What a hard topic to resist commenting on. This was all over twitter and the general media this week after the New England Journal published the following paper; Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. The fact that it is the NEJM publishing such a paper in and of itself suggests this is a top notch study…or does it?
Is there a benefit to giving antenatal steroids from 34 0/7 – 36 5/7 weeks?
That is the central question the authors here sought to answer. Would women who had a high risk of delivering during this time period have less risk of a composite primary outcome of treatment in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation) or stillbirth or neonatal death within 72 hours after delivery.
On the surface this seems like a very worthwhile set of outcomes to look at and the authors found in the end some pretty remarkable findings in a total of 2827 women randomized to placebo or betamethasone.
Looking at the results one sees that the primary outcome showed a significant difference with 2.8% less infants experiencing these conditions. However, when one looks at the details the only contributor to this difference was the need for CPAP or HFNC for >= 2 hours. A need for over 30% FiO2 for > 4 hours was also not different. No differences were noted in mechanical ventilation, ECMO, deaths whether stillbirths or neonatal deaths. Curiously, significant differences for secondary outcomes were seen with incidence of severe respiratory distress, and need for CPAP for over 12 hours.
These results are not truly that surprising at least for the primary outcome as if you asked most people working in the field of Neonatology how likely death, need for ECMO or even mechanical ventilation are from 34 – 36 weeks they would tell you not very likely. The other thing to consider is that the only real significant difference was noted for infants needing CPAP or HFNC for at least 2 hours. While this would interrupt maternal infant bonding, it wouldn’t necessarily mean an admission but rather in some cases observation and then transfer to the mother’s room.
Is it worth it?
To answer this question you need to know the best and worst case scenarios I suppose. Based on the reduction of 2.8%, you would need to treat 35 women with betamethasone to avoid the primary outcome but of course there is a range based on the confidence intervals around this estimate. The true estimate lies somewhere between 18 – 259 to avoid the outcome. Having said that, the estimate to avoid severe distress is 25 patients with a range of 16 – 56 which is pretty good value. In a perfect world I would probably suggest to women that there seems to be a benefit especially if one notes that in this study only 60% of the women received 2 dose of betamethasone so if rates of administration were higher one might expect and even better outcome. Ah but the world is not perfect….
There is only so much betamethasone to go around.
I find it ironic but the same day that this article came across my newsfeed so did a warning that we were about to run out of betamethasone vials in a certain concentration and would need to resort to another manufacturer but that supply may also run out soon as well. The instructions were to conserve this supply in the hospital for pregnant women.
In Canada as reported by the Canadian Neonatal Network in 2010, 38.1% of babies admitted to NICUs were below 34 weeks. Given that all babies would be admitted to NICUs at this gestational age and below that likely represents the percentage of births in those ages. An additional 31.8% or almost an equal number of babies will be born between 34 0/7 to 37 0/7 weeks meaning that if we were to start treating women who were deemed to be at risk of preterm delivery in that age range we would have a lot of potential women to choose from as these are the exact women in this strata who actually delivered early in Canada.
If I am forced to choose whether to give betamethasone to the mothers under 34 weeks or above when the resource we need is in scarce supply I don’t think there is much choice at all. Yes, this article comes from a reputable journal and yes there are some differences some of which are highly significant to consider but at least at this time my suggestion is to save the supply we have the babies who will benefit the most.
The scenario is often the same. Faced with a child born to a mother with risk factors for sepsis you decide to start antibiotics. The time comes closer to 36 – 48 hours when you must decide whether or not to continue. Each time we examine our results and look at cultures and try to do what is right. Yet defining right is sometimes hard for so many. If we had 100% sensitivity and specificity for all our tests it would be easy but we don’t. So what can we do?
