Using the printed word to treat apnea of prematurity

Using the printed word to treat apnea of prematurity

As the saying goes, sometimes less is more.  In recent years there has been a move towards this in NICUs as the benefits of family centred care have been shown time and time again.  Hi tech and new pharmaceutical products continue to develop but getting back to the basics of skin to skin care for many hours and presence of families as an integral team member have become promoted for their benefits.  The fetus is a captive audience and hears the mother’s heart beat and voice after the development of hearing sometime between 24-26 weeks gestational age.  This is a normal part of development so it would stand to reason that there could be a benefit to hearing this voice especially after hearing has developed and the fetus has grown accustomed to it.  Hospital including my own have developed reading programs for our patients and some companies have developed speakers in isolettes designed to limit the maximum decibel to 45 but allowing parents to make recordings of their voices.  Music may be played through these speakers as well but today we will focus on the benefit of voice.

Could reading to your baby reduce apnea of prematurity?

This is the question that Scala M et al sought to answer in their paper Effect of reading to preterm infants on measures of cardiorespiratory stability in the neonatal intensive care unit.  This was a small prospective study of the impact of parental reading on cardiorespiratory stability in preterm NICU infants. Eighteen patients were enrolled who were born between 23-31 weeks gestation.  The study was carried out when the babies were between 8-56 days old at a mean postnatal age of 30 weeks. Each patient served as their own control by comparing episodes of oxygen desaturation to <85% during pre-reading periods (3 hours and 1 hour before) to during reading and then 1 hour post reading.  Parents were asked to read or create a recording lasting a minimum of 15 min but up to 60 min of recorded reading.  The parents were offered a standard set of books that had a certain rhythm to the text or could choose their own.  Recorded reading was played for infants up to twice per day by the bedside nurse. While it was small in number of patients the authors point out that the total exposure was large with 1934 min of parental bedside reading analyzed (range 30–270 min per infant, mean 123, median 94 min).  Patients could be on respiratory support ranging from ventilators to nasal cannulae.

Was it effective?

It certainly was. I should mention though that the authors excluded one patient in the end when it was found that they failed their hearing screen.  Arguably, since the infant could not have benefited from the intervention effect this makes sense to me.  As shown from table 3 there was a statistical reduction in desaturation events during the reading period which was sustained in terms of a downward trend for one hour after the intervention was completed.  In case you are asking was the difference related to oxygen use the answer is no.  There was no difference in the amount of oxygen provided to patients.  While the events were not eliminated they were certainly reduced.  The other point worth mentioning is that there appears to be a difference between live (through open portholes) vs prerecorded reading (through a speaker in the isolette).

Now for a little controversy

Does source of the reading matter?  The authors found that maternal had a greater effect than paternal voice.  As a father who has read countless books to his children I found this a little off-putting.  As a more objective critic though I suppose I can buy the biologic plausibility here.  I suspect there is an independent effect of voice having a positive impact on development.  If we buy the argument though that the voice that the fetus has most been accustomed to is the mothers, then the findings of an augmented effect of the maternal voice over fathers makes some sense.  I will have to put my ego aside for a moment and acknowledge that the effect here could be real.

There will no doubt need to be larger studies done to drill down a number of questions such as what is the ideal type of reading, duration, rhythmic or non etc but this is a great start.  I also think this falls into the category of “could this really be a bad thing?”.  Even if in the end no benefit is shown to this type of intervention, the potential for family bonding with their preterm infant alone I think is cause for embracing this intervention.

Lastly, with the move to single patient rooms there is one study that demonstrated the isolation encountered from infrequent contact with their newborn can have a long lasting effect on development.  The article by Pineda RG et al Alterations in brain structure and neurodevelopmental outcome in preterm infants hospitalized in different neonatal intensive care unit environments. had a mean parental visitation of 19 +/- 19 hours a week or a little over 2 hours a day but with a very large standard deviation meaning many infants had almost no visitation.  The message here is that while quiet is good for infant development, too much can be a bad thing.  Maybe live reading or even recordings are a way around that.

Is skin to skin care truly good for the developing brain?

Is skin to skin care truly good for the developing brain?

