Some time ago Nick Hall from Graham’s Foundation posted the following question on Linkedin:
Private room vs open bay for the NICU. Can always get a quote from a parent saying it is great but….? At what cost? Impact on staff? Is parent time in those NICUs greater now? Other alternatives?
Included in the post was an article discussing the benefits of such a design. Below I will look at the benefits and risks and conclude with an answer to his last question.
The NICUs of the 1970s through late 1990s have been described as “barn like” or “open concept” but in recent years the belief that single patient rooms (SPR) would offer greater benefit to infants led to the adoption of such a unit design across North America. The imagined benefits would be related to improved parent comfort, creating a desire for families to spend more time with their children. As we move to a “family centred” approach to care, a key goal of all units should be to make their families as comfortable and stress free as possible in order to have a positive experience.
Detractors meanwhile, speak of concern regarding isolation of such infants when families do not visit and moreover a risk that such infants deprived of sensory experience will have impaired development. Last year a paper was published that did not help quell such fears; Alterations in Brain Structure and Neurodevelopmental Outcome in Preterm Infants Hospitalized in Different Neonatal Intensive Care Unit Environments (full article in link). This study which compared infants cared for in SPR to an open unit (the hospital in this study had a mixture of both in their NICU) found a worrisome finding at 2 year follow-up in that the infants in SPR had lower scores on language and a trend towards lower motor scores as well. Additionally, partly explaining such findings may have been differences noted at term equivalent age in both the structure and activity of the children’s brains compared to those cared for in an open environment. We were starting construction on a new NICU at the time this paper was published and I can tell you the findings sent shockwaves through our hospital as many wondered whether this was the right decision.
Devil Is in The Details
Looking further into this study, the urban population bore little resemblance to our own. In our hospital all women are taught how to perform skin to skin care and the majority of our mothers spend a great deal of time with their infants. To see how successful have a look at our recent Kangaroo Care drive results! The families in this study however the average hours per week of parent visitation over the length of stay ranged from 1.8-104 hours with a mean of 19+/- 19 hours. The average number of days held per week over the length of stay was 0-6 days with a mean of 2.4 +/-1.5 days. The average number of days held skin-to-skin over the length of stay ranged from 0-4 days, with a mean of 0.7 +/- 0.9 days. In short they were hardly there.
Second Study Finds The Opposite
Later on in 2014 a second study on this subject was published; Single-family room care and neurobehavioral and medical outcomes in preterm infants. Infants < 1500g who were admitted to an NICU between 2008 and 2012 were compared with respect to medical and neurobehavioral outcomes at discharge. Participants included 151 infants in an open-bay NICU and 252 infants after transition to a SPR NICU.
Statistically significant results (all Ps ≤.05) showed that infants in the SPR NICU weighed more at discharge, had a greater rate of weight gain, required fewer medical procedures, had a lower gestational age at full enteral feed and less sepsis, showed better attention, less physiologic stress, less hypertonicity, less lethargy, and less pain.Nurses reported a more positive work environment and attitudes in the SPR NICU.
This study in fact demonstrated greater maternal involvement in a SPR with improvement in outcomes across the board. It would seem then that in a SPR environment, provided there is enough family visitation and involvement this model truly is superior to the open concept. Furthermore despite concerns by some nurses that the loss of line of sight to their patients will make for a more stressful working environment this does not seem to be the case.
What About Families Who Cannot or Simply Aren’t Visiting Frequently?
The reality is that there are many reasons for parents to be absent for long periods during their newborns stay. Having a home outside of the city with other children to care for, work obligations, or loss of custody and abandonment due to apprehension are just some of these reasons. In our hospital, at least 15-20% of all patients admitted are from outside Winnipeg. The evidence as I see it supports the move to a SPR but what do we do for those children who need more visitation? The solution is a cuddler program. In our new hospital we are grateful for the generosity of our Children’s Hospital Foundation who secured a donor to pay for a coordinator of such a program. The veteran parent who is leading this program ensures that no infant goes beyond a set period of time without feeling the touch or hearing the sound of a voice. Such a program is in fact already in place at our other tertiary hospital and was featured in a lovely article attached here. Taking all the information together that is out there I think that if we can provide the necessary stimulation from both touch and auditory stimuli as well we can provide these infants with the developmental needs that each of them requires.
The SPR is the right design in my mind for families with many benefits that spring forth in such an environment. This need not be a win-lose scenario for your hospital. Do not underestimate the power of a cuddler and don’t hesitate to seek support to initiate such a program. It could mean the difference from going from good to great!
