Long-chain Triglyceride Emulsion Research Articles

The role of nutrition in analysis of risk factors and short-term outcomes for late-onset necrotizing enterocolitis among very preterm infants: a nationwide, multicenter study in China

BackgroundNecrotizing enterocolitis (NEC) is a serious gastrointestinal disease, primarily affects preterm newborns and occurs after 7 days of life (late-onset NEC, LO-NEC). Unfortunately, over the past several decades, not much progress has been made in its treatment or prevention. This study aimed to analyze the risk factors for LO-NEC, and the impact of LO-NEC on short-term outcomes in very preterm infants (VPIs) with a focus on nutrition and different onset times.MethodClinical data of VPIs were retrospectively collected from 28 hospitals in seven different regions of China from September 2019 to December 2020. A total of 2509 enrolled VPIs were divided into 2 groups: the LO-NEC group and non-LO-NEC group. The LO-NEC group was divided into 2 subgroups based on the onset time: LO-NEC occurring between 8 ~ 14d group and LO-NEC occurring after 14d group. Clinical characteristics, nutritional status, and the short-term clinical outcomes were analyzed and compared among these groups.ResultsCompared with the non-LO-NEC group, the LO-NEC group had a higher proportion of anemia, blood transfusion, and invasive mechanical ventilation (IMV) treatments before NEC; the LO-NEC group infants had a longer fasting time, required longer duration to achieve the target total caloric intake (110 kcal/kg) and regain birthweight, and showed slower weight growth velocity; the cumulative dose of the medium-chain and long-chain triglyceride (MCT/LCT) emulsion intake in the first week after birth was higher and breastfeeding rate was lower. Additionally, similar results including a higher proportion of IMV, lower breastfeeding rate, more MCT/LCT emulsion intake, slower growth velocity were also found in the LO-NEC group occurring between 8 ~ 14d when compared to the LO-NEC group occurring after 14 d (all (P < 0.05). After adjustment for the confounding factors, high proportion of breastfeeding were identified as protective factors and long fasting time before NEC were identified as risk factors for LO-NEC; early feeding were identified as protective factors and low gestational age, grade III ~ IV neonatal respiratory distress syndrome (NRDS), high accumulation of the MCT/LCT emulsion in the first week were identified as risk factors for LO-NEC occurring between 8 ~ 14d. Logistic regression analysis showed that LO-NEC was a risk factor for late-onset sepsis, parenteral nutrition-associated cholestasis, metabolic bone disease of prematurity, and extrauterine growth retardation.ConclusionActively preventing premature birth, standardizing the treatment of grade III ~ IV NRDS, and optimizing enteral and parenteral nutrition strategies may help reduce the risk of LO-NEC, especially those occurring between 8 ~ 14d, which may further ameliorate the short-term clinical outcome of VPIs.Trial registrationChiCTR1900023418 (26/05/2019).

A comparative study of pain on injection with propofol long-chain triglycerides versus propofol medium/long-chain triglycerides with lignocaine

Background: Propofol long-chain triglyceride (LCT) is the most commonly used intravenous anesthetic drug, which has pain on injection as its major disadvantage. Many drugs have been used to alleviate this pain with variable efficacy, among them lidocaine pretreatment is most popular. Propofol medium-chain triglyceride (MCT)/LCT emulsion has the ability to decrease pain on injection. The availability of propofol with two different formulations necessitates a comparison of pain on injection with lidocaine pretreatment. Aim: The aim of this study was to study the incidence and intensity of pain on injection with propofol LCTs versus propofol MCT/LCTs with lignocaine. Materials and Methods: This prospective, double-blind, and randomized controlled study included 120 American Society of Anesthesiology Grade I and II participants undergoing General Anesthesia. In Group A, patients were induced with 1% propofol LCT (2 mg/kg) with 2% lidocaine 2 ml and in Group B 1% propofol MCT/LCT (2 mg/kg) with 2% lidocaine 2 ml. Assessment of pain on injection was performed after 30% of total induction dose was injected at a rate of 1 ml/s by Verbal Rating Scale. Results: Group A reported an incidence of pain in 28.4% and Group B with 13.3%. There was a statistically significant difference in the incidence and intensity of pain with propofol MCT/LCT along with lignocaine. Sixteen patients in Group A and eight patients in Group B had mild pain, whereas one patient in Group A and none of them in Group B had moderate pain. Conclusion: Premixing lignocaine with MCT/LCT propofol significantly reduces both the incidence and intensity of pain as compared to LCT propofol with lignocaine.

