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  1. I met the author of this article at a CPS meeting a few years ago, she immediately impressed me with her unique perspective. Paige is a developmental pediatrician who does long-term follow-up of preterms, and is involved in developmental evaluation and intervention of children with other challenges, including Spina Bifida. Church P. A personal perspective on disability: Between the words. JAMA Pediatrics. 2017. As you will see if you read the article, Paige has a form of Spina Bifida herself, a Lipomyelomeningocele, with a neurogenic bladder and neurogenic bowel, requiring life-long interventions. She discusses the poor tolerance many medical people have of disability, and such how things are often discussed as black or white, whereas having a profound personal experience of disability has made her much more nuanced. She recounts being involved in a discussion regarding a "selective reduction" of a twin pregnancy where the twin being considered for "reduction", i.e. abortion, had a similar lesion to her own. That is an experience that I can barely understand: how would I react if a family was considering terminating a pregnancy because of a condition that I had? Paige recounts the episode with tact and humanity. I can imagine, as I have heard them many times, the words of the other physicians involved in such a decision, I am sure they talked about handicaps and limitations, poor quality of life, pain, and restrictions on family life. Most of which is said with good intentions but with no real knowledge of the literature, or of the range of experiences of families living with the challenges. Just as with similar discussions regarding extreme preterm infants, a list of complications, interventions, disabilities, and long-term problems is often presented, but with no similar list of benefits, achievements, abilities, long-term adaptation, and happiness. Near the end of her moving piece Paige writes: Like most things in life, and medicine, disability is sharp, painful, humbling, as well as tremendous, giving, awe-inspiring. It is human. It is not easily distilled to an all or none discussion. Medicine sets the tone for this discussion and, to date, has done a miserable job. More is needed to appreciate the incredible opportunities that disability poses. More education is needed to provide the counselling families deserve: balanced, sensitive, thoughtful, and individualized rather than “objective.” I sincerely hope that this piece by Paige will be part of a new discussion about these issues. (Of note, even though the article is behind a paywall, JAMA lets you see the first page of the article before buying, in this case there is only one page, so you can read the whole thing for free!)
  2. The PREMILOC trial was a multi-center RCT of hydrocortisone, 0.5mg/kg twice per day for 7 days followed by 0.5 mg/kg per day for 3 days, given starting within 24 hours of age to infants of 24 to less than 28 weeks gestation. Neurological and developmental follow-up has just been published (Baud O, et al. Association between early low-dose hydrocortisone therapy in extremely preterm neonates and neurodevelopmental outcomes at 2 years of age. JAMA. 2017;317(13):1329-37.) There were 523 infants initially enrolled and 406 who survived to 2 years of age, 93% of those were seen at between 21 and 23 months corrected age, for examination and evaluation with standardized instruments. You probably remember that the primary outcome of the trial was survival without BPD, which was somewhat reduced by the intervention (51% compared to 60% in controls). This was as a result of fewer deaths (18% compared to 23%) and less BPD (22% compared to 26%) neither of which component of the primary outcome was individually significant. In this follow-up study the authors not that after the 36 week end of the main data collection there were a further 8 deaths, 7 in the control group and 1 in the hydrocortisone group, 5 of which were from severe BPD (4 vs 1). (These deaths were also reported as the deaths before discharge in the initial publication, but I don't think the causes were noted). All of the babies followed had a standardized neurologic evaluation, but unfortunately only 80% of them had the revised Brunet-Lézine evaluation of developmental progress, which gives a developmental quotient, standardized, as usual, with a population mean of 100 and SD of 15. Basically there were no differences between the groups on neurological signs of impairment, or developmental scores. For example there were 6% of the hydrocortisone and 5% of the control group who developed cerebral palsy. Mean Global Development score was 91.7 in the hydrocortisone group and 91.4 in the control group. I guess one could say that if there is less BPD and no increase in neuro or developmental adverse effects, we should think of using this as routine therapy? But the group also report clinically important respiratory outcomes up to 2 years of age : You can see from their table 2 that there is no sign of better respiratory health (or incidentally any effect on growth outcomes) among the survivors, with some of the minor differences being in one direction, some in the other direction. Which calls into question again the use of oxygen at 36 weeks, as an outcome for RCTs even when combined with an oxygen reduction test, as in this trial. If kids are more likely to be out of oxygen at 36 weeks, but no more likely to go home on oxygen (14 babies in each group) and not more likely to have respiratory problems in follow-up, then the significance of getting extubated earlier, or needing oxygen for fewer days is questionable, at least the significance to families. I think those outcomes are indeed benefits to families, its much better to see your baby with CPAP or non-invasive ventilation than intubated, but if there is on clear long-term benefit then we should be pretty certain that there is no harm before instituting this as routine therapy. Currently, is there any other evidence of harm from this approach? In the initial data from this trial, late onset sepsis was higher (31% vs 25% had at least one episode), NEC was higher (7% vs 5%) GI perforation was higher (5% vs 4%) use of insulin for hyperglycemia was higher (38% vs 34%) and severe RoP was higher (2% vs 1%) all of which could be due to chance effects, but the study was not powered to detect such small, but potentially important, differences; indeed in one subgroup, the most immature infants, the impact of steroids on late onset sepsis was, indeed quite different, 40% vs 23%, and their analysis showed this was unlikely due to chance. Its interesting in the on-line supplementary appendix that the major difference in late onset sepsis arose after the end of the treatment period. It is also interesting that this dose of hydrocortisone had no evident impact on blood pressures, nor on the use of dopamine. I think that all of these worrying differences between the groups, favoring control, with no evidence of long-term benefit, and the only evidence of short-term benefit being shorter intubation and shorter duration of oxygen therapy, that we should not introduce this regime as a routine in our patients. There is a minor difference in survival with the hydrocortisone treatment though, with 19% mortality before discharge (and before 2 years) compared to 25% in the control group. I calculate the 95% confidence intervals of this 6% difference as being between 13% fewer deaths and 1% more deaths, using early low dose hydrocortisone in similar babies. Unfortunately, I think I have to say that this therefore warrants further study. A larger trial with enough power to detect a 5% difference in mortality, perhaps in a region where the survival at 24 and 25 weeks is above 65% (as in this French multi-center trial; compared to for example 78% in the CNN database from 2015) should be performed. I think a future trial should not use this as a definition of bronchopulmonary dysplasia, other definitions have been suggested, such as this recent publication from the CNN (Isayama T, et al. Revisiting the Definition of Bronchopulmonary Dysplasia: Effect of Changing Panoply of Respiratory Support for Preterm Neonates. JAMA Pediatr. 2017;171(3):271-9.) In this study the best discrimination between those who had serious respiratory morbidity after discharge (when seen at 18 month follow up) from data collected during the neonatal period, was the need for oxygen or respiratory support (anything that gave positive pressure including high-flow cannulae at more than 1.5 litres per minute) at 40 weeks post-menstrual age. Serious respiratory morbidity was defined as either (1) 3 or more rehospitalizations after NICU discharge owing to respiratory problems (infectious or noninfectious); (2) having a tracheostomy; (3) using respiratory monitoring or support devices at home such as an apnea monitor or pulse oximeter; and (4) being on home oxygen or continuous positive airway pressure at the time of assessment between 18 and 21 months corrected age. Just as important, a recognition that lung injury in the newborn is a continuous spectrum, and that artificially dividing that into 2 categories, with and without lung injury is an artificial distinction designed to aid research design, not to help babies, or their families. A description of long term respiratory morbidity between groups is essential, rather than a label based on an intermediate outcoem. Mortality, in contrast, is truly a dichotomous outcome, and if it can possibly be improved by low dose early hydrocortisone, than we should pursue that possibility with more studies.