Anyone who works in the NICU is more than familiar with the sad moment when you find out an infant has suffered a severe IVH (either grade III or IV) and the disclosure to the family. The family is in a state of shock with the fear of ventricular drainage a reality that will likely come to pass. We have spent many years trying to find ways to reduce this risk and antenatal steroids and delayed cord clamping are two relatively recent interventions that have had a real impact. Unfortunately we have not been able to eliminate this problem though. What if something as simple as an exclusive human milk diet could be that magic bullet to further reduce this problem in our NICUs?
Exclusive human milk diets
I have written about this topic before but as a refresher this generally refers to all sources of nutrition being derived from human milk. Ideally we would provide mothers own milk (MOM) but when this is not available units rely on pasteurized donor human milk (PDHM) as the base feed. Added to this is human derived human milk fortifier (H2HMF) as opposed to bovine powdered or liquid fortifier usually to provide a base caloric density of 24 cal/oz.
Reducing IVH Through Exclusive Human Milk Diets
It would be nice to have a prospective multicentre trial with this as the outcome but there is a significant problem when doing this type of study. The H2HMF is costly with a price tag of about $13-15000 per treatment course so to do a prospective RCT would not be easy for units that don’t use the product already. Moreover, for those units that are already sold on the product it would seem unethical if there was no equipoise to randomize to bovine or human fortifier. As such, when we talk about getting the best evidence it is most likely going to come in the form of a retrospective study as has been done here by Carome K et al in their paper Exclusive human milk diet reduces incidence of severe intraventricular hemorrhage in extremely low birth weight infants.
The authors in this study chose to look at three different time periods with different approaches to feeding of ELBW infants. They were as follows with all diets providing H2HMF going until 34 weeks. Aside from the source of nutrition, starting of and incremental advancement of feedings was protocolized as per unit approach.
2012 to 2014 – MOM was given when available. Preterm formula was the alternative as a supplement Fortification of was with bovine milk-derived liquid fortifier 2014 to 2015 – H2HMF used in those infants receiving exclusively MOM. All others received preterm formula as supplement or alternative. If MOM was available but in insufficient quantities for sole diet, it was fortified with bovine-HMF 2015 to 2017 – all ELBW infants received an EHM diet consisting of MOM if available and PDHM as a supplement to MOM or as full diet, each fortified with H2HMF
The maternal demographics were similar between those receiving exclusive human milk diets and those without except for a higher antenatal steroid provision in the EHM group. This of course bears consideration in the results as steroids have been shown to reduce IVH.
Looking at the results below shows some very promising findings. The incidence of Grade III/IV IVH and/or PVL was 7% in the EHM group and 18% in the non-EHM group. Also noted to be quite different was the incidence of NEC which was 5% in the EHM and 17% in the non group. The authors also did a subgroup analysis looking at the use of MOM vs PDHM and found no difference in outcomes regardless of source of human milk used. As the authors point out this might mean that the pasteurization process does not denature the components of milk responsible for these protective effects if the results are to be believed.
One strength of the study was that the authors performed a logistic regression to control for the higher rate of antenatal steroid use and lower rates of NEC in the EHM group since both would be expected to influence rates of IVH/PVL and found that the results remained significant after this analysis. The findings were an OR of 2.7 CI 1.2–6.0, p = 0.012 so that is promising!
What They Weren’t Able to Do
It’s possible I missed it in the article but like several other papers on this topic the babies who received formula and those who received human milk with bovine fortifier were grouped together. As such what we don’t know from this study is whether the addition of just the bovine fortifier vs H2HMF would have yielded the same results.
Nonetheless what the article does suggest is that use of EHM diets are protective against severe IVH/PVL regardless of the source of human milk when you compare it to receipt of any bovine sources. The caveats about retrospective studies of course exist as per usual but if this is the best evidence we have how do we use it? At the very least this calls out for strategies to maximize milk production for mothers and to use PDHM when MOM is not available. It certainly is suggestive that the use of H2HMF may confer benefit as well. What you unit does with this information I suppose will need to be determined based on the totality of the evidence. I suspect there is more of this story to be told and this adds yet another chapter in the tale of EHM.
For some time a recommendation has existed to keep blood sugars at or above 2.6 mmol/L at least for the first 48-72 hours. Afterwards the threshold as per our recommedation is to increase the target to 3.3 mmol/L or above. As the authors of the paper above pointed out, the evidence for these thresholds impacting long term neurodevelopmental outcome in a positive way is shaky and therefore they set out to examine two different thresholds of less than 2.0 mmol/L vs the traditional less than 2.6 mmol/L in a non-inferiority trial. They used a fairly standard Bayley test at 18 months to determine if there were any difference in outcomes between groups. I gather this had been presented in abstract form earlier and many were eagerly awaiting the publication as the scuttlebut was that there was no difference seen which would favour a change in practice to accept the lower threshold. As with many studies though the devil is in the details and did this study actually address this question properly?