Supplement of Lipid Emulsion to Epinephrine Improves Resuscitation Outcomes of Asphyxia-Induced Cardiac Arrest in Aged Rats.

ObjectiveThe goal of the study was to investigate the efficacy of lipid supplement to epinephrine-based therapy in resuscitation of asphyxia-induced cardiac arrest in aged rats.MethodsThe study included two parts: in experiment A, rats underwent asphyxial cardiac arrest and cardiopulmonary resuscitation, randomized to receive epinephrine and normal saline (control group, n=22), epinephrine and intralipid 20% (long-chain triglycerides (LCT) group, n=22) or epinephrine and lipovenoes 20% (LCT/medium-chain triglcerides (MCT) group, n=22). Return of spontaneous circulation, recurrence of asystole after resuscitation, hemodynamic metrics, arterial blood gas values, neurological assessment score and indexes of pulmonary transudation were recorded. In experiment B, rats using the same model and resuscitation protocol were randomly divided into 21 groups: Control 0, Control 20, Control 40, Control 60, Control 80, Control 100, Control 120, LCT 0, LCT 20, LCT 40, LCT 60, LCT 80, LCT 100, LCT 120, LCT/MCT 0, LCT/MCT 20, LCT/MCT 40, LCT/MCT 60, LCT/MCT 80, LCT/MCT 100 and LCT 120 (n=10, the subscripts represent respective endpoint of observation in minutes). Myocardial bioenergetics were determined.ResultsIn experiment A, the LCT and LCT/MCT groups had a shorter time to return of spontaneous circulation (ROSC) (P=0.001and P<0.001, respectively) and higher survival rate (P=0.033 and P=0.014, respectively) compared with the Control group. The LCT/MCT group had higher MAP (P<0.001 and P=0.001, respectively), HR (P<0.001 and P=0.004, respectively) and RPP (P<0.001 and P<0.001, respectively) compared with the Control and LCT groups, respectively. In experiment B, the LCT/MCT group had a higher energy charge compared with the control group at 20 (P<0.001) and 40 (P<0.001) minutes. The LCT group had higher energy charge compared with the Control group at 40 (P<0.001) and 60 (P<0.001) minutes.ConclusionThe supplement of lipid emulsion to epinephrine improves resuscitation outcomes of asphyxia-induced cardiac arrest than epinephrine alone in our in vivo model of aged rat. LCT/MCT emulsion may be superior to LCT emulsion in epinephrine-based resuscitation.

Immunomodulation by an Omega-6 Fatty Acid Reduced Mixed Lipid Emulsion in Murine Acute Respiratory Distress Syndrome.

Background: Acute respiratory distress syndrome (ARDS) is associated with both high morbidity and mortality in intensive care units worldwide. Patients with ARDS often require parenteral nutrition with lipid emulsions as essential components. In the present study, we assessed the immunomodulatory and apoptotic effects of a modern, n-6-reduced lipid emulsion mixture in murine ARDS. Methods: Mice received an infusion of either normal saline solution, pure long-chain triglyceride (LCT) emulsion, or SMOF (soybean oil, medium-chain triglycerides, olive oil, and fish oil) before a lipopolysaccharide (LPS) challenge. Mice were sacrificed at different time points (0, 24, or 72 h) after ARDS induction, and an analysis of inflammatory cytokines, protein concentrations, and the cellular composition of the alveolar and interstitial compartments was performed with special focus on alveolar apoptosis and necrosis. Results: Mice infused with SMOF showed decreased leukocyte invasion, protein leakage, myeloperoxidase activity, and cytokine production in alveolar spaces after LPS challenge compared to animals that received LCT. There were fewer cells in the lung interstitium of the SMOF group compared to the LCT group. Both lipid emulsions exerted pro-apoptotic and pro-necrotic properties on alveolar immune cells, with significantly increased necrosis in mice infused with LCT compared to SMOF. Conclusion: SMOF has both anti-inflammatory and pro-resolving influences in murine ARDS. Partial replacement of n-6 fatty acids with n-3/n-9 fatty acids may therefore benefit critically ill patients at risk for ARDS who require parenteral nutrition.