  3. In this rather weird, but interesting study from Italy, 10 mothers of preterm babies (less than 32 weeks or less than 1500 grams) without ultrasound brain injury or severe retinopathy, and 11 mothers of full term babies were shown photos of their own baby or photos of an unknown baby (from one of the other mothers) while they had their head in an MRI magnet. (Montirosso R, et al. Greater brain response to emotional expressions of their own children in mothers of preterm infants: an fMRI study. J Perinatol. 2017). The photos were of their baby's face while happy, neutral, or crying. Using functional MRI the researchers determined the activation of several different brain areas, at 3 months corrected age. All the mothers had more activation in several areas when looking at their own baby's face than when looking at the unknown baby. When they compared the responses between the groups, the preterm mothers had greater activation in several areas both when looking at their own baby's face, and also when looking at the unknown baby's face, than the term mothers, and when viewing their own infant's face they showed increased activation in an emotion processing area (i.e., inferior frontal gyrus) and areas for social cognition (i.e., supramarginal gyrus) and affiliative behavior (i.e., insula). The mothers were reasonably well matched, and not suffering from postnatal depression or anxiety. The weeks of stress in an NICU watching their baby and being able to do little to protect them look like they change a mother's brain function. Now what about the dads? Another article (Paules C, et al. Threatened preterm labor is a risk factor for impaired cognitive development in early childhood. Am J Obstet Gynecol. 2017;216(2):157 e1- e7). and a very interesting editorial, compared 3 groups of children at 2 years corrected age. Babies born late preterm and infants who had been born at term, after an episode of preterm labour. And a group born at term, without a history of preterm labour. The groups were fairly small, (22, 23 and 42 respectively). The episode of threatened preterm labour occurred between 25 and 36 weeks gestation, and isn't described in this paper, in terms of actual gestational age or other complications associated, except that the membranes were not ruptured. Some of the mothers received steroids, and that was different between the late preterm born babies (55%) and the term delivering babies (100%). The babies born after threatened preterm labour, whether they delivered at term or late preterm had scores on the developmental/cognitive/motor function screening test which were very similar to each other in almost all domains, and also lower in almost all domains than the controls. Overall, the Odds Ratio for what they call "mild delays in development" (more than 1 standard deviation below the mean, which is really in the lower part of the normal distribution), at 2 years was about 2.0, after an episode of preterm labour. A very interesting editorial confirms that this is probably the first study to have published such outcomes, although previous studies have shown an increase in SGA after threatened preterm labour. In this new study, also, the threatened preterm labour babies born at term weighed 200 grams on average less than the controls despite being born only 1 day earlier. If this finding is true (and in such a small study we should be careful about relying on it too much) then the big question is: why? Why should an episode of threatened preterm labour, which resolves with eventual delivery at term have an effect on cerebral development? Is it an antenatal influence of perhaps increased intra-amniotic inflammation? Does such an episode affect the home environment? Is it related to the somewhat higher educational level of the control mothers? (Although this was included in the logistic regression model, the differences are quite large, 30% of term delivering babies after preterm labour only had primary education, compared to 14% of controls). If this finding is confirmed it might lead the way to further research studying the mechanisms, and help us get a handle on the impacts of preterm birth after preterm labour also.
  4. I have never been convinced that fluid restriction is a good thing for kids with BPD. I think the common practice came about because of the short-term improvements in lung function that sometimes follow if you start diuretics. The idea being that if diuretics improve lung function, then giving less fluid will also. But this is a false equivalency, diuretics cause sodium depletion, and therefore decrease total body water, and probably lung water content also. Fluid restriction in contrast leads to a reduction in urine output, and, within clinically reasonable limits, will not have an impact on total body water, and there is no reason to believe that they will reduce lung water content either. Diuretics may have other direct effects on pulmonary function, that will not occur with fluid restriction. Inhaled furosemide, for example, improves pulmonary mechanics in BPD, presumably by acting on the same sort of ion pump that loop diuretics block in the kidney. Even in adults with fluid overload (those with oedematous congestive heart failure) RCTs of fluid restricion show no effect, unless sodium intake is also severely restricted. Sodium restriction alone works as well, so the fluid restriction adds nothing. Despite this, there are recommendations from usually reliable people that babies with BPD should have their fluid intake restricted, such recommendations are often accompanied by a reference, usually a reference to another recommendation or to a narrative-type review article. I have been planning for years to do a systematic review for the Cochrane library, of fluid restriction as treatment for early or established BPD. We have finally finished the review and it has just appeared. (Barrington KJ, Fortin-Pellerin E, Pennaforte T. Fluid restriction for treatment of preterm infants with chronic lung disease. Cochrane Database of Systematic Reviews. 2017(2).) Using the usual search procedures we could only find one relevant trial. In fact the initial search didn't find the article (Fewtrell MS, et al. Randomized trial of high nutrient density formula versus standard formula in chronic lung disease. Acta Paediatrica. 1997;86(6):577-82.) even though I knew it existed; the Pubmed key words did not mention fluid volumes or restriction, so we tweaked the search to ensure that we found the article, and to make sure that we would find any others that exist. So the only RCT evidence addressing fluid restriction is a study of 60 preterm babies with early chronic lung disease (needing oxygen at 28 days of age) who were randomized to either get 180 mL/kg/day of a regular formula, or 145 mL/kg/d of a concentrated formula. Unfortunately they didn't report on one of our outcomes, oxygen requirement at 36 weeks, as it wasn't the standard outcome that it has since become. That study showed no benefit of fluid restriction on any outcome. The fluid restricted group had more apneas, a finding unlikely to be due to chance, and also had more babies who needed more than 30% oxygen during the trial, a difference which may have been due to chance. Fluid restriction risks nutritional restriction also; even though the idea may be to reduce the free water intake, babies often get fewer calories and less protein when fluid restricted, while babies with BPD actually need more calories. They will also produce more concentrated urine, which might increase the risk of nephroclacinosis as well. The final message is that there is no evidence to support the practice of fluid restriction of babies with early or established BPD. There is no physiologic rationale either. There are potential risks to the practice. We should stop doing it.
