Physical stability of an all-in-one parenteral nutrition admixture for preterm infants upon mixing with micronutrients and drugs.

Objectives: The main objective was to investigate Y-site compatibility of intravenous drugs with one standard total parenteral nutrition (TPN) admixture for preterm infants. Since micro-precipitation was observed in the water phase after addition of trace elements, the concentration effect on micro-precipitation 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 1 hour and again after 4 hours. Precipitation was studied in a lipid-free version called TPNaq by light obscuration, turbidimetry and visual examination. Emulsion stability data were assessed by light obscuration and laser diffraction. pH was measured to assess the theoretical risk of precipitation and emulsion destabilisation. 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 led to precipitation after mixing with TPNaq. In some samples of TPN and fluconazole, metronidazole and paracetamol, the emulsion droplet size was above the acceptance limit, although this might also be inherent to the TPN admixture. An unexpected formation of micro-precipitate correlating with increasing amounts of added trace elements might be caused by an interaction of cysteine and copper, and complicated the compatibility assessment with drugs. Conclusions: The micro-precipitate resulting from the addition of trace elements should be investigated further. This study did not provide sufficient evidence to recommend Y-site infusion of the tested drugs and the preterm admixture; however, it might offer some additional support to other compatibility data.

Physical compatibility of total parenteral nutrition and drugs in Y-site administration to children from neonates to adolescents.

OBJECTIVES: Infusion of precipitate or destabilized emulsion can be harmful. The purpose of this study was to obtain Y-site compatibility data on intravenous drugs and total parenteral nutrition (TPN) relevant for children. METHODS: Two three-in-one TPN admixtures (Olimel N5E and Numeta G16E) used for children of different age groups were tested with ten drugs (ampicillin, ceftazidime, clindamycin, dexamethasone, fluconazole, fosphenytoin, furosemide, metronidazole, ondansetron and paracetamol). Drug : TPN ratios were estimated from a wide range of age and weight classes, and the most extreme mixing ratios (drug > TPN, TPN > drug) in addition to 1 + 1 were chosen. Assessment of potential precipitation was performed by subvisual particle counting, visual examinations and measurements of turbidity and pH. Emulsion stability was investigated by estimation of percentage of droplets above 5 µm (PFAT5), mean droplet diameter and pH measurements. Complimentary theoretical evaluations were performed. KEY FINDINGS: Ampicillin, fosphenytoin and furosemide precipitated when mixed with TPN. The results for ceftazidime, clindamycin, dexamethasone, fluconazole, metronidazole, ondansetron and paracetamol suggest that they were compatible with either TPN in the tested concentrations. None of the drugs were found to destabilize the emulsions. CONCLUSION: Three drugs showed clear signs of precipitation when mixed with TPN and these products should not be co-administered in the same infusion line.

Development and evaluation of a test program for Y-site compatibility testing of total parenteral nutrition and intravenous drugs.

BACKGROUND: There 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. METHODS: Eight 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. RESULTS: Light 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. CONCLUSIONS: Testing of these complex blends should be based on a combination of several methods and accompanied by theoretical considerations.

Utilization of the tyndall effect for enhanced visual detection of particles in compatibility testing of intravenous fluids: validity and reliability.

PURPOSE: This study investigates the validity, reliability, and detection limit of a visual examination method utilizing the Tyndall effect to enhance visible detection of particles. The suitability of the method for compatibility testing of intravenous fluids in a hospital pharmacy context is discussed. METHODS: A panel of 20 inspectors examined 20 samples, with and without particles, using two light sources (halogen lightbulb in a focused desk lamp and a red pocket laser pointer). The samples contained particles of different origin (precipitate, polystyrene standards), varying size, and concentrations. Light obscuration and turbidimetric measurements were used to obtain numeric references. The samples were divided into rejection probability zones, and the validity (sensitivity, specificity, and likelihood ratios) and reliability (inter-rater agreement coefficients Fleiss' kappa and Gwet's AC1) were estimated. RESULTS: The sensitivity of the laser pointer for detecting microprecipitates was quite high; however, it also showed a high false rejection rate. The specificity was slightly higher for the focused desk lamp than the laser pointer. The likelihood ratios were not within the recommended limits of a useful test, indicating that the method could not securely confirm the presence/absence of particles in the samples. The inter-rater agreement coefficients indicated fair to moderate agreement between the inspectors. CONCLUSIONS: The validity and reliability were not satisfactory for either of the light sources. The visual detection limit seemed to be around 5 µm, although we propose that an exact detection limit is not that relevant for compatibility testing. Based on the current findings, the visual examination method cannot be recommended as the sole method for judging compatibility of parenteral nutrition and drugs, but rather in a program of several methods. In the hospital pharmacy, the method may be a resource, together with theoretical considerations, in situations where other methods are unavailable; however, use of in-line-filters is essential to protect the patient. LAY ABSTRACT: Many patients under intensive care are in need of several intravenous drugs simultaneously. These drugs cannot be given in the same infusion line unless compatibility has been documented. Incompatibilities can result in, for example, precipitation of particles. Injected particles can harm the patient and should be avoided. Visual screening of blends of drugs for possible incompatibility, using a focused light source to enhance visual detection based on the Tyndall effect, could be a quick and easy methodology to identify incompatibility. In the following study the objective was to investigate how reliable visual inspection, with the utilization of the Tyndall effect, is at detecting particles and precipitations in blends of intravenous drugs and parenteral nutrition mixtures. Twenty inspectors each examined 20 different samples with two different light sources. Some of the samples were without particles (clean), and some contained different types and degrees of particle contamination. The inspectors' judgment of the samples was recorded and validity and reliability parameters were calculated to evaluate the method's suitability. The conclusion was that because of false positive and negative findings the visual inspection method alone is not enough to securely document compatibility/incompatibility, but it is more suitable as support together with additional methods.