INJECTION PAIN OF PROPOFOL IN CHILDREN WITH MEDIUM PLUS LONG CHAIN TRIGLYCERIDES AND LONG CHAIN PROPOFOL MIXED WITH LIGNOCAINE

Introduction: Propofol is widely accepted drug because of its rapid and smooth induction, short context-sensitive time, rapid terminal half-life time and low incidence of postoperative nausea and vomiting. It is used for sedation and anaesthesia for almost all types of surgeries. During a propofol injection, pain due to the long-chain triglyceride (LCT) emulsion is experienced by 70% of adults and up to 85% of children. Despite various strategies to reduce propofol injection pain, this still poses a clinical problem in adults and children, and the incidence reported to be 30–90%. A medium-chain triglyceride/long-chain triglyceride (MCT/LCT) emulsion has been advised to reduce injection pain as compared to propofol LCT in adults and teenagers&#x0D; Material and Methods: 100 children aged 5–13 years, in American Society Anaesthesiologists (ASA) class I or II, undergoing elective general anaesthesia without any contraindication to propofol anaesthesia were included in the study. Injection pain following injection propofol was assessed in all patients, but the anaesthetist was blinded for which formula was being used.&#x0D; Results: The demographic characteristics like age, sex, weight, amount of propofol given, ASA physical status and recovery period was calculated. No statistically significant difference was observed in both the groups. Incidence of pain and severe pain in LCT group was 24 (48%) and 7 (14%) respectively while incidence of pain and severe pain in MCT/LCT group was 15 (30%) and 1 (2%) respectively. Pain score was found less in group MCT / LCT.&#x0D; Conclusion: Medium plus long chain triglycerides and long chain propofol along with lignocaine significantly reduces the incidence as well as the severity of injection pain in the paediatric age group and can be used in children for sedation or induction of anaesthesia.

Immunomodulation by fish-oil containing lipid emulsions in murine acute respiratory distress syndrome

IntroductionAcute respiratory distress syndrome (ARDS) is a major cause of mortality in intensive care units. Patients with ARDS often require parenteral nutrition with lipid emulsions as essential components. Besides being an energy supply, these lipid emulsions might display differential modulatory effects on lung integrity and inflammation.MethodsIn a pre-emptive strategy, we investigated the impact of three different intravenously infused lipid emulsions on lung morphology, leukocyte invasion, protein leakage and cytokines in a murine model of ARDS. Mice received an infusion of normal saline solution, a pure long-chain triglycerides (LCT) emulsion, a medium-chain triglycerides (MCT) containing mixed emulsion (LCT/MCT), or a fish oil (FO) containing mixed emulsion (LCT/MCT/FO) before lipopolysaccharide (LPS) challenge.ResultsMice pre-infused with fish oil-containing lipid emulsion showed decreased leukocyte invasion, protein leakage, myeloperoxidase activity, and cytokine production in their alveolar space after LPS challenge compared to mice receiving LCT or LCT/MCT. In line with these findings, lung morphology assessed by histological staining after LPS-induced lung injury improved faster in the LCT/MCT/FO group. Concerning the above mentioned parameters, no significant difference was observed between mice infused with LCT or the combination of LCT and MCT.ConclusionFish oil-containing lipid emulsions might exert anti-inflammatory and pro-resolving effects in the murine model of acute lung injury. Partial replacement of n-6 fatty acids with n-3 fatty acids may thus be of benefit for critically ill patients at risk for ARDS which require parenteral nutrition.

Lipid Emulsion Recommendations

To the Editor: We read with interest the work of Ruan et al. 1in the February 2012 issue of ANESTHESIOLOGY; the article explored the effect of both triglyceride chain length and pH modulation on lipid sequestration of cardiotoxic local anesthetics in human serum in vitro . The authors are to be lauded for their efforts to expound the physicochemical interaction known widely as the “sink,” purported to be primarily responsible for the beneficial effects demonstrated in animal models and human subjects suffering local anesthetic systemic toxicity. Their results in many respects epitomize the difficulties associated with forwarding a therapy such as lipid rescue – itself a product of a chance laboratory observation, when definitive knowledge of mechanistic action for lipid remains to be fully elucidated.Ruan et al. demonstrated the superiority of mixed medium and long-chain triglyceride preparations in sequestration of lipophilioc local anesthetics, seemingly independent of pH, when compared with long-chain triglyceride in in vitro human serum. These results, nevertheless, conflict with the findings of Li et al. 2(from the December 2011 issue of ANESTHESIOLOGY), who demonstrated advantages with long-chain triglycerides in an intact animal model. The observed disparity in outcomes between such bench-top and whole animal experiments was discussed expertly in an accompanying editorial.3Although the advancement of any therapy is necessarily paved with conjecture and discourse, such as evidenced in microcosm with these two papers, conclusions drawn from such work must be tempered against the findings of prior investigators' and the associated relevant (and, in the case of lipid therapy, substantial) bodies of work. It is therefore concerning that in their concluding remarks Ruan et al. “call into question the current advanced cardiac life support guidelines specifying use of a long-chain triglyceride emulsion” in local anesthetic systemic toxicity on the basis of their findings alone, before the existence of a body of work supporting alternative lipid emulsion preparations as clearly superior. The work of Ruan et al. clearly represents one step of many in the evolution of lipid emulsion therapy. Their results, however, are insufficient to alter current recommendations4for lipid infusion in local anesthetic systemic toxicity.