  5. In 2007, when I was chair of the CPS Fetus and Newborn Committee, we published a guideline regarding the approach to term and late preterm infants with perinatal risk factors for sepsis. Obviously any infant with clinical signs consistent with sepsis needs immediate work up and antibiotics, but the management of infants with risk factors for sepsis and no clinical signs evident was the focus of that guideline. This is what we said about chorioamnionitis, based on what we thought was the most reliable literature: The risk of sepsis (which may be due to a variety of different organisms, including GBS, E coli and other Gram-negative organisms) in an infant whose mother had definite chorioamnionitis is approximately 8%, and is approximately 3% to 4% if ‘possible’ and ‘definite’ chorioamnionitis are considered together [31][32] (evidence level 2b); among all mothers with fever, the incidence is 2% to 6% depending on the height of the fever [31] (evidence level 2b). Infants who do not have signs at birth are unlikely to develop sepsis, the odds ratio for sepsis among infants who are well at birth is 0.26 (95% CI 0.11 to 0.63) [31]. The incidence of invasive infection in the present study in an initially well-appearing infant with a maternal history of fever or chorioamnionitis was less than 2%, and this is confirmed by other data [33] (evidence level 2b). Therefore, it seems reasonable to perform a CBC and closely observe such an infant, and to only perform a full diagnostic evaluation and treat with antibiotics if the CBC is strongly suggestive of infection (low total WBC count) or if clinical signs develop. A requirement for extensive resuscitation at birth should be considered a sign of possible infection in such infants [32][33]. At that time the CDC guidelines recommended cultures and empiric antibiotics for all such infants, the CDC guidelines were updated in 2010, and continue to recommend the same thing, with the clarification that you should talk to the obstetricians (always a good idea!) Well-appearing newborns whose mothers had suspected chorioamnionitis should undergo a limited evaluation and receive antibiotic therapy pending culture results (AII). The evaluation should include a blood culture and a CBC including white blood cell differential and platelet count; no chest radiograph or lumbar puncture is needed. Consultation with obstetric providers to assess whether chorioamnionitis was suspected is important to determine neonatal management (CIII). Is there anything new recently? I think you all know the answer to that question. Braun D, et al. Low Rate of Perinatal Sepsis in Term Infants of Mothers with Chorioamnionitis. Amer J Perinatol. 2016;33(02):143-50. This database analysis from Kaiser Permanent Southern California found an incidence of maternal fever in labour (38 degrees or more) at or after 35 weeks to be 9% and chorioamnionitis (based on ICD-9 codes from discharge data) to be 4%, chorioamnionitis based on a fever of 38 degrees followed by antibiotic treatment was 5%. There were around 30,000 deliveries in this cohort and in total there were 19 babies with culture positive early onset sepsis, 14 were symptomatic and 5 had bacteremia without clinical signs. That gives an overall incidence of culture positive symptomatic sepsis of 0.45 per 1000, and of culture positive bacteremia without clinical signs of 0.16 per 1000. Among mothers without fever the rate of sepsis was 0.5 per 1000, if they had fever without chorioamnionitis it was 0.6 per 1000, and if they had chorioamnionitis it was 4 per 1000. One interesting thing in this study is that many physicians do not follow the CDC guidelines, the rate of neonatal treatment with antibiotics after maternal chorio, which should be close to 100%, ranged from 7 to 76% in different hospitals. The authors don't say how many of the babies without clinical signs were from the maternal chorio group, there were 5 babies who did not have clinical signs, if all of them were from mothers with chorioamnionitis (which I think is unlikely) then you would have to treat 250 clinically well infants after maternal chorioamnionitis with antibiotics to be sure to cover 1 baby with bacteremia. Of course if some of those babies were symptomatic, then you would have to treat many more without clinical signs for each baby infected, for example if the proportion of asymptomatic babies is the same as in the next study (about 1/3) then you would have to treat over 700 asymptomatic babies to cover that 1 with bacteremia. The authors also calculated that if the CDC guidelines had been followed (for chorioamnionitis, but also for other indications for neonatal antibiotic treatment) then 8% of all the term and late preterm babies would have received 48 hours of antibiotics. Another very large study Wortham JM, et al. Chorioamnionitis and Culture-Confirmed, Early-Onset Neonatal Infections. Pediatrics. 2016;137(1). instituted prospective surveillance for early onset sepsis among nearly 400,000 deliveries. In contrast to the other study they did not collect data from mothers whose babies did not get septic, so we don't know overall incidence of chorioamnionitis in this study, and you can't make some of the same calculations. They found 389 cases of early onset, culture positive, infections, in the cohort which included both preterm and term babies. Eighty-one of those infections were in term babies (37 weeks and more; from 350,000 term deliveries) 58 of which had clinical signs at birth. Which leaves 23 term infants who had no signs at birth but had culture positive sepsis, from mothers with chorioamnionitis, and 6 preterm babies with the same combination. The authors include some babies, 1 at term and 4 preterm, who only had histological evidence of chorioamnionitis, which doesn't help our decision-making as you don't know about those unless you did placental pathology and got the results back. If the prevalence of chorioamnionitis is 4 to 5% (as in the first study), then there would have been about 16,000 cases of chorio among the term deliveries, which gives the incidence of early neonatal sepsis (81/16,000) of 5 per 1000 which is very similar to the Kaiser Permanent data. We know 23 were without signs at birth (but one of those would not have had a diagnosis of chorio) so to ensure that 22 those asymptomatic babies with sepsis received early treatment, you would have to screen, culture and treat 16,000 babies, which is a number needed to treat of over 700. I think that is too many. NICE in the UK seems to have a similar opinion in their guideline from 2012, their guidance is a little more complicated, but goes like this (the links should work to take you to the tables): Use the following framework based on risk factors and clinical indicators, including red flags (see tables 1 and 2), to direct antibiotic management decisions: In babies with any red flags, or with two or more 'non-red flag' risk factors or clinical indicators (see tables 1 and 2), perform investigations (see recommendations– and start antibiotic treatment. Do not delay starting antibiotics pending the test results (see recommendations– In babies without red flags and only one risk factor or one clinical indicator, using clinical judgement, consider: whether it is safe to withhold antibiotics, and whether it is necessary to monitor the baby's vital signs and clinical condition – if monitoring is required continue it for at least 12 hours (at 0, 1 and 2 hours and then 2-hourly for 10 hours). In their scheme chorioamnionitis is a risk factor, but not a "red flag", so if the baby does not have any of the clinical indicators they would be observed, but not treated. As I said I think that an NNT of over 700 is too many, but others may not agree, specifically the parents may not agree. Shouldn't they be involved in that decision? A decision aid may help them to decide, with the medical team, between one or multiple IV installations, antibiotics for 36 hours (you can stop them before the 48 hour dose if cultures are negative) and hospitalisation for at least that long. Depending on how your hospital is organized term newborns on antibiotics may also not be in the room with the mother. The contrasting choice is close observation with the option of starting antibiotics later if clinical signs appear (which happened in 18 of the 23 initially asymptomatic term babies with positive cultures). Also there is no difference in mortality (there was one death in the Wortham study, a baby who died soon after cultures and never had antibiotics, 2 deaths in the Braun study both of whom were symptomatic) shown in these recent studies. Very frequent use of antibiotics of course affects colonization and resistance patterns in an environment, and will affect the development of the infant's microbiome, perhaps for many months or years. I think in these days of shared decision-making and family centered care, when a term baby is born after maternal chorioamnionitis but is clinically well, we should inform the parents that the baby has a very small risk of having an infection, (1 in several hundreds) and that there are 2 options. We should also organize our care so that both close repeated observation, and/or antibiotic administration, can be performed in a mother and infant room, without interfering with breastfeeding and the evolution of the new family, and then give the parents a big place in that decision.
  6. I hope this link stays active for ever as it is a great resource... Courtney Wusthoff from Stanford has developed a web-based educational tool, designed initially, I think, for medical (pediatric) residents. Their team has evaluated whether or not this works by showing pediatric residents videos of actual examinations of asphyxiated newborn infants, and asking them to identify whether the babies were normal or had encephalopathy that was either mild moderate or severe. They repeated the process after using the web-based tool described above. They showed substantial improvements in the skills of residents in evaluation of such infants. Ivy AS, et al. Improving the Identification of Neonatal Encephalopathy: Utility of a Web-Based Video Tool. American journal of perinatology. 2016. Hey, the internet works, sometimes!