Skin to skin care or kangaroo care is all the rage and I am the first one to offer my support for it.  Questions persist though as to whether from a physiological standpoint, babies are more stable in an isolette in a quiet environment or out in the open on their mother or father’s chests. Bornhorst et al expressed caution in their study Skin-to-skin (kangaroo) care, respiratory control, and thermoregulation.  In a surprising finding, babies with an average gestational age of 29 weeks were monitored for a number of physiological parameters and found to have more frequent apnea and higher heart rates than when in an isolette.  The study was small though and while there were statistical differences in these parameters they may not have had much clinical significance (1.5 to 2.8 per hour for apnea, bradycardia or desaturation events).  Furthermore, does an increase in such events translate into any changes in cerebral oxygenation that might in turn have implications for later development?  Tough to say based on a study of this magnitude but it certainly does raise some eyebrows.

What if we could look at cerebral oxygenation?

As you might have guessed, that is exactly what has been done by Lorenz L et al in their recent paper Cerebral oxygenation during skin-to-skin care in preterm infants not receiving respiratory support.The goal of this study was to look at 40 preterm infants without any respiratory distress and determine whether cerebral oxygenation (rStO2)was better in their isolette or in skin to skin care (SSC).  They allowed each infant to serve as their own control by have three 90 minute periods each including the first thirty minutes as a washout period.  Each infant started their monitoring in the isolette then went to SSC then back to the isolette.  The primary outcome the power calculation was based on was the difference in rStO2 between SSC and in the isolette.  Secondary measures looked at such outcomes as HR, O2 sat, active and quiet sleep percentages, bradycardic events as lastly periods of cerebral hypoxia or hyperoxia.  Normal cerebral oxygenation was defined as being between 55 to 85%.

Surprising results?

Perhaps its the start of a trend but again the results were a bit surprising showing a better rStO2 when in the isolette (−1.3 (−2.2 to −0.4)%, p<0.01).  Other results are summarized in the table below:

Mean difference in outcomes
Variable SSC Isolette Difference in mean p
rStO2 73.6 74.8 -1.3 <0.01
SpO2 (median) 97 97 -1.1 0.02
HR 161 156 5 <0.01
% time in quiet sleep 58.6 34.6 24 <0.01

No differences were seen in bradycardic events, apnea, cerebral hypoexmia or hyperoxemia.  The authors found that SSC periods in fact failed the “non-inferiority” testing indicating that from a rStO2 standpoint, babies were more stable when not doing SSC!  Taking a closer look though one could argue that even if this is true does it really matter?  What is the impact on a growing preterm infant if their cerebral oxygenation is 1.3 percentage points on average lower during SSC or if their HR is 5 beats per minute faster?  I can’t help but think that this is an example of statistical significance without clinical significance.  Nonetheless, if there isn’t a superiority of these parameters it does leave one asking “should we keep at it?”

Benefits of skin to skin care

Important outcomes such as reductions in mortality and improved breastfeeding rates cannot be ignored or the positive effects on family bonding that ensue. Some will argue though that the impacts on mortality certainly may be relevant in developing countries where resources are scarce but would we see the same benefits in developed nations.  The authors did find a difference though in this study that I think benefits developing preterm infants across the board no matter which country you are in.  That benefit is that of Quiet Sleep (QS).  As preterm infants develop they tend to spend more time in QS compared to active sleep  (AS).  From Doussard- Roossevelt J, “Quiet sleep consists of periods of quiescence with regular respiration and heart rate, and synchronous EEG patterns. Active sleep consists of periods of movement with irregular respiration and heart rate, and desynchronous EEG patterns.”  In the above table one sees that the percentage of time in QS was significantly increased compared to AS when in SSC.  This is important as neurodevelopment is thought to advance during periods of QS as preterm infants age.

There may be little difference favouring less oxygen extraction during isolette times but maybe that isn’t such a good thing?  Could it be that the small statistical difference in oxygen extraction is because the brain is more active in laying down tracks and making connections?  Totally speculative on my part but all that extra quiet sleep has got to be good for something.

To answer the question of this post in the title I think the answer is a resounding yes for the more stable infant.  What we don’t know at the moment except from anecdotal reports of babies doing better in SSC when really sick is whether on average critically ill babies will be better off in SSC.  I suspect the answer is that some will and some won’t.  While we like to keep things simple and have a one size fits all answer for most of our questions in the NICU, this one may not be so simple.  For now I think we keep promoting SSC for even our sick patients but need to be honest with ourselves and when a patient just isn’t ready for the handling admit it and try again when more stable.  For the more stable patient though I think giving more time for neurons to find other neurons and make new connections is a good thing to pursue!

Stubborn PDAs despite prophylactic indomethacin!

Stubborn PDAs despite prophylactic indomethacin!