If I had to have one wish though it would be that we could improve upon our diagnostic accuracy when it comes to treating suspected infections in the newborn. As health care providers we have an extremely loud inner voice trying to tell us to minimize risk when it comes to missing a true bacterial infection. On the other hand so much evidence has come forth in the last few years demonstrating that prolonging antibiotics beyond 48 hours is not just unwise in the absence of true infection but can be dangerous. Increased rates of necrotizing enterocolitis is just one such example but other concerns due to interfering with the newborn microbiome have arisen in more recent years. What follows are some general thoughts on septic workups that may help you (and myself in my own practice) as we move ahead into the New Year and may we cause less harm if we consider these.
The Role of Paired Blood Cultures
Although not published by our centre yet, we adopted this strategy for late onset sepsis a couple years back and have seen a significant reduction in work-ups deemed as true infections since adoption. While the temptation to do only one blood culture is strong as we have a desire to minimize skin breaks consider how many more there will be if you do one culture and get a CONS organism back. There will be several IV starts, perhaps a central line, repeat cultures etc. If you had done two at the start and one was positive and the other negative you could avoid the whole mess as it was a contaminant from the start. On my list of do no harms I think this may have the greatest benefit.
The Chest X-Ray Can Be Your Friend
While I am not a fan of routine chest x-rays I do believe that if you are prepared to diagnose an opacification on a chest x-ray as being due to a pneumonia (VAP or in those non-ventilated) that you need to follow this up with a repeat x-ray 24 – 48 hours later. If the opacity is gone it was atelectasis as a true pneumonia will not clear that easily. Well worth the radiation exposure I say.
If You Are Going To Do a Work-up Make It A Complete One
We hear often in rounds the morning after a septic work-up that the baby was too sick to have an LP and that we can just check the CSF if the blood is positive. There are two significant problems to this approach. The first which is a significant concern is that in a recent study of patients with GBS meningitis, 20% of those who had GBS in the CSF had a negative blood culture. Think about that one clearly… relying on a positive culture to decide to continue antibiotics may lead to partially treated GBS meningitis when you discontinue the antibiotics prematurely. Not a good thing. The second issue is that infants with true meningitis can have relatively low CSF WBC counts and may drift lower with treatment. Garges et al in a review of 95 neonates with true meninigits found that CSF WBC counts >21 cells per mm3 had a sensitivity of 79% and specificity at 81%. This means that in those with true meningitis 19% of the time the WBC counts would be below 21 leading to the false impression that the CSF was “fine”. If antibiotics were effective it could well be by 48 hours that the negative CSF culture you find would incorrectly lead you to stop antibiotics. Message: Do the CSF sampling at the time of the septic work-up whenever possible.
If We Aren’t Prepared To Do a Supra Pubic Aspirate Should We Not Collect Urine At All?
This provocative question was asked by a colleague last week and is based on the results of a study which was the topic of the following post: Bladder Catherterizations for UTI: Causing more harm than good? The gist of it is that it would appear that in many cases the results of a catheter obtained urine cannot be trusted. If that is the case then are we ultimately treating infections that don’t actually exist when the only positive culture is from a urine. I believe using point of care ultrasound to obtain specimens from a SPA will be the way to go but in the meantime how do we address the question of whether a UTI is present or not? May need to rely on markers of inflammation such as a CRP or procalcitonin but that is not 100% sensitive or specific either but may be the best we have at the moment to determine how to interpret such situations.
Lastly, Slow Down And Practice Good Hand Hygiene
So much of what I said above is important when determining if an infection is present or not. The importance of preventing infection cannot be understated. Audits of hand hygiene practice more often than not demonstrate that physicians are a group with some of the lowest rates of compliance. Why is that? As a physician I think it has nothing to do with ignorance about how to properly perform the procedure but rather a tendency to rush from patient to patient in order to get all the things done that one needs to do well on service or call. If we all just slow down a little we may eventually have less need to run from patient to patient as the rate of infections may drop and with it demand for our time.
If slowing down is something that you too think is a good idea you may want to have a look at the book In Praise of Slowness by Carl Honore (TED Talk by Carl Below) which may offer some guidance how to do something that is more easily said than done. Here is hoping for a little slower pace in the new year. We could reap some fairly large benefits!
