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    • By AllThingsNeonatal in All Things Neonatal
         0
      This post is special to me. A redemption of sorts. When I was a fellow in Edmonton in the early 2000s my fellowship project was to see whether heliox (helium/oxygen) given to piglets with meconium aspiration syndrome (MAS) would improve ventilation and measures of pulmonary hypertension vs controls. Why heliox? There had been work done with this gas for other conditions and the lower viscosity of the gas (who hasn’t sucked on a helium balloon to see the effect of helium) means that the flow of the gas in a tube is more linear that regular air. Turbulent flow as with air/oxygen mixtures creates more resistance to flow than linear flow with heliox. Imagine if you will this linear flow slipping more easily past particles of meconium partially blocking airways and you get the idea of why heliox might work. One thing to bear in mind though is that as your FiO2 goes up the percentage of helium drops so the properties described work best at low FiO2 so flow is more linear.
      I collected meconium from diapers in the NICU and created a NS slurry of meconium and then instilled it into the trachea’s of these piglets through a tracheostomy (they were too small to intubate for me at least). A flow probe was put around the pulmonary artery to look for evidence of pulmonary hypertension. We saw some interesting trends but the paper never saw the light of day for a variety of reasons that I won’t go in to here. Originally I had wanted to do the study as a small RCT in humans but I was advised that although heliox is an inert gas I should do the animal study first. That was the end of the heliox story as far as I was concerned as I hadn’t thought much about it since that time. I will admit though that anytime I had a baby with bad meconium aspiration syndrome though the thought did pop into my head.
      The Study Has Arrived
      Imagine my surprise when this week an RCT from China entitled A randomized single‐center controlled trial of synchronized intermittent mandatory ventilation with heliox in newborn infants with meconium aspiration syndrome came across my inbox. The authors used a power calculation based on some previous work in RDS using heliox to determine they needed 28 neonates in each arm to show a difference. In the end they managed 71 total with 35 in the heliox and 36 in the control arm. Inclusion criteria were a diagnosis of MAS on x-ray, GA ≥37 weeks and ≤42 weeks, need for intubation due to a pH <7.2/PCO2 >60 mmHg. The study could not be blinded as one would not be able to hide the large tanks for heliox so for any study like this it would be unavoidable. One thing that differs in terms of management from my own practice is that the authors in this study used SIMV pressure limited ventilation as the ventilatory strategy as opposed to AC/VG that my unit would typically use. Initial ventilator PIP of 15–28 cmH2O, PEEP of 4–10 cmH2O, and RR of 15–45 breaths/min; FiO2 of 0.21 to 1 to reach the target oxygen saturation (SpO2) of 90%–95%. The intervention group received heliox for 6 hours and then switched over to air/oxygen while the control group was ventilated with air/oxygen from the start. The extubation criteria included PIP ≤15 cmH2O, gradually enhanced effective spontaneous breathing, a ventilator breathing frequency ≤10/min, and normal blood gas analysis results. The main outcomes were PaO2/FiO2 (P/F), the extubation time and the hospital length of stay in the NICU. Aside from measuring the ventilatory responses and time of extubation the authors also examined the effect of heliox as an anti-inflammatory agent based on previous results demonstrating markers of inflammation can be attenuated by use of the gas.
      The Results
      To start with, the babies in both arms were equivalent at the start of the study in terms of inflammatory markers and some clinical variables.
      As you will see from the following figures a number of important findings are noted. The main marker of oxygenation used for this study was the PaO2/FiO2 ratio and this was statistically different (301 ± 22 vs. 260.64 ± 24.83, p < .001). Secondly, extubation time (78 ± 30 vs. 114 ± 28.07, p < .001 and length of hospital stay in days were also shorter 15.3 ± 4.2 vs. 19.11 ± 4.01, p < .001.
      The authors state that the following markers of pO2, pH and pCO2 shown in the graphs were all significantly improved in the heliox group but looking at the first two I find that hard to believe as the curves look almost superimposed. pCO2 however could be different in particular given the linear flow described above so ventilation might be improved.
