This post is a written as a tribute to John Minski RRT who taught me much about ventilation over the years and has been a champion for innovation in our unit. As he prepares to move on to the next phase of his life I thought it would be a nice send off to talk about something that he has been passionate about for some time. That passion is inhaled nitric oxide for more than just pulmonary hypertension.
This is actually nothing really new. For a review on the background behind the theory you can read The potential of nitric oxide releasing therapies as antimicrobial agents. While we think of iNO as being a drug for pulmonary hypertension it has other capabilities. It can diffuse across cell membranes and damage pathogens by causing nitrosative and oxidative damage. The amount of iNO needed though to accomplish this bactericidal action is much higher than the typical levels of 20 – 40 ppm that we use. Last year in August Bogdanovski et al published Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease. They describe a protocol of providing 30 minute doses of 160 ppm for 21 days in a 24 year old patient with cystic fibrosis who was infected with mycobacterium abscessus. While they were not able to eradicate the organism, they were able to demonstrate functional improvement in the patient. Also notable was the absence of adverse effects in terms of methemoglobin levels. Other prior research in-vitro has shown iNO at high levels to be truly bacteriocidal as per the review above.
In this paper they describe the use of iNO at 160 ppm in 5 spontaneously breathing patients with confirmed COVID19 infection. This was provided as a rescue therapy in the absence of any high quality therapies for this disease. The protocol was to give them the same dose of 160 ppm for 30 minutes at a time until resolution of their symptoms with those that received multiple treatments getting anywhere from 5-9 courses. In each case after each 30 minute period the treating physicians measured levels of methemoglobin and nitrogen dioxide and found in each patient acceptable levels after these brief exposures.
Of the 5 patients treated 2 died from COVID19 and three survived. The two patients who died interestingly were the ones who each only received one treatment each. The other three received 5, 8 and 9 treatments respectively. The authors recorded mean arterial pressure, heart rate, respiratory rate, SpO2/FiO2 and finally measurements of inflammatory markers in the two patients who died (E) and the 3 who survived in (F) in the figure below.
What is interesting from the figure above is the reduction in respiratory rate during treatment (certainly could be placebo from believing they will get better) but the oxygenation during the treatment improved as well. Could this be from a reduction in associated pulmonary hypertension? Certainly could be. Looking at the patients who died in (E) vs the ones in (F) who survived (patient 3 not shown) demonstrate that use of iNO stopped the rise in CRP and in the case of those who died reduced it significantly. There could be an argument made then that the changes in respiratory pattern observed during treatment are associated with a concomitant attenuation of inflammation. This treatment just might work but of course needs far more studies to be certain of that. On that note a review of iNO for this type of indication reveals there are currently 16 studies enrolling in this area of research so I imagine there will be more info to come with this story.
What about the neonate with pneumonia?
I sent this paper around to my colleagues and it generated some great discussion. I am no Ethicist but the question raised was could this be considered a “last ditch” treatment for the neonate succumbing to a pneumonia? I have no doubt if you are reading this that you will have seen in neonatal units around the world that there are infants who develop pneumonia unresponsive to traditional treatments such as iNO at regular doses, antibiotics, higher PEEP, surfactant etc. If we have this knowledge with respect to the potential use of iNO at high dose and a positive impact on pulmonary infective disease is this something that should be offered to parents?
We have no date to my knowledge in babies on the use of this type of dosing but it comes down to a question of what is the alternative? If a patient is dying on the ventilator are we at the point of knowledge here that it is worth offering the family this treatment? One could do so with full disclosure about the lack of neonatal data both for effectiveness and safety. Or do you fall on the side of it could be harmful and expedite death so should not be used. If you use it though and wait till the patient is in extremus on 100% oxygen might it be too late? Do parents have the right to know when they ask the question “is there anything else you can do?” For me I think the answer is that there should be a discussion with this evolving research out there. I am comfortable with it as long as the parents understand the potential for it to make things worse and shorten their time with their child. Alternatively if they choose not to that is their prerogative but should they have the choice when the competing outcome is death?
I can’t tell you whether you should or shouldn’t offer this in your institution but my suspicion is that you will be discussing this among colleagues before long. Who knows you might just one day say you saw it here first!
Thanks John M for the inspiration and keep sending those articles!
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!
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).”
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.
In the book Outliers by Malcolm Gladwell he talked about 10000 hours being the threshold at which if you practiced or gained that much experience with something you could become an expert. In Sweden the approach to 22 week pregnancies and above is to resuscitate all as a strategy. I wrote about this before in At 22 weeks of gestation does your faith matter most to outcome? The information gleaned from that paper was that if you have a policy of resuscitation at these gestational ages and you compare outcomes to a centre that is selective in who they resuscitate the outcomes are better when you believe all should be resuscitated.
New Study Expands Data
The same group has published this time around the results of the same cohort from 2006-2015 but this time with developmental outcome data. The paper is entitled Outcomes of a uniformly active approach to infants born at 22-24 weeks of gestation In this paper they discuss outcomes at 234 and 24 weeks respectively in addition to the findings for 22 weeks which they covered in the paper mentioned above. The reason for sharing this study is that if I asked you to imagine going into a room right now and talking to a family at 22 – 24 weeks and predicting the outcome of their infant, my hunch is that you would not provide as rosy a picture as the group in Uppsala, Sweden.
