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May I ask whether anyone has experience with a prolonged hanging time of a parenteral nutrition (PN) bag (incl lipids) of up to 48h? We are probably changing our PN regimen into an all-in-one bag. Since the bag contains >400 mL, it would suffice for most premature infants for 2 days. One strategy could thus be to prolong hang time from 24h to 48h to cut PN costs by half. A recent Australian study (attached) also suggests this would be a feasible approach: https://www.ncbi.nlm.nih.gov/pubmed/23320598 Since our pharmacy will do all additions to the bag in an aseptic environment, including connection and filling the line, I think it could be an attractive solution. Also there is an air-filled dripping chamber in the line, so there exists no continuous fluid-filled connection from the patient to the PN-bag. On the other hand, the line would be in place for 48h as well, so this could form a potential risk. We must be sure it is a safe approach though… What are your thoughts and experiences on this matter? Thank you so much, best wishes, Chris van den Akker, neonatologist Amsterdam UMC, the Netherlands

Oral immune therapy (OIT) has really taken off at least in our units. The notion here is that provision of small amounts (0.2 mL intrabucally q2or 24 hours) can prime the immune system. Lymphoid tissue present in the oropharynx and intestine exposed to this liquid gold in theory will give the immune system a boost and increase levels of IgA. Such rises in IgA could help improve the mucosal defence barrier and therefore lessen the incidence of late onset sepsis. Rodriguez et al described this in their paper Oropharyngeal administration of colostrum to extremely low birth weight infants: theoretical perspectives in 2009. They followed it up the next year with a pilot study demonstrating how to actually administer such therapy. The fact that this approach has been adopted so quickly I think speaks to the principle that this kind of therapy falls into the category of “can’t hurt and might help”. The real question though is does it actually make a difference? Recently, authors from Brazil presented their findings from a single centre double blind RCT entitled Randomized Controlled Trial of Oropharyngeal Colostrum Administration in Very-low-birth-weight Preterm Infants. This authors are commended for studying this practice in such a fashion and included infants <34 weeks who were <1500g at birth to receive the above mentioned intervention. These infants were compared to placebo who received the same intervention except instead of mother’s own colostrum they were given sterile water. In total there were 149 infants randomized with 81 receiving OIT vs 68 who received a placebo. The primary outcome of interest on which a power calculation was performed was the incidence of late onset sepsis. Other typical outcomes including NEC, ROP, BPD, IVH and death were also followed. Did they find a difference? Sadly to many of you I am sure they did not as is shown in the table below. Surprisingly the authors also looked at levels of IgA in infants in both arms and also found no difference. There is a big problem with this study however that no doubt will lead to a repeat version at some point. While the authors enrolled the numbers above, the numbers that were analyzed in the table are 34 lower in the OIT arm and only 2 lower in the placebo group. In essence, a large number of mothers after enrollment were not able to provide the colostrum that was needed for the study. The study called for 48 applications over a 48 hour period and a little more than half of the mothers were able to do it. Do not be dismayed then that no difference was found here. There is no need to “throw the baby out with the bathwater” and abandon OIT based on this one study. I think what is needed in the future though is a study that enrolls far more than needed to account for attrition due to loss of mothers who can complete the study. Without another study I think the practice will continue but does it really make a difference to rates of sepsis? Who knows but there is no doubt it helps parents who are feeling that they have lost control of a pregnancy that has gone wrong, a positive experience and the feeling that they are doing something for their child.

