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  • Latest Blog Entries

    • By AllThingsNeonatal in All Things Neonatal
         0
      A couple years back at the Canadian Pediatric Society annual meeting a discussion broke out about extubating infants to higher levels of CPAP. Conventional thinking had been to use levels between 5 – 8 cm H2O typically. I shared with the group the experience we had in Winnipeg (unpublished) of using higher levels from 9 -12 cm H2O with some degree of success in allowing earlier extubation. The group thought it was interesting but pointed out the lack of robust research in the area so were not so keen to “try it out”. Non-invasive positive pressure ventilation (NIPPV) has been used for some time in the neonatal world and has been compared to CPAP for extubation success and found to be superior as in this review Comparison of Complications and Efficacy of NIPPV and Nasal CPAP in Preterm Infants With RDS. In this review though as in others more typical CPAP levels are used so the question is whether the same efficacy would be seen with high level CPAP vs NIPPV.
      Canadian Study to the Rescue
      The study here is by Ahmad HA et al Comparison of High CPAP versus NIPPV in Preterm
      Neonates: A Retrospective Cohort Study and seeks to answer this question albeit in a retrospective fashion. The study is not well controlled since it is retrospective but it may be the best we have for now. Over a 3 year period the authors examined the outcomes for babies trialed on high CPAP (hCPAP of at least 9 cm H20) vs NIPPV. In each case they looked at the first episode of use. The modalities could have been used for extubation or as a primary means of support. The primary outcome was failure of the modality as defined by either intubation or change to the other strategy within 7 days. A total of 53 infants received hCPAP vs 119 NIPPV. Why the big difference? Since this was retrospective and not randomized it was up to the individual practioner which modality they wanted to try. If the majority of the unit favoured NIPPV this is why there would be such a difference. Herein lies the benefit of the primary outcome as if “conventional wisdom” was wrong and the other modality would be better then we should see a greater movement to the other strategy or more intubations in one group suggesting superiority of one vs the other.
      The groups however aren’t entirely equivalent at baseline. The babies in the hCPAP group are quite a bit smaller on the one hand which would favour the NIPPV group. On the other hand there is almost a significant difference in surfactant provision for the hCPAP arm which might favour the hCPAP group. The other thing also nearing statistical significance is when the intervention was trialed. The median time is 2 days for teh NIPPV group and 7 for hCPAP suggesting one may have been used more prophylactically and the other post extubation. Different strategies might make a difference to outcome? Also no infants received MIST or INSURE and all were started on traditional lower levels of CPAP prior to surfactant.
      Results
      The results tell an interesting story (I think) with the primary outcome being no different 62% in the hCPAP vs 55% with NIPPV. Looking at the patient outcomes in the figure from the paper one gets a little more detail and can surmise how people viewed the two modalities as a strategy and can see they were a bit different.
      There seems to have more confidence in the unit with NIPPV as a way to prevent intubation. For those that failed hCPAP 12/33 were intubated as the next step (about a third) while the other 2/3 were trialed on NIPPV. Looking at those started out on NIPPV, 38/66 were intubated directly 58% or almost 2/3 while 28/66 were trialed on hCPAP. Of the ones trialed on hCPAP 20/28 or 71% were still intubated. Comparatively of those who were changed from nCPAP to NIPPV 11/21 were intubated or about 50%.
      The authors find no difference in the primary outcome which is true. The problem of course with this analysis though is that there was no standardization with determining when one would choose to intubate. This issue can really play with the results. Let’s say for example that one Neonatologist really believes for the most part that NIPPV is the mode that can really prevent intubation more than hCPAP. It is conceivable that the reason in crossover intubations are less with NIPPV is that people were willing to tolerate a slightly higher pCO2 or a couple more apneas since they believe the modality is best and the infant will “get better soon”. On the other hand, infants already on NIPPV who are deteriorating might be intubated more readily as the attending might think “this hCPAP is a bunch of malarky”
      It is worth mentioning that the incidence of air leak was no different between the two, nor was NEC or feeding intolerance from exposing the babies to such high pressures.
      Conclusions
      The study doesn’t “prove” anything. I don’t see it as a complete waste though as it does a number of things. It does show that small infants can be managed with hCPAP in NICU without any significant increase in complications. It also sets the stage for a couple future prospective trials I can see. Firstly, a trial of traditional CPAP vs hCPAP is needed as some units don’t have access to NIPPV or simply don’t use. The second is a prospective trial with clear parameters for failure between hCPAP and NIPPV.
      Lastly, the authors ran the NIPPV and CPAP off ventilators in the units. The work of breathing would be potentially different with the use of devices solely designed for CPAP with fluidic flips. It would be important to use optimal devices for both modalities in such a trial and I for one can’t wait to see them.
    • By AllThingsNeonatal in All Things Neonatal