  7. When there is a threatened delivery in the periviable period, one of the decisions that have to be made is about the mode of delivery. In my opinion (IMHO, I think those young'uns say) we should consider the different parts of the decision-making to be linked but separate. A decision to give antenatal steroids, for example, does not mandate a cesarean delivery or intensive care of the baby. A decision to not perform a cesarean does not mean that fetal heart rate monitoring should not be performed, or that a live-born baby might not have active resuscitation. One might decide, for example, that a mother will receive betamethasone, with a goal of improving the chances of a good outcome, and we might then decide to plan on providing active intensive care for the baby, but then the decision may be that the risks and benefits, for this particular mother, of performing a cesarean are not consistent with her goals and values; in which case a cesarean for fetal indications will not be performed. We might still want to monitor the fetal heart rate, as knowledge of the heart rate during the last minutes prior to delivery could help in resuscitation decisions; if the fetus has been bradycardic for a prolonged period prior to delivery, and is then born asystolic, a decision to not attempt resuscitation could be quite reasonable, compared to a fetus with good heart rate patterns just before delivery. One part of this decision-making matrix that has been somewhat lacking is good data about maternal complication rates in this time period. What are the risks to the mother of a classical cesarean, a lower segment cesarean, or a vaginal delivery before 26 weeks? What are the risks for this pregnancy, and for the next pregnancy? Several recent articles, one still on-line only, help to clarify the risks (although the relative benefits of each mode of delivery need RCTs for reliable scientific data, which may well never be done). These articles are all therefore observational studies, which describe the frequency of various maternal outcomes after preterm delivery. The first article answers a question for which I last did a literature search a couple of years ago, at that time I wasn't able to find any good data, : "what is the risk of a classical, or an extremely preterm lower transverse, cesarean on uterine rupture in future pregnancies?" This risk is often stated by obstetricians to be a major part of their reluctance to perform a cesarean in the periviable period, and although the risks are clearly greater than for a vaginal delivery I was never sure what was the magnitude of that risk. In this publication the authors state that they also could find no good data, so my lit review was not inadequate, there just was no data. Their study, in contrast, gives very clear information about those risks. Lannon SM, et al. Uterine rupture risk after periviable cesarean delivery. Obstetrics and gynecology. 2015;125(5):1095-100. The authors used linked databases from Washington state to determine the risks of uterine rupture in a subsequent pregnancy after a cesarean delivery performed at 20-26 weeks gestation, and compared the risks to a cesarean performed at term. Overall, the risks of future uterine rupture after a periviable cesarean were about 1.8% (2.4% if you restrict the analysis to classical scars) compared to 0.4% after a cesarean at term. The results are also presented as an Odds Ratio (which is 4.9, 95% CI 1.7-13.1); unfortunately few physicians understand what an Odds Ratio is (but when the risks are small there isn't much difference between the Odds Ratio and the Relative Risk). I think for individual mothers making a decision, that the absolute risks are more useful numbers; also a comparison to cesarean deliveries performed at term is an interesting and useful comparison to put the risks in context, but doesn't help in decision-making much as that isn't the option that would be on the table. There is also a comparison of other maternal morbidities in the current (or "index") pregnancy; periviable cesarean deliveries are a little more morbid (14% of mothers have one or more of transfusion, bleeding, coagulopathy, chorioamnionitis, sepsis, maternal infection or hysterectomy as recorded in the hospital discharge diagnoses, which means that bleeding is not strictly defined) than term cesareans, which I was a bit surprised to see were also pretty morbid (10% had the same complications) but the difference was consistent with a chance finding. Mothers who have a periviable cesarean are different in many ways from mothers having a term cesarean, so how much of the increase in maternal morbidity is due to the classical incision (almost all of the term cesareans are lower segment transverse incisions) and how much to their other demographic and clinical differences? Also important, does having a cesarean delivery at periviable gestation have other effects on subsequent pregnancies, other than the risk of uterine rupture? The same group (Lannon S, et al. Mode of delivery at periviable gestational ages: impact on subsequent reproductive outcomes. Journal of perinatal medicine 2013. p. 691.) has looked at the risks for a subsequent pregnancy, and compared a vaginal birth in the periviable period to a cesarean delivery. Overall having a delivery in the periviable period led to the same outcomes in a subsequent pregnancy regardless of mode of delivery, the gestational age at birth of the subsequent pregnancy were almost identical; the only individual outcome which was affected was uterine rupture. There were some very small differences, which were statistically significant because of the large numbers of pregnancies being evaluated, for example after a periviable vaginal delivery the median gestational age of the subsequent pregnancy was 38 weeks, and after a cesarean it was 37 weeks. the authors interpret this difference as the wish to perform cesarean in the subsequent pregnancy prior to labour to avoid uterine rupture if possible. The next study compared the maternal outcomes of classical cesarean to low transverse cesarean on maternal morbidity (for the index pregnancy only). Kawakita T, et al. Maternal Outcomes associated with early preterm cesarean delivery. Am J Obstet Gynecol. 2016. They looked at hospital records of mothers who delivered between 23 and 32 weeks gestation, and then looked at the stratum under 28 weeks. They showed that in the higher gestational age stratum (28 to 32 weeks) that classical cesareans had more morbidity, in particular more transfusion and more need for ICU admission. But in the lower GA group the risks were the same for both types of cesarean incision, for example about 10% needed a blood transfusion in each group. Another paper from the NIH MFM network examined deliveries between 23 weeks and 34 weeks. Reddy UM, et al. Serious maternal complications after early preterm delivery (24-33 weeks' gestation). Am J Obstet Gynecol. 2015;213(4):538 e1-9. Deliveries at 23 to 27 weeks gestation were more morbid, with 7% having hemorrhage, compared to 3% for the group at 31 to 33 weeks, in this study hemorrhage was clearly defined, as it was part of the prospective data collection, as blood loss ≥1500 mL, blood transfusion, or hysterectomy for hemorrhage. The absolute risks associated with an extremely preterm cesarean delivery are not noted in this publication, but the adjusted relative risk of a cesarean delivery at 23 to 27 weeks compared to a vaginal delivery is presented. The combined relative risk of hemorrhage, postpartum infection, and ICU admission is 3.22 for a classical cesarean delivery and it is 2.8 for a low segment delivery, both compared to vaginal delivery at the same gestational age. I can't tell you based on these data what are the absolute risks, but I guess-timate from these data (about half of the deliveries were vaginal) that about 6% of mothers delivering vaginally between 23 and 27 weeks will have a serious complication, (hemorrhage infection or ICU) and about 18% of mothers who had a cesarean in this time interval. That is a bit higher than Kawakita if I have estimated the absolute risks correctly, but not too much different, and of course definitions and data finding are different. Another study from the Canadian Perinatal Network (Crane J, et al. Maternal and Perinatal Outcomes of Pregnancies Delivered at 23 Weeks’ Gestation. JOGC 2015;37(3):214-24.) included only deliveries at 23 weeks, serious maternal outcomes were common (about 40% of mothers had at least one serious outcome), but the large majority of them were chorioamnionitis, about 38%; after that the next most common was blood transfusion which was required in about 4% of women. About 10% of the 230-ish mothers had a cesarean, and the authors don't compare the maternal outcomes between Cesarean and vaginal deliveries, but most of the data are from the vaginal deliveries. To summarize, having babies is dangerous. Having a baby by cesarean section at term has risks, including a frequent need for transfusion. The overall risks of having a cesarean delivery in the periviable period for the current pregnancy are somewhat greater than at term, but the magnitude of the increase is probably less than 5%, most of those risks are short-term and treatable, with the most common being the need for a transfusion. A vaginal delivery in the periviable period has fewer risks for the mother Uterine rupture in the next pregnancy, if there is one, occurs less than 3% of the time. I want to emphasize here that uterine rupture is a big deal. I am not trying to minimize it, and we should find a way to explain to mothers the importance of uterine rupture in future pregnancies, but we should do that without exaggerating its incidence (perhaps a visual decision aid?), and ensuring that mothers understand the major impact of a uterine rupture, and that the risk of rupture persists even when the obstetrician tries to take steps to avoid it. Of course that is a risk which is important for a woman who will have a future pregnancy, and may be of little importance for a woman who has decided against that option. I think that it is good for the neonatal team to have an understanding of the risks to the mother, so that we can be reasonable and well-informed as we participate in decision-making; but clearly the final decision about route of delivery should be made between the mother and her obstetrician.
