The 10th Annual Bowman Symposium did not disappoint! World class presenters gathered to provide a top to bottom update on a variety of topics spanning from the nervous system to Genetics. After a day and a half of presentations though I was left with some concerning (scary) thoughts and it seemed Halloween was the perfect time to share them with you!
How Much Oxygen is Just Right?
Dr. Ola Saugstad provided a wonderful history of the use of oxygen in Neonatology. After his talk it was clear that oxygen is most definitely a drug with its most concerning side effect being the production of oxygen free radicals in the body. If we are too restrictive aiming for saturations of 85 – 89% we spare our infants ROP but put them at greater risk of death. Too high at 91 – 95% and they may survive but with more ROP (BOOST and SUPPORT). If we resuscitate with 100% oxygen that is associated with worse outcomes but so too is 21% in our newborns < 28 weeks. The NRP would advise us to use 21 – 30% to start in this group for resuscitating but he recommends 30%. Certainly the recent publication by Jack Rabi out of Calgary suggests room air may in fact be harmful in this group as a starting point! After 50 years of research we still don’t know what to give newborns to help them start their life outside the womb. Scary.
It’s All In The Name
Next up is Dr. Aviva Goldberg who raised a very important point that I had not considered before. In every researchers quest to come up with a catchy name for their study that people will remember, the connotation is equally important. The SUPPORT study came under heavy fire (commentary here) after a surprising increase in mortality was found in the arm randomized to 85 – 89% saturations. Families sued the investigators and in their complaints they were angry about being misled. How could a study that was named the SUPPORT study do anything other than help their children? The title in and of itself they argued misled them as they never would have thought increased mortality could be a risk. Researchers make sure you test out your clever names with parents before finalizing your studies. The decision otherwise could come back to haunt you…
Jury Still Out on Bevicizumab (Avastin) for ROP
Dr. Ian Clark provided an overvue of the current state of thinking on treating ROP. For central disease in Zone 1 Avastin is preferred but for more peripheral disease laser seems to still be recommended due to its decisiveness in eliminating the disease without affecting future vision. Concerns continue though with respect to potential systemic effects of putting an anti-VEGF medication in the eye. Can it leak out and cause disruption to angiogenesis in other organs and in particular the brain? A recent poster at the CPS meeting in Toronto entitled Neurodevelopmental outcomes of extremely preterm infants treated with bevacizumab for severe retinopathy of prematurity indicates that there may be greater impairment in those receiving injections. There are several flaws in this paper though including greater numbers of males (we always do worse), more sepsis and worse SNAP-II scores in the injection group but the results have been making it into discussions leaving Ophthalmologists wondering if they are doing the right thing…very scary.
Cow’s Milk Human Milk Fortifier Is Safe For Premature Infants… Or is it?
Next up was Dr. Bill Diehl Jones who presented in vitro data on the effect of these supplements with respect to their contribution to oxidative stress. Such stress has been associated with BPD, NEC and ROP to name a few disorders in preemies. A paper published this week in which intestinal cells were exposed to human milk with HMF experienced significantly increased intracellular oxidation, cell damage, and cell death compared to those exposed to just breast milk. A paper from 2013 indicates that premature infants fed HMF experience increasing levels of urinary isoprostanes (a measure of oxidative stress). We know that infants receiving these products experience better growth and bone density than those without exposure but is there a cost? Will further research in this area drive us towards exclusive human milk based diets? The seed that has been planted in my head now questioning the safety of this product I use every day…a little frightening.
Curtailing Antibiotic Use And The Coming Black Swan
John Baier spoke about practice variation between Neonatologists in terms of the decision to prolong antibiotics or not in the face of negative cultures. While we do have variation, the good news is that we overall have cut down our tendency to prolong past 48 hours in the face of negative cultures. If we practice long enough though, the Black Swan will eventually rear its ugly head. The Black Swan is an exceptionally unusual event but one that has dramatic impact. How will we respond when a patient becomes septic after 48 hours and the antibiotics were stopped? Will we panic and change our practice entirely to avoid the internal pain again of feeling like we made a mistake or remember that we have saved countless infants from the long-term effects of indiscriminate use such as NEC, atopic disease and obesity in childhood just to name a few. It is this nagging doubt I have about how we will react that gives me cause to worry!
Finishing With a Miracle
It doesn’t seem right to end on a down note so I thought it would be worth celebrating that a cure has been found for something very scary. Hypophosphatasia is a rare disorder of the bone which was previously lethal in many cases. Thanks to research that our own Dr. Cheryl Greenberg led here in Canada we are able to successfully treat these children now. The Bowman symposium showed us incredible videos of such treated children and to end this post I found this video from Youtube of Gideon who was one of these patients treated with FDA Okays Asfotase Alfa (Strensiq). If you would like to leave this post with a smile on your face until next Halloween have a look at the video!
