Necrotizing Enterocolitis and Surgery

Hull MA, Fisher JG, Gutierrez IM, Jones BA, Kang KH, Kenny M, et al. Mortality and Management of Surgical Necrotizing Enterocolitis in Very Low Birth Weight Neonates: A Prospective Cohort Study. Journal of the American College of Surgeons. 2014;218(6):1148-55. This data is drawn from the Vermont Oxford Network of infants with a diagnosis of NEC. About 50% of the 17,000 infants required surgery, mortality prior to discharge was 30% among surgical cases, mortality among surgical cases was similar for the tiniest babies and for larger ones. Non-surgical NEC had a mortality that was greater among the smallest infants. The age at death is not reported, but prolonged hospitalization and delayed death do occur unfortunately in this group of babies.

Among 182 preterm infants at Great Ormond Street who had surgical NEC, 15 were too sick to go to ‘theater’ and had surgery in the NICU. Wright NJ, Thyoka M, Kiely EM, Pierro A, De Coppi P, Cross KMK, et al. The outcome of critically ill neonates undergoing laparotomy for necrotising enterocolitis in the neonatal intensive care unit: a 10-year review. Journal of Pediatric Surgery. 2014;49(8):1210-4.
They did not do well. 10 of them died within a few hours, another 2 died after prolonged NICU stays. Although this is a very small group, it suggests that if your reason for having surgery in the NICU is that you are too sick to move (rather than doing it in the NICU as a policy) then you should maybe consider if it is really a good idea.

Murthy K, Yanowitz TD, DiGeronimo R, Dykes FD, Zaniletti I, Sharma J, et al. Short-term outcomes for preterm infants with surgical necrotizing enterocolitis. J Perinatol. 2014. And from the Children’s hospitals neonatal consortium, a report of over 700 cases of surgical NEC, the babies were outborn (as it was from children’s hospitals) and were transferred for surgery. The study shows a hospital mortality of about 37% for the less mature babies (<28 weeks), and a little lower for the larger ones, 30%. Two additional outcomes, the frequency of short bowel syndrome was high at about 25% (it was defined as needing TPN for more than 90 days), but all except 2 of them were able to go home without TPN: Hospital stay tended to be very long for survivors, with a median of over 100 days, and a upper third quartile for the immature babies of 168 days. In other words a quarter of surgical NEC babies, <28 weeks, are hospitalised for 6 months or more. The total number of surgical procedures was over 2,800, or about 4 per patient, some were re-anastamosis of ostomies, only 124 had a single laparotomy.

These three very recent studies demonstrate quite clearly how serious surgical NEC is, and how important it is to continue to find ways to prevent it. Probiotics, even though they are effective, are by no means 100% effective.

They also give very clear data from very large groups which we can use to counsel parents. It is not a case of just going to the OR and taking out the sick bowel; starting surgical intervention for NEC often leads to prolonged TPN, prolonged hospitalisation, multiple further interventions, surgical and medical, and, of course, in the long term, reduced developmental and motor abilities.

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Can we share decisions?

I found this article quite insightful. (Joseph-Williams N, Edwards A, Elwyn G: Power imbalance prevents shared decision making. Bmj 2014, 348).

Shared decision making is a buzz-word (buzz-phrase I guess) to describe how to pursue good decision making with patients (or in our case parents). The general idea being that the physicians have the knowledge, the training and the insight to know what options are appropriate, and the risks and benefits of each option. The patient has their values, their opinions, and their preferences, and by putting these aspects together we can come to a decision which is in the best interests of the patient and consistent with their values.

This new article is an analysis piece based on the authors systematic review of the literature of barriers to shared decision-making, as a result of which the authors conclude:

  • Many patients currently feel they can’t participate in shared decision making

  • Power imbalances in the clinical encounter are a key barrier even if patients have the required knowledge

  • Patients need to know that their input is valued and won’t damage their care

  • The attitudes of both patients and clinicians need to change to enable shared decision making

I think the power imbalance in neonatology maybe even more important, many parents do not feel free to express their wishes, their doubts, their hopes, because of the different status of the persons involved, but also because parents are often completely lost at the start of the hospitalisation. It is an experience so far outside of what they have lived before that few have any relevant knowledge when we first meet them and the ‘power imbalance’ is really marked. What to do about this? How do we empower parents, and help them recognize the importance of their part in the shared decisions?