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      Precision medicine is a growing field in which genetic factors, environment, metabolism and even lifestyle are taken into account when deciding who should receive a treatment or not. When it comes to bronchopulmonary dysplasia I believe anyone who works in Neonatal care can attest it is a mystery why some infants go on to develop BPD while others don’t. We do know that certain treatment strategies may increase risk such as using excessive volumes or pressure to ventilate and in the last 25 years the notion that your level of cortisol in the blood may make a difference as well. I have written about prophylactic hydrocortisone use before in Hydrocortisone after birth may benefit the smallest preemies the most! When looking at the literature thus far and taking into account the results of the individual patient meta-analysis the following table can be generated highlighting a summary of benefits.
      The question thus becomes if there is benefit for some infants under 26 weeks and then for some that are 26 and 27 weeks but there is also risk of harm, is there a way to select out those who are most likely to benefit with the least risk of harm.
        A baby’s initial cortisol level may be the answer
      The PREMILOC study was a double-blond multicentred trial of 523 infants randomly assigned to either prophylactic hydrocortisone in the first 24 hours of life or placebo. All infants were under 28 weeks at birth and received 1 mg/kg/d of hydrocortisone 1 mg/kg/d for 7 days followed by 3 days of 0.5 mg/kg/d for three days. In a pre-planned study coming out of the PREMILOC study, researchers looked at the role of baseline cortisol in predicting response to treatment or risk of adverse outcomes.
      What they found in examining baseline levels for both treatment and placebo groups was that a relationship exists between the baseline level and such outcomes.
      From Table 4 they found a relationship between survival without BPD and a higher initial level of cortisol but found no such relationship in the treatment arm. The threshold of what was considered high was 880 nmol/L although the mean cortisol was in the 400-500 nmol/L range. in other words, if having adequate physiologic levels of cortisol is the goal and a baby already has that, giving more non-antiinflammatory dosing of hydrocortisone doesn’t yield benefit.
      Similarly, when looking at side effects a positive correlation was found between higher baseline levels of cortisol and risk of grade III/IV IVH and spontaneous intestinal perforation. It would seem therefore that if a baby has the level of cortisol that they would normally have from a physiologic perspective they are no different than a placebo arm patient when given hydrocortisone as you bring them to where they need to be. When you double the dose however that they should have, side effects begin to rear their ugly head.
      How can you use this information?
      From personal conversations I know that many centres are struggling with what to do about giving hydrocortisone. On the one hand there isn’t much benefit (if at all) for BPD in the 24 and 25 week infants but they do better from a neurodevelopmental standpoint. On the other hand there is a benefit in the 26 and 27 week infants but you may predispose them to side effects as well.
      This is where precision medicine comes in. One option for centers unsure of who to provide this to (if at all) could be to use a threshold of 880 nmol/L and if the initial level is above this you would not treat but if below offer treatment. This level while found in the study to be predictive of side effects in particular if high does seem very high to me. I would think most babies would qualify which is not necessarily a bad thing but in our center we have typically used levels above 400 or 500 as an adequate stress response. Regardless of the level picked one would be using physiologic data to determine who to give hydrocortisone to as a way to try and maximize benefit and minimize harm for the individual patient.
      Make no mistake. Regardless of whether you decide to try this for your patients I don’t believe this is a magic bullet. The best chances for our patients come from having bundles of evidence based based practices and applying them to the patient population if we hope to reduce BPD and minimize risk from any side effects of our treatments. The question is whether prophylactic hydrocortisone should be part of this bundle.
      What do you think?
    • By AllThingsNeonatal in All Things Neonatal
         1
      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!
       
  • Upcoming Events

    • 18 June 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 
       
       
       



    • 01 July 2021 07:00 PM
      0  
      This is the third in a series of FREE online guest lectures in pulmonology from the NOTE and ESPR collaboration. For an application form to attend please email  noteteam20@gmail.com
       

    • 06 July 2021 07:00 PM
      0  
      This is the final lecture in a series of FREE online guest lectures in pulmonology from the NOTE and ESPR collaboration. For an application form to attend please email  noteteam20@gmail.com

    • 01 October 2021 Until 03 October 2021
      2  
      First announcement of 
      Recent advances in neonatal medicine
      IXth International symposium honoring prof. Richard B. Johnston, MD, Denver, US
      1-3 Octobe 2021, in Würzburg, Germany
      Find more information in the attached folder.
      First_Announcement_01.2020.pdf
    • 17 November 2021
      1  
      The 17th of November each year is the World Prematurity Day. Originally started by parent organisations in Europe in 2008, the World Prematurity Day is an international event aiming at high-lighting the ~15 million infants born preterm each year.
      Read more about this day on the March of Dimes web site, and on Facebook.
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