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!