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Gastric acid is good for you

I might have used that title previously, but new data published in JAMAPediatrics supports the concept. In a prospective cohort study the authors cultured fluid from gastroscopies, and bronchoscopies in children, and compared the results between those who were on acid suppression or not.

Gastric cultures were much more likely to be positive if the child was on acid suppression (46% vs 18%). This evidence supports what had been assumed, that the increase in infections which accompanies use of acid suppressants (both in RCTs and observational studies) is due to intestinal bacterial overgrowth, followed by invasive infection.

The bronchoscopies showed fewer differences, but bronchoscopically obtained broncho-alveolar lavage samples are often positive, even in healthy individuals (such a study has never as far as I know been done in children, at least I hope not, but in adult volunteers), so it would be harder to find a difference. Among multiple analyses performed on the bronchoscopy data, there was a correlation between the burden of high non-acid reflux on MII testing, and bacterial concentrations, which suggests that possibly if you reflux, you are better to have acid in order to have fewer bugs in the fluid that you reflux. Maybe.

Another line of evidence to avoid suppressing gastric acid.

In the same episode of release of on-line first articles, a systematic review of the safety and efficacy of ranitidine and similar histamine receptor antagonists in infants and children. They included 8 trials in all with about 275 children, including newborns; the final conclusion:

Evidence to support the efficacy and safety of H2RAs in infants and children is limited and of poor quality.

Released at the same time is an editorial, the opening paragraph of which ends with the following summary phrase :

With a growing body of literature that illustrates a lack of efficacy and alarming adverse effects, there is increasing reason to limit the empirical use of acid suppression therapy in children

And, after outlining the new articles ends with a paragraph which includes the following phrases, which I cannot help but agree with:

Evidence supporting the effectiveness of H2RAs and PPIs in raising gastric pH is undoubtedly strong but evidence supporting the efficacy for symptom treatment is not…… It is becoming clearer that in many circumstances, prescribing acid-reducing medication in infants is doing no good and increasing the risk of harm.

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Inhaled Nitric Oxide in Preterms

Kinsella JP, Cutter GR, Steinhorn RH, Nelin LD, Walsh WF, Finer NN, et al. Noninvasive Inhaled Nitric Oxide Does Not Prevent Bronchopulmonary Dysplasia in Premature Newborns. The Journal of pediatrics. 2014. My Cochrane review (which is in the process of being updated) shows that none of the tested strategies of inhaled NO use in the preterm infant improve survival, or survival without chronic lung disease; with the possible exception of prolonged treatment started at a later postnatal age to prevent BPD. Our individual patient data meta-analysis was also largely negative. One strategy that had not previously been tested was to use iNO in a group of babies who were on non-invasive respiratory support within the first 72 hours of life. In this study 124 babies less than 34 weeks and between 500 and 1250 g, who were on CPAP or receiving O2 via nasal cannulae, were randomized to iNO at 10 ppm or placebo. Both allocation and intervention were masked and 100% of the babies were followed to masked outcome assessment. iNO was given for at least 2 weeks and at least until 30 weeks post-menstrual age.

There were no differences in any important outcome, death, BPD, combined death and BPD or other common complications of prematurity.

Ballard PL, Keller RL, Black DM, Durand DJ, Merrill JD, Eichenwald EC, et al. Inhaled Nitric Oxide Increases Urinary Nitric Oxide Metabolites and Cyclic Guanosine Monophosphate in Premature Infants: Relationship to Pulmonary Outcome. American journal of perinatology. 2014(EFirst). Secondary analysis of data from the pilot study of late surfactant administration (in which babies in both groups were all getting iNO) and from some babies in the full study. There were also a few controls who were not enrolled in the study. The urinary excretion of nitrates and nitrites and GMP were increased during iNO treatment. Nitrate excretion was higher in those babies who did not develop BPD.

Truog WE, Nelin LD, Das A, Kendrick DE, Bell EF, Carlo WA, et al. Inhaled nitric oxide usage in preterm infants in the NICHD neonatal research network: inter-site variation and propensity evaluation. J Perinatol. 2014. Analysis of data from the NICHD network generic database from baies under 29 weeks or under 1 kg. Use of iNO is very variable between centers, and has dropped markedly since the consensus statement was published. Most babies who still get treated are over 7 days of age, and the proportion has dropped from 4.6% among 3000 odd babies before the statement, to 1.6% among 1000 babies afterward.

