David F. Driscoll

Postoperative fluid overload: not a benign problem.

The incidence and consequences of fluid overload in the surgical ICU (SICU) have not been well defined, but may influence length of stay, days requiring mechanical ventilation, and mortality. Forty-eight consecutive patients admitted to our SICU were prospectively monitored for acute changes in weight and its impact on clinical management and outcome. When defined as a gain greater than 10% from their preoperative or premorbid weight (or an approximately 20% increase in total body water), 40% of patients had fluid overload. Patients were divided into three groups: those who had gained less than or equal to 10%, those with a weight gain between 11% and 20%, and those with greater than 20% increase in weight. Significant differences were found with respect to vasopressor dependence, colloid administration, and mortality. When indexed by initial Acute Physiology and Chronic Health Evaluation (APACHE II) mortality prediction scores, all groups had similar degrees of illness. On average, presumably due to volume limitations, patients were inadequately nourished during 85% of their SICU stay. Our results suggest that the morbidity of fluid overload can be significant, and warrants a fresh look at the methods of intraoperative fluid resuscitation.

Early enteral feeding in postsurgical cancer patients : Fish oil structured lipid-based polymeric formula versus a standard polymeric formula

OBJECTIVES The authors compared the safety, gastrointestinal tolerance, and clinical efficacy of feeding an enteral diet containing a fish oil/medium-chain triglyceride structured lipid (FOSL-HN) versus an isonitrogenous, isocaloric formula (O-HN) in patients undergoing major abdominal surgery for upper gastrointestinal malignancies. SUMMARY BACKGROUND DATA Previous studies suggest that feeding with n-3 fatty acids from fish oil can alter eicosanoid and cytokine production, yielding an improved immunocompetence and a reduced inflammatory response to injury. The use of n-3 fatty acids as a structured lipid can improve long-chain fatty acid absorption. METHODS This prospective, blinded, randomized trial was conducted in 50 adult patients who were jejunally fed either FOSL-HN or O-HN for 7 days. Serum chemistries, hematology, urinalysis, gastrointestinal complications, liver and renal function, plasma and erythrocyte fatty acid analysis, urinary prostaglandins, and outcome parameters were measured at baseline and on day 7. Comparisons were made in 18 and 17 evaluable patients based a priori on the ability to reach a tube feeding rate of 40 mL/hour. RESULTS Patients receiving FOSL-HN experienced no untoward side effects, significant incorporation of eicosapentaenoic acid into plasma and erythrocyte phospholipids, and a 50% decline in the total number of gastrointestinal complications and infections compared with patients given O-HN. The data strongly suggest improved liver and renal function during the postoperative period in the FOSL-HN group. CONCLUSION Early enteral feeding with FOSL-HN was safe and well tolerated. Results suggest that the use of such a formula during the postoperative period may reduce the number of infections and gastrointestinal complications per patient, as well as improve renal and liver function through modulation of urinary prostaglandin levels. Additional clinical trials to fully quantify clinical benefits and optimize nutritional support with FOSL-HN should be undertaken.

Lipid Injectable Emulsions: Pharmacopeial and Safety Issues

AbstractLipid injectable emulsions have been routinely used in patients worldwide for over 40 years as a nutritional supplement in patients requiring parenteral nutrition. They can be given as a separate infusion or added into total parenteral nutrition admixtures. Despite such broad use, no pharmacopeial standards exist with respect to the optimal pharmaceutical characteristics of the formulation. Several attempts to establish standard physical and chemical attributes have been attempted by various pharmacopeias around the world, but without success largely due to technical issues regarding the creation of globule size limits. Recently, the United States Pharmacopeia has revised its previous efforts and developed two methods and criteria (under Chapter <729>) to measure the mean droplet size (Method I), and the large-diameter tail > 5 μm (Method II) of the globule size distribution to verify the stability of lipid injectable emulsions. Importantly, it is the latter size limits of Method II that have the greatest implications for infusion safety. The major safety issues involving lipid injectable emulsions include impairments in plasma clearance in susceptible patients, and the infusion of an unstable emulsion containing large quantities of potentially embolic fat globules. Recent animal studies investigating the toxicity from the infusion of unstable lipid injectable emulsions have shown evidence of oxidative stress and tissue damage to the liver when recommended globule size limits determined by Method II of the USP are exceeded. Adoption of Chapter <729> of the USP seems appropriate at this time.

