The administration of parenteral medications poses a particular challenge in the pediatric population as compatibility data are often limited since these drugs are studied and administered in different concentrations than are used in adults. Incompatible medications may form particles that are subvisible (i.e., not visible to the naked eye) that can cause microcirculatory impairment, pulmonary dysfunction, cardiovascular arrest, multiorgan failure, kidney injury, myocardial damage, and negative immune-modulating effects. This is especially problematic when Y-sites are used in pediatric patients, as relatively slow infusion rates are employed, increasing the risk of a physical incompatibility before the drug enters the bloodstream.
To assist in the identification of these substances, the USP <788> chapter on particulate matter in injections describes two testing methods: Method 1 (Light Obscuration [LO] Particle Count Test) and Method 2 (Microscopic Particle Count Test). When examining injections and parenteral infusions for subvisible particles, Method 1 is preferred. Method 1 is not applicable when preparations have reduced clarity or increased viscosity such as emulsions, colloids, or liposomal preparations. In this case, Method 2 testing should be employed. Newer techniques such as flow imaging (FI) and backgrounded membrane imaging (BMI) may allow for improved identification of particulate matter. FI is a complementary test that provides additional data, allowing particle classification according to morphology. BMI is an automated form of light microscopy that assists in sizing, quantification, and morphological characterization of particles.
The researchers conducted a study to determine the physical simulated Y-site incompatibilities of specific combinations of commonly used IV medications at standard pediatric concentrations. To determine incompatibilities, they used both USP <788> particulate matter detection method (LO) and the newer techniques of FI and BMI. A total of 29 different combinations of medications were tested.
Visual inspection immediately after mixing and at 4 hours was the first method of incompatibility testing performed. FI results were assessed using USP <788> Method 1 criteria, whereas BMI results were assessed using USP <788> Method 2 criteria.
While none of the combinations were incompatible based on visual inspection, only five combinations met the criteria for compatibility using LO, FI, and BMI. These included cisatracurium 2 mg/mL with bumetanide 0.25 mg/mL, ampicillin/sulbactam 20 mg/mL in normal saline (NS) with heparin 500 units/mL in NS, ampicillin/sulbactam 20 mg/mL in NS with bumetanide 0.25 mg/mL, rocuronium 10 mg/mL with vasopressin 1 unit/mL, and bumetanide 0.25 mg/mL with alprostadil 20 mcg/mL in 5% dextrose in water. The other 24 combinations were found to be incompatible based on one of the three testing methods. Concerningly, four combinations were incompatible by all three testing methods. These included cisatracurium 2 mg/mL with ketamine 10 mg/mL, dexmedetomidine 4 mcg/mL with ketamine 10 mg/ml, rocuronium 10 mg/mL with ketamine 10 mg/mL, and vancomycin 5 mg/mL in NS with cefepime 40 mg/mL in NS.
Despite the limitations of this study, such as the use of simulated Y-site compatibility testing within a syringe, which did not account for physiochemical interactions that may occur in the actual IV administration between medications and with the tubing, this study called into question the utility of current USP <788> particle matter incompatibility testing methods for medications used in pediatric patients. Pharmacists need to be aware of shortcomings of the current incompatibility testing methods and should consider if more stringent and novel approaches should be utilized in this vulnerable population.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
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Published March 6, 2023