Lipid Resuscitation of Bupivacaine Toxicity

The superiority of Intralipid, a long-chain triglyceride (LCT) emulsion versus Lipovenoes, a long- and medium-chain triglyceride (LCT/MCT) emulsion, in reversing local anesthetic-induced cardiac arrest is poorly defined and needs to be determined. The study included two parts: in experiment A, bupivacaine (20 mg/kg) was injected to produce asystole. Either Intralipid 20% (LCT group, n = 30) or Lipovenoes 20% (LCT/MCT group, n = 30) with epinephrine was infused immediately. Return of spontaneous circulation and recurrence of asystole after resuscitation were recorded. In experiment B, 80 rats using the same model and resuscitation protocol were divided into 10 groups: LCT₀, LCT₁₅, LCT₃₀, LCT₆₀, and LCT₁₂₀ and LCT/MCT₀, LCT/MCT₁₅, LCT/MCT₃₀, LCT/MCT₆₀, and LCT/MCT₁₂₀ (n = 8 each; the subscripts represent respective observation period). LCT₁₅-LCT₁₂₀ and LCT/MCT₁₅-LCT/MCT₁₂₀ groups received Intralipid 20% or Lipovenoes 20%, respectively. Plasma and myocardial bupivacaine and triglyceride concentrations, as well as myocardial bioenergetics, were determined. In experiment A, 24 rats in LCT group and 23 in LCT/MCT group achieved return of spontaneous circulation (P = 0.754); among them, 2 (8.3%) and 8 (34.8%) rats suffered a repeated asystole, respectively (P = 0.027). In experiment B, plasma and myocardial bupivacaine concentrations in LCT₁₅ and LCT₆₀ groups were lower than LCT/MCT₁₅ and LCT/MCT₆₀ groups, respectively. Furthermore, the plasma bupivacaine level in LCT/MCT₆₀ group was higher than LCT/MCT₃₀ group (P = 0.003). LCT emulsion may be superior to LCT/MCT emulsion in treating bupivacaine-related cardiotoxicity as it was associated with fewer recurrences of asystole after resuscitation and lower myocardial bupivacaine concentrations.

Immunomodulatory and physical effects of oil composition in vaccine adjuvant emulsions

Squalene-based oil-in-water emulsions have been used for years in some seasonal and pandemic influenza vaccines. However, concerns have been expressed regarding squalene source and potential biological activities. Little information is available regarding the immunomodulatory activity of squalene in comparison with other metabolizable oils in the context of oil-in-water emulsions formulated with vaccines. The present work describes the manufacture and physical characterization of emulsions composed of different classes of oils, including squalene, long chain triglycerides, a medium chain triglyceride, and a perfluorocarbon, all emulsified with egg phosphatidylcholine. Some differences were apparent among the non-squalene oils in terms of emulsion stability, including higher size polydispersity in the perfluorocarbon emulsion, more rapid visual instability at 60°C for the long-chain triglyceride and perfluorocarbon emulsions, and an increased creaming rate in the medium-chain triglyceride emulsion at 60°C as detected by laser scattering optical profiling. The biological activity of each of these emulsions was compared when formulated with either a recombinant malaria antigen or a split-virus inactivated influenza vaccine. Overall, vaccines containing the squalene emulsion elicited higher antibody titers and more abundant long-lived plasma cells than vaccines containing emulsions based on other oils. Since squalene-based emulsions show higher adjuvant potency compared to the other oils tested, non-squalene oils may be more suitable as carriers of amphiphilic or hydrophobic immunostimulatory molecules (such as TLR agonists) rather than as stand-alone adjuvants.