Lipid injectable emulsions: 2006.

Lipid injectable emulsions are an essential source of fatty acids, as well as a daily source of calories. They have been used in the clinical setting for almost 40 years, but despite this, there are no established official standards governing pharmaceutical quality. After 15 years of development, the United States Pharmacopeia (USP), which writes such standards for all FDA-approved pharmaceuticals, is poised to adopt an official monograph for lipid injectable emulsions that sets pharmaceutical requirements on all manufacturers placing limits on pH, free fatty acid concentrations and globule size (both mean droplet size and the population of large fat globules larger than 5 micrometers). Recent animal data has shown pathophysiologic changes in vital organs for lipids that fall outside the USP-proposed globule size limits. From a clinical perspective, newer lipid injectable emulsions show great promise in certain patient settings, most notably in the intensive care unit in both adults and infants. The clinical use of alternative oils, such as medium-chain triglycerides, fish oil and olive oil show benefits over conventional soybean oil formulations. In adults, for example, the administration of omega-fatty acids via soybean oil-based lipids produces a heightened inflammatory response via production of 2-series prostaglandins, whereas substitution of a portion of the lipid with omega-3 fatty acids via fish oil can favorably dampen the inflammatory response. In infants, for example, substitution of soybean oil with fish oil has recently been shown to reverse parenteral nutrition-associated liver disease. These advances should lead to safer infusion therapy in patients receiving lipid injectable emulsions.

Physicochemical Stability of Two Types of Intravenous Lipid Emulsion as Total Nutrient Admixtures

BACKGROUND Recent data have demonstrated that total nutrient admixtures (TNAs) are unstable when the percentage of fat (PFAT) globules >5 microm in diameter constitute >0.4% of the total fat present and therefore can be considered pharmaceutically unfit for human administration. METHODS We studied five nutritionally balanced TNAs using two different products of different oil composition designed to feed adult patients weighing 40 to 80 kg in 10 kg increments, which were given in final volumes equal to 25 mL/kg. Final concentrations of amino acids, dextrose, and lipids were held constant for each weight level. To provide cationic stress within clinical limits, calcium and magnesium were given in amounts equal to three times the usual daily dose, at 15 mmol each. Five TNAs were made in duplicate and for each product (n = 20) and studied over 5 days. Lipid droplet counts were determined by laser light extinction and conducted at five intervals; immediately after preparation at time 1 (T1), after 4 days at 4 degrees C +/- 2 degrees C (T2), and then at 6 (T3), 24 (T4), and 30 (T5) hours during storage at 25 degrees C +/- 1 degree C. At T3, a simulated patient infusion, set at a rate to deliver the entire volume over the next 24 hours, was begun. Samples taken at T3, T4, and T5, equal to 0, 18, and 24 hours, respectively, of the simulated patient infusion, were collected from the terminal infusion port of the i.v. administration set. Mean particle size (MPS) was determined by dynamic light scatter at T1, T3, and T5. Dependent variable analyses included the PFAT globules > 1.75 and 5 microm and MPS. A repeated-measure two-way ANOVA assessing treatment and time was performed. RESULTS The MCT/LCT-based TNAs had significantly fewer enlarged fat globules >1.75 microm (p < .0001) and >5 microm (p = .046), and smaller MPS (p < .0001) than TNAs made with the pure LCT emulsion. Of the 20 TNAs studied, 4 demonstrated visible evidence of instability (ie, heavy creaming or free oil), each occurring on day 5 only with the 70- and 80-kg LCT-based TNAs, and no evidence of instability with admixtures prepared from MCT/LCT lipid emulsions (chi2 analysis: p < .05). CONCLUSIONS Because the final macronutrient concentrations were held constant, the instability seen with the LCT-based TNAs of higher volumes may result from dilution of the electrolyte concentrations that unfavorably alters the electrical double layer and irreversibly commits the emulsion to an unstable state. The greater physicochemical stability achieved with the MCT/LCT-based TNAs, in turn, likely results from the smaller lipid droplet sizes, which may be an inherent property of MCTs.