      Finally, across the board, markers of inflammation were noted to improve with administration of heliox as well as markers of myocardial injury. The gas may have done what it was supposed to do.
      I wish the conclusions were that easy
      I want to like this paper so badly. Sadly, I have some pretty significant reservations. It is helpful to see that the two groups began at a similar PaO2/FiO2 ratio. What is missing though is the ventilatory requirements to get to that point. There is no information provided as to the mean airway pressures or PIP/PEEP for each group over time to get a sense of whether the two groups in terms of severity of illness were the same. Yes we know that the inflammatory markers at the start were similar but could the difference in changes of inflammation relate to a progressive rise in the control group that were just sicker rather than a protective effect of heliox to reduce inflammation? Also when one looks at the change in pCO2 how do you interpret that without knowing the minute ventilation to achieve those data points? It is really unfortunate that the authors did not use oxygenation index (MAP X FiO2/PaO2) as this would have taken the ventilation component at least into account. Would be helpful as well to know the weaning strategy in each group as without blinding might the authors have reacted more aggresively with weaning of the ventilator to get to extubatable settings knowing that the babies were receiving the intervention. As there was no weaning strategy planned out from the start we can only guess. Lastly, one could have possibly gotten around the inability to hide the heliox tanks by having a Neonatologist not on service take each blood gas data and sight unseen suggest changes to ventilation without being able to see which arm a baby was in.
      I will end on a positive note though. It has been almost twenty years since I did the piglet study using heliox. I had always hoped that this research would see the light of day in a human model although my piglet data didn’t show much benefit however the intervention was shorter than this study. I think this study is worthy of being repeated using a different mode of ventilation that does not rely on manual changes to PIP but rather by using a VG mode the baby would be gradually weaned as compliance improves. Any further study needs to address differences that were missing from this paper as well. I don’t think this is the last we will see of heliox and I look forward to seeing another paper although if it takes another twenty years I may be out of this line of work.
    • By AllThingsNeonatal in All Things Neonatal
         0
      If you work in NICU you will have seen many babies who have passed through the stages of apnea, weaned off respiratory support and have reached a sufficient weight for discharge but alas will just not feed. Different strategies have been employed to get these infants feeding that rely in many cases on a cue based approach but in the end there are some that just won’t or can’t do it. Many of these babies will be sent home either with NG feedings or if it appears to be a more long term situation a gastrostomy tube. For this blog post I am going to present to you some novel research that suggests there may be another way to approach this and would like to thank one of the followers of my social media for alerting me to this work. You know who you are as the saying goes!
      Transcutaneous Auricular Vagus Nerve Stimulation taVNS
      This was an open label Phase 0 trial (few patients as a pilot) using taVNS to help improve feeding in ex-preterm or 3 recovering from HIE infants who were now past term and all headed towards a gastrostomy tube. The hospital carrying out the study entitled Transcutaneous Auricular Vagus Nerve Stimulation-Paired Rehabilitation for Oromotor Feeding Problems in Newborns: An Open-Label Pilot Study by Badran BW et al did not come out of thin air. Prior research in adult patients recovering from stroke found in multiple studies (all referenced in the paper) that motor stimulation accompanied by VNS improves motor function recovery. The objective here then was to see if stimulation of the auricular nerve along with assessment and motor treatments from an occupational therapist once a day could help improve feeding and avoid GT placement. The trial overview is as shown below.
      The centre in which the study was done had a historical rate in this population of <10% of such patients avoiding a GT (all reaching term equivalent age and not showing an improvement in feeds). This was demonstrated in previous work by at the Medical University of South Carolina (MUSC). “Preterm infants who have not reached full PO feeds by 40-week gestational age (GA) and/or after 40 days of attempting PO feeds have a >90% chance of eventually needing G-tube implantation to achieve full enteral feeds (Ryan and Gehle, 2019).”
      The Intervention
      taVNS was done once a day during a bottle feed and timed with observed suckling and swallowing by an OT. The stimulation was stopped during a pause in feeding.