  8. Acupuncture is nonsense. There I have said it. I'll probably get at least a few comments for this post, but I'm not backing down. Acupuncture is based on pre-scientific ideas about how the body works, believing that some sort of vital energy flows along meridians in the body, and that sticking a needle into the skin at certain specific points can have distant effects, by letting out the Xi. Xi is non-existent, meridians are non-existent and there are no acupuncture points, they just don't exist. This is all ridiculous, and people with a medical education should know better. Trials of acupuncture in adults have shown that it doesn't matter where you put the needles, or even if you puncture the skin or not. The better controlled the trials are the less effect there is, and trials with really good sham procedures don't show a difference between the sham procedure controls and the actually needled groups. Any effect is simply a placebo effect, and the whole procedure with its insertion of needles and fake explanations has been characterized as a "theatrical placebo". For a sampling of deconstructions of acupuncture studies just search acupuncture on the blog "respectful insolence" which you can do by following this link . Unfortunately there are many who have been taken in by the pseudoscience of this quackery, even in neonatology. A few trials have even been published, including those using electrical stimulators of non-existent acupuncture points, and a few where lights have been shone onto those same points. The two most recent studies I glimpsed are examples of those 2 methods, Abbasoglu A, et al. Laser acupuncture before heel lancing for pain management in healthy term newborns: a randomised controlled trial. Acupuncture in medicine. 2015;33(6):445-50. 42 term babies having a heelstick were randomized to laser acupuncture or sucrose. The study found that sucrose was better than shining a light on the Yintang point (the non-existent acupuncture points, scattered along the non-existent meridians, all have names, this one is between the eyebrows and is also called EX2). Mitchell AJ, et al. Does Noninvasive Electrical Stimulation of Acupuncture Points (NESAP) reduce heelstick pain in neonates? Acta Paediatrica. 2016. This study used different fake acupuncture points (ZuSanLi (ST36), SanYinJiao (SP6), KunLun(Bl60), and TaiXi (KI3) which are on the legs) and randomized babies undergoing heelstick to 4 groups, sucrose with "Sham NESAP", NESAP plus water, NESAP with sucrose, and sham NESAP with water. They randomized 142 term infants who were undergoing a heelstick procedure and analyzed the videos of their faces for PIPP scoring. In the Sham NESAP groups the electrodes were placed adjacent to these fantasy acupuncture points but the stimulator was not turned on, All babies at least had facilitated tucking and a soother, which are both effective at reducing pain from heelstick, which was shown by the relatively small mean increases in PIPP scores in all the groups. Sucrose limited the increases in PIPP compared to the groups which didn't get sucrose, and electrical stimulation of ZuSanLi etc didn't do anything. This study did at least have the potential for a measurable effect, because, unlike shining a light on the skin, there is at least a potential that the transcutaneous electrical stimulation could have an analgesic effect. As it appears to for, in particular, chronic pain. Although the NESAP groups without sucrose didn't have a large mean increase in PIPP scores, the mean peak scores were up to 4.9 and 5 (compared to 4 or less for the sucrose groups), but the standard deviations of those scores were much larger than the sucrose groups, (4 compared to less than 2) which means that there were probably substantially larger numbers of babies who had pain scores of over 6, and had appreciable pain. Which means that yet again I can say that we shouldn't be performing heelsticks without using all the proven evidence-based methods for reducing pain prior to such procedures, of which sucrose is top of the list. Lets stop investigating this nonsense in neonatology, we should be using our time and efforts and resources to examine therapies that have some basis in reality and science. Whatever next, ear candling, or craniosacral therapy for newborns? OH NO!
  9. There is a reason we don't perform pupillary reactions to light in preterm babies, and that is that they don't react. They also tend to be large. This post is in response to my trying to find out what had been published about this phenomenon, when a case in our NICU raised a teaching point. I decided to go back through the literature to find out what was actually documented in peer-reviewed publications, and found, for a change, some good quality data. The first of these, chronologically, is from 1989 Isenberg SJ, et al. The pupils of term and preterm infants. Am J Ophthalmol. 1989;108(1):75-9. This group from UCLA studied prospectively pupils of 100 babies from 26 weeks through to 46 weeks, with a standardized methodology; pupils were larger in mm for more immature infants, even though their eyes are a bit smaller. Pupillary light responses were usually absent before 30 weeks PMA, and only reliable after 32 weeks. Robinson J, Fielder AR. Pupillary diameter and reaction to light in preterm neonates. Arch Dis Child. 1990;65(1 Spec No):35-8. A similar study from Birmingham, England followed 50 babies, and found similar things, the few babies who responded before 31 weeks all had a slow reaction. Isenberg SJ, et al. The fixed and dilated pupils of premature neonates. Am J Ophthalmol. 1990;110(2):168-71. The UCLA group again, this time with a cohort of 30 babies who were examined every week, they were all less than 31 weeks at the first examination and none of them reacted at that time. The proportion having a detectable response to light increased, and most were reacting by 32 weeks. Isenberg SJ, Vazquez M. Are the pupils of premature infants affected by intraventricular hemorrhage? J Child Neurol. 1994;9(4):440-2. The answer to the question in the title is no. The pupils of babies with any grade of hemorrhage (1 to 4) are not larger and do not have different reactions to light than those without hemorrhage. There are a couple of more recent publications, but they don't really add anything. Until the baby has passed 32 weeks post-menstrual age, there is no point looking for pupillary light reflexes, and the pupils will look fixed and dilated.
  10. This publication appeared on-line a couple of months ago, and still isn't in print. Prentice T, et al. Moral distress within neonatal and paediatric intensive care units: a systematic review. Arch Dis Child. 2016. It is a systematic review from Melbourne, with the help of Annie Janvier, of the literature surrounding moral distress in health care workers in the NICU and the PICU. All of the studies included nurses, and some of them also studied other health care workers. Moral Distress refers to subjective feelings of distress in response to the ethical challenges of health care work. It is a term which first appeared in the nursing literature, and, although other terms have been suggested, I think it fits. Moral residue is another term these authors refer to, which is the lingering feelings which persist after the "morally distressing" case has ended. As we deal with children and babies who are fragile, dependent, and may have life-long complications, the NICU and PICU are places where moral distress is likely to be frequent. How frequent it is, and what causes the situations most likely to lead to distress, where the questions that lay behind this systematic review. They found 13 articles, of varying size and quality, (including one of ours); from the results of the systematic review article: One of their findings is the different ways in which moral distress is discussed in the articles, publications in the nursing literature frequently emphasize the subjective experience of the nurses, and the fact that they lack power and are having to provide interventions that they do not always agree with; they are sometimes portrayed as the victims of the aggressive care being perpetrated by the physicians. Whereas in the medical literature moral distress is described in terms of the objective situations that create confrontations or dilemmas. The reality is though, that physicians also experience moral distress (with about the same frequency as nurses), they also find themselves sometimes performing tasks and providing care which is against their own conception of what the best interest is for their patients. What has been shown previously is that moral distress may lead to burnout, and decrease retention of staff. It is also probably unavoidable in intensive care, but we should, and could, work harder to minimize it, and minimize its impact.
