BackgroundThere is no standardized procedure or consensus to which tests should be performed to judge compatibility/incompatibility of intravenous drugs. The purpose of this study was to establish and evaluate a test program of methods suitable for detection of physical incompatibility in Y-site administration of total parenteral nutrition (TPN) and drugs.MethodsEight frequently used methods (dynamic light scattering, laser diffraction, light obscuration, turbidimetry, zeta potential, light microscopy, pH-measurements and visual examination using Tyndall beams), were scrutinized to elucidate strengths and weaknesses for compatibility testing. The responses of the methods were tested with samples containing precipitation of calcium phosphate and with heat destabilized TPN emulsions. A selection of drugs (acyclovir, ampicillin, ondansetron and paracetamol) was mixed with 3-in-1 TPN admixtures (Olimel® N5E, Kabiven® and SmofKabiven®) to assess compatibility (i.e. potential precipitates and emulsion stability). The obtained compatibility data was interpreted according to theory and compared to existing compatibility literature to further check the validity of the methods.ResultsLight obscuration together with turbidimetry, visual inspection and pH-measurements were able to capture signs of precipitations. For the analysis of emulsion stability, light obscuration and estimation of percent droplets above 5 μm (PFAT5) seemed to be the most sensitive method; however laser diffraction and monitoring changes in pH might be a useful support. Samples should always be compared to unmixed controls to reveal changes induced by the mixing. General acceptance criteria are difficult to define, although some limits are suggested based on current experience. The experimental compatibility data was supported by scattered reports in literature, further confirming the suitability of the test program. However, conflicting data are common, which complicates the comparison to existing literature.ConclusionsTesting of these complex blends should be based on a combination of several methods and accompanied by theoretical considerations.

Three drugs showed clear signs of precipitation when mixed with TPN and these products should not be co-administered in the same infusion line.

Objectives: The main objective was to investigate Y-site compatibility of intravenous drugs 23 with one standard TPN admixture for preterm infants. Since micro-precipitation was observed in the water phase after addition of trace elements, the concentration effect on microprecipitation formation developed as a sub goal. Methods: Seven drugs (ampicillin, ceftazidime, fluconazole, fosphenytoin, furosemide, metronidazole and paracetamol) were mixed in three mixing ratios with one preterm TPN admixture. Samples were investigated within one hour and again after four hours. Precipitation was studied in a lipid-free version called TPNaq by light obscuration, turbidimetry and visual examination. Emulsion stability data was assessed by light obscuration and laser diffraction. pH was measured to assess theoretical risk of precipitation and emulsion destabilization. The influence of different concentrations of trace elements on precipitation was investigated by visual examination, turbidimetry and light obscuration. Results: Ampicillin, ceftazidime, fosphenytoin and furosemide lead to precipitation after mixing with TPNaq. In some samples of TPN and fluconazole, metronidazole and paracetamol, 36 the emulsion droplet size was above the acceptance limit, although this might also be inherent 37 to the TPN admixture. An unexpected formation of micro-precipitate correlating to increasing 38 amounts of added trace elements, might be caused by an interaction of cysteine and copper, 39 and complicated the compatibility assessment with drugs. 40 Conclusions: The micro-precipitate resulting from addition of trace element should be 41 investigated further. This study did not provide sufficient evidence to recommend Y-site 42 3 infusion of the tested drugs and the preterm admixture; however it might offer some additional support to other compatibility data.