      As you read this you may be concerned about side effects (as I was) of passing an electrical current to the ear and stimulating the auricular branch of the vagus nerve. This has been shown in other work to activate both afferent and efferent pathways of the vagus nerve and enhance plasticity and functional motor recovery. Could you then apply the same to improving development of the motor pathways of the preterm newborn or patient recovering from HIE? The authors examined skin irritation, pain scores and incidence of bradycardia before and during feeding while stimulation was occurring and found no difference in any of the measures. In order to minimize pain the authors increased the current by 0.1 mA until they perceived stimulation by change in facial expression, shrugging or fidgety movements. In the event of an increase in pain scoring by 3 the dose was decreased by the same amount. in the end the intervention was deemed safe without any adverse effects.
      The primary outcome was ability to increase and maintain full daily PO intake for 4 days (>120 mL/kg/d and maintain a weight gain of >20 g/day until discharge.
      Why you should care about the results
      If you work in a hospital like mine you would probably find that once the discussion about a GT placement begins, few miraculously avoid it. In this study they found that 8 of the 14 patients or 57% avoided the GT. Their historical achievement in this regard was <10%. This could be by chance of course since the study is a small one but when looking at the PO intake between non-responders and responders they demonstrate the following.
      The authors found no statistically significant increase in the non-responders after the taVNS in PO feeds but also note there were three infants born to mothers with diabetes in this group. I have commented before on the effect of diabetes on successful feeding so this certainly could have affected the success of this group. If you look at the change over time in the responder group they look graphically like there was an upwards trend in the feeding ability prior to the intervention although the increase or slope of the improvement due to small numbers was not significant. The takeoff in feeding afterwards was.
      The findings in this study are extremely exciting to me. As units across the globe struggle with patient flow, one of the most common reasons for these patients to stay in hospital is no longer BPD or apnea but inability to feed. The idea that such a simple intervention that is done once daily for 30 minutes might influence the development of feeding coordination in these at risk infants is phenomenal in terms of its impact on patient flow.
      If you wonder about whether this is a one off study, there is a lot of active research in this area. A quick search of clinicaltrials.gov uncovers 61 studies on taVNS recruiting at the moment for a variety of ailments. In fact the next study is a Phase 1 trial aiming to recruit 40 patients and is underway. If interested the link to the study is here.
      Stay tuned!
       
    • By AllThingsNeonatal in All Things Neonatal
         1
      With American Thanksgiving coming up this weekend a post about “cold turkey” seemed apropos. You can’t work in Neonatology and not be familiar with CPAP. We have learned much about this modality in the last couple decades as clinicians have moved more and more towards non-invasive support as the preferred strategy for supporting newborns regardless of gestational age. Ask a Neonatologist how they use CPAP and you will find varied opinions about how high to go and how quickly to wean. I have written about one weaning strategy before on this blog using monitor oxygen saturation histogram data to make such decisions Improve your success rate in weaning from CPAP. One question though that has often been asked is what level of CPAP is best to remove a baby from? In particular for our smallest infants who may have BPD or reduced pulmonary reserve due to lower numbers of alveoli as they continue to develop should you discontinue at +5, +4 or +3? This question is what some creative authors from Texas sought to answer in the paper being discussed today.
      To Wean or Not To Wean?
      Kakkilaya V et al published Discontinuing Nasal Continuous Positive Airway Pressure in Infants ≤32 Weeks Gestational Age: A Randomized Control Trial in the Journal of Pediatrics this October. The authors studied infants from 23+0 to 32+6 weeks gestational age at birth and looked at whether a strategy of discontinuing from +5 or weaning from +5 to +3 then stopping resulted in fewer failures from stoppage. Infants were recruited in two ways. Some infants were intubated with planned extubation to pressures from +5 to +8 while others were on CPAP always. The study included 226 infants or which 116 were assigned to control so had removal of CPAP at +5 if after 24 hours they met the stability criteria below. The other 110 infants reduced CPAP from +5 once every 24 hours if the same criteria were met. Reasons for restarting CPAP were also as shown below at the bottom of Table 1. If an infant failed then they went back to the level of CPAP they had been on previously when stability criteria were met. Once they had stability criteria at that level again for 24 hours the wean could resume.
