Much has been written about methylxanthines over the years with the main questions initially being, “should we use them?”, “how big a dose should we use” and of course “theophylline vs caffeine”. At least in our units and in most others I know of caffeine seems to reign supreme and while there remains some discussion about whether dosing for maintenance of 2.5 -5 mg/kg/d of caffeine base or 5 – 10 mg/kg/d is the right way to go I think most favour the lower dose. We also know from the CAP study that not only does caffeine work to treat apnea of prematurity but it also appears to reduce the risk of BPD, PDA and duration of oxygen therapy to name a few benefits. Although initially promising as providing a benefit by improving neurodevelopmental outcomes in those who received it, by 5 and 11 years these benefits seem to disappear with only mild motor differences being seen.
Turning to a new question
The new query though is how long to treat? Many units will typically stop caffeine somewhere between 33-35 weeks PMA on the grounds that most babies by then should have outgrown their irregular respiration patterns and have enough pulmonary reserve to withstand a little periodic breathing. Certainly there are those who prove that they truly still need their caffeine and on occasion I have sent some babies home with caffeine when they are fully fed and otherwise able to go home but just can’t seem to stabilize their breathing enough to be off a monitor without caffeine. Then there is also more recent data suggesting that due to intermittent hypoxic episodes in the smallest of infants at term equivalent age, a longer duration of therapy might be advisable for these ELBWs. What really hasn’t been looked at well though is what duration of caffeine might be associated with the best neurodevelopmental outcomes. While I would love to see a prospective study to tackle this question for now we will have to do with one that while retrospective does an admirable job of searching for an answer.
The Calgary Neonatal Group May Have The Answer
Lodha A et al recently published the paper Does duration of caffeine therapy in preterm infants born ≤1250 g at birth influence neurodevelopmental (ND) outcomes at 3 years of
age? This retrospective study looked at infants under 1250g at birth who were treated within one week of age with caffeine and divided them into three categories based on duration of caffeine therapy. The groups were as follows, early cessation of caffeine ≤ 14 days (ECC), intermediate cessation of caffeine 15–30 days (ICC), and late cessation of
caffeine >30 days (LCC). In total there were 508 eligible infants with 448 (88%) seen at 3 years CA at follow-up. ECC (n = 139), ICC (n = 122) and LCC (n = 187). The primary outcome here was ND at 3 years of age while a host of secondary outcomes were also examined such as RDS, PDA, BPD, ROP as typical morbidities. It made sense to look at these since provision of caffeine had previously been shown to modify such outcomes.
Did they find a benefit?
Sadly there did not appear to be any benefit regardless of which group infants fell in with respect to duration of caffeine when it came to ND. When looking at secondary outcomes there were a few key differences found which favoured the ICC group. These infants had the lowest days of supplemental oxygen, hospital stay ROP and total days of ventilation. This middle group also had a median GA 1 week older at 27 weeks than the other two groups. The authors however did a logistic regression and ruled out the improvement based on the advanced GA. The group with the lowest use of caffeine had higher number of days on supplemental oxygen and higher days of ventilation on average than the middle but not the high caffeine group. It is tempting to blame the result for the longer caffeine group on these being babies that were just sicker and therefore needed caffeine longer. On the other hand the babies that were treated with caffeine for less than two weeks appear to have likely needed it longer as they needed longer durations of oxygen and were ventilated longer so perhaps were under treated. What is fair to say though is that the short and long groups having longer median days of ventilation were more likey to have morbidities associated with that being worse ROP and need for O2. In short they likely had more lung damage. What is really puzzling to me is that with a median GA of 27-28 weeks some of these kids were off caffeine before 30 weeks PMA and in the middle group for the most part before 32 weeks! If they were in need of O2 and ventilation for at least two weeks maybe they needed more caffeine or perhaps the babies in these groups were just less sick?
What is missing?
There is another potential answer to why the middle group did the best. In the methods section the authors acknowledge that for each infant caffeine was loaded at 10 mg/kg/d. What we don’t know though is what the cumulative dose was for the different groups. The range of dosing was from 2.5-5 mg/kg/d for maintenance. Lets say there was an over representation of babies on 2.5 mg/kg/d in the short and long duration groups compared to the middle group. Could this actually be the reason behind the difference in outcomes? If for example the dosing on average was lower in these two groups might it be that with less respiratory drive the babies in those groups needed faster ventilator rates with longer durations of support leading to more lung damage and with it the rest of the morbidities that followed?
It would be interesting to see such data to determine if the two groups were indeed dosed on average lower by looking at median doses and total cumulative doses including miniloads along the way. We know that duration may need to be prolonged in some patients but we also know that dose matters and without knowing this piece of information it is tough to come to a conclusion about how long exactly to treat.
What this study does though is beg for a prospective study to determine when one should stop caffeine as that answer eludes us!
Caffeine seems to be good for preterm infants. We know that it reduces the frequency of apnea in the this population and moreover facilitates weaning off the ventilator in a shorter time frame than if one never received it at all. The earlier you give it also seems to make a difference as shown in the Cochrane review on prophylactic caffeine. When given in such a fashion the chances of successful extubation increase. Less time on the ventilator not surprisingly leads to less chronic lung disease which is also a good thing.