Combined hypertriglyceridemic and insulin-glucose clamps for the characterization of substrate oxidation and plasma elimination of a long-chain triglyceride emulsion in healthy men

This study examines the effect of glucose and insulin on the plasma elimination rate and oxidation of a fat emulsion by using indirect calorimetry in conjunction with lipid and insulin-glucose clamp techniques. Ten healthy subjects were studied on 2 occasions in a randomized, open, crossover study. On one occasion, a hypertriglyceridemic (HTG) clamp was administrated alone; and, on the other, HTG and insulin-glucose (IG) clamps were administrated simultaneously. During HTG clamps, serum triglyceride (TG) concentration was maintained at 4 mmol × L −1. During the IG clamp, insulin was administered at a rate of 20 mU × m −2 × min −1; and the glucose level was maintained at 7 mmol × L −1. Continuous indirect calorimetry was carried out throughout the study period. The infusion rate required to maintain stable serum TG concentrations did not differ between the 2 clamps. Mean free fatty acid concentration was lower during the HTG/IG than during the HTG clamp (0.40 ± 0.04 vs 0.82 ± 0.07 mmol × L −1; P < .001). However, the increases in β-OH-butyrate levels were significantly lower in the HTG/IG compared with the HTG clamp (0.09 ± 0.04 vs 0.55 ± 0.09 mmol × L −1; P < .001). Energy expenditure and the respiratory quotient were significantly higher at steady state in the HTG/IG than in the HTG clamp: 1.47 ± 0.06 vs 1.34 ± 0.04 kcal × min −1 ( P < .01) and 0.85 ± 0.01 vs 0.79 ± 0.01 ( P < .01), respectively. Insulin and glucose did not significantly change plasma TG disposal rate ( P = .0987) or total lipid oxidation ( P = .3204) in this metabolic situation with an abundant supply of both carbohydrates and lipids. β-OH-butyrate increased during both clamps, indicating an ongoing hepatic fatty oxidation despite the administration of glucose/insulin.

External validation of pharmacokinetic and pharmacodynamic models of microemulsion and long‐chain triglyceride emulsion propofol in beagle dogs

This study aimed at assessing the predictive performance of a target-controlled infusion (TCI) system, which incorporates canine PK-PD models for microemulsion and long-chain triglyceride emulsion (LCT) propofol and at investigating time independency of propofol effect on the observed electroencephalographic approximate entropy (ApEn) in TCI. Using a crossover design with a 7-day washout period, 28 healthy beagle dogs were randomized to receive TCI of both formulations in a stepwise or constant manner. Plasma propofol concentrations and ApEn were measured at preset intervals. Pooled biases, inaccuracies, divergences, and wobbles in pharmacokinetic and pharmacodynamic predictions were 2.1% (95% CI: -0.8 to 4.9), 18.1% (15.6-20.5), 1.9%/h, 7.3% (5.4-9.3), and -0.5% (-2.6 to 1.6), 8.7% (7.3-10.1), 2.5%/h, 6.0% (4.1-7.2) for microemulsion propofol, and -9.3% (-11.6 to -6.9), 20.1% (18.2-22.0), 5.1%/h, 7.6% (6.1-9.1) and 5.6% (4.1-7.1), 8.0% (6.9-9.3), 4.7%/h, 4.1% (3.1-5.1) for LCT propofol. Observed ApEn values over time were statistically not different across all time points in a TCI with constant manner. Canine PK-PD model of microemulsion propofol showed good predictive performances. Propofol effect (ApEn) was time independent as long as time is allowed for equilibration.

Reversal of Bupivacaine-Induced Cardiac Electrophysiologic Changes by Two Lipid Emulsions in Anesthetized and Mechanically Ventilated Piglets

Accidental IV administration of bupivacaine can compromise cardiovascular function by inducing lethal arrhythmias whose hemodynamic consequences may be alleviated by lipid emulsions. However, little is known about the electrophysiologic effects of lipid emulsions. In this study, we assessed whether 2 different lipid emulsions can reverse cardiac electrophysiologic impairment induced by the IV administration of bupivacaine in anesthetized and mechanically ventilated piglets. Bupivacaine (4 mg . kg(-1)) was injected over a 30-second period in 26 piglets. Thirty seconds after the end of bupivacaine injection, 1.5 mL . kg(-1) saline solution for the control group, and long-chain triglyceride emulsion (LCT group) or a mixture of long-chain and medium-chain triglyceride emulsion (LCT/MCT group) were infused over 1 minute. Cardiac conduction variables and hemodynamic variables were monitored for 30 minutes after injection. Bupivacaine induced similar electrophysiologic and hemodynamic changes. After 3 minutes, His ventricle intervals (median and interquartiles) were 100 (85-105), 45 (35-55), and 53 (48-73) milliseconds in the control, LCT, and LCT/MCT groups, respectively (P < 0.001 between control and both lipid emulsion groups). Lipid emulsions also reversed the effects on QRS duration, atrial-His, and PQ (the onset of the P wave to the Q wave of the QRS complex) intervals. LCT/MCT emulsion restored the decrease in maximal first derivative of left ventricular pressure (P < 0.01 after 3 minutes versus control group). LCT and LCT/MCT emulsions reversed the lengthening of His ventricle, QRS, atrial-His, and PQ intervals induced by the IV injection of 4 mg . kg(-1) bupivacaine.