The influence of medium-chain triglycerides on the stability of all-in-one formulations

When mixed with parenteral nutrients as an all-in-one admixture, previous data have demonstrated that lipid emulsions composed of medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs) yield more stable formulations compared with those compounded with pure LCT lipid emulsions. We investigated the physical stability of various preparations of intravenous lipid emulsions as all-in-one admixtures. Each final lipid emulsion used to compound the all-in-one formulation was a 20% w/v mixture containing MCTs and LCTs as either a single emulsion containing both triglycerides, or an emulsion made extemporaneously from separate starting emulsions of pure MCT and LCT. The first emulsion was composed of a 50:50 (by weight) physical mixture of MCTs and LCTs, and consisted of 50% MCT:40% omega-6 LCT (soybean oil):10% omega-3 LCT (fish oil) that was available as a single 20% w/v lipid emulsion. The second and third emulsions were specially prepared from separate stock dispersions containing pure 20% w/v MCT and pure 20% w/v LCT (soybean oil) lipid emulsions, and were made in volume ratios of 75% MCT:25% omega-6 LCT and 50% MCT:50% omega-6 LCT, respectively. This was done in order to investigate whether the method of emulsion preparation and/or ratio of MCT to LCT influenced all-in-one admixture stability. Each all-in-one admixture was studied at four intervals over 30 h at room temperature conditions by light extinction (or obscuration) using a single-particle optical sensing (LE/SPOS) technique. The data, performed in duplicate at each interval, is expressed as the volume-weighted percent of fat (PFAT) globules >5 microm. The results confirm the stabilizing effects of MCTs when made as a physical oil mixture as a single lipid emulsion. However, stabilization is lost if the MCT and LCT emulsions are mixed from separate starting emulsions and then compounded as an all-in-one formulation. The extemporaneous mixing of commercial lipid emulsions is not recommended.

Effect of a fish oil structured lipid-based diet on prostaglandin release from mononuclear cells in cancer patients after surgery.

BACKGROUND The authors compared the effect on eicosanoid production (prostaglandin E2 [PGE2], 6-keto PGF 1 alpha, and thromboxane B2) from peripheral blood mononuclear cells (PBMC) of feeding an enteral diet containing a fish oil/medium-chain triglyceride structured lipid (FOSL-HN) vs an isonitrogenous, isocaloric formula (O-HN) in patients undergoing major abdominal surgery for upper gastrointestinal malignancies. A previous study, which used the same formulas and experimental design, suggested improved renal and liver function as well as a reduced number of gastrointestinal and infectious complications with the use of fish oil structured lipids. This study sought to investigate the potential mechanism for these effects by assessing eicosanoid production from PBMC with the two diets. METHODS This prospective, blinded, randomized trial was conducted in 20 patients who were jejunally fed either FOSL-HN or O-HN for 7 days. Serum chemistries, hematology, urinalysis, gastrointestinal complications, liver and renal function, and eicosanoid production from isolated PBMC, either unstimulated or stimulated with endotoxin, were measured at endotoxin baseline and on day 7. Comparisons were made in 10 and 8 evaluable patients based a priori on the ability to reach a tube feeding rate of > 40 mL/h. RESULTS Patients receiving FOSL-HN experienced no untoward side effects compared with patients given O-HN and demonstrated the same general trend toward improved hepatic, renal and immune function found in the previous study. There was a significant reduction in PGE2 (p < .03) and 6-keto PGF 1 alpha (p < .01) production from PBMC with endotoxin stimulation in patients receiving FOSL-HN. CONCLUSIONS The results of early enteral feeding with FOSL-HN after surgery in this follow-up study provide further support to claims of safety, tolerance, and improved physiologic function. There was an associated reduction in eicosanoid production from PBMCs, which is presumed to be the principal mechanism for these effects.