      Did they manage to find a difference?
      Table 5 reveals the significant finding here which is that for the primary outcome there was no difference and it didn’t matter whether the infants were ventilated or not. One finding that was different was the number of neonates who failed to stop CPAP two or more times. This favoured the weaning approach. Aside from that the groups were comparable and there really wasn’t much benefit seen from one approach versus the other.
      Thoughts About the Study
      The study was a fairly straightforward one and although there wasn’t a significant result found there are some questions that I think we can think about.
      The stability criteria did not have results from histogram analysis included as a measure of stability. I can’t help but wonder if addition of this approach would have identified some infants who were actually not ready to wean. Having said that, one challenge is to come to an agreement on what a stable histogram is. Based on a survey from my own colleagues recently I would say like many things in Neonatology, we are all over the map. If this study were to be repeated using histograms for decisions on weaning some sort of agreement would be needed on what qualifies as a stable histogram. Our group has already tended to use +4 as the final weaning step for our ELBW and VLBW infants based on anecdotal experience that many of these kids if stopped at +5 will fail even when they seem to be stable. Repeating this study looking at weaning from +4 to +3 before stopping vs stopping at +4 could be interesting as well. Finally, I do wonder if the wean was too fast to show a difference. It is not uncommon practice in the smallest infants to keep them on +4 for a couple days even if it seems that the histograms would indicate the baby is ready to stop CPAP. Perhaps a weaning strategy of allowing a minimum of q48h instead of q24h would have found different results? I do think the authors explored a great question and I would be reluctant here to “throw the baby out with the bathwater”. There is something here but based on the methodology (which I don’t think is flawed per se) I think they just couldn’t prove what I suspect is true.
    • By AllThingsNeonatal in All Things Neonatal
         1
      This could turn into a book one day I suppose but I have become interested in chalenging some of my long held beliefs these days. Recently I had the honour of presenting a webinar on “Dogmas of Neonatology” for the Indian Academy of Pediatrics which examined a few practices that I have called into question (which you can watch in link). Today I turn my attention to a practice that I have been following for at least twenty years. I have to also admit it is something I have never really questioned until now! In our institution and I suspect many others, infants born under 1250g have been fed every two hours while those above every three. The rationale for this has been that a two hour volume is smaller and causes less gastric distention. This in theory would benefit these small infants by helping to not compromise ventilation or lead to reflux. Overwhelming the intestine with large distending boluses would also in theory lead to less necrotizing enterocolitis. All of this of course has been theoretical and I can thank those who preceded me in Neonatology for coming up with these rules!
      Study Challenges This Old Belief
      Yadav A et al published Two-hourly versus Three-hourly Feeding in Very Low Birthweight Neonates: A Randomized Controlled Trial out of India (well timed given my recent talk!). The authors randomized 175 babies born between 1000-1500g to either be fed q2h vs q3h once they began protocol feeding. The primary outcome was time to full feedings. Curiously, the paper indicates they decided to do a preplanned subgroup analysis of the 1000-1250 and 1251 -1500g groups but in the discussion it sounds like this is going to be done as a separate paper so we don’t have that data here.
      The study controlled conditions for determining feeding intolerance fairly well. As per the authors:
      “Full enteral feed was defined as 150 mL/Kg/day of enteral feeds, hypoglycaemia was defined as blood glucose concentration <45mg/dL [15]. Feed intolerance was defined as abdominal distension (abdominal girth ≥2 cm), with blood or bile stained aspirates or vomiting or pre-feed gastric residual volume more than 50% of feed volume; the latter checked only once feeds reached 5 mL/kg volume [16]. NEC was defined as per the modified Bells staging.”
      We don’t use gastric residuals in our unit to guide cessation of feedings anymore but the groups both had residuals treated the same way so that is different but not somethign that I think would invalidate the study. The patients in the study had the baseline characteristics shown below and were comparable.