Does the newer preparation of propofol, an emulsion of medium/long chain triglycerides cause less injection pain in children when premixed with lignocaine?

Injection pain during propofol administration can be particularly distressing in children. The newly available emulsion of propofol in medium and long chain triglycerides (LCT) is reported to cause less injection pain because of lower concentrations of free propofol. This study compared the incidence of injection pain during administration of propofol emulsion of LCT and propofol emulsion of medium and long chain triglycerides (MCT/LCT) both premixed with lignocaine in children. This prospective, randomized, double blind study was conducted after obtaining institutional ethics committee approval, parental consent and included 84 children aged 5-15 years. Preoperatively, an intravenous cannula was inserted in all children. four children were excluded. Those included, depending on the randomization, received 3 mg x kg(-1) of either propofol LCT or propofol MCT/LCT both premixed with lignocaine (0.1%). The incidence and intensity of injection pain was assessed. Pain on injection of propofol LCT with lignocaine was observed in 16/40 children (40%), five of these children complained of severe pain. In comparison, 14/40 (35%) children complained of pain following propofol MCT/LCT premixed with lignocaine (P = 0.644), the intensity being severe in two children (P = 0.698). Propofol MCT/LCT and propofol LCT premixed with lignocaine are both associated with pain on injection in children; the incidence and intensity of the injection pain are similar.

Pharmacokinetics and pharmacodynamics of a new reformulated microemulsion and the long-chain triglyceride emulsion of propofol in beagle dogs

Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose proportionality, pharmacokinetic and pharmacodynamic characteristics of both formulations. The study was a randomized, two-period and crossover design with 7-day wash-out period. Microemulsion and LCT propofol were administered by zero-order infusion (0.75, 1.00 and 1.25 mg kg(-1) min(-1)) for 20 min in 30 beagle dogs (male/female = 5/5 for each rate). Arterial samples were collected at preset intervals. The electroencephalographic approximate entropy (ApEn) was used as a measure of propofol effect. Dose proportionality, pharmacokinetic and pharmacodynamic bioequivalence were evaluated by non-compartmental analyses. Population analysis was performed using nonlinear mixed effects modelling. Both formulations showed dose proportionality at the applied dose range. The ratios of geometric means of AUC(last) and AUC(inf) between both formulations were acceptable for bioequivalence, whereas that of C(max) was not. The pharmacodynamic bioequivalence was indicated by the arithmetic means of AAC (areas above the ApEn time curves) and E(0) (baseline ApEn)-E(max) (maximally decreased ApEn) between both formulations. The pharmacokinetics of both formulations were best described by three compartment models. Body weight was a significant covariate for V(1) of both formulations and sex for k(21) of microemulsion propofol. The blood-brain equilibration rate constants (k(e0), min(-1)) were 0.476 and 0.696 for microemulsion and LCT propofol respectively. Microemulsion propofol was pharmacodynamically bioequivalent to LCT propofol although pharmacokinetic bioequivalence was incomplete, and demonstrated linear pharmacokinetics at the applied dose ranges.