If you work in the NICU then you have seen your fair share of septic workups for late onset sepsis. Sepsis is such a common diagnosis that if I had to guess I would say that at least 50% of all discharge summaries would include this in a list of final diagnoses for any VLBW infant. If you were to look through the chart though you would find that while workups are common, the recovery of a pathogenic bacterium is not as much. This is in part due to the low threshold that many people have for doing such workups. A little bit of temperature instability, a few more apneic events than normal or a rise in O2 requirements may all trigger such investigations. When they come back negative we all feel good that we looked but we also are then quick to blame the etiology on something else. Mild fluctuations in temperature are written off as overbundling, apnea due to outgrowth of caffeine and a rise in FiO2 to evolving CLD. Maybe though the explanation at least in some cases is that there was a pathogen but we didn’t test for it. Viruses are everywhere Tis the season so to speak so everyone is on high alert for viruses in our homes, schools, malls etc but many of us consider the NICU to be mostly free of such pathogens. The truth is we mostly are provided that we all wash our hands well, keep sick contacts from visiting and put on a mask when our coughing starts. Alas, if you have done a handwashing audit as we have you would know that when looking at technique and duration of handwashing, we don’t always hit 100%. These audits are for health care practitioners but I have often wondered what sort of results we would see were we to do the same for parents and visitors. When we know the viruses are out there such as during outbreaks of RSV and influenza we can’t help but send off our samples for respiratory viruses more frequently but what if we did this with intention for every late onset septic workup? Lucky For Us Someone Did Just That! Back in 2014 the following study was published. Viral respiratory tract infections in the neonatal intensive care unit: the VIRIoN-I study. This was a simple prospective and elegant study in which any infant in the NICU who had never been home and was greater than 72 hours had respiratory samples sent for viral panels within 72 hours of starting antibiotics for presumed late onset sepsis. The findings were certainly interesting in that 6% of 135 sepsis evaluations tested positive for a virus. In the analysis, the infants had the following characteristics: tended to be older (41 vs 11 days; P = .007) exposed to individuals with respiratory tract viral symptoms (37% vs 2%; P = .003) lower total neutrophil counts (P = .02) best predictor of viral infection was the caregivers’ clinical suspicion of viral infection (P = .006) What interests me about these results are a couple things. The first is that as I was once told, the sensitivity of asking if someone has been around sick people is low during peaks in viral outbreaks as who hasn’t? Perhaps what this study tells us is that within the NICU environment we actually do a reasonable job of keeping such contacts away but when they slip through infections happen. The second point worth mentioning is that a low neutrophil count is associated which is interesting given how often neutropenia is pointed to as a reason to start antibiotics. These viruses are troublesome creatures indeed! Further Evidence Arrives At the end of last year a similar study was published by the same group Viral Respiratory Infections in Preterm Infants during and after Hospitalization. They took a different approach this time out and took nasopharyngeal samples from 189 infants in the NICU (96 term and 93 preterm) within 7 days of birth and then sent samples weekly while in hospital followed by monthly for four months after discharge. In this collection of infants a mere 4 patients tested positive in NICU and all of them under 28 weeks of age at birth! How do we account for the remarkable reduction in risk while in hospital? To answer that you can read through the NICU environment in the full article if you have access. In short, they had a very rigorous infection control set of precautions set up. Interestingly only one of the infections was with RSV and the unit did not provide prophylaxis for infants in hospital. Perhaps with precautions like theirs they felt it was unnecessary. Once discharged a little over a third of patients acquired a viral infection in the first four months at home. Given the potential risk for readmission and with that to a PICU this rate of viral infection is concerning. Vision for the future! Taken together we can state that viruses do make their way into the NICU but fortunately not as commonly as one might think. What the last study in particular does remind us though is that we need to ensure that as part of discharge teaching parents take home many of the practices that we have used in the hospital with respect to hand hygiene, limiting visitors and not being afraid to holster some hand sanitizer for those times when soap and water are not so easy to come by. To be sure viruses are out there but at least for the first few months after discharge for our most vulnerable babies a little paranoia about viruses could go a long way.