  11. In the UK an "intensive care" day for a newborn is defined as a day where the baby is intubated and ventilated, or is on non-invasive respiratory support (CPAP of non-invasive ventilation) AND parenteral nutrition, or on the day of surgery, or on the day of death, or a day when they have any of the following: Presence of an umbilical arterial line Presence of an umbilical venous line Presence of a peripheral arterial line Insulin infusion Presence of a chest drain Exchange transfusion Therapeutic hypothermia Prostaglandin infusion Presence of replogle tube Presence of epidural catheter Presence of silo for gastroschisis Presence of external ventricular drain Dialysis (any type) The next level of care is referred to as "high-dependency" and includes for example CPAP with full enteral feeds, or parenteral nutrition without positive pressure respiratory support. The British Association of Perinatal Medicine standards state that on an intensive care day a baby should have a 1:1 nurse ratio, on a high-dependency day they should have 1 nurse per 2 babies. A new publication from a group in the UK has found that in 2008 only 9% of intensive care days had 1:1 staffing, and in 2012 that had fallen to 6%, when examining data from 30 to 40 NICUs around the country. As you are all aware, the severity of illness of babies who would be classified as "intensive care" using the BAPM criteria varies hugely. In order to determine whether there is an impact of nursing ratios on outcomes, it is necessary to try to adjust for this severity. But just crudely, if the reduction of days of 1:1 ratio is because the babies are less sick (and someone thought they didn't really need 1:1) then mortality should have fallen. In fact it increased. Over the years where the proportion of days with less 1:1 nursing was falling mortality increased from 4 out of every 100 babies receiving intensive care to 4.5, passing a peak of 5.3 in 2010 and 2011. Of course the authors have much more sophisticated analysis than that, and after doing all the adjustments that they could, they calculate that, from a median mortality rate of 4.5, every time you decrease the proportion of 1:1 days by 10% you increase mortality by 0.6, that is, to 5.1, then to 5.7... An accompanying editorial says it all: The data may not be directly applicable to other health care systems, where some of the roles of NICU nurses in the UK are covered by other professionals, in the UK, for example they do not have respiratory therapists, and it is the nurses who do the tasks that RTs do in our NICU. Nevertheless I am convinced that the same principle applies in North American NICUs, when the workload is higher, and we can provide fewer 1:1 nurse assignments, then infection rates are higher, and probably, mortality also. I also think that maybe the BAPM should rethink their criteria. Does every child with an Umbilical Venous Line really need 1:1 nursing? A full term baby with hypoglycemia who has a UVC placed for glucose administrator would be classified as "intensive care" and would be supposed to have 1:1. A nurse could probably safely look after 2 babies whose only criteria for "intensive care" was the presence of a chest tube. If you could rationalize the criteria you would probably be able to put more pressure on the system to provide 1:1 for those babies that really need it. On the other hand a baby who no longer needs parenteral nutrition, but who has just been extubated to CPAP would not be "intensive care" but really needs expert dedicated nursing at a high ratio to prevent re-intubation, and should maybe be considered "intensive care" if they are under 28 weeks for the first 48 hours at least. I have said many times that I think the most important factor in mortality and morbidity of the extremely immature babies is the quality of the nursing care they receive. In order to give care of good quality, as this study shows, you need adequate quantity.
  12. Singh N, et al. Comparison of animal-derived surfactants for the prevention and treatment of respiratory distress syndrome in preterm infants. Cochrane database of systematic reviews (Online). 2015;12:CD010249. This is the sort of systematic review that I find really helpful. Some (including some of my own) end up finding little good evidence, and summarizing the results of only one or 2 small trials. That may help to point out the lack of evidence, and to stimulate future trials, but doesn't often give enough information to really inform practice, and individual treatment decisions. In contrast, this review includes a significant number of trials, some with respectable sample sizes, and ends up finding significant differences between some of the surfactants that are available. The review divides the surfactants into the following: bovine lung lavage surfactant extract, which includes Infasurf, bLES (the Canadian one) and Alveofact bovine minced lung surfactant extract, which includes Survanta and Surfacten (the old surfactant TA, the Japanese one) porcine minced lung surfactant extract, which I know as Curosurf, porcine lung lavage surfactant, which is apparently called Surfacen. The authors searched for all the comparisons that had been studied. Most of the comparisons showed no difference in important clinical outcomes, (although some comparisons had relatively little power,) for example, bovine minced lung and bovine lung lavage surfactants were basically equivalent for all the outcomes. This was true both for prophylactic use and for rescue use. The comparison that did show different effects was the comparison between minced bovine lung, and minced porcine lung (that is between Survanta and Curosurf), these were all rescue/treatment trials: The first outcome was mortality. As you can see the studies are all fairly small, and individually do not show a difference, that is always a bit of a worry, as multiple small studies can inflate an effect. Nevertheless, the summary effect shows higher mortality with the bovine minced lung preparations than the porcine surfactants. The next outcome is 'BPD' or oxygen requirement at 36 weeks. Here there is no sign of a difference, when the outcome is expressed as a proportion of those who were enrolled into the study. The authors of the review also present the outcome "death or BPD" which, as those of you who were at my talk in Baltimore know, I think is not an appropriate composite outcome, and those who were at the International Neonatal Collaboration INC meeting in Bethesda recently know that many of the leaders in the field are of the same opinion. The outcomes of death and BPD have different value for parents (and for society as a whole) and may not change in the same direction. I think the outcomes of Death as one outcome, and BPD as a separate outcome among surviving infants, make much more sense. Unfortunately you can't always tell from data as presented, but, in this case, if we make the probably unsafe, but probably not very wrong, assumption that all the deaths were before 36 weeks, then you can estimate the BPD among survivors. You come up with a relative risk of exactly 1.0, (95% CI 0.85, 1.18). So overall it seems that porcine minced surfactant leads to more survivors, but the same proportion of BPD (that is O2 requirement at 36 weeks) among surviving infants. As I mentioned, the confidence intervals are wide, and there are several small studies, but despite these concerns, there are relatively fewer deaths with porcine surfactant, with a risk difference of 0.05 and an NNT, for one fewer death, of 20. These data suggest therefore, that if you treat 20 babies with poractant rather than a minced bovine lung preparation, there would be one more survivor. Also there are substantially fewer babies who need a second treatment. The NNT here is 7, which means that for every 7 babies you treat, one extra baby will need a second dose. (In the babies in the review, a second dose was required for about 40% of the bovine and about 25% of the porcine treated). Pneumothoraces were a bit less frequent with porcine, maybe due to chance, and if all airleak syndromes were put together, there were fewer airleaks with porcine. For the other comparison which is of specific interest to me, that is minced bovine lung to bovine lung lavage surfactants, almost all of the data comes from the trials of Bloom which compared calfactant (Infasurf) to beractant (Survanta). Neither the prophylactic nor rescue trials showed any differences. The manufacturers will I am sure moan that not all the surfactants within each of these groups are identical, and indeed there are some differences in the details. Calfactant, for example has around twice as much Surfactant Protein B and C compared to bLES. But there is almost no comparative data available for bLES. Why is the porcine preparation better, that is it works faster, leads to fewer airleaks and has lower mortality? The studies generally used the manufacturers recommended dose, which is higher for poractant than for the bovine preparations. That may be the only reason, I am not sure about that, but in any case poractant alpha is concentrated enough that the higher initial dose is easily tolerated, whereas it would mean quite large fluid volumes for the other preparations. In Canada we are still waiting for Curosurf. It has been approved, over a year ago, but is still not being marketed. Come on Chiesi! We are waiting...