I will admit it. I resist change at times just like many others. This may come as a surprise to some of you who have worked with me and accused me of bringing too much change at times to the units. The truth though is that when one understands something and is enthusiastic about implementation the change does not seem so difficult. When it isn’t your idea though we may find ourselves a little uneasy about adopting this unfamiliar practice.
Such has been my experience with nasal HFOV. It is a strategy that has been around for over five years but has seen slow adoption among centres in Canada and has trickled into practice in Winnipeg on a few occasions. In each occasion when I have been asked about either continuing or perhaps starting this therapy I have shrugged my shoulders and confessed my inexperience with the modality. Sure I have used HFOV through an ETT but through prongs or a mask?! How would it work? Could it cause harm? What would the actual indications be? How would our in house physicians and NNPs respond to abnormal gases overnight even if I felt comfortable with using it? These sorts of questions have led to virtual inertia in my acceptance of the strategy.
Before I go on it would be good to see an example of how it is set up. The MedinCNO device is capable of delivering such non-invasive HFOV and can be seen in this short video.
One could use the strategy either prophylactically to extubate an infant or as rescue to prevent reintubation if trials of either CPAP or NIPPV were unsuccessful. HFOV is known to be very effective at clearing CO2 when used through an ETT so perhaps nasal application could also lower pCO2 and achieve a similar effect. This was tested using a neonatal lung simulator by Mukeji A et al Nasal high-frequency oscillation for lung carbon dioxide clearance in the newborn. In this study CO2 was introduced into the manequin and the amount of exhaled CO2 determined while on CPAP, NIPPV and nasal HFOV. Interestingly during CPAP no exhaled CO2 could be detected while CO2 clearance occurred during NIPPV and nasal HFOV although it was three-fold greater with HFOV. In theory then CO2 clearance would appear to be better so in the case of ventilatory failure as evidenced by CO2 retention this modality would seem to win out.
Clinical Evidence for Use
There is one RCT in term infants with TTN to support the practice while the rest are unblinded case series with no controls. Four Canadian NICUs recently described their experience however using a retrospective analysis. Included were 79 instances of HFOV distributed as follows; 73% utilized as rescue from another mode and in 27% used as the primary mode for extubation. The outcomes are shown in the table:
In 45% of cases the patients needed intubation after first trialing CPAP or NIPPV while in 33% of cases following extubation the infants needed replacement of the endotracheal tube. The numbers here are small so it is difficult to truly compare them to other studies with confidence but reintubation rates of 40-44% have been noted recently when using NIPPV or CPAP so the numbers are at least consistent.
One aspect though that caught my eye was the duration of use for HFOV across these 79 patients. The median use was 57 hours with the longest duration being just over 400 hours. It would seem that the use of this modality for the most part is as a bridge to something else. The median duration of 2.5 days is much shorter than the weeks that some of our smallest infants remain on CPAP/NIPPV for. Whether for rescue or prophylaxis this is not a long term option.
Another point worth noting though is the question of whether it is the pressure or oscillatory wave that is leading to success. As the authors note, there were a wide range in applications of MAP, delta P and frequency.
MAP ranges from 8 – 24 cm H2O while frequency from 6 – 14 hz and amplitude varied widely depending on the device used but was as high as 100%. While high MAP has been used invasively though an ETT I can’t help but wonder if in some cases the real benefit was the high MAP. What would happen for example if the centres had simply raised the CPAP to 10, 12 or even higher?
In the end it would seem that in principal it is an effective therapy that may be able to remove CO2 more efficiently than the other modes. What we don’t have are RCTs in the smallest babies comparing HFOV to NIPPV or CPAP with adequate power to detect differences. I suspect these will come soon enough but what do we do in the meantime? The main reservation I have has to do with safety. We truly have little if any data on this without proper trials to ease such worry. When a patient is in front of us though and is failing CPAP or NIPPV what are we to do? Should we intubate or trial this modality based on the evidence thus far?
