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!
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.
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?