Go to any NICU these days and you will no doubt hear about the toxicity of oxygen. Oxygen as we say is a drug and like any such product has both good and bad effects. On the good side is the ability to increase the fraction of inspired oxygen to deal with transient changes in observed saturations. In extreme cases where the patient is desaturating into the 20’s and 30’s with accompanying bradycardia this can be life saving. On the other hand the “bad” is related to toxicity from oxygen free radicals which can increase rates of ROP, BPD and in the case of resuscitation with O2 vs room air may increase the chances of death.
It is for this reason that NICU teams pay particular attention to saturation targeting. The optimal goal remains elusive as oxygen restriction to 85-89% has been linked to higher mortality as in the Support Trial (full article) while higher saturations may increase the rate of ROP and BPD. Many units are falling somewhere in the middle such as goals of 90-95% or as in our units 88-93%. If during your visit to an NICU you were to observe the nurses at the bedside you would see them or the Respiratory Therapists tweaking the oxygen up and down many times a day as they strive to keep the saturations within these ranges. As a Neonatologist I greatly appreciate the efforts of everyone on the team who try to keep maintain these goals but in the end how do they really do?
This was the subject of a 2006 paper by Hagadorn et al. Eighty four infants from 14 centres all less than 28 weeks were enrolled in this study looking at how successful staff were at keeping infants within a desired range. The findings were somewhat discouraging in that 16-64% of the time saturations were in range, while 20-73% of the time they were above range depending on the centre studied. In a different study by Laptook et al published in the same year, the results were not much better with saturations higher than goal about 15% of the time and lower by nearly 26% of the time. What impact might swings in oxygen saturation have on the brain when the saturations are low and similarly on rates of BPD and ROP when the tendency is to overshoot the goals? There is no doubt that everyone is trying to do a good job but how deflating is it to nursing and other staff members when despite their best efforts they are only in range about 60% of the time?
Fortunately I believe change is coming. With improvements in technology it is now possible to have a closed loop system in which a patient who is receiving oxygen has their saturation measured and the information via a feedback loop triggers an automated response. This response either raises or lowers the FiO2 in an automatic way which eliminates the need for health care staff to make such changes. Such technology is actually not that new as it was tested in 2001 by Claure et al and was found to be at least as effective as manual changes by a dedicated nurse. Several other small studies followed, all demonstrating an improved accuracy in maintaining target saturations. This July the same group published the following article Automated versus Manual Oxygen Control with Different Saturation Targets and Modes of Respiratory Support in Preterm Infants. This study compared the accuracy in maintaining saturations using a target of 91-95% and another of 89-93% with 80 patients participating. Patients in this study received both invasive and non-invasive ventilation. When comparing the two target ranges the automatic adjustments showed greater benefit with the results being 62 +/- 17% vs 54 +/- 16% for the 91-95% range and 62 +/- 17% vs 58 +/- 15% in the lower range. Both of these results were statistically different with p values of <0.001. When looking at episodes of significant hypoxemia as defined by a saturation < 80% the findings were interesting showing in the high range 13 vs 4 and in the low range 15 vs 4 favouring the use of autosaturations. The authors were surprised at the lack of large disparity in the accuracy between manual and auto adjustment of FiO2 but this may be related to the Hawthorne effect. Since the nurses in this study were not blinded to the intervention they may have changed their behaviour in essence to try and prove that they were just as good. How this would translate into a real world situation when a study is not being performed I suspect would favour the automated system more.
Perhaps the most interesting part of the study though was the number of Manual FiO2 adjustments per 24 hours between the two groups. For the 89%-93% SpO2 target range this was 1 [0-3] vs 102 [73-173], P < .001 and for the 91%-95% SpO2 target range 1 [0-3] vs 109 [79-156], P < .001. For me this is the crux of the discussion. In a twenty four hour period there is a reduction of about 100 interventions using the saturation range similar to our own. Take note as well that some patients required over 150 interventions in 24 hours as 100 was the mean! While the targeting is improved somewhat with the use of the auto FiO2 adjustment this is where the biggest benefit to the patient lies as I see it. Nurse and respiratory therapists are very busy on any given shift. One hundred adjustments a day translates into 4 changes in FiO2 per hour on average. Although not measured I can’t help but wonder what impact these interruptions have on the rest of the care for a given patient. What is the “ripple effect” of such interruptions in a person’s train of thought. Could this translate into a med error or delay care for another patient to whom the nurse is responsible for as well? If one didn’t have to pay as much attention to the FiO2, what other goals could their attention be put towards? Might this provide them with more time to educate parents, do skin care, or a host of other responsibilities which in the current state get interrupted every time an alarm goes off.
As this technology is improved I see this being a welcome addition to the NICU. As with anything though that promises a hands free environment it will be essential to have an override built in. Furthermore we can never take our eyes off the patient as no matter how safe these systems may be there is always the chance that a computer will freeze as we all know. The impact of such a “glitch” in the algorithm that these systems use could be catastrophic to outcome so as good as these may be we will always need the human presence to ensure that what we think we are getting from the system is actually there.