Binding of Long-lasting Local Anesthetics to Lipid Emulsions

Rapid infusion of lipid emulsion has been proposed to treat local anesthetic toxicity. The authors wanted to test the buffering properties of two commercially available emulsions made of long- and of long- and medium-chain triglycerides. Using the shake-flask method, the authors measured the solubility and binding of racemic bupivacaine, levobupivacaine, and ropivacaine to diluted Intralipid (Fresenius Kabi, Paris, France) and Medialipide (B-Braun, Boulogne, France). The apparent distribution coefficient expressed as the ratio of mole fraction was 823 +/- 198 and 320 +/- 65 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, at 500 mg in the Medialipide/buffer emulsion; and 1,870 +/- 92 and 1,240 +/- 14 for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively, in the Intralipid/buffer emulsion. Decreasing the pH from 7.40 to 7.00 of the Medialipide/buffer emulsion led to a decrease in ratio of molar concentration from 121 +/- 3.8 to 46 +/- 2.8 for bupivacaine, and to a lesser extent from 51 +/- 4.0 to 31 +/- 1.6 for ropivacaine. The capacity of the 1% emulsions was 871 and 2,200 microM for the 1% Medialipide and Intralipid emulsions, respectively. The dissociation constant was 818 and 2,120 microM for racemic bupivacaine and levobupivacaine, and ropivacaine, respectively. Increasing the temperature from 20 to 37 degrees C led to a greater increase in affinity for ropivacaine (55%) than for bupivacaine (27%). When the pH of the buffer was decreased from 7.40 to 7.00, the affinity was decreased by a factor of 1.68, similar for both anesthetics. The solubility of long-acting local anesthetics in lipid emulsions and the high capacity of binding of these emulsions most probably explain their clinical efficacy in case of toxicity. The long-chain triglyceride emulsion Intralipid appears to be about 2.5 times more efficacious than the 50/50 medium-chain/long-chain Medialipide emulsion. Also, because of their higher hydrophobicity, racemic bupivacaine and levobupivacaine seem to clear more rapidly than ropivacaine.

Clinical evaluation of a new formulation of propofol in a medium‐chain and long‐chain triglycerides emulsion in dogs

Propofol formulated in a mixed medium-chain and long-chain triglycerides emulsion has been recently introduced for clinical use as an alternative to the conventional long-chain triglycerides formulation. This prospective multicentric study evaluated the clinical effectiveness and the complications associated with the use of this new formulation of propofol in dogs. Forty-six Spanish veterinary clinics participated in this study. A total of 541 anaesthesias (118 ASA I, 290 ASA II, 101 ASA III and 32 ASA IV) performed for various diagnostic and therapeutic purposes were evaluated. The anaesthetic protocol was not controlled, with the exception that propofol had to be used at least for induction of anaesthesia. The induction dose of propofol and the incidence of anaesthetic complications throughout the procedure were recorded. A chi-square test compared the incidence of complications according to the maintenance agent used (propofol vs. inhalatory anaesthesia), anaesthetic risk (ASA classification) and the reason for the anaesthesia. The patients premedicated with alpha2 agonists needed lower doses (mean +/- SD, 2.9 +/- 1.3 mg/kg i.v.) than the animals premedicated with phenothiazines (3.9 +/- 1.4 mg/kg i.v.) or benzodiazepines (4.0 +/- 1.4 mg/kg i.v.). The most frequent complications were difficult endotracheal intubation (1.3%), postinduction apnoea (11.3%), cyanosis (0.6%), bradypnoea (2.6%), tachypnoea (2.8%), bradycardia (2%), tachycardia (2.6%), hypotension (0.2%), shock (0.2%), vomiting (4.6%), epileptiform seizures (2.8%), premature awakening (7.4%) and delayed recovery (0.9%). There were no cases of pain on injection or aspiration pneumonia. Three dogs died (0.55%), one during induction and two during recovery from anaesthesia. This study demonstrates that the new formulation of propofol is an useful and effective drug to induce general anaesthesia in dogs.

A Short‐Term Long‐Chain Triglycerides Infusion Has No Influence on Immune Function of Adult Patients Undergoing Gastrointestinal Surgery

Parenteral nutrition (PN) support containing long-chain triglycerides (LCT) plays a critical supportive role in surgical patients' management. This study aims to investigate the effects of intravenous (IV) LCT emulsion on human immune function in adult patients receiving a gastrointestinal surgical procedure. Sixty adult patients were randomly assigned either to the LCT treatment group (n = 32) or to the control group (n = 28). After an abdominal operation, the subjects received PN treatment with or without LCT for 5 days. Neutrophil, peripheral blood mononuclear cell (PBMC), lymphocyte and CD4/CD8, serum immunoglobulin A (IgA), IgG, IgM, complement C3 and C4, interleukin (IL)-2, IL-4, IL-10, IL-12, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma were measured and statistically analyzed. The LCT and control groups did not differ significantly at entry in terms of general features. Except for a significant increase of neutrophil number at 24 hours after the surgery in both groups (p < .01), all parameters representing the patients' immune function had no significant difference between the LCT and the control groups with respect to neutrophil and PBMC count, lymphocyte, CD4/CD8, serum IgA, IgG, IgM, complement C3, C4, IL-2, IL-4, IL-10, IL-12, TNF-alpha, and IFN-gamma (p > .05, respectively) 24 hours before the operation, and 24 hours and 120 hours after the operation. The regimens of LCT administration may have diverse effects on human immune function in different patient populations. However, LCT emulsion at an appropriate dose and infusion speed does not alter human immune function of adult patients undergoing moderate gastrointestinal surgery.