The authors looked at a group of infants with the following breakdown by gestational age.
Not surprisingly as gestational age declines the incidence of complications rise but looking at Table 3 even at 22 weeks there was no difference in rate of NEC or need for PDA surgery. Nor was there a difference in rates of severe IVH/PVL. Rates of BPD were higher and likely attributable to the longer durations of positive pressure ventilation. Are these rates for these complications terrible though when the other option is non-intervention which for certain means death?
What about outcome?
Looking at the outcome at 2.5 years, the rate of cerebral palsy is about 1:10 to 1:20 for all GA. Hearing impairment is almost non-existent and while developmental delay is detected in 50 percent of survivors at 22 weeks only about a quarter of the infants have severe impairment.
Deciding what to do
There is no question that many of you seeing what this post was about would simply say “NO WAY” but in the end isn’t it really about a shared decision with the family? It wasn’t that long ago that we had to have a real paradigm shift in thinking about resuscitating 23 week infants. The amount of mental energy spent for teams worldwide coming to this decision was tremendous and now if you were to suggest compassionate care at 24 weeks you get a look back like you are crazy! It wasn’t that long ago that 24 weeks was considered viability in many places and now that 23 is the new 24 this is the struggle some people have now. Should we go to 22 weeks everywhere as the Swedes have? Clearly this is a decision that institutions need to look at critically and determine if they have the space to accomodate. Each infant should they survive will occupy a bed for at least 6 months. This needs to be looked at before one can just say sure this is a good idea.
In the end what the study demonstrates I believe is that the outcome at 22 and 23 weeks for that matter need not be universally dismal. There certainly is a good chance that a surviving infant will have one or more deficits but in the end I would advocate this is a conversation all units need to be having and critically look at whether each institution has the capactity to consider.
My bet is that five years from now this discussion will be moot as we will be mostly in that direction but at this time I think we are still in evolution.
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.
Testing for COVID19 has become so much the norm in society that in casual conversation you might ask someone if they have been tested. Chances are you know someone who has and even more likely that it is many people at this point. If you have been following this blog for awhile you would know that one of the issues with testing is that it is extremely sensitive. The RT-PCR test can pick up even trace viral particles whether alive or dead and therefore a test in and of itself tells you one thing. There is virus present but whether it is alive or dead is another matter. Virus can be shed for weeks after symptoms develop so what information can we obtain that might tell us whether the patient is at risk of infecting another person. Moreover, when can we relax precautions around the patient themselves and no longer worry that they are a risk to others?
Winnipeg Researchers May Have the Answer
Given that I know many of the authors of the paper personally that I will discuss and the quality of the work they do I am delighted to cover this important work. The paper Predicting Infectious Severe Acute Respiratory Syndrome Coronavirus 2 From Diagnostic Samples by Bullard J et al tackles the question above using cycle times and times to positivity after initial symptoms. First off it is important to understand the concept of cycle time. When you use RT-PCR to amplify pieces of RNA there are 40 cycles of amplification that a sample is put through. The lower the number of cycles required to detect the RNA the more viral material was present to begin with. As the cycle times get well into the 30s the possibility of there being just trace amounts of virus exists or that the patient themselves had no virus present but the sample was contaminated with a very small quantity of virus. The time to positivity is the amount of hours/ days it takes after initial symptoms develop until an RT-PCR test becomes positive.
The authors analyzed 90 samples either from naso-pharyngeal swab or ETT secretions with a median age of 45 years (I know not neonatal). Collected samples included from day 0 to day 21 after symptom onset. What the authors did that was interesting in this paper was that in addition to the samples being tested by RT-PCR, for each positive sample they went through the laborious task of performing tissue culture to attempt to grow the virus. By doing so the authors were then able to compare the time to positivity (STT) and Ct thesholds to determine if there were numbers for each that could be used to predict which samples would have live virus that could be grown,
The Results Please
The two main findings in the paper were that no patient after day 8 from symptom onset with a positive RT-PCR could actually have live virus grown in tissue culture. This is shown in Figure 3 from the paper
Secondly, no patient with a cycle time greater than 24 could also have live virus grown. In fact for every 1 unit increase of Ct the odds ratio for infectivity decreased by 32%.
The size of the study is fairly large when it comes to COVID19 studies like this but as the authors say the results are for adults and given how few children have been infected especially in our location in Canada we should be hesitant to generalize to children and in particular neonates.
What the study does give us
This study I felt was worth sharing with you for the reassurance that I think it may give especially if it leads to further validation by even larger studies including children and those who are immunocompromised who may have prolonged shedding. What it suggests though is that the next time you encounter a patient who you are told tests positive there are a couple important questions to ask from your lab. The first is how many days from the start of symptoms was the RT-PCR done? Secondly, ask them for the Ct value. As per the authors
“Receiver operating characteristic curves constructed using Ct vs positive culture showed an area of 0.91 (95% CI, .85–.97; P < .001) with 97% specificity obtained at a Ct of > 24. Similarly, STT vs positive culture showed an area of 0.81 (95% CI .73–.90; P < .001), with 96% specificity at > 8 days”
In other words, if the answers to those questions are >8 days and a value for Ct >24 you should be able to leave the patient with reasonable expectation that they are either no longer infectious or at worst almost clear of live virus.
Interesting work that I hope will be helpful to someone out there!