I might be tempted to trial HFOV in this circumstance but as with any new therapy we need education for all staff. Everyone caring for our infants need to understand what they are using and how to respond based on clinical findings. This is the real issue with safety that I see and until such time that we have widespread education across RRT, nursing and medicine I would suggest we use this with trepidation. This is not a rejection of the modality in the least but rather a call to come together as a team and see how implement this in such a way that will provide direction to caregivers, provide a consistent approach with respect to length of use, indications and when to change direction entirely. Time to call a meeting of the minds I think.
It is one of the first things that a medical student pledges to do; that is to do no harm. We are a fearful lot, wanting to do what is best for our patients while minimizing any pain and suffering along the way. This is an admirable goal and one which I would hope all practitioners would strive to excel at. There are times however when we can inadvertently cause more harm than good when we try to avoid what we perceive is the greater harm.
This is the case when it comes to collecting a sample of urine for culture as part of a full septic workup. If you ask most healthcare providers they will freely acknowledge that the gold standard for determining whether an infant has a UTI is a supra pubic aspirate (SPA). We so rarely do them these days however due to a whole host of reasons. Problems with collection include the timing and accuracy of needle placement both of which may often lead to an empty tap. Secondly after a number of missed attempts and a crying infant who appears to be in pain it is understandable why bedside nurses may become frustrated with the entire experience and urge the person performing such procedures to settle on a bladder catheterization (BC) to obtain the specimen.
All in all the BC performed quite poorly when compared to the gold standard. The false positive rate compared to SPA was 71.1%! That is to say that only 28.9% of SPA samples were positive compared to BC. Similarly urinalysis sensitivity and specificity from BC were 66.7% (95% CI, 44.68% to 84.33%) and 93.22% (95% CI, 83.53% to 98.08%), respectively. This means that only 2/3 of the time was the urinalysis abnormal on a BC in the presence of a true UTI. Somewhat reassuring is that when there really was no UTI the urinalysis was mostly negative but in almost 1/10 patients it would not by itself rule out a UTI.
What Is The Harm in Continuing BC Instead of SPA?
When we try to avoid the perceived painful experience of a SPA we are going to wind up treating a large number of patients for a presumed UTI who don’t have one. The harm in this is the exposure of such infants to prolonged courses of antibiotics which has been a subject discussed many times over on this site. We put our patients at risk of antibiotic resistance and shifts in the gut microbiome which in the case of the preterm infant puts them at risk of necrotizing enterocolitis. There are many other concerns with prolonging antibiotics but these few should be reason enough to strive for accuracy in obtaining the right specimen in the right way. Putting it in a slightly different perspective, would you settle for an alternative test to a lumbar puncture which claimed to miss 1 in 10 cases and also found meningitis where there was none 71.1% of the time?!
A Way Forward – A Recipe For Success
As the saying goes, measure twice and cut once. With the use of bedside ultrasound there should be no need to guess as to whether the bladder is full or not. Secondly the placement of the needle should no longer need to rely on landmarking but actually seeing where the best place for needle placement is. Assessing the bladder by ultrasound is easy and is already employed at the bedside by nurses in many areas of the hospital. There should no longer be a reason for the empty tap as the practitioner can be called when the baby is ready as evidenced by a good amount of urine in the bladder.
Given that we have some time to do the blood culture and LP, while we wait for the SPA to be done either sucrose in the premature infant or IV analgesic may be given for the SPA while in the term or older infant there is an opportunity to put a topical analgesic cream over the site. There really is little need for pain to factor into this any longer.
Ask any health care provider and they will tell you they want to do the best they can for their patient. This study shows us that performing a BC is failing to meet that goal. We need to change our ways and return to the practice of the SPA but this time we have to get it right.