Although the proportion has dropped, why is iNO still being used in some babies? I think that there are still questions to be answered; although early rescue iNO does not have a benefit in a group of critically ill preterm infants, it is not clear whether a group of preterm babies selected with clear evidence of PPHN, (such babies often have a dramatic acute oxygenation response to iNO), would benefit in terms of clinical outcomes or not. When I am treating a deeply hypoxic 26 week infant who has a serious pre- post-ductal gradient, and who has already had their surfactant, I certainly ask for the iNO, I think that is still reasonable, unless it can be shown that survival is equally good without. The other (larger) group who often get iNO are infants with evolving lung disease who have periods of serious deterioration, often during sepsis. They may become hypoxic and may have echocardiographic evidence of Pulmonary hypertension; a short-term oxygenation response to iNO is not as reliable in such babies, but some of them do saturate better, or with lower oxygen needs. But there were likely few such infants in the RCTs, and I think it is unclear whether iNO helps them or not, in terns of clinical outcomes.

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Diaphragmatic Hernia Stuff

Several recent articles which have some importance for diaphragmatic hernia management

Madenci AL, Sjogren AR, Treadwell MC, Ladino-Torres MF, Drongowski RA, Kreutzman J, et al. Another dimension to survival: predicting outcomes with fetal MRI versus prenatal ultrasound in patients with congenital diaphragmatic hernia. J Pediatr Surg. 2013;48(6):1190-7. Counselling parents about how likely it is that their infant may survive is very tricky. In general. And especially for diaphragmatic hernia patients where the mortality and morbidity are high, but the long term outcome is generally excellent. This study looks at several different indices of lung hypoplasia to determine which, if any, are better than others. It points out, as we already knew, but it bears emphasizing, that the lung head ratio differs during pregnancy, so rather than a single number, the ratio between observed lung-head ratio and the expected ratio is what is predictive of important outcomes. Also fetal MRI with calculation of lung volume (which also obviously should increase during gestation, so the percentage of normal is used as the measure) is a better discriminant of survival, need for ECMO, and ventilator dependency.

Walleyo A, Debus A, Kehl S, Weiss C, Schonberg SO, Schaible T, et al. Periodic MRI lung volume assessment in fetuses with congenital diaphragmatic hernia: prediction of survival, need for ECMO, and development of chronic lung disease. AJR American journal of roentgenology. 2013;201(2):419-26. In this study there were 226 mothers whoer fetuses had repeated fetal MRI. The percentage of expected lung volume was strongly assocaited with survival and need for ECMO. They didn’t compare to ultrasound, though.

Hagelstein C, Weidner M, Kilian AK, Debus A, Walleyo A, Schoenberg S, et al. Repetitive MR measurements of lung volume in fetuses with congenital diaphragmatic hernia: individual development of pulmonary hypoplasia during pregnancy and calculation of weekly lung growth rates. Eur Radiol. 2014;24(2):312-9. This article from the same group, presumably with many of the same babies, calculated the rate of antenatal lung growth. They found :

Individual development of FLV in patients with CDH during pregnancy is extremely variable. Follow-up MR-FLV measurements are advisable before deciding upon pre- and postnatal therapeutic options.

Babies could change from poor to reasonable prognosis lung volumes during pregnancy, and vice versa. Something to keep in mind.

Kays DW, Islam S, Larson SD, Perkins J, Talbert JL. Long-term Maturation of Congenital Diaphragmatic Hernia Treatment Results: Toward Development of a Severity-Specific Treatment Algorithm. Annals of Surgery. 2013;258(4):638-45. An observational study that suggests that one size does not fit all. Suggests different treatment algorithms for different severities of lesion, which makes sense, they suggest that less severe lesions should have delayed surgery, more severe lesoins should have surgery prior to ECMO, rather than after. Interesting but far from conclusive.