  13. The trial this time is from Japan, Nakamura T, et al. Early inhaled steroid use in extremely low birthweight infants: a randomised controlled trial. Archives of Disease in Childhood - Fetal and Neonatal Edition. 2016. 211 babies with a birth weight less than 1000 grams were randomized between June 2006 and Dec 2009; if they were still intubated at 24 hours they received a metered-dose inhaler with either fluticasone or placebo, from which they had 2 'puffs' (total dose of 100 microgams) per day for as long as they were intubated (maximum 6 weeks). The initial plan was to randomize about twice as many babies, but they ran out of money. The primary outcome variable was going home on oxygen, which I think is a more important outcome than oxygen need at 36 weeks, needing oxygen at home has much more impact on the family than O2 at 36 weeks. However, even in a blinded trial, criteria for needing home oxygen should be clear, so that the external validity of the result can be assessed. I don't know if the criteria for home oxygen in Japan are the same as for my babies, for example. I can't find any criteria for home oxygen in the trial report. The babies were followed until 3 years of age with a very high rate of retention of the subjects, almost all of the survivors were evaluated. Basically there was no effect. No improvement in discharge without oxygen, and no impact on neurological or developmental progress. There were a couple of subgroups that had a difference in the primary outcome, the middle stratum of gestational ages, 24 to 26 weeks, had a different (possible positive effect of the steroids) effect to the other 2 strata, but I don't see a statistical evaluation of the interaction, so even though the result is different to the other strata we don't know if that difference is itself statistically significant. Babies who had a history of chorioamnionitis also might have had more of an effect, and babies with evidence of RDS might also have had more of an effect, again, for neither of these sub-group comparisons is there a test of the significance of the interaction term. One surprising aspect of this study is how few of the babies received antenatal steroids; less than 43% in each group. Why? I think its questionable ethically to perform studies when a simple, safe, proven, intervention is not being applied. Similar studies in other populations will usually have over 80% antenatal steroid use, and most of the missed patients are those that deliver too quickly to get a benefit. (80% of the babies were delivered by cesarean section, in contrast, so they were getting active perinatal care). To give the authors the benefit of some doubt, the trial entry criteria may have partially selected babies without antenatal steroid coverage, as they are the ones more likely to be still intubated at 24 hours of age. But I don't think this can be the entire reason for this very low coverage with antenatal steroids, the recent Neurosis trial for example had 90% antenatal steroid use for a similar group of babies. What this study shows is that in babies with a totally inadequate level of coverage with antenatal steroids, postnatal inhaled steroids don't have much detectable effect on long term oxygen requirements, or on longer term development. So where do we stand now, with these recent early pulmonary steroid studies? I think there is still room for a well-powered trial; I'm not sure if budesonide mixed with surfactant and given a few times, with each dose of surfactant for example, would be preferable, or an inhalation (of budesonide of even fluticasone) given over the first days and weeks of assisted ventilation make most sense. This new trial and the modest benefits in the Neurosis trial make me wonder if an inhaled aerosol is likely to give much benefit. Needing oxygen at hospital discharge, and other effects which are of consequence for the life of the family (such as re-admission for respiratory indications during the first year of life) and developmental and neurological progress of the infants should be the outcomes of interest, I think, but a wide consultation of parents to ask them what is most important as an outcome for such a trial would be even better.
  14. TPN toxic?

    Humans, after they are born, are supposed to receive their nutrition via the gut. Before that of course, they receive a continuous infusion of nutrition via the umbilical vein. We are far from having an intravenous nutrition mixture for sick preterm infants which closely reflects what the fetus receives from the placenta, but it is clear that we can affect the usual catabolic state of an unfed newly born preterm infant by initiating intravenous nutrition immediately. Whether this is safe and whether it improves clinical outcomes has not been proven in a strictly scientific sense, but immediately starting amino acid solutions for small preterm infants has become the "norm" in the NICU. Once we leave the immediate neonatal period of course, there is no similar analogy; parenteral nutrition is abnormal, and could well have a different balance of risks and benefits. Which is not to say that we should ignore data from older patients such as these from this new publication. A high quality new large 3 center RCT (Fivez T, et al. Early versus Late Parenteral Nutrition in Critically Ill Children. The New England journal of medicine. 2016), the PEPaNIC trial, challenges the benefits of early intravenous nutrition in critically ill children, and is consistent with other data in adults. In studies from the adult ICU, early initiation of parenteral nutrition (I will call it PN) may increase infections, had no clear benefits, and, even among those who are extremely high risk of malnutrition, has not been shown to have benefit. This seems to be particularly true in adults who can receive early oral or enteral nutrition, adding early PN may be detrimental. The new RCT is in children admitted to the PICU with an expectation that they would have to stay for at least 24 hours. They were randomized to have early PN, or late PN. The protocol for early PN varied among the units, which is both a strength and a weakness of this study, all children received enteral nutrition as soon as it was thought to be safe; in one center the early PN was started on day 1 with an amino acid mixture, the other two centers started with a glucose infusion alone. All 3 centers added lipids on day 2, one of the centers started amino acids on day 2, the third added the amino acids on day 3. The late-PN group had no intravenous nutrition until day 8. The main finding of the study was that early PN led to an increase in the proportion of patients who developed a new infection during hospitalisation. The biggest increase was in respiratory infections, which brings me to one question I have about this study; there is no definition of the primary outcome in the paper, nor in the study protocols, which are available from the FPNEJM (formerly prestigious new england journal of medicine). In the supplemental appendix it is noted that the diagnosis of infection was made by "infectious disease specialists" blinded as to treatment allocation, who reviewed the hospital charts of every patient who had more than 48 hours of antibiotics, started after arriving in the PICU. They give a reference at that point, (Horan TC, et al. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. American journal of infection control 2008;36:309-32) which does contain widely used definitions of infections, but the manuscript, and the appendix, don't explicitly say if those were the definitions that had to be followed in each case. If we assume that to be so, then the blood stream infections are easy-ish, diagnosing respiratory infections is much more difficult, especially in the newborn were there are no validated definitions of ventilator associated pneumonia. If the infectious disease specialists were indeed effectively masked to treatment allocation, this may not produce a bias, but might add some random noise. I am going into some detail about this study, as, even though it was in a PICU population, 209 of the 1440 patients were newborns who had been born at full term, that is they were less than 28 days old on admission to the study. Subgroup analysis revealed no statistically significant differential effect between the newborns and the remaining patients. By which I mean to say that early PN was just as harmful in the newborns as it was in the older children. The overall study outcomes were: an increase in new infections from 10.7% with delayed PN to 18.5% with early PN, airway infections increased from 4.2% to 8.2%, and bloodstream infections from 1.4% to 3.2%. Other infections were rarer and not affected. So the Odds ratio for developing a new infection was 0.48. It was 0.47 among the newborn subgroup, (95% CI for the adjusted OR for the overall analysis, 0.35, 0.66). The other primary outcome was length of PICU stay, which was substantially longer with early PN, from an average of 6.5 days to an average of 9.2 days. The newborns also had a longer PICU stay if they had early PN. Among the secondary outcomes, the duration of mechanical ventilation was longer with early PN, 6.4 days on average compared to 4.4 days. Mortality was almost unchanged in the study, 6.1% with early PN and 5.3% with late. there was more hypoglycemia with the late PN, but that was the only potential advantage of early PN. As I mentioned above, the results are similar to other studies in adults, in particular a study of over 4000 adult ICU patients run by the same group from Leuven. In