As time goes by, I find myself gravitating to reviews of Canadian research more and more.  We have a lot of great research happening in this country of ours and especially when I see an author or two I know personally I find it compelling to review such papers.  Today is one of those days as the lead author for a paper is my colleague Dr. Louis here in Winnipeg.  Let me put his mind at ease in case he reads this by saying that what follows is not a skewering of the paper he just published using Canadian Neonatal Network data (CNN).  Over the last twenty years that I have had the privilege of working in the field of Neonatology we continue to discuss the same things when it comes to the PDA.  Does it really cause problems or is it an association for many outcomes? Does treatment make a difference?  If you treat then what should you use (ibuprofen, indomethacin, paracetamol)? When should you treat and if you treat early should it be in the first few days or right after birth using a prophylactic approach (provided within 12 hours of delivery)?  It is the prophylactic approach which is the subject of this post!

Why treat prophylactically?

The TIPP trial reported the results in 2001 of the study whose goal was to determine if prophylactic indomethacin use could improve neurosensory impairment at 18 months by reducing rates of severe IVH.  The results of the study are well known and showed that while the rates of severe IVH and PDA ligations were reduced through this approach, there was no actual effect on long term outcome.  The use of this approach fell off after that for many years but recently resurfaced as some units in Canada opted to start the practice again as the two benefits seen above appeared to be worth using the approach.  The thought from a family centred approach, was that eliminating the stress for families of informing them their tiny preterm infant had a serious intracranial bleed and potentially avoiding a surgical ligation with probably vocal cord impairment afterwards were good enough outcomes to warrant this practice.  Having used this approach myself I have to admit one consequence is that indomethacin was so effective at closing the PDA most of the time that over time one begins to assume the PDA is in fact closed and is less likely to go hunting for one when the baby is misbehaving later on in their course.  What if it didn’t close though?  Are there any predictors that can increase our index of suspicion?

Answering the question

The CNN provides a large database to look retrospectively to answer such a question.  In this article, the authors looked at a period from 2010 to 2015 including all infants < 28 weeks gestational age at birth yielding a very large sample of 7397 infants.  Of these 843 or 12% received prophylactic indomethacin and from there a little over half (465) still had a PDA.  From there, 367 received treatment with eventually 283 needing only medical, 11 having a PDA ligation and 73 having both medical and surgical closure.  From this analysis so far I can tell you that providing prophylactic indomethacin certainly does not guarantee closure!

When a myriad of risk factors were put into logistic regression a number of interesting risk factors arose accounting for more of less risk of a PDA that needed surgical ligation despite prophylactic treatment.  Much like all infants in the NICU, the risk for a persistent PDA was highest with declining GA.  The combination of outborn status and short interval of ruptured membranes predicted higher risk.  No doubt this is reflective of less frequent antenatal steroid use and even if provided time for it to work.  Looking at medical or surgical treatment, surfactant therapy increased risk which may be explained by an improvement in oxygenation contributing to increased left to right shunting as PVR drops.  Maternal hypertension and longer duration of rupture of membranes again play a role in reducing risk likely through the mechanism of the former increasing endogenous steroid production and the latter again allowing for steroids to be provided.

What can we learn from this paper?

I suppose the biggest benefit here is the realization that even with prophylactic indomethacin we are not assured of closure.  In particular if there is a lack of antenatal steroid use or a stressed fetus one should be vigilant for the PDA.  Interestingly, all of the risks seem to point towards antenatal steroid use.  The bottom line then is that this reinforces what is already known and should be the focus of improvement strategies for centres.  Increase the rate of antenatal steroid use and you will reduce the risk of a PDA even in the baby receives prophylactic indomethacin.  I am happy to report that our centre has taken one step towards this goal by reinforcing to our Obstetrical colleagues that when they receive a call from a referring centre and have a woman who might be in labour it is better to err on the side of caution and just give the steroid course.  If they are wrong on arrival then one can always repeat a course later on as we do although repeated courses of steroids are in and of themselves a contentious issue.  What can your centre do to improve your results when it comes to antenatal steroid coverage?

Maybe we shouldn’t be in such a rush to stop caffeine.

Maybe we shouldn’t be in such a rush to stop caffeine.

