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!
This has been a question that has befuddled Neonatologists for years. Get ten of us in a room and you will get a variety of responses ranging from (talking about caffeine base) 2.5 mg/kg/day to 10 mg/kg/day. We will espouse all of our reasons and question the issue of safety at higher doses but in the end do we really know? As I was speaking to a colleague in Calgary yesterday we talked about how convinced we are of our current management strategies but how we both recognize that half of what we think we know today we will be questioning in 10 years. So how convinced should we really be about caffeine?
Even the Cochrane Review Suggests There Is Something Amiss
Back in 2010 the Cochrane Collaboration examining 6 trials on caffeine for treating apnea of prematurity concluded “Methylxanthine is effective in reducing the number of apnoeic attacks and the use of mechanical ventilation in the two to seven days after starting treatment.” Notice the bolded section. Two to seven days. Interesting that we don’t see the effect last in perpetuity. Why might that be? Do babies become resistant with time or is there a change in the way these infants metabolize the drug such that levels in the bloodstream drop after that time point. It is almost certainly the latter and in the last 7 years have we really seen any response to this finding? I would say no for the most part although I don’t work in your unit so hard to say for sure. At least where I practice we pick a dose somewhere between 2.5-5 mg/kg/day and give a load of 10 mg/kg when we start the drug. From time to time we give a miniload of 5 mg/kg and may or may not increase the dose of maintenance based on the number of apneic events the babies are having. What if we could be proactive instead of reactive though. Do the babies need to have multiple events before we act or could we prevent the events from happening at all?
Proactive Treatment With Caffeine
We have known that caffeine clearance increases with postnatal age. The half-life of the drug shortens from about a week at the earliest gestational ages to 2-2.5 days by term equivalent age. For those infants who are older such as 32 weeks and above we expect them to be off caffeine (if they need it) within 2-3 weeks so I am not really talking about them but what about the babies born earlier than that or certainly MUCH earlier at 23 and 24 weeks who will be on caffeine possibly till term. Should one size (dose) fit all? No it really shouldn’t and some crafty researchers led by Koch G have published a paper that demonstrates why entitled Caffeine Citrate Dosing Adjustments to Assure Stable Caffeine Concentrations in Preterm Neonates.
In this paper the authors armed with knowledge of the half life of caffeine at different gestational ages were able to calculate the clearance of the drug at different postnatal ages to demonstrate in a model of a 28 week male infant weighing 1150g. The authors further took into account predicted weight changes and were able to calculate what the expected caffeine levels would be in the fictional infant at various time points. The target caffeine levels for this patient were a trough level of 15 -20 mg/L which are the currently acceptable ranges in the literature. The testing was first done using a standard load of 10 mg/kg (base) followed by 2.5 mg/kg/d (base) and demonstrated levels which yielded the following graph over time. What this demonstrates is that if the dose is unchanged over the first 7 weeks, this hypothetical infant will only achieve effective concentrations for the first week. Interesting isn’t it that the Cochrane review found clinical effect over the first 2-7 days? What if you were to double the dose to really “hit” the infant with a good dose of caffeine from the start and maintain at that level based on their weight gain as shown next. Well, you will get what you are hoping for and keep the trough level above 15 mg/L but you will hit 30 mg/L that some have said is too high and can lead to adverse effects (ever seen SVT with these high doses? I have). Like Goldilocks and the Three Bears could there be a dosing strategy that might be just right? The authors put in another model based on the knowledge of caffeine clearance over time and suggested a strategy in which after the first week the adjusted maintenance doses would be 3 mg/kg/day and 3.5 mg/kg/day in the third to fourth weeks and lastly 4 mg/kg/d in the 5th to 8th week. Using that dosing schedule the model produced this curve. As you can see, the infant would have a therapeutic target without reaching levels above 30 mg/L and potential for side effects. As many of you read this however you may ask the obvious question. Each of us have seen infants who require higher doses than this to rid themselves of significant apnea and escape reintubation. Given that this is a mathematical model it assumes that this fictional infant will respond beautifully to a trough level of 15 to 20 mg/L but some will not. Even in the curve shown it is clear that there is some room to go higher in the dosing as the curve is just touching 20 mg/L.
A Suggestion For The Future
What grabbed my attention here is the possibility that we could take a proactive rather than reactive approach to these infants. Once a small baby is controlled on their dose of caffeine whether it is 2.5, 3, 5 or even 6 mg/kg/d of caffeine should we wait for more events to occur and then react by increasing caffeine? What if we are too late to respond and the patient is intubated. What effect does this have on the developing lung, what about the brain that is subjected to bradycardic events with resultant drops in cardiac output and cerebral perfusion. Perhaps the solution is to work with our pharmacists and plan to increase dosing at several time points in the infants journey through the NICU even if they aren’t showing symptoms yet. No doubt this is a change in approach at least for the unit I work in but one that should start with a conversation!
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!
For those of you who know me and my practice as a Neonatologist you may find the title of this piece odd. I have and will likely continue to be an advocate for the use of caffeine in premature infants. I recommend it both very early in the caseroom for those under 32 weeks to help stave off intubation and often continue caffeine until late in an infants’ stay in the NICU. Truth be told I also send children home on caffeine on occasion when all other markers needed for discharge have been met but they continue to have episodes of apnea and bradycardia that are not resolving and prolonging their stay in hospital.