The Answer
To be fair, I think the authors here had a great goal in mind. What if we have been targeting the wrong threshold? How many babies would be needlessly tested and retested for glucose levels that really don’t make much of a difference to outcome? Before delving into the results though it is important to really look at what population here was studied. In order to qualify for this prospective study you had to be at risk of hypoglycemia defined by these four subgroups; Late-preterm infants (gestational age from 35 to 37 weeks), newborns who were small (below the 10th percentile) or large (above the 90th percentile) for gestational age, and infants of mothers with diabetes. Not included here are mothers who were on medications such as labetolol and those whose mothers had hypertensive disorders and were small but not small enough as examples. Importantly, none of the infants in the study could have an initial blood glucose < 1.9 mmol/L as they would be classified as severe. So we are looking at patients at risk who have moderate hypoglycemia. Already the field has been narrowed a fair bit. The next thing you had to have to get in the study if you were at risk was a blood glucose from 3-24 hours of age <2.6 mmol/L. Those kids were then randomized to either use the lower or higher thresholds for determining intervention. The authors determined to show non-inferiority they would need 200 babies in each group of at risk newborns to prove no-difference.
What Did They Find?
The authors managed to recruit 689 infants out of 5958 potential infants that were considered. The limits they put above to create moderate risk excluded many so we are talking about 10% of those at risk with hypoglcyemia who entered the trial. The findings were as follows; “Bayley-III-NL scores were assessed in 287 of the 348 children (82.5%) in the lower-threshold group and in 295 of the 341 children (86.5%) in the traditional-threshold group. Cognitive and motor outcome scores were similar in the two groups (mean scores [±SE], 102.9±0.7 [cognitive] and 104.6±0.7 [motor] in the lower-threshold group and 102.2±0.7 [cognitive] and 104.9±0.7 [motor] in the traditional-threshold group). The prespecified inferiority limit was not crossed.”
So they didn’t find a difference. When you look into why though it becomes clear this was a tough study to really help answer the question. Here are the problems.
They didn’t enroll the 800 babies they needed for their power calculation. Failing to find a difference may not mean as much if they didn’t get enough infants. Out of the 689 they also didn’t follow up everyone so in the end they only had 582 infants.
The second issue has to do with the setting of the two thresholds. If you look at glucose at randomization they were almost equal at 41.4 mg/dL vs 41.2 mg/dL. In table three the big issue with the study becomes evident.
These kids were so low risk for recurrent hypoglycemia by excluding the more severe patients at entry that very few regardless of threshold actually became hypoglcyemic again. Roughly half of both groups never had another low. Of those that had another low blood glucose, 70% in the low group and 82% in the high group had either no or only one other episode after entry in the study. Looking at the previous work of Allan Lucas who demonstrated five or more low readings could impact long term outcomes, only 9% in the low and 2% of the high group had another low blood sugar,
3. Also from table 3 one can see that the number of patients with true severe hypoglcyemia which might be expected to impact long term outcome was also low at only 10% and 5% of the study population.
4. The authors did note in the secondary outcomes that there was a much higher need for IV therapy 21% in the high vs 6% in the low group. Moreover, bolus glucose was 12% vs 6%. This study though recruited patients before the adoption of glucose gel so we have to take the benefit here with a grain of salt since use of glucose gel would in the modern era lessen the effect.
Finally would you put your money where your mouth is?
Looking at this from a practical standpoint, in this at risk population, the vast majority would have at most one more episode of hypoglcyemia after randomization. You can’t avoid the needle poke to recheck a low glucose and with glucose gel the need for IV therapy is less. The question I guess is whether you would be confident enough in these results to be find for the first 48 hours with your own child having blood sugars of 2.1. 2.0, 2.2 etc. I suspect if many people were forced to answer that question with their own child they might based on this study alone feel more comfortable with a supplemental feed +/- glucose gel.
I suspect there is more to be told regarding this topic but for the time being I don’t think this one study is enough to move the needle and change our approach to hypoglcyemia thresholds.
This past week I was very appreciative of efforts by readers on my Facebook page and Twitter accounts who were able to secure a copy of an article that really grabbed my attention. I could only go by the abstract at the time but the post suggesting that the use of azithromycin could reduce BPD garnered a lot of attention. Now that I have had a chance to read the paper I believe there are some very big caveats to that claim. What was done in this study I find very interesting and the results yield even more questions and make for what I think will be a great discussion.
