Intravenous drug co-administration in neonatal and paediatric intensive care patients – examining clinically relevant multi-drug compatibility

Abstract

Neonatal and paediatric intensive care patients are in need of numerous intravenous (i.v.) drugs. The majority of drugs, including parenteral nutrition (PN) and buffered electrolyte solutions, used in the intensive care setting are administered via the central venous catheter. Due to limited venous access ports two or more drugs have to be co-administered in the same i.v. line and a major challenge associated with co-administration of multiple i.v. drugs is the risk of physical incompatibility. Incompatibilities may be presented as precipitation, effervescence, changes in colour, or for emulsions, destabilisation, of one or more of the components that are co-administered. Consequences range from transient catheter obstruction to lethal embolism. This Thesis investigated the compatibility of drugs including PN and buffered electrolyte solutions with focus on the neonatal and paediatric population. In addition, this Thesis explored new methodology, such as Raman spectroscopy, for rapid detection and identification of precipitates in multi-drug mixtures. Numeta G13E, the PN used for preterm neonates, was tested in two-component mixtures with vancomycin, fentanyl, paracetamol, dopamine, cefotaxime and morphine, respectively, which all were shown to be compatible. In addition, Numeta G13E was tested in three-component mixtures with morphine+cefotaxime and morphine+dopamine. No signs of precipitation nor signs of emulsions destabilization were seen. The investigation of a five-component case of incompatibility from the paediatric intensive care unit where fentanyl, ketamine, midazolam and potassium chloride had been coadministered with the buffered electrolyte solution Plasmalyte, revealed that both midazolam and ketamine were precipitating, which could be explained by reduced solubility due to pH change governed by the buffered electrolyte. Midazolam also precipitated when replacing Plasmalyte with Plasmalyte Glucos, but to a much lower degree corresponding to the more suitable pH in this version of the product. Fentanyl and potassium chloride were compatible with both Plasmalyte and Plasmalyte Glucos. Raman spectroscopy was shown to be a powerful tool to identify the nature of precipitated compounds in a multi-drug mixture of ampicillin, calcium chloride, cefotaksime, ceftriaxone, metoclopramide and paracetamol. Using the same model system, single particle Raman microscopy could be used to identify a sub-visual precipitated particle as ceftriaxone calcium in a three-component mixture of calcium chloride, cefotaxime and ceftriaxone. These results are promising and show that Raman spectroscopy could be a useful tool for compatibility assessment of complex i.v. regimes.