20 to 25 cmH2O and a positive end-expiratory pressure (PEEP) of 3 to 5 cmH2O, with a ventilator rate of 40 to 60/min) or high frequency ventilation (mean airway pressure 13 to 17 cmH2O, frequency 10 to 12 Hz, delta P 30 to 50 cmH2O depending on chest wall vibration). There were a fairly complex list of signs of failure of the initial ventilation mode (If these things happen for at least 3 hours: inability to maintain preductal saturations above 85% or postductal saturations above 70% ; increase in CO2 > 65 mm Hg despite optimization of ventilatory management; PIP > 28 cmH2O; mean airway pressure >17 cmH2O; inadequate oxygen delivery with metabolic acidosis defined as lactate 5 mmol/L and pH < 7.20; hypotension resistant to fluid therapy and inotropic support resulting in a urine output <0.5 ml/kg/hour; oxygenation index of 40). In which case they could be switched to the other ventilation mode, and if that didn’t work they could be placed on ECMO.

The primary outcome of the study was survival without chronic lung disease (oxygen requirement at 28 days). Over 5 years they enrolled 171 patients, far short of the hoped for 200 per group. In the Conventional group 45% died or had chronic lung disease compared to 53% in the HFO group, a difference which may have been due to chance, (p= 0.3). Many of the secondary outcomes were better in the conventional group, there was much less need for ECMO (26% vs 51%), they were ventilated for fewer days,
less often received inhaled nitric oxide, or sildenafil, had a shorter duration of
vasoactive drugs, and less often failed treatment.

I think the study is a remarkable achievement, as far as I can see this is by far the largest RCT of infants with CDH that has ever been performed. Even though it was unfortunately stopped before the full sample size, it looks unlikely that an advantage of initial HFO would have been shown. As we are unlikely to have any other data of this quality for a very long time, I think the conclusion should be that the starting assisted ventilation mode for infants with CDH should be conventional ventilation, unless there is some very good reason for choosing HFO.

We can only hope that this collaborative group will continue to perform important clinical studies in these babies, who remain a group with very high mortality despite the advances of the last several years. I would vote for a good trial of sildenafil, a comparison of different criteria for ECMO, and more studies of different aspects of assisted ventilation. Maybe a study of muscle relaxation as well, if that wasn’t asking too much!

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A New Publication

Janvier A, Farlow B, Barrington KJ. Cardiac surgery for children with trisomies 13 and 18: Where are we now? Seminars in Perinatology. 2016. Annie and Barb and I have just published this review of the current situation regarding cardiac surgery for infants with the aneuploidies in the title. (For those who don’t know, Barb Farlow is a mother of a child, who has sadly died, who had trisomy 13.) In addition to discussing the literature we make some recommendations about how to help families making difficult decisions. The literature review is limited by the common practice of lumping together all kinds of cardiac surgery, from ASD repairs to Fontan procedures and Norwoods. Also few papers describe whether there was withholding or withdrawal of life-sustaining interventions at any time.

Nevertheless, it is clear that prolonged survival after cardiac surgery is possible.

Our hope is that we will move away from the universal denial of cardiac surgery, which still occurs in some places. On the other hand it is not appropriate, for any patient, to ignore their other problems pretending they don’t exist, infants with aneuploidies often have other difficulties, which may be serious, but which are very variable. Only by making a decision with the parents which is medically appropriate, likely to improve their life, and consistent with the families values, will we be able to truly act in their best interests.

We offer some guidance which will hopefully be helpful, this is an abbreviated version of our suggestions.

(1) Words are important, avoid these words: “vegetable,” “futile,” “lethal,” “incompatible with life,” “waste of time/resources/emotions,” “Tee 13 or 18,” “it, that,” “product of conception,” “hopeless,” “nothing we can do.”

(2) Avoid unfounded and biased predictions: do not tell parents that this child will have a negative impact on their family, their other children, or their lives.

(3) Recognize that each child and family is unique

(4) Provide balanced counseling: which includes recent medical information, as well as the experience of families who live(d) with children with these conditions.

(5) Personalize the information: all infants are different, even if they carry the same label.

(6) One step at the time: decisions about potential complex cardiac interventions need not be discussed and decided upon prenatally, but be forthright about care options for stable children.

(7) Provide parents with different possible outcomes for their fetus/child (including stillbirth): emphasize the spectrum and uniqueness of each child and the lack of control you and they have on many of these outcomes.

(8) Empower parents: recognize that this diagnosis is difficult for parents, that they are doing their best.

(9) Offer reasonable hope:  hope that their child might defy the odds and hope that her life, however long, will have an enriching and positive influence on all who love her.

(10) Support parents: ask them how you can help them.

We hope that families facing these decisions will find caregivers who are sensitive to their needs, willing to consider the options, and supportive.

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