A little history
BPD is known to be a condition that develops at least in part due to the effects of inflammation on the preterm lung. The combination of infections, inflammation from mechanical ventilation and the susceptibility of the developing tissue to damage make for a cocktail with a foul taste in the end. Previous work by Ballard HO et al in 2011 Use of azithromycin for the prevention of bronchopulmonary dysplasia in preterm infants: a randomized, double-blind, placebo controlled trial found that the risk of death or BPD at 36 weeks PMA was no different in an RCT using azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for a maximum of 6 weeks. There was a suggestion in this study that in those with ureaplasma urealyticum there might be an affect. Researchers from Calgary had also published Azithromycin and Other Macrolides for Prevention of Bronchopulmonary Dysplasia: A Systematic Review and Meta-Analysis which suggested prophylaxis helps with a NNT of 10 to reduce BPD. In spite of this it just hasn’t grabbed hold so maybe a new study would add some strength to the concept.
What was done this time around?
In the most recent paper by Nunes CR et al Use of Azithromycin for the Prevention of Lung Injury in Mechanically Ventilated Preterm Neonates: A Randomized Controlled Trial, the authors set out again to test the effect of azithromycin on modulating risk for BPD. They used the results of the Ballard trial to determine a number needed in their power calculation and came up with 38 per group and achieved 40 so they were powered to find a difference. They incuded all neonates who met inclusion criteria (invasive MV within 72 h of birth and, necessarily, invasive ventilatory support for, at least, 12 h until randomization) who were born under 1500g and randomized them to five days of azithromycin vs placebo. The strength of the study was that they also measured cytokine levels before starting azithromycin and then at 5 days after treatment. It is the outcome of interest that really puzzles me. They chose oxygen dependency at 28 days as their outcome of interest rather than 36 weeks PMA which is the more modern choice of end point for BPD. They also chose a much shorter course of 5 days compared to the study by Ballard which had previously shown no difference in outcome which I find odd as well. The baseline characteristics given that this was a small study also revealed an important difference between the two groups.
The babies in the treatment arm were on average 1.5 weeks more mature at birth which matters a great deal when you are alking about BPD. Additionally they were about 200g larger in size which was close to reaching statistical significance. Otherwise the infants were the same and the authors eventually control for these differences in the final analysis but to me at least this seems like a stark difference between groups favouring a higher expected risk of BPD from the outset regardless of treatment arm.
The main outcomes are where the authors lay claim to finding support for the intervention. At 28 days there was a statistically significant reduction in both oxygen dependency and oxygen dependency/death. As shown below though those differences did not extend to 36 weeks for either outcome.
Not surprisingly there were other differences in the groups reflective of the younger patients in the placebo arm such as higher rates of postnatal steroid use and days of TPN. One strength I suppose here is that since both groups were exposed to mechanical ventilation durations that were not different when their cytokine profiles were checked the effect of invasive positive pressure might be similar between groups. What is not known however is the mean airway pressures between groups or for that matter if any were put on high frequency ventilation so we have quantity but not quality. One could postulate that while durations were similar over 5 days, the smaller and younger patients may have been exposed to much higher pressures and/or volumes which could of course influence degree of inflammation. Looking at the cytokine profiles is interesting nonetheless.
The cytokines IL-2 and 8 were found to be significantly lower in the treatment arm and in general all others at least trended in the same direction after completing treatment with azithromycin. With less inflammation it seems probable then that the reduction in need for O2 at 28 weeks might be real and after the autors controlled for such things as gestational age and weight the finding bore out but at 36 weeks (the more meaningful outcome) the difference was gone.
What can we take from the study
Am I ready to start azithromycin in all my infants under 1500g? Not yet. This study raises too many questions for this to become standard of care. It really troubles me that the authors here used a shorter duration of azithromycin than the Ballard study and then used a less meaningful outcome of 28 days to demonstrate their difference. While they did find a difference I am concerned that there is a bit of “smoke and mirrors” here in that there is a difference in an outcome that in todays world isn’t that meaningful. I cringe at saying this but what is really needed is a larger multicentre study in which hopefully the gestational ages and weights at the outset are balanced. Even if we didn’t see a big difference in outcome at 36 weeks for BPD I would wonder if the cytokine profiles showed similar trends whether other conditions such as ROP and PDAs which can also be influenced by inflammation would demonstrate a difference between groups. We need a larger sample size and balancing of factors such as tidal volumes and ventilator pressures though to answer this in a more conclusive manner.
In our new hospital we are grateful for the generosity of our Children’s Hospital Foundation who secured a donor to pay for a coordinator of such a program. The veteran parent who is leading this program ensures that no infant goes beyond a set period of time without feeling the touch or hearing the sound of a voice. Such a program is in fact already in place at our other tertiary hospital and was featured in a lovely article attached here. Taking all the information together that is out there I think that if we can provide the necessary stimulation from both touch and auditory stimuli as well we can provide these infants with the developmental needs that each of them requires.