Kays DW, Islam S, Richards DS, Larson SD, Perkins JM, Talbert JL. Extracorporeal Life Support in Patients with Congenital Diaphragmatic Hernia: How Long Should We Treat? Journal of the American College of Surgeons. 2014;218(4):808-17. When you start ECMO for a diaphragmatic hernia, you know you may be in for the long run. this review of a large experience (96 ECMO cases of a total of 240), by the sam eauthors as the study above showed :

Of patients still on ECMO at 2 weeks, 56% survived, at 3 weeks 46% survived, and at 4 weeks, 43% of patients still on ECMO survived to discharge. After 5 weeks of ECMO, survival had dropped to 15%, and after 40 days of ECMO support there were no survivors.

Babies on ECMO up to 4 weeks still had good long term pulmonary outcomes. So be patient, but after 4 weeks it looks pretty desperate.

Wright T, Filbrun A, Bryner B, Mychaliska G. Predictors of early lung function in patients with congenital diaphragmatic hernia. J Pediatr Surg. 2014;49(6):882-5. This study looked at lung function in follow up of a group of very high risk CDH patients, during the first 3 years of life. They are actually pretty good. Things that you would expect to be predictors of somewhat poorer function (such as need for ECMO) were indeed, but even with those factors, only moderate abnormalities were found.

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Neonatal Updates

Garel C, Moutard ML. Main congenital cerebral anomalies: how prenatal imaging aids counseling. Fetal diagnosis and therapy. 2014;35(4):229-39. An excellent review article that can assist in prenatal counselling if you have a mother whose fetus has a CNS anomaly.

Baylis R, Ewald U, Gradin M, Nyqvist KH, Rubertsson C, Blomqvist YT. First time events between parents and preterm infants are affected by the designs and routines of neonatal intensive care units. Acta Paediatrica. 2014. How your unit is designed and organized affects the first interactions between parents and their preterm babies.

Finn D, Collins A, Murphy B, Dempsey E. Mode of neonatal death in an Irish maternity centre. Eur J Pediatr. 2014:1-5. A study which points out how different certain countries might be, the persistent influence of the Catholic church in Ireland makes pregnancy termination for any indication very rare, and largely impossible for fetal malformations. The babies who die in an Irish neonatal unit are therefore much more commonly babies with extremely high risk congenital anomalies, who receive comfort care. A much higher proportion of neonatal deaths being in this category than in our NICU, or others which have reported their experience. However there are also similarities, most deaths in the NICU occur after a decision to limit intensive care efforts, and only just over 10% occurred despite on-going full intensive attempts at life-sustaining efforts.

Niemarkt HJ, Kuypers E, Jellema R, Ophelders D, Hutten M, Nikiforou M, Kribs A, Kramer BW: Effects of less-invasive surfactant administration on oxygenation, pulmonary surfactant distribution, and lung compliance in spontaneously breathing preterm lambs. Pediatr Res 2014.In this study the clinical effects (on oxygenation) of surfactant therapy delivered via a thin catheter passed through the larynx were smiliar to the effects of standard intubation and surfactant, even though much less surfactant was delivered to the lungs, and the compliance was not as good in the thin catheter group.

Vasudevan C, Johnson K, Miall LS, Thompson D, Puntis J: The Effect of Parenteral Lipid Emulsions on Pulmonary Hemodynamics and Eicosanoid Metabolites in Preterm Infants: A Pilot Study. Nutrition in Clinical Practice 2013, 28(6):753-757. 5 preterm infants received a lipd emulsion based on olive oil, 10 others received standard soy-based emulsion. I don’t know why they weren’t randomized, even in a small pilot study, and no indication is given why some babies received the one oil or the other. Echocardiography was performed and eicosanoid analysis. Estimated pulmonary artery pressures fell faster in the olive oil group, the ratio between urinary thromboxane B2 and 6-keto-PGF1-alpha fell in the olive oil group and remained unchanged in the soy group. Interesting if limited data, confirming that we need to do a good clinical trial of fat emulsions from different sources.




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Should we all be wearing gloves? Every time we touch a baby?

Two new articles over the summer suggest that the answer to that question may well be yes. The first is the best quality of the studies, an RCT in a single center in the USA. Kaufman DA, Blackman A, Conaway MR, Sinkin RA: Nonsterile glove use in addition to hand hygiene to prevent late-onset infection in preterm infants: Randomized clinical trial. JAMA Pediatrics 2014. 124 babies less than 1kg or less than 29 were randomized. There was a sign placed on a stand next to the incubator informing the caregivers that the baby was in a study; also on the stand was a box of non-sterile gloves for the babies randomized to the gloving group. There was a bottle of alcohol hand rub within arms length of the baby’s bed for babies in both groups.