As I read through the new NRP recommendations and began posting interesting points on my Facebook Page I came across a section which has left me a little uneasy. With respect to a newborn 36 weeks and above who is born asystolic and by ten minutes of age continues to remain so and has an apgar score of zero the recommendation that has been put forward is this:
An Apgar score of 0 at 10 minutes is a strong predictor of mortality and morbidity in late-preterm and term infants. We suggest that, in babies with an Apgar score of 0 after 10 minutes of resuscitation, if the heart rate remains undetectable, it may be reasonable to stop resuscitation; however, the decision to continue or discontinue resuscitative efforts should be individualized. Variables to be considered may include whether the resuscitation was considered to be optimal, availability of advanced neonatal care, such as therapeutic hypothermia, specific circumstances before delivery (eg, known timing of the insult), and wishes expressed by the family (weak recommendation, very-low-quality evidence).
There are some significant problems with this part of the statement.
They claim that the apgar score at ten minutes is a strong predictor but when you look at the analysis of the evidence presented in the body of the paper it is weak at best. I am not clear how one declares the prediction is strong in the face of poor evidence but I will acknowledge intuitively that this makes some sense but do challenge them on the use of the word “strong”.
2. They are correct in acknowledging that the introduction of hypothermia in such settings has changed the landscape in as much as I find it quite difficult to prognosticate unless a child is truly moribund after resuscitation. Given such uncertainty it is concerning to me that this recommendation may be committed to memory incorrectly in some places that do have access to cooling and may be used more rigidly as though shalt stop at 10 minutes.
3. In the middle of a resuscitation it is quite difficult to process all of the facts pertaining to a particular newborn while orders for chest compressions, emergency UVCs and epinephrine are being given. Can we really individualize within ten minutes accurately and take the families wishes truly into account? This just does not seem practical.
4. The families wishes are taken into account but inserted as a “weak recommendation”. How can the wishes of the family in any family centred model of care be minimized in such a way even if we believe the situation to be dire?
5. Since the introduction of hypothermia there appears to be a near 50% survival rate in such newborns and as the authors state 27% of survivors who received cooling had no moderate or severe disability. Here in lies my greatest issue with this guideline and that is the hypocrisy this position takes when you compare populations at 23 and 24 weeks gestational age. Survival at these GA in the recent NEJM study of almost 5000 preterm infants under 27 weeks were 33 and 57 % respectively at 23 & 24 weeks with rates of survival without moderate or severe disability being 16 and 31% in the two groups. The fallout from this and other studies at the extremes of gestational age have been that we should be more aggressive as the outcomes are not as bad as one would predict. How can we argue this for the 23-24 week infants and for term infant with the same likelihood of outcomes we would unilaterally stop in many centres?!
So Now What Do We Do?
We are supposed to be practising family centred care and much like the argument at the edge of viability the same should apply here. The wishes of the family should never be minimized. Arguably it may be very difficult in such an unexpected scenario to appraise a family of the situation and have clarity around the issue but if a heart rate can be restored after a few more minutes do we not owe it to the family and the child to bring the infant back to the NICU and see what transpires especially if cooling is available?
The million dollar question of course is where do we draw the line? No heart rate at 15, 20 minutes? Based on the evidence thus far it seems to me that a little longer than 10 minutes is reasonable especially in well equipped centres with access to cooling and modern ventilation and treatments for pulmonary hypertension. How long though must be individualized and should be determined in partnership with the team caring for the patient which must include the family.
Another year has passed and another World Prematurity Day is upon us. I thought about what to write for this day that draws attention to premature infants worldwide and was hit with many ideas which no doubt will form the basis for many posts to come. There was one thought that struck me though as being so important to think about as we push forward, striving to improve survival across the globe for our smallest patients. There is no doubt that you will have heard the expression “just because we can do something, should we?” In 2015 I don’t think this applies more than at this very moment.
