Evaluation of the compatibility of sildenafil during simulated Y-site and multi-lumen administration in a paediatric intensive care unit

Sildenafil, a phosphodiesterase type-5 inhibitor, is used for the treatment of infants with pulmonary hypertension (PH). Intravenous (IV) sildenafil (Revatio®) is approved for the treatment of PH in adults but is used off-label in paediatrics. The absence of compatibility data between sildenafil and other commonly used IV medications such as adrenaline, noradrenaline, vasopressin, milrinone and heparin necessitates the use of a dedicated IV line for sildenafil. In the critically unwell child, limited IV access can make the delivery of multiple IV infusions particularly problematic. The application of devices known as Y-site or multi-lumen connectors allows multiple drug infusions to converge and enter through a single venous port of entry. However these devices can only be utilised if compatibility studies are available demonstrating the drug mixture stability.

Chemical incompatibilities can lead to drug-drug interactions, potentially resulting in sub-therapeutic outcomes. The overall aim of this thesis was to establish the physical and chemical compatibility of sildenafil with the commonly administered drugs in the management of PH in paediatrics. This study evaluated the Y-site and multi-lumen chemical and physical compatibility, of 42 different combinations of sildenafil with (adrenaline, noradrenaline, milrinone, vasopressin and heparin), and different diluents (NaCl 0.9%w/v, Glucose 5%w/v, and Glucose 10%w/v), in two environmental conditions frequently encountered in the Paediatric Intensive Care Unit (PICU) (room temperature 18-22°C and 37°C). Prior to drug combination analysis, HPLC methods were developed and optimised to allow for the quantification of drugs in accordance with current pharmaceutical guidance as outlined in Chapter 2. In first part of Chapter 3, binary drug mixtures of sildenafil were examined for physical and chemical compatibility to establish Y-site compatibility. All drugs proved to be compatible when combined with sildenafil, except the binary mixture of heparin that lead to a physical and chemical incompatibility. In the second part of Chapter 3, multiple drug combinations of four and five drugs were combined with sildenafil to establish multi-lumen compatibility. The limited and incomplete data presented in the literature for the compatibility of drugs administered via Y-site in combination with sildenafil, makes studies such as this one invaluable to clinicians. The overall aim of this work is to provide a complete compatibility chart of all five drugs identified as critical in combination with Sildenafil at RT and at 37°C. This preliminary data provides a starting point in the investigation of the compatibility of Sildenafil in combination with commonly used ICU drug infusions. This research will help inform clinical judgement to allow for the safe IV Y-site and multi-lumen drug administration in the PICU.