In recent years I have noticed a creep of practice to begin pushing doses of caffeine base beyond the 5 mg/kg level that has been generally accepted as the upper limit of the 2.5 to 5 mg/kg range that most use in practice. The standard dosing was justified based on the CAP study by Schmidt et al indicating that it was effective in reducing the risk of bronchopulmonary dysplasia and success at earlier extubation. While there appeared to be an initial benefit to neurodevelopment favouring caffeine treatment by school age the difference disappeared. This creep effect to using higher daily maintenance dosing of 7 or 8 mg/kg/d has occurred likely for some good reasons not the least of which is a dose effect in which clinicians could see a reduction in clinical events for some patients as they increased the dose. We are no different as doctors than others in that success tends to shape our practice. Now before you accuse us of being mavericks, we did have some evidence to support the use of higher dosing beyond the 5 mg/kg dosing that had been recommended. Published in 2004, Steer and colleagues studied the effect of using a loading dose of 80 mg/kg caffeine citrate (take 50% reduction to get the base formulation we normally use) followed by 20 mg/kg maintenance dosing vs 20 mg/kg loads and 5 mg/kg maintenance in a cohort of infants < 30 weeks gestation who were having a planned extubation. The full article may be found here. The results of the study demonstrated greater success in extubation and less apnea in the group treated with the higher doses as shown here.
The results of this study certainly made some waves in the Neonatal community as can be seen by the “creep” in practice over the last number of years to increase the caffeine dose in our units to 6, 7 and sometimes 8 mg/kg of caffeine base in an effort to essentially titrate to effect especially in infants who are on CPAP. The motivation to prevent a reintubation secondary to apnea has been so compelling that the theoretical concerns over lack of long-term outcome data on high dose caffeine treatment have been largely ignored.
At this point it is important to also recognize that the way in which we use caffeine in terms of initiation of treatment has also changed. Many units have adopted the “Golden Hour” approach to neonatal resuscitation and are driven to use non-invasive means of support after encouraging results from several trials such as the Support, Boost and the more recent Canadian NIPPV trial. While not demonstrating improvements in outcomes necessarily, the fact that BPD rates are mostly unchanged means that with the use of early caffeine in the delivery room and the use of CPAP one can avoid invasive ventilation in many infants. As such, there has been a departure from the practice as described by Steer and colleagues to using caffeine to facilitate extubation to trying to prevent it in the first place.
In discussions with some of my colleagues we have expressed some reservation over the use of the higher doses of caffeine beyond 5 mg/kg and with the publication of a study this week by McPherson et al, these concerns may be quite warranted. For the complete study click here. This study of 74 preterm infants randomized them in the first 24 hours of life to either 80 mg/kg or 20 mg/kg caffeine citrate loads and then in both groups they followed these loads with 10 mg/kg per day maintenance. The primary outcome of the study was white matter structural development by MRI. Previous research by Doyle had found an improvement in this outcome with the use of standard caffeine therapy of 10 mg/kg/d so the real question here was “If a little is good, then is more better?”
Sadly the answer to the last question is a resounding NO!
None of the respiratory outcomes were any different between the standard caffeine and high dose groups but the following came out as a worrisome outcome:
Furthermore when the infants were followed up at 2 years of age a statistically significant percentage of 2 year olds previously randomized to the high dose caffeine regimen were found to be hypertonic (2.3 vs. 1.5%). Overall neurodevelopment was no different between groups but it should be pointed out that the study was not powered to detect such differences.
One question that must come up with these findings is whether or not it is plausible that a 2 day exposure to high dose caffeine followed by standard dosing for the remainder of the time could lead to cerebellar hemorrhage. I think the answer is yes given the findings from a single dose of 25 mg/kg caffeine (equivalent to 50 mg of caffeine citrate/kg as studied by Hoecker et al
As noted by the authors, this single dose was responsible for reducing cerebral blood flow velocity by about 20% from baseline. The regimen over 48 hours in the above study was to give 80 mg/kg in divided doses as a load so it is reasonable to conclude these infants would have experienced a reduction in cerebral blood flow as well, and possibly to a greater degree than the patients in the Hoecker study. Add to this that these are infants under 30 weeks of age who have a fragile arterial and venous network to begin with and it seems reasonable that a period of hypoperfusion possibly combined with hypoxemia and then reperfusion injury could account for these cerebellar bleeds.
So where does this leave us? As the authors conclude it is not wise to plan a larger study looking at the same strategy given the findings in this pilot. What remains unclear at least to me is whether 6, 7 or 8 mg/kg during the maintenance phase of treatment offers any true long-term advantage. With anything there are tradeoffs though and finding the right balance is never easy. If we use lower caffeine doses and in some patients they require intubation, is the increased risk of CLD and possible neurodevelopmental impairment from that worth the limitation of risk? After the first week of life is the risk of cerebellar hemorrhage lower as the blood vessels mature? I think so which would make the argument for using higher doses at that point but in truth we just don’t know about safety in terms of long-term outcomes. For now at least it would seem that in the absence of guidance from research all we can really say is that 2.5 to 5 mg/kg/d of caffeine base is safe but that doses higher than that need to be used with caution. It may be wise to seek informed consent for the use of higher doses in light of these findings but it is up to each unit to decide if this is justified based on your views of the data. What do you think?