In the usual care group caregivers were told to use the rub before touching the baby, in the gloving group they also were supposed to clean their hands in the same way, and then put on the gloves. I say ‘supposed to’ because of course we know how lousy hospital staff are at washing their hands.

In the gloving group there were fewer Gram Positive infections, and fewer catheter related infections (at least when using a pragmatic definition, rather than the more stringent CDC definition). As a modestly sized study the authors did not find other differences that you might hope for, such as decreased mortality, decreased length of stay, or decrease in costs, but those things are all driven by multiple factors, and would need a much larger study to prove.

I think this is the only neonatal RCT of this intervention, but it is consistent with 2 before/after studies, one of which was also published during the summer (Janota J, Šebková S, Višňovská M, Kudláčková J, Hamplová D, Zach J: Hand hygiene with alcohol hand rub and gloves reduces the incidence of late onset sepsis in preterm neonates. Acta Paediatrica 2014) This study was restricted to larger preterm infants from 32 weeks gestation onward. Their rationale for excluding the smaller babies was that the CDC already recommends routine glove use for very preterm infants. I do not actually think this is true, the reference they give is to the 3rd article (which ic not from the CDC) that I will refer to briefly, and a search of the CDC website did not turn up any recommendation for universal gloving for care of the very preterm infant; rather gloves are recommended whenever there may be contact with any body fluid. If anyone knows of such a guideline perhaps they would let me know. In this study the authors introduced universal glove use prior to touching any preterm baby in that gestational age range. They compared 7 months before introducing gloves and 7 months after, and found 5 of the 111 babies in the first group developed late-onset sepsis, and none of the 89 in the second group.

The third neonatal study I am aware of was published in 2004 (Ng PC, Wong HL, Lyon DJ, So KW, Liu F, Lam RKY, Wong E, Cheng AFB, Fok TF: Combined use of alcohol hand rub and gloves reduces the incidence of late onset infection in very low birthweight infants. Archives of Disease in Childhood – Fetal and Neonatal Edition 2004, 89(4):F336-F340.). With about 160 VLBW babies per group, they saw a reduction the proportion of babies who had at least 1 infection, from 53% to 31% after they introduced universal glove use.

Readers of this blog will all know that before and after studies are a less reliable source of data than an RCT, and that we should be thoughtful about introducing changes in the care of the very preterm infant. It is also interesting that the 2 observational studies required the caregivers to re-apply the alcohol antiseptic wash after putting on the gloves, and then wait another 15 seconds for the alcohol to dry. In Dr Kaufman’s study they did not do that. In their publicaiton they do not describe all pf the things they did not do (!) so I wrote him to sepcifically ask him about that point, he kindly replied immediately to tell me that they did not require alcohol re-application after putting on the gloves.

Are there other data supporting the universal use of gloves for patient care? An observational study from a pediatric hospital (which included an NICU, Haem/Onc, PICU, and bone marrow transplant unit) compared their infections during RSV season, when the hospital had a policy of universal gloving for all patient contact, to non-RSV season when selective glove use was the norm. Their rates of invasive bacterial infections were lower over the 9 year period whenever universal gloving was the policy, in the NICU, the PICU and the transplant unit. Their overall conclusion was :

Universal gloving is a simple, practical, and feasible prevention strategy that requires minimal time and economic resources. In our study, the routine use of gloves to prevent spread of RSV in pediatric units also prevented other HAIs, such as BSIs and CLABSIs. These secondary benefits support the continuation of universal gloving throughout the year in high-acuity PICUs.

I am not sure why they only state that for the PICU, the data seem just as strong for the NICU and the Bone Marrow Transplant unit.

So are there enough data to start doing this right away? There are a few reasons to be cautious I think, the main one being that there are observational data showing that people are even worse at washing their hands when they are required to wear gloves. Gloves easily get contaminated when you put them on, so you still have to wash your hands properly before putting on the gloves (and when you take them off!). During a clinical trial the results might be different to what would happen over a long time in routine practice, would the benefits decrease as caregivers became blasé about hand-washing, because ‘I am going to wear gloves anyway’?

I think this requires some more thought and some more study, but it may be the way to go.

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