      Results
      It will be little surprise to you that the results indicate no difference in time to full feedings as shown in Figure 2 from the paper.
      The curves for feeding advancement are essentially superimposed. Feeding every two vs three hours made no difference whatsoever. Looking at secondary outcomes there were no differences as well in rates of NEC or hypoglycemia. Importantly when examining rates of feeding intolerance 7.4% of babies in the 2 hour and 6.9% in the 3 hour groups had this issue with no difference in risk observed.
      Taking the results as they are from this study there doens’t seem to be much basis for drawing the line at 1250g although it would still be nice to see the preplanned subgroup analysis to see if there were any concerns in the 1000-1250 group.
      Supporting this study though is a large systematic review by Dr. A. Razak (whom I have collaborated with before). In his systematic review Two-hourly versus three-hourly feeding in very low-birth-weight infants: A systematic review and metaanalysis. he concluded there was no difference in time to full feeds but did note a positive benefit of q3h feeding in the 962 pooled infants with infants fed 3-hourly regainin birth weight earlier than infants fed 2-hourly (3 RCTs; 350 participants; mean difference [95% confidence interval] -1.12 [-2.16 to -0.08]; I2 = 0%; p = 0.04). This new study is a large one and will certainly strengthen the evidence from these smaller pooled studies.
      Final Thoughts
      The practice of switching to q2h feedings under 1250g is certainly being challenged. The question will be whether the mental barriers to changing this practice can be broken. There are many people that will read this and think “if it’s not broken don’t fix it” or resist change due to change itself. The evidence that is out there though I would submit should cause us all to think about this aspect of our practice. I will!
       
      This could turn into a book one day I suppose but I have become interested in chalenging some of my long held beliefs these days. Recently I had the honour of presenting a webinar on “Dogmas of Neonatology” for the Indian Academy of Pediatrics which examined a few practices that I have called into question (which you can watch in link). Today I turn my attention to a practice that I have been following for at least twenty years. I have to also admit it is something I have never really questioned until now! In our institution and I suspect many others, infants born under 1250g have been fed every two hours while those above every three. The rationale for this has been that a two hour volume is smaller and causes less gastric distention. This in theory would benefit these small infants by helping to not compromise ventilation or lead to reflux. Overwhelming the intestine with large distending boluses would also in theory lead to less necrotizing enterocolitis. All of this of course has been theoretical and I can thank those who preceded me in Neonatology for coming up with these rules!
      Study Challenges This Old Belief
      Yadav A et al published Two-hourly versus Three-hourly Feeding in Very Low Birthweight Neonates: A Randomized Controlled Trial out of India (well timed given my recent talk!). The authors randomized 175 babies born between 1000-1500g to either be fed q2h vs q3h once they began protocol feeding. The primary outcome was time to full feedings. Curiously, the paper indicates they decided to do a preplanned subgroup analysis of the 1000-1250 and 1251 -1500g groups but in the discussion it sounds like this is going to be done as a separate paper so we don’t have that data here.
      The study controlled conditions for determining feeding intolerance fairly well. As per the authors:
      “Full enteral feed was defined as 150 mL/Kg/day of enteral feeds, hypoglycaemia was defined as blood glucose concentration <45mg/dL [15]. Feed intolerance was defined as abdominal distension (abdominal girth ≥2 cm), with blood or bile stained aspirates or vomiting or pre-feed gastric residual volume more than 50% of feed volume; the latter checked only once feeds reached 5 mL/kg volume [16]. NEC was defined as per the modified Bells staging.”
      We don’t use gastric residuals in our unit to guide cessation of feedings anymore but the groups both had residuals treated the same way so that is different but not somethign that I think would invalidate the study. The patients in the study had the baseline characteristics shown below and were comparable.
      Results
      It will be little surprise to you that the results indicate no difference in time to full feedings as shown in Figure 2 from the paper.