I have written about caffeine more than once though so why is this post different? The question now seems to be how much caffeine is enough to get the best outcomes for our infants. Last month I wrote about the fact that as the half life of caffeine in the growing preterm infant shortens, our strategy in the NICU might be to change the dosing of caffeine as the patient ages. Some time ago though I wrote about the use of higher doses of caffeine and in the study analyzed warned that there had been a finding of increased cerebellar hemorrhage in the group randomized to receive the higher dosing. I don’t know about where you work but we are starting to see a trend towards using higher caffeine base dosing above 5 mg/kg/d. Essentially, we are at times “titrating to effect” with dosing being as high as 8-10 mg/kg/d of caffeine base.
Does it work to improve meaningful outcomes?
This month Vliegenthart R et al published a systematic review of all RCTs that compared a high vs low dosing strategy for caffeine in infants under 32 weeks at birth; High versus standard dose caffeine for apnoea: a systematic review. All told there were 6 studies that met the criteria for inclusion. Low dosing (all in caffeine base) was considered to be 5- 15 mg/kg with a maintenance dose of 2.5 mg/kg to 5 mg/kg. High dosing was a load of 5 mg/kg to 40 mg/kg with a maintenance of 2.5 mg/kg to 15 mg/kg. The variability in the dosing (some of which I would not consider high at all) makes the quality of the included studies questionable so a word of warning that the results may not truly be “high” vs “low” but rather “inconsistently high” vs. “inconsistently low”.
The results though may show some interesting findings that I think provide some reassurance that higher dosing can allow us to sleep at night.
On the positive front, while there was no benefit to BPD and mortality at 36 weeks PMA they did find if they looked only at those babies who were treated with caffeine greater than 14 days there was a statistically significant difference in both reduction of BPD and decreased risk of BPD and mortality. This makes quite a bit of sense if you think about it for a moment. If we know that caffeine improves the chances of successful extubation and we also know it reduces apnea, then who might be on caffeine for less than 2 weeks? The most stable of babies I would expect! These babies were all < 32 weeks at birth. What the review suggests is that those babies who needed caffeine for longer durations benefit the most from the higher dose. I think I can buy that.
On the adverse event side, I suppose it shouldn’t surprise many that the risk of tachycardia was statistically increased with an RR of 3.4. Anyone who has explored higher dosing would certainly buy that as a side effect that we probably didn’t need an RCT to prove to us. Never mind that, have you ever taken your own pulse after a couple strong coffees in the morning?
What did it not show?
It’s what the study didn’t show that is almost equally interesting. The cerebellar hemorrhages seen in the study I previously wrote about were not seen at all in the other studies. There could be a lesson in there about taking too much stock in secondary outcomes in small studies…
Also of note, looking at longer term outcome measures there appears to be no evidence of harm when the patients are all pooled together. The total number of patients in all of these studies was 620 which for a neonatal systematic review is not bad. A larger RCT may be needed to conclusively tell us what to do with a high and low dosing strategy that we can all agree on. What do we do though in the here and now? More specifically, if you are on call tomorrow and a baby is on 5 mg/kg/d of caffeine already, will you intubate them if they are having copious apneic events or give them a higher dose of caffeine when CPAP or NIPPV that they are already on isn’t cutting it? That is where the truth about how you feel about the evidence really comes out. These decisions are never easy but unfortunately you sometimes have to make a decision and the perfect study hasn’t been done yet. I am not sure where you sit on this but I think this study while certainly flawed gives me some comfort that nothing is truly standing out especially given the fact that some of the “high dose” studies were truly high. Will see what happens with my next patient!
A question that we are asked from time to time is whether a home apnea monitor should be purchased after discharge from the hospital. The typical parent is one who has experienced the ups and downs of apnea of prematurity and is faced with the disturbing notion of coming off monitors and going home. “What if he has an event at home and I don’t know”? This leads to a search on the web for home monitors which finds numerous options to choose from. This is where things get interesting from a North American perspective.
In the two centres I have worked at in Canada our answer to such a question is to save your money and not buy one. Contrast this with two families I know in the US who were sent home by the hospital with home apnea monitors. How can the advice between the two nations be so different? I suspect the great risk of a lawsuit in the US is responsible at least in part but it may have to do with risk tolerance as well.
What does the evidence say?
First off, one might surmise that the use of a home apnea monitor helps hospitals move patients to the home faster than those centres that don’t prescribe them. A 2001 Cochrane systematic review on the subject noted that this was not the case and determined that out of nearly 15000 neonates studied the greatest predictor of sending such babies home on monitors was physician preference.
In the largest home monitoring study of its kind, the Collaborative Home Infant Monitoring Evaluation (CHIME) demonstrated some very important information. First off, ex-preterm infants have events and some of them quite significant after discharge. What the study which followed discharged infants at risk of SIDS in the home environment found though was that term infants also have events although less severe. Does this mean that everyone should run out and buy such monitoring equipment though? No! The main reason was that while the study did show that events may continue after discharge, it failed to show that these events had any relation to SIDS. The apneic events noted in hospital disappeared long before the arrival of a risk for SIDS. They really are separate entities.