that study adults who were mostly able to tolerate some oral or enteral nutrition were randomized to a similar comparison to the PEPaNIC trial. That study also showed an increase in infections and increased duration of ICU stay with early PN, and no difference in mortality. In contrast another study in 1372 adults with contraindications to enteral nutrition showed no difference in infections and shorter duration of assisted ventilation when they were randomized to early PN, compared to delayed PN. In yet another, much smaller study among 300 adults randomized after 3 days in the ICU if they were receiving less than 60% of their nutritional needs enterally. In that study the group that did better was the early PN group, who actually had fewer nosocomial infections. Which is all a bit confusing, but in general, I would suggest the following interpretation: it seems to me that if you can get very little or none of your nutrition by the enteral route, that early PN has benefits, with maybe a reduction in ventilator days, and an uncertain effect on infections. If there is no contra-indication to increasing nutrition by the enteral route as quickly as possible, then adding early PN, just to try and get the numbers right in terms of calorie and protein administration, may have a balance of negative effects with an increase in infections. What are we neonatology folks going to do about this? I don't know, is the simple answer. I don't routinely start PN on admission for full-term babies in the NICU, but many of them get started very quickly afterward, often ordered the next morning, unless enteral nutrition can be increased quickly. Some full term babies with gastrointestinal anomalies who we can't feed get PN very quickly, and get it increased rapidly So the question is relevant to our babies, if we delayed PN for a few days while increasing enteral nutrition, might they do better? How are our babies different to those in PEPaNIC? In my NICU, most of our full term babies are admitted on day 1 or 2, with a few others through to the end of the first week, thereafter they are admitted to the PICU. Very few of the babies in the PEPaNIC study would have been admitted on day 1, if admission patterns in Belgium (and the 3rd site in Edmonton Alberta) are like ours. How much difference might that make? We worry that a period of low calorie intake after birth leads to a catabolic state, which can be reversed by good PN. But, many acutely sick older children are also catabolic on admission to the PICU. So it may not be that much different a situation. As for the diagnostic mix, The authors state that diagnostic group did not interact with the benefits of delaying PN. The frequency of new infections among these children seems high compared to what I can find from NICU publications. In the latest CNN annual report for example, the incidence of blood stream infections more than 48 hours after birth was 1% (The definition is "after birth" not "after admission" so this definition leaves the possibility that there might be a few babies admitted with a diagnosis of sepsis at 3 days of age who would be included in the CNN definition, but not in PEPaNIC) , 64 babies among 6,200 babies of 37 weeks gestation or more admitted to the NICU and surviving more than 2 days. Some of these babies will likely be of lower risk than the babies in the PEPaNIC trial, but I think most term admissions to the NICU have a predicted length of stay of at least 48 hours, and many are critically ill. Having been attending staff in both NICU and PICU, I don't think PICU very young infants have an overall systematically different severity of illness than the NICU term babies. Overall, I would guess that I have to say that the newborn stratum of the PEPaNIC trial are potentially relevant to NICU term babies. The differences with preterm infants are much greater, but even there the relevance is not so far-fetched. As these authors note, prior observational studies showed associations of early nutritional support with improved outcomes. Which shows again the importance of randomized controlled trials. Which means (drum roll) I think we need a large enough trial in the NICU term population to investigate the risks of early PN. It should be stratified according to whether enteral nutrition is extremely limited or nil, in one stratum, compared to rapidly advancing in the other, and should compare very early PN to PN delayed until.... when? Perhaps for our population, a good date for late starting of PN would be when the nutritional deficits are accumulating, rather a strict number of days; but the size of the potential effects seems quite large, and certainly worth investigating. If a term NICU trial shows the same adverse effects if early PN as PEPaNIC, then a further preterm trial might be warranted even though, at present, all the data we have supports giving PN immediately in the very preterm; as science-based medicine advocates, we have to always be ready to admit, "I might be wrong".
  15. An important high quality trial has just been published, it has taken me a bit longer than usual to process the new info. Among other reasons a nice review was posted on the "other neonatal blog", but I wanted to try and put this in context of the other similar published trials. The new trial is Baud O, et al. Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial. The Lancet. 2016. 523 babies of less than 28 weeks, and at least 24 weeks, were enrolled and randomized (23 week gestation infants are not generally actively treated in France, so they weren't included) in the first 24 hours of life. Infants who were severely growth restricted or asphyxiated were not included. They didn't have to be on a ventilator or even requiring oxygen, so it was a true trial of prophylaxis. Babies received 1 mg/kg/d of hydrocortisone (divided in 2 doses) for 7 days followed by 0.5 mg/kg/d for 3 days, or placebo. The primary outcome was survival without bronchopulmonary dysplasia at 36 weeks. The study had a sequential analysis design, so sample size is not specified strictly in advance, an interim analysis was done every time an additional 100 patients reached the primary outcome. The maximum sample size that they were aiming for was 786 infants, but the study was stopped prior to that, not because they crossed the analysis lines showing efficacy or futility, but because they were running out of money and resources, so in March 2013 they decided they would have to stop in January 2014. They found an improvement in the primary outcome, that was just "statistically significant", that is, the estimated probability that such a difference would occur due to chance alone is 0.04, or 1 in 25. Neither of the 2 components of the primary outcome were individually statistically significant, but both were improved in the hydrocortisone group compared to control. This study has something in common with several other prior trials. I have summarized the previous trials that randomized all very preterm infants, or all very preterm infants on ventilators to low dose hydrocortisone starting before 48 hours. As you can see they all used relatively similar doses of hydrocortisone, and all except the latest study required babies to be intubated. Some of the babies were a bit larger than Baud's subjects. Publication Patient characteristics Dose per kg per day used. Watterberg 1999 N=40, MV, 500-999g, <48h 1 mg x 9d, 0.5 x 3d Biswas 2003 N=253, MV, <30 wk, <9h 1 mg x 5d, 0.5 x 2d (plus T3) Watterberg 2004 N=360, MV, 500-999g, 12-48h 1 mg x 12d, 0.5 x 2d Peltoniemi 2005 N=51, MV, 500-1250g, <36h 2 mg x 2d, 1.5 x 2d, 0.75 x 6d Bonsante 2007 N=50, MV, <1250g (24-30wk), <48h 1 mg x 9d, 0.5 x 3d Baud 2016 N=523, 24-<28 wk, <24h 1mg x 7d, 0.5 x 3d The Biswas study also treated the experimental group with tri-iodothyronine, but T3 is not effective in improving survival or BPD so it could be left in a review for now. I haven't found any other trial data so far, if anyone knows of any, please let me know. I did my usual thing and put the data in Revman to see what the Forest plots now look like. The first is the meta-analysis of the effects on Death, which doesn't look very impressive The next is the impact of hydrocortisone prophylaxis on BPD, which is similarly not "statistically significant" Finally the combined outcome of "death or BPD", which is an outcome that should perhaps be junked, suggests a possible 11% reduction, but with an upper 95% confidence interval that is very close to 1.0 These trials were all of reasonably good quality, with some heterogeneity in the 3rd of these analyses, if you do some sensitivity analyses, taking out the Biswas trial because it also used T3, the results are almost identical. I think at this point we have to say the benefits of early low-dose universal hydrocortisone prophylaxis are "Not Proven", either among all very preterm babies or among those who are ventilated. If there is a real effect it is probably not huge, but there is a potential for as much as a 32% reduction in mortality if you look at the confidence intervals for death. Unfortunately you will all guess what comes next, we need another bigger trial. Before designing such a trial however, the long term follow up of these trials should be collated, there have been some indications of adverse effects of adverse long term effects from the small Peltoniemi trial, but the data from the follow-up of Watterberg's 2004 trial were reassuring. Long term outcomes of the new PREMILOC trial will be essential before either instituting this therapy, or performing another larger trial.