      The curves for feeding advancement are essentially superimposed. Feeding every two vs three hours made no difference whatsoever. Looking at secondary outcomes there were no differences as well in rates of NEC or hypoglycemia. Importantly when examining rates of feeding intolerance 7.4% of babies in the 2 hour and 6.9% in the 3 hour groups had this issue with no difference in risk observed.
      Taking the results as they are from this study there doens’t seem to be much basis for drawing the line at 1250g although it would still be nice to see the preplanned subgroup analysis to see if there were any concerns in the 1000-1250 group.
      Supporting this study though is a large systematic review by Dr. A. Razak (whom I have collaborated with before). In his systematic review Two-hourly versus three-hourly feeding in very low-birth-weight infants: A systematic review and metaanalysis. he concluded there was no difference in time to full feeds but did note a positive benefit of q3h feeding in the 962 pooled infants with infants fed 3-hourly regainin birth weight earlier than infants fed 2-hourly (3 RCTs; 350 participants; mean difference [95% confidence interval] -1.12 [-2.16 to -0.08]; I2 = 0%; p = 0.04). This new study is a large one and will certainly strengthen the evidence from these smaller pooled studies.
      Final Thoughts
      The practice of switching to q2h feedings under 1250g is certainly being challenged. The question will be whether the mental barriers to changing this practice can be broken. There are many people that will read this and think “if it’s not broken don’t fix it” or resist change due to change itself. The evidence that is out there though I would submit should cause us all to think about this aspect of our practice. I will!
  • Upcoming Events

    • 06 May 2021 04:00 PM
      0  
      MRI in the Term Neonate and Long Term Follow-Up, Linda de Vries, Netherlands MRI in the Preterm Neonate and Long Term Follow-Up, Terrie Inder, USA Free event, registration required: https://us02web.zoom.us/webinar/register/WN_LLRiX3WYTYap_k4yq4vcEA?timezone_id=Europe%2FHelsinki12th International Newborn Brain Conference Series Agenda.pdf
    • 07 May 2021 12:00 PM
      0  
      Perinatal Care of the Preterm Baby-Epidemiology and Ethics
      This is an online module being organised by the MPROvE Academy starting from the 12th of February till the end of April 2021. The content covered includes limits of viability, prenatal counselling, communication, prognostication, decision making, and a lot more as outlined below. The course has been broken up into content that can be imbibed weekly with a webinar covering that topic. The course has online content, and videos for review by the participants. Participants can access this from anywhere in the world. For more details a video of the course is attached.
      For registration please contact Dr Alok Sharma Consultant Neonatologist on draloksharma74@gmail.com 
       
       
       



    • 13 May 2021 04:00 PM
      0  
      The Impact of Socioeconomic Status on Outcome After Preterm Birth, James Boardman, UK Outcome Following Preterm Birth 25 Years On, Neil Marlow, UK Free event, registration required: https://us02web.zoom.us/webinar/register/WN_mMyKKWYuT4-P7DAp5WqJ6Q
    • 20 May 2021 04:00 PM
      0  
      Machine Learning for Neonatal Brain Monitoring, Sabine van Huffel, Belgium
      Sleep as a Biomarker of Brain Integrity in Neonates and Can Automated Analysis Help? Renee Shelhaas, USA
      Machine Learning to Aid Clinical Decision Making in Perinatal Asphyxia, Deirdre Murray, Ireland
      Free event, registration required: https://us02web.zoom.us/webinar/register/WN_oapC3m5cR0GBpZX3PgQfTQ12th International Newborn Brain Conference Series Agenda.pdf
    • 25 May 2021 09:00 PM
      0  
      A one day virtual course providing the essential skills to perform and interpret neonatal cranial ultrasound scans on the neonatal unit.
      This course will cover:
      · How to use an ultrasound scanner and get the best quality images
      · Standard images and normal anatomy
      · Germinal matrix and intraventricular haemorrhage
      · Linear measurements of ventricular dilatation
      · Preterm white matter abnormalities
      · HIE and Doppler measurements
      · Perinatal stroke
      Fee: full rate - £50.00
      Register here: http://training.ucheducationcentre.org/home/viewcourse/515/
       
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