Given that many preterm infants as they near term equivalent age are ready to go home it is common practice to discontinue caffeine sometime between 33-34 weeks PMA.  We do this as we try to time the readiness for discharge in terms of feeding, to the desire to see how infants fare off caffeine.  In general, most units I believe try to send babies home without caffeine so we do our best to judge the right timing in stopping this medication.  After a period of 5-7 days we generally declare the infant safe to be off caffeine and then move on to other issues preventing them from going home to their families.  This strategy generally works well for those infants who are born at later gestations but as Rhein LM et al demonstrated in their paper Effects of caffeine on intermittent hypoxia in infants born prematurely: a randomized clinical trial., after caffeine is stopped, the number of intermittent hypoxic (IH) events are not trivial between 35-39 weeks.  Caffeine it would seem may still offer some benefit to those infants who seem otherwise ready to discontinue the medication.  What the authors noted in this randomized controlled trial was that the difference caffeine made when continued past 34 weeks was limited to reducing these IH events only from 35-36 weeks but the effect didn’t last past that.  Why might that have been?  Well it could be that the babies after 36 weeks don’t have enough events to really show a difference or it could be that the dose of caffeine isn’t enough by that point.  The latter may well be the case as the metabolism of caffeine ramps up during later gestations and changes from a half life greater than a day in the smallest infants to many hours closer to term.  Maybe the caffeine just clears faster?

Follow-up Study attempts to answer that very question.

Recognizing the possibility that levels of caffeine were falling too low after 36 weeks the authors of the previous study begun anew to ask the same question but this time looking at caffeine levels in saliva to ensure that sufficient levels were obtained to demonstrate a difference in the outcome of frequency of IH.  In this study, they compared the original cohort of patients who did not receive caffeine after planned discontinuation (N=53) to 27 infants who were randomized to one of two caffeine treatments once the decision to stop caffeine was made.  Until 36 weeks PMA each patient was given a standard 10 mg/kg of caffeine case and then randomized to two different strategies.  The two dosing strategies were 14 mg/kg of caffeine citrate (equals 7 mg/kg of caffeine base) vs 20 mg/kg (10 mg/kg caffeine base) which both started once the patient reached 36 weeks in anticipation of increased clearance.  Salivary caffeine levels were measured just prior to stopping the usual dose of caffeine and then one week after starting 10 mg/kg dosing and then at 37 and 38 weeks respectively on the higher dosing.  Adequate serum levels are understood to be > 20 mcg/ml and salivary and plasma concentrations have been shown to have a high level of agreement previously so salivary measurement seems like a good approach.  Given that it was a small study it is work noting that the average age of the group that did not receive caffeine was 29.1 weeks compared to the caffeine groups at 27.9 weeks.  This becomes important in the context of the results in that earlier gestational age patients would be expected to have more apnea which is not what was observed suggesting a beneficial effect of caffeine even at this later gestational age.  Each patient was to be monitored with an oximeter until 40 weeks as per unit guidelines.

So does caffeine make a difference once term gestation is reached?

A total of 32 infants were enrolled with 12 infants receiving the 14 mg/kg and 14 the 20 mg/kg dosing.  All infants irrespective of assigned group had caffeine concentrations above 20 mcg/mL ensuring that a therapeutic dose had been received.  The intent had been to look at babies out to 40 weeks with pulse oximetry even when discharged but owing to drop off in compliance with monitoring for a minimum of 10 hours per PMA week the analysis was restricted to infants at 37 and 38 weeks which still meant extension past 36 weeks as had been looked at already in the previous study.  The design of this study then compared infants receiving known therapeutic dosing at this GA range with a previous cohort from the last study that did not receive caffeine after clinicians had determined it was no longer needed.

The outcomes here were measured in seconds per 24 hours of intermittent hypoxia (An IH event was defined as a decrease in SaO2 by ⩾ 10% from baseline and lasting for ⩾5 s).  For graphical purposes the authors chose to display the number of seconds oxygen saturation fell below 90% per day and grouped the two caffeine patients together given that the salivary levels in both were therapeutic.  As shown a significant difference in events was seen at all gestational ages.

Putting it into context

The scale used I find interesting and I can’t help but wonder if it was done intentionally to provide impact.  The outcome here is measured in seconds and when you are speaking about a mean of 1200 vs 600 seconds it sounds very dramatic but changing that into minutes you are talking about 20 vs 10 minutes a day.  Even allowing for the interquartile ranges it really is not more than 50 minutes of saturation less than 90% at 36 weeks.  The difference of course as you increase in gestation becomes less as well.  When looking at the amount of time spent under 80% for the groups at the three different gestational ages there is still a difference but the amount of time at 36, 37 and 38 weeks was 229, 118 and 84 seconds respectively without caffeine (about 4, 2 and 1 minute per day respectively) vs 83, 41, and 22 seconds in the caffeine groups. I can’t help but think this is a case of statistical significance with questionable clinical significance.  The authors don’t indicate that any patients were readmitted with “blue spells” who were being monitored at home which then leaves the sole question in my mind being “Do these brief periods of hypoxemia matter?”  In the absence of a long-term follow-up study I would have to say I don’t know but while I have always been a fan of caffeine I am just not sure.