Stability and compatibility assessment techniques for total parenteral nutrition admixtures: setting the bar according to pharmacopeial standards

Purpose of reviewThe stability and compatibility of total parenteral nutrition mixtures compounded for patients requiring nutritional support is paramount to their safety on intravenous infusion. The most significant pharmaceutical issues associated with mixing total parenteral nutrition formulations affecting their safety involve the stability of lipid-injectable emulsions and the compatibility of calcium and phosphate salts. Methods of analysis for stability and compatibility have varied, and the assessments have mostly been largely qualitative. Recent findingsAlthough pharmacopeial standards have been primarily applicable to pharmaceutical manufacturers, recent efforts by the United States Pharmacopeia have been directed at standardizing pharmacy practices involved in the safe mixing of compounded sterile preparations. The adoption of chapter 797 entitled ‘Pharmaceutical compounding – sterile preparations’ on 1 January 2004 has had a dramatic impact on pharmacy practice in the United States. More recently, the United States Pharmacopeia has also proposed a new chapter 729 entitled ‘Globule size distribution in lipid-injectable emulsions’, setting specific limits on the sizes and concentrations of lipid droplets in the formulation, which may have implications for all-in-one mixtures. Finally, new efforts are under way to establish limits on the level of acceptable amounts of particulates intrinsically introduced by the manufacturer, and thus may have ramifications for particulates extrinsically introduced or initiated during compounding by the pharmacist. SummaryWith careful monitoring and the development of appropriate pharmacopeial-based specifications that limit the size and concentration of large-diameter fat globules and eliminate the possibility of dibasic calcium phosphate precipitates, improved patient outcomes may be achieved.

Essential fatty acid deficiency and home total parenteral nutrition patients

The requirements for essential fatty acids in patients on home parenteral nutrition are not well described. We therefore studied the needs of 12 patients receiving parenteral nutrition for at least 4 mo (range: 4 mo-17.3 yr; mean 7.0 +/- 5.2 yr). Prior to the study, each patient had been receiving intravenous lipids either weekly or biweekly and had a triene to tetraene ratio (TTR) on plasma phospholipids performed at least annually. A TTR > or = 0.2 was considered diagnostic for essential fatty acid deficiency (EFAD). The purpose of this study was to determine the required intravenous lipid supplementation in patients on home total parenteral nutrition (HTPN). Patients with an initial TTR of < 0.2 had their intravenous lipid stopped and changes in their serum phospholipid fatty acids were followed every 3-4 wk. Nine of 12 patients had TTRs > 0.2 at some point in the study. Phase I consisted of patients who at initiation of the study had normal TTRs and were taken off lipid supplementation until their TTR became abnormal. Phases II, III, IV, and V consisted of lipid delivered in total nutrient admixtures in biweekly doses of 0.6, 1.2, 1.8, and 2.4 g of fat/kg bodyweight, respectively. Eight patients normalized their TTRs on the biweekly lipid regimens; one patient expired before his ratio normalized; and three patients could not be made deficient in essential fatty acids after 26 or more wk of fat-free parenteral nutrition. Most patients required 1.2 to 2.4 g of lipid/kg bodyweight/biweekly to correct serologic EFAD. The clinical background, as well as the length of small bowel remaining, did not seem to identify those patients who required lipid supplementation nor the final dose of lipid needed to normalize their TTRs.

Physicochemical stability of intravenous lipid emulsions as all-in-one admixtures intended for the very young.

BACKGROUND & AIMS Intravenous lipid emulsions (IVLEs) are unstable when growth of lipid droplets into large fat globules is detected by appropriate particle sizing techniques. Specifically, instability is evident when the volume-weighted percent fat (PFAT)>5 microm exceeds 0.4% of the total lipids present. This represents an approximate 10-fold increase in the population normally present in the large-diameter tail of stable lipid emulsions. The composition of the oil phase of an IVLE, however, has been shown to exhibit different stability characteristics. We investigated the stability of various IVLEs containing physical mixtures of medium-(MCT) and/or long-chain triglycerides (LCT) in three different all-in-one (AIO) admixtures intended for neonatal and infant patients. METHODS The 20% (w/v) IVLEs used in this study were composed of the following oils (by weight): 1). 1:1-soybean/safflower (SS); 2). 1:1-MCT:soybean (MS); and 3). 5:4:1-MCT:soybean:fish (MSF). Stability was assessed by light obscuration or light extinction to count large fat globules, and by aided (microscopic) and unaided (naked eye) visual assessments for up to 48 h at room temperature. RESULTS The stability of SS-based admixtures significantly and rapidly deteriorated in one of the three AIO compositions studied, whereas the AIOs made from MS or MSF were stable for all formulations. CONCLUSION The results suggest that AIOs made from MCT/LCT-containing IVLEs are more stable than those made from pure LCTs.