Pathological Consequences From the Infusion of Unstable Lipid Emulsion Admixtures in Guinea Pigs
The pathophysiologic effects of infusing unstable lipid emulsions are unclear, but these were shown to cause reticuloendothelial system (RES) dysfunction in animals and humans. We investigated the effects of unstable lipid emulsions in RES organs defined by 2 levels of the percent fat >5 µm (percentage of fat, PFAT > 5 µm) in a guinea pig model. Two identical injectable lipid emulsions with differing (stable vs unstable) PFAT >5 µm levels were infused for over 24 h into 2 groups of animals (n = 5/group). The PFAT >5 µm concentration was measured before and at the end of the infusion to ascertain the dose range of enlarged fat globules in each group. Animals were killed and specimens from the upper, middle, and lower lung and a single liver sample were examined histologically and for micromolar concentrations of malondialdehyde (MDA) per g (µmol–1 g) of wet tissue. The PFAT >5 µm concentrations preinfusion were 0.004 ± 0.001 and 2.418 ± 0.273 for the stable and unstable injectable lipid emulsions, respectively. At 24 hours, the PFAT >5 µm level increased in both the groups (stable: 0.161 ± 0.008; unstable: 7.861 ± 0.291). MDA concentrations were significantly higher in the lungs of animals receiving the unstable (47.2 ± 26.2 µmol–1 g) vs stable (32.4 ± 11.2 µmol–1 g) injectable lipid emulsions (p = .033), but were not different for the liver specimens (stable: 16.9 ± 7.6 µmol–1 g vs unstable: 17.7 ± 2.2 µmol–1 g, p = .944). These preliminary data suggest that infusion of unstable injectable lipid emulsions has pathologic consequences showing greater evidence of oxidative stress in the lungs. (Clin Nutr. 2005;24:105–113.) COMMENT: Most (76%) institutional and homecare organizations report using a once-daily PN infusion system, most commonly as total nutrient admixtures (TNAs) based on the latest safe practices for PN survey.1 Unfortunately, the survey found that less than half (46%) of organizations monitor the quality control of their PN compounding for patient safety. A TNA is a highly complex admixture, containing 30 or more components, including amino acids, dextrose, fat emulsion, sterile water, electrolytes, trace elements, vitamins, and other medications (eg, regular insulin, histamine-2 receptor antagonists). The addition of fat emulsion to the TNA transforms the PN solution into an oil-in-water emulsion with different physicochemical stability concerns.2 Phase separation of a TNA results in the release of free oil and a liquid precipitate. This is rarely reported clinically because most clinicians are not familiar with the risks associated with liquid precipitates as well as they are for solid precipitates (eg, calcium-phosphate).3 Unfortunately, visual observation is the most commonly used quality assurance method in practice by pharmacists and nurses, which is obviously not ideal given that the terminal stage of fat emulsion destabilization is the coalescence of small lipid particles forming large droplets that may vary in size from 5 to 50 µm, escaping visual detection. Clinicians preparing and administering TNA must be able to identify the physical signs of instability and know the presence of free oil in any form should be considered unsafe for administration. Interestingly, the existence of lipid globules 5 µm in diameter comprising 0.4% of the total fat present in a TNA has been shown to be pharmaceutically unstable and is considered unsuitable for IV administration.4 This is one of the first published articles to investigate the physiologic effects of infusing such an unstable TNA into an animal model. The adult male Hartley guinea pigs used in this trial received a low-osmolarity, high-fat TNA prepared from ProcalAmine (3% amino acids and 3% glycerin with electrolytes; B. Braun, Irvine, CA) and Liposyn III 20% fat emulsion (Abbott Laboratories, Chicago, IL) for 24 hours IV. This specific TNA had been previously found by the authors to be unstable according to the volume-weighted percentage of fat >5 µm (PFAT >5 µm). The physicochemical stability of the stable and unstable TNAs was determined with a laser-based counting and sizing method using light extinction with a single-particle optical sensing technique. Unfortunately, this is not a device and process that is performed in most US IV pharmacy compounding areas. The stable version of this TNA was prepared the day of infusion, and the unstable TNA was prepared 48 hours earlier before infusion into the guinea pigs. After 24 hours of TNA infusion, the animals were killed, with their lungs and livers excised. Malondialdehyde (MDA) concentrations were measured from the tissues of the guinea pigs specifically because they represent free radical production, a marker of oxidative stress. The authors viewed increases in MDA concentrations in the specific tissues to be primarily from phagocytosis because it is one of the mechanisms of producing reactive oxygen species and, thus, oxidative stress. The pathologist of the study identified the presence and distribution of fat globules in the tissues and characterized them as normal or abnormal (presence of fat deposits), as well as limited, moderate, or diffuse in their presentation, while being blinded to the stable and unstable TNA groups. The stable TNA was determined to be pharmaceutically stable because it only contained a PFAT >5 µm of 0.004% (below the 0.4% cutoff) immediately before infusion but increased to 0.161% at 24 hours, whereas the unstable TNA clearly exceeded the cutoff at all times. As expected, the lung tissue of the guinea pigs receiving the unstable TNA was found to have higher amounts of MDA concentrations, due most likely to the reticuloendothelial system clearance of fat. Surprisingly, 47% of the guinea pigs receiving the stable TNA had abnormal lung specimens. This likely represents the "normal" appearance of fat globules in lung tissue because it may be an alternative clearance pathway for these large triacylglycerols. Clearly, this may have pathologic clinical significance in humans if an unstable TNA (or possibly even stable TNA) is infused in states of pulmonary compromise (ie, acute lung injury or acute respiratory distress syndrome). Another interesting finding of this study was in the liver specimens of the stable and unstable TNAs because they were comparable and did not show any significant cellular toxicity at 24 hours. Further study on the effects of this liver histologic abnormality is needed in states of prolonged TNA infusion, as in patients dependent on receiving PN support solely. This study has many implications for nutrition support professionals in that it questions what we consider to be truly a pharmaceutically stable TNA (PFAT >5 µm of 0.4%) and how safe it is to infuse these TNAs into patients with pulmonary dysfunction. The authors are to be commended for providing evidence in an animal model that has pertinence for patient safety and compounding expertise when preparing these highly complex admixtures for human administration.
Contributing Editor—Todd Canada, PharmD, BCNSP University of Texas MD Anderson Cancer Center, Houston, Texas Driscoll DF, Ling P, Quist WC, Bistrian BR Laboratory of Nutrition/Infection and Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
Nutrition in Clinical Practice, Vol. 21, No. 6,
636-637 (2006)
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