It is one of the first things that a medical student pledges to do; that is to do no harm. We are a fearful lot, wanting to do what is best for our patients while minimizing any pain and suffering along the way. This is an admirable goal and one which I would hope all practitioners would strive to excel at. There are times however when we can inadvertently cause more harm than good when we try to avoid what we perceive is the greater harm. This is the case when it comes to collecting a sample of urine for culture as part of a full septic workup. If you ask most healthcare providers they will freely acknowledge that the gold standard for determining whether an infant has a UTI is a supra pubic aspirate (SPA). We so rarely do them these days however due to a whole host of reasons. Problems with collection include the timing and accuracy of needle placement both of which may often lead to an empty tap. Secondly after a number of missed attempts and a crying infant who appears to be in pain it is understandable why bedside nurses may become frustrated with the entire experience and urge the person performing such procedures to settle on a bladder catheterization (BC) to obtain the specimen. The Study That Compares BC and SPA Head to Head A recent Turkish study by Eliacik K et al published A Comparison of Bladder Catheterization and Suprapubic Aspiration Methods for Urine Sample Collection From Infants With a Suspected Urinary Tract Infection and should give us all cause for concern. The authors performed SPA on 83 infants under 12 months with a positive urine culture by BC but who had not yet started antibiotics. The outcome of interest was both the comparison with the culture result and to see if urinalysis from the BC could increase the strength of the information gleaned from a BC. All in all the BC performed quite poorly when compared to the gold standard. The false positive rate compared to SPA was 71.1%! That is to say that only 28.9% of SPA samples were positive compared to BC. Similarly urinalysis sensitivity and specificity from BC were 66.7% (95% CI, 44.68% to 84.33%) and 93.22% (95% CI, 83.53% to 98.08%), respectively. This means that only 2/3 of the time was the urinalysis abnormal on a BC in the presence of a true UTI. Somewhat reassuring is that when there really was no UTI the urinalysis was mostly negative but in almost 1/10 patients it would not by itself rule out a UTI. What Is The Harm in Continuing BC Instead of SPA? When we try to avoid the perceived painful experience of a SPA we are going to wind up treating a large number of patients for a presumed UTI who don't have one. The harm in this is the exposure of such infants to prolonged courses of antibiotics which has been a subject discussed many times over on this site. We put our patients at risk of antibiotic resistance and shifts in the gut microbiome which in the case of the preterm infant puts them at risk of necrotizing enterocolitis. There are many other concerns with prolonging antibiotics but these few should be reason enough to strive for accuracy in obtaining the right specimen in the right way. Putting it in a slightly different perspective, would you settle for an alternative test to a lumbar puncture which claimed to miss 1 in 10 cases and also found meningitis where there was none 71.1% of the time?! A Way Forward - A Recipe For Success As the saying goes, measure twice and cut once. With the use of bedside ultrasound there should be no need to guess as to whether the bladder is full or not. Secondly the placement of the needle should no longer need to rely on landmarking but actually seeing where the best place for needle placement is. Assessing the bladder by ultrasound is easy and is already employed at the bedside by nurses in many areas of the hospital. There should no longer be a reason for the empty tap as the practitioner can be called when the baby is ready as evidenced by a good amount of urine in the bladder. Given that we have some time to do the blood culture and LP, while we wait for the SPA to be done either sucrose in the premature infant or IV analgesic may be given for the SPA while in the term or older infant there is an opportunity to put a topical analgesic cream over the site. There really is little need for pain to factor into this any longer. Ask any health care provider and they will tell you they want to do the best they can for their patient. This study shows us that performing a BC is failing to meet that goal. We need to change our ways and return to the practice of the SPA but this time we have to get it right.

I read an article about 10 years ago that suggested that foul smelling amniotic fluid was NOT a strong risk factor for sepsis (I remember this well because this went against my residency teaching-either that or I am losing my faculties!). The article stated the smelliest bugs at delivery were not usually the ones that caused the most trouble in infants. Am I losing my mind or can anyone else recall this? I often teach students and I want to have my facts straight. I was able to find a few studies with small samples that listed smelly fluid as a risk factor. On the Cochrane database the article on neonatal sepsis lists chorioamnionitis as a risk but says nothing specifically about smelly fluid. Thanks, Mike