Are we overdosing preemies on caffeine?

Are we overdosing preemies on caffeine?

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.outcome high dose caff

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?

Can a little Caffeine and Viagra Save a Preemie’s Life?!

Can a little Caffeine and Viagra Save a Preemie’s Life?!

If that is not a title designed purely to gather attention I don’t know what is.  I can’t take credit for the title thought as I borrowed it from the following video and article link.  In late 2014 and January of 2015 the subject of using these two medications to improve survival without chronic lung disease-CLD  (for a review see here) started making the rounds of many websites and news agencies.

Caffeine is given to premature infants to stimulate breathing via blockade of adenosine receptors in the brainstem.  As adenosine inhibits breathing in this part of the brain it is an effective treatment to address apnea in the newborn.  In 2006 Schmidt B et al published the Caffeine For Apnea of Prematurity (CAP) Trial (Full Article) and demonstrated that infants 500 – 1250g who received caffeine versus those who did not, spent less time on a ventilator and furthermore had less chronic lung disease in the long run.  A win on both fronts and in essence established early caffeine use as a standard therapy in NICUs.  Further research has demonstrated that early use of caffeine has other benefits when given shortly after delivery such as fewer intubations, greater success supporting infants using CPAP alone rather than invasive ventilation.  Although many mother’s around the world avoid caffeine during pregnancy it has become one of the most common drugs used in the premature newborn and to allay any anxiety about outcome, a follow-up study from the CAP study above has shown no harm in long-term neurodevelopment from the exposure to caffeine.

What then about Sildenafil otherwise known by it’s trade name Viagra?  Sildenafil is a phosphodiesterase V  inhibitor which works by increasing levels of cGMP which in turn cause the smooth muscle in arterial vessels to relax.

Action of Sildenafil

It may surprise some of you to learn that Sildenafil was originally designed to treat high blood pressure in the lungs or pulmonary hypertension. It was a well-known side effect that took it’s marketing in a completely different direction.  Previous research however, studying the impact on patients with pulmonary hypertension in the newborn demonstrated that sildenafil alone or in combination with inhaled nitric oxide could reduce pulmonary vasoconstriction.  Approximately 10-25% of premature infants with CLD have accompanying pulmonary hypertension depending on how one defines it’s presence.  Sildenafil then could arguably be used to treat patients who have established CLD or perhaps even evolving CLD to prevent the oxygenation problem from pulmonary hypertension that accompanies CLD.

“Save your preemie with Caffeine and Viagra!” seems to indicate that the evidence is out there and that it is VERY positive but sadly it just isn’t.  The evidence for use of sildenafil in established CLD is weak and limited to small observational or retrospective studies in which patients were put on long-term sildenafil and over time improved.  The challenge with these types of studies is that it is difficult to say with any certainty that the patient wouldn’t have improved over many months anyway.  Certainly, in those reports where the medication was stopped and ultrasound evidence of pulmonary hypertension returned, it is suggestive but these one-off cases are not enough to convince me that it should be considered as a standard of care.

Rat models of evolving CLD have demonstrated improved angiogenesis and alveolar growth with additional findings in the heart of less right ventricular enlargement and pulmonary hypertension.  If confirmed in humans this would certainly be a wonderful treatment to prevent CLD from developing, as these findings are largely what contribute to this diagnosis.  So what is the evidence for a preventative effect of sildenafil?

One Tiny RCT

In this study of 20 patients, half were randomized to sildenafil 3 mg/kg/d and half to placebo for a 4 week course starting at day 7 of age in patients who were still ventilated.  In the end only 7 patients in the sildenafil arm finished the study.  No differences in any outcomes were found so no benefit could be demonstrated.  The study was underpowered to find a difference and aside from that the dose chosen was low compared to other studies using as much as 8 mg/kg/d.  Could a larger dose shown a difference in outcome?  Maybe but again a larger sample size would have helped and I suspect will come with time.  The bottom line is that it was a small study that does not add anything to the pool of evidence suggesting a benefit of sildenafil in either treatment of patients with CLD or to prevent it.

This is the danger of course in the lay press hearing about information like this.  It is sensational and will attract a lot of readers but in the end should parents be asking their health care providers in NICU to use sildenafil as a standard treatment for CLD or to prevent it?  For the time being I would say not but with the provision that I actually believe there may be a role but for the right patient.

In our unit we have an Integrated Targeted Neonatal Echocardiography program that allows us to take measurements of pulmonary vascular resistance that are quite different from traditional measures reported using a standard echocardiogram.  Using this technique, patients with pulmonary hypertension can be identified and treated whether it be with inhaled nitric oxide or sildenafil or both.  It is also tempting to speculate that there may be early predictors of patients who may develop CLD with pulmonary hypertension and it is those premature infants that would like be the best to target such therapies in.  By selecting out those patients only who would develop this condition a therapy to prevent it would be better studied in a pure sample.  Treating the 75-90% of patients who will not develop this condition with a drug will dilute out your results for sure compared to studying only those patients with a high likelihood of disease.  I will have to dream of this type of study for the time being though as I am unaware of such work being done at the moment.

Finally I think it is worth mentioning that Sildenafil should not be used without some caution.  In 2012 the US FDA issued a warning (read warning here) on the use of high doses of Sildenafil for the treatment of pulmonary hypertension due to a higher mortality rate in a Pediatric clinical trial (Free article here) involving children at least a year of age.  The high dose group received a dose from roughly 3-6 mg/kg/day which is in keeping with the dosing used in the trials in infants.  Since that time the FDA has softened it’s stance (clarification) but it need to be acknowledged that the use of Sildenafil under a year of age is considered off label and with the aforementioned concerns it would seem prudent if using the medication to use a lower dose.

Taking all of this information in I would suggest it seems wise to continue giving our premature infants a morning cup of coffee each day but for the time being I would leave more frequent use of Viagra to the adults.