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.

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