The other issue with such monitors pertains to false alarms which can lead to sleepless nights, anxiety in parents and eventual abandonment of such technology. This led the AAP in 2005 to declare that they did not endorse such practice. Having said that, it is clear from my own experience with two US ex-preterm infants that this practice remains alive and well.
This monitor has me a little excited as it brings the home apnea monitor into the modern era with smart phone connectivity and at the same time helps the developers of this technology use data collected every two seconds to get a clearer picture on breathing patterns in infants that have been sent home. The saturation monitor in a sock is at the core of this technology which is meant to keep the probe in a relatively stable location. It brings another angle to the concept of wearable tech! What I find most interesting is the claim by the manufacturer that the device has a false alarm rate similar to that of a hospital saturation probe which would make it quite reliable.
I note though that the product has not received FDA approval yet (at least on the source I looked at) but is being worked on. The challenge though is whether this will truly make a difference. It may well have an excellent detection rate and it may in fact detect true apnea leading to bradycardia and cyanosis. What it won’t do though is change the natural history of these events once home. It may capture them very well but I suspect the four events that the mother in the video describes may have been self resolving if she hadn’t intervened. We know from the CHIME study that the events seen in the home did not lead to death from SIDS so I see no reason why these would be different.
Is it useless?
I suppose that depends on your perspective. From a data collection point, obtaining data every two seconds in a cloud based storage environment will allow this company to describe the natural history of respiratory patterns in ex-preterm infants better than I suspect has ever been done before. From a population standpoint I suppose that is something! At an individual level I suppose it depends on your strength of “needing to know”. This may well be the best monitor out there and it may one day be the most reliable. Will it save your baby’s life? I doubt it but might it give you piece of mind if it false alarms very infrequently? I think it just might but based on the low likelihood of it changing the outcome of your baby you won’t see me recommending it. If I come across one make no mistake about it, I will want to play with it myself!
Now that I have caught your attention it is only fair that I explain what I mean by such an absurd title. If you work with preterm infants, you have dealt with apnea of prematurity. If you have, then you also have had to manage such infants who seemingly are resistant to everything other than being ventilated. We have all seen them. Due to increasing events someone gives a load of methylxanthine and then starts maintenance. After a couple days a miniload is given and the dose increased with the cycle repeating itself until nCPAP or some other non-invasive modality is started. Finally, after admitting defeat due to persistent episodes of apnea and/or bradycardia, the patient is intubated. This, in the absence of some other cause for apnea such as sepsis or seizures is the methylxanthine resistant preterm infant. Seemingly no amount of treatment will amount to a reduction in events and then there is only so much that CPAP can do to help.
Other strategies have been attempted to deal with such infants but sadly none have really stood the test of time. Breathing carbon dioxide might make sense as we humans tend to breathe quickly to excrete rising CO2 but in neonates while such a response occurs it does not last and is inferior to methylxanthine therapy. Doxapram was used in the past and continues to be used in Europe but concerns over impacts on neurodevelopment have been a barrier in North America for some time. Stimulating infants through a variety of methods has been tried but the downside to using for example a vibrating mattress is that sleep could be interfered with and there are no doubt impacts to the preterm infant of having weeks of disturbed sleep states on developmental outcomes.
The stimulation is likened to that felt when a cell phone vibrates as this was the size of device used to generate the sensation. The authors note that during the periods of stimulation the nurses noted no signs of any infant waking or seeming to be disturbed by the sensation. The results were quite interesting especially when noting that 80% of the infants were on caffeine during the time of the study so these were mostly babies already receiving some degree of stimulation
Should we run out and buy these?
The stimulation does appear to work but with any small study we need to be careful in saying with confidence that this would work in a much larger sample. Could there have been some other factor affecting the results? Absolutely but the results nonetheless do raise an eyebrow. One thing missing from the study that I hope would be done in a larger sample next time is an EEG. The authors are speculating that by placing the vibration over the hand and foot the brain is perceiving the signal as limb movement but it would have been nice to see the motor areas of the brain “lighting up” during such stimulation. As we don’t have that I am left wondering if the vibration was simply a form of mild noxious stimulus that led to these results. Of course in the end maybe it doesn’t matter if the results show improvement but an EEG could also inform us about the quality of sleep rather than relying on nursing report of how they thought the baby tolerated the stimulus. I know our nursing colleagues are phenomenal but can they really discern between quiet and active sleep cycles? Maybe some but I would guess most not. There will also be the naysayers out there that will question safety. While we may not perceive a gentle vibration as being harmful, with such a small number of patients can we say that with certainty? I am on the side of believing it is probably insignificant but then again I tend to see the world through rose coloured glasses.
Regardless of the filter through which you view this world of ours I have to say I am quite excited to see where this goes. Now we just have to figure out how to manage the “real estate” of our infant’s skin as we keep adding more and more probes that need a hand or a foot for placement!