Pharmacodynamic considerations in the treatment of pulmonary hypertension in infants: challenges and future perspectives

Abstract

Introduction: Pulmonary hypertension (PH) in infants is a life-threatening disease with a high mortality. It is treated with different drugs that act upon the three different pathways involved in its development. Studies on the drug pharmacodynamics are sparse, however.

Areas covered: This review reports a search on the currently available literature in English on drug pharmacodynamics in infants with PH. The search yielded 2499 citations in the EMBASE, MEDLINE, COCHRANE, Web of Science, PubMed Publisher and Google Scholar databases since 1961. Of these, 1691 did not meet the research question. Eventually, 655 articles were of interest, including 44 randomized controlled trials on PH in infants. These articles cover all PH medications used in infancy.

Expert opinion: Mortality of PH in infancy has dropped considerably over the past years. iNO is widely used, followed by sildenafil – both orally and intravenously in contrast to the exclusively oral use in adults. In adults, the pharmacodynamic effects of the different medications are tested using the 6-minute walking test, changes in the NYHA classification, or by invasive measurement of pulmonary pressure. Reliable data of pharmacodynamics tested in adequate series or in randomized controlled trials in children are lacking, however, for most of these medications.

Keywords:

• infants
• medication pharmacodynamics
• pulmonary hypertension

Article highlights.

• All medications influencing the three major pathways of PH are also used in infants. Only for iNO there is sufficient evidence for its positive effect in PPHN and a favorable effect in post-cardiac surgery patients.

• Sildenafil is used increasingly even though only a few RCTs showed a decrease in OI and mortality in resource-limited settings. This effect needs to be validated in comparison to for example iNO.

• To date, Bosentan cannot be recommended due to a lack of valid data. Availability of an intravenous formulation might make (selective) endothelin receptor blockers drugs of choice in the future.

• The lack of noninvasive and continuous methods to monitor actual changes of PH in infants complicates pharmacodynamic research. Advanced echocardiography including tissue Doppler imaging, strain and strain rate imaging and new plasma biomarkers will hopefully solve this problem in the future.

• Only large international RCTs can include sufficient numbers of patients and yield valid data to further improve treatment of infants with PH.

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