Should we be in a rush to stop caffeine?  Well, given that the long term results of the CAP study suggest the drug is safe in the preterm population I would suggest there is no reason to be concerned about continuing caffeine a little longer. If the goal is getting patients home and discharging on caffeine is something you are comfortable with then continuing past 35 weeks is something that may have clinical impact.  At the very least I remain comfortable in my own practice of not being in a rush to stop this medication and on occasion sending a patient home with it as well.

Use of A Rescue Exclusive Human Milk Diets in Infants < 1250g. The Winnipeg Experience

Use of A Rescue Exclusive Human Milk Diets in Infants < 1250g. The Winnipeg Experience

Exclusive human milk (EHM) diets using either mother’s own milk or donor milk plus a human based human milk fortifier have been the subject of many papers over the last few years. Such papers have demonstrated reductions is such outcomes as NEC, length of stay, days of TPN and number of times feedings are held due to feeding intolerance to name just a few outcomes. There is little argument that a diet for a human child composed of human milk makes a great deal of sense. Although we have come to rely on bovine sources of both milk and fortifier when human milk is unavailable I am often reminded that bovine or cow’s milk is for baby cows.

Challenges with using an exclusive human milk diet.

While it makes intuitive sense to strive for an exclusive human milk diet, there are barriers to the same. Low rates of maternal breastfeeding coupled with limited or no exposure to donor breast milk programs are a clear impediment. Even if you have those first two issues minimized through excellent rates of breast milk provision, there remains the issue of whether one has access to a human based fortifier to achieve the “exclusive” human milk diet.

The “exclusive” approach is one that in the perfect world we would all strive for but in times of fiscal constraint there is no question that any and all programs will be questioned from a cost-benefit standpoint. The issue of cost has been addressed previously by Ganapathy et al in their paper Costs of Necrotizing Enterocolitis and Cost-Effectiveness of Exclusively Human Milk-Based Products in Feeding Extremely Premature Infants. The authors were able to demonstrate that choosing an exclusive human milk diet is cost effective in addition to the benefits observed clinically from such a diet. In Canada where direct costs are more difficult to visualize and a reduction in nursing staff per shift brings about the most direct savings, such an argument becomes more difficult to achieve.

Detractors from the EHM diet argue that we have been using bovine fortification from many years and the vast majority of infants regardless of gestational age have little challenge with it. Growth rates of 15-20 g/kg/d are achievable using such fortification so why would you need to treat all patients with an EHM diet?

A Rescue Approach

In our own centre we were faced with these exact questions and developed a rescue approach. The rescue was designed to identify those infants who seemed to have a clear intolerance to bovine fortifier as all of the patients we care for under 1250g receive either mother’s own or donor milk. The approach used was as follows:

A. < 27 weeks 0 days or < 1250 g
          i. 2 episode of intolerance to HMF
ii. Continue for 2 weeks

This month we published our results from using this targeted rescue approach in Winnipeg, Human Based Human Milk Fortifier as Rescue Therapy in Very Low Birth Weight Infants Demonstrating Intolerance to Bovine Based Human Milk Fortifier with Dr. Sandhu being the primary author (who wrote this as a medical student with myself and others. We are thrilled to share our experience and describe the cases we have experienced in detail in the paper. Suffice to say though that we have identified value in such an approach and have now modified our current approach based on this experience to the following protocol for using human derived human milk fortifier in our centre to the current:
A. < 27 weeks 0 days or < 1250 g
i. 1 episode of intolerance to HMF
ii. Continue for 4 weeks
B. ≥ 27 week 0 days or ≥ 750g
i. 2 episodes of intolerance to HMF
ii. Continue for 4 weeks or to 32 weeks 0 days whichever comes sooner

We believe given our current contraints, this approach will reduce the risk of NEC, feeding intolerance and ultimately length of stay while being fiscally prudent in these challenging times. Given the interest at least in Canada with what we have been doing here in Winnipeg and with the publication of our results it seemed like the right time to share this with you.  Whether this approach or one that is based on providing human based human milk fortifier to all infants <1250g is a matter of choice for each institution that chooses to use a product such as Prolacta.  In no way is this meant to be a promotional piece but rather to provide an option for those centres that would like to use such products to offer an EHM diet but for a variety of reasons have opted not to provide it to all.