At a Tipping Point
You see we are at a tipping point as Malcolm Gladwell explained so brilliantly in his book by the same name. In April of 2015 Rysavy et al published the results of survival and morbidity data for infants born in 24 US hospitals between the ages of 22 – 26 weeks. The nearly 5000 infants included demonstrated two very important things. Firstly, survival is possible at 22 and 23 weeks and there is a chance, albeit less than 50% that these infants will survive without moderate or severe disability. Secondly, at these gestational ages 75% of hospitals included provided active resuscitation to these infants. Given that this is the largest study out there and shows that survival is possible and we can expect to see some good outcomes it would seem logical to move forward with universal resuscitation of these infants would it not?
You Are Going To Practice on What?!
As the saying goes though, “Perfect Practice Makes Perfect”. Not all hospitals have equal performance at these gestational ages which is demonstrated in the ranges of outcomes across hospitals as shown in the Rysavy paper. To even suggest that we need to practice on premature babies will no doubt leave many of you feeling queasy but in essence that is what is truly needed to improve our outcomes further. An infant born at 22 – 24 weeks is vastly different than one born at a later gestational age. Their skin is extremely fragile and prone to breakage with resultant risk of infection. Their lungs are in a stage of development that has yet to produce any real abundance of gas exchanging alveoli and their brains lacking the sulci and gyri that are to come many weeks later. They are in need of meticulous “best practice” care and without that their outcomes are certainly to be influenced. Depending on the centre though, you may see 5, 10, 15, 20 patients a year at these ages. How can a team possibly gain enough experience in treating these children appropriately if they see 1 or 2 every two months? Add to this that you may have 10 different Neonatologists so on average each of you may take care of one patient a year at birth. This is a recipe prone to poor outcomes if you ask me.
The Evolution of the Small Baby Unit
The answer no doubt will lie in creating smaller teams; so called “Small Baby Units”. Such units have small groups of health care providers dedicated to treating such infants thereby increasing the frequency of individuals exposure to these babies. There is some recent evidence published in Pediatrics that supports this notion. Small Baby Unit Improves Quality and Outcomes in Extremely Low Birth Weight Infants. In this study a period of two years before and four years after opening such a unit were compared across a number of measures. The findings were as follows “There was a reduction in chronic lung disease from 47.5% to 35.4% (P = .097). The rate of hospital-acquired infection decreased from 39.3% to 19.4% (P < .001). Infants being discharged with growth restriction (combined weight and head circumference <10th percentile) decreased from 62.3% to 37.3% (P = .001). Reduced resource utilization was demonstrated as the mean number per patient of laboratory tests decreased from 224 to 82 (P < .001) and radiographs decreased from 45 to 22 (P < .001).” I hope you would agree that achievements such as these are worth the effort to create such an environment. Future studies I believe will confirm these findings although having the gold standard RCT may be difficult to achieve as I suspect we will have lost equipoise.
This brings me to the final point though and that is whether we are ready as a health care system for the increase patient load that this change will bring about. Based on an expected stay of 4 months for a baby born at this age and knowing the average number of such babies delivered per year, we would be looking at about 600 patient days per year added to each hospital’s occupancy in our two centres. This represents about a 5% increase in patient bed days per year. Five percent may not seem like a large increase at first blush but when we like many hospitals have been trying to deal with staffing issues and many days in which we are at or near capacity, this is not an insignificant challenge. It is a challenge though that we must face head on. Resources must be found, and space provided to accommodate for these children. We live in a world now where it is not solely up to us but to the family as well who must be integral to any such decision to either pursue or withdraw care. News of such infants surviving has spread to the public and I have no doubt that many families will have heard stories of such survivors. The next phase of care for these infants must address the shortcomings in care at the moment.
How do we educate families about what to expect in the long run?
How do we support these families when they make such difficult decisions either way?
How do we support our front line staff who may hold quite discrepant viewpoints about what is “right” yet expect them to function as one team moving clearly in a direction that supports the family?
How do we ensure that our focus on our smallest infants does not distract us from the attention needed by those born at later gestational ages?
I could go on but these are just some of the questions that I hope the next year begins to tackle. We are in the midst of an evolutionary point in Neonatology and we owe it to ourselves and the families we care for to navigate this change as best we can.