Triglycerides in fish oil affect the blood clearance of lipid emulsions containing long- and medium-chain triglycerides in mice.

Lipid emulsions containing long-chain triglycerides (LCT) and medium chain triglycerides (MCT) are widely used in parenteral nutrition. Recently, fish oil (FO) triglyceride (TG)-derived emulsions are considered therapeutic because of their many beneficial biological modulatory actions. We investigated in mice whether adding 10% FO to an intravenous lipid emulsion with MCT and LCT (MCT:LCT:FO -50:40:10% by wt) would affect particle blood clearance and tissue targeting in comparison to LCT (100% by wt) and MCT:LCT (50:50% by wt) emulsions. The 3 emulsions were labeled with [3H] cholesteryl oleoyl ether and administered by bolus injection (400 microg TG/mouse) to C57BL/6J mice. Contributions of LDL receptor (LDL-R) and LDL-R-related protein to emulsion catabolism were assessed using LDL-R-deficient mice and preinjection of lactoferrin, and the effects of lipoprotein lipase (LPL) were determined by preinjection of heparin and Triton WR 1339. Although fractional catabolic rates did not differ among the 3 emulsions, blood removal at each time point after injection was greater for MCT:LCT:FO particles due to their higher initial margination volume. Compared with MCT:LCT and LCT emulsions, patterns of tissue uptake of the MCT:LCT:FO emulsions were different, e.g. MCT:LCT:FO emulsion particle uptake was lower in heart, adipose tissue, and muscle, and higher in lung, and the removal of MCT:LCT:FO emulsion particles was less dependent on LPL, LDL-R, and lactoferrin-sensitive pathways. These data suggest that the addition of a low percentage of FO to MCT:LCT emulsions substantially changes their particle clearance and tissue uptake mechanisms.

The hypertriglyceridemic clamp technique. Studies using long-chain and structured triglyceride emulsions in healthy subjects

In a randomized crossover study, plasma kinetics of 2 different types of fat emulsions were studied in 8 healthy volunteers by using a hypertriglyceridemic clamp technique. The method involves the stabilization of serum triglyceride (TG) concentration during 180 minutes at a predetermined level (4 mmol/L) by adjustment of TG infusion rate by repeated online measurements of serum TG concentration. The fat emulsions under study were a long-chain fatty acid triglyceride (LCT) emulsion (Intralipid 20%, Fresenius Kabi, Sweden) and a structured triglyceride (STG) emulsion (Structolipid 20%, Fresenius Kabi) where medium- and long-chain fatty acids have been interesterified within a TG molecule. The hypertriglyceridemic clamp was found to have acceptable reproducibility when tested in 3 healthy individuals on 2 different occasions, as similar steady-state TG levels were obtained by infusing similar amounts of fat. The average (±SEM) TG concentration during the 180-minute clamp was similar for STGs and LCTs (4.0 ± 0.1 vs 3.9 ± 0.1 mmol/L; not significant), but the amount of fat that had to be infused was significantly higher during STG than during LCT clamping (0.31 ± 0.04 vs 0.21 ± 0.02 g TG per minute; P < .05). Higher serum levels of free fatty acids (1.80 ± 0.13 vs 0.96 ± 0.09 mmol/L; P < .05), free glycerol (1.30 ± 0.07 vs 0.76 ± 0.08 mmol/L; P < .001), and β-OH butyrate (1.61 ± 0.44 vs 1.17 ± 0.23 mmol/L; not significant) were obtained at the end of the clamp during infusion of STGs compared with LCTs. During infusion of STGs the medium-chain fatty acids octanoic (C:8) and decanoic acid (C:10) constituted approximately half of circulating fatty acids that correspond to the compositional ratio of the emulsion. Plasma lipoprotein lipase (LPL) concentration was higher during STG than during LCT clamping (6.06 ± 0.62 vs 3.15 ± 0.40 mU/mL; P < .05), and there was a positive correlation between the mean LPL concentration and the amount of infused TG during the steady-state period ( r = 0.58; P < .05). In conclusion, the hypertriglyceridemic clamp method was found to give reproducible results and could be considered for comparison of metabolic clearance properties of different types of fat emulsions. The capacity of healthy subjects to eliminate STGs from blood was greater than for LCTs. An increased LPL activity induced by the higher TG infusion rate may have contributed to the increased metabolic clearance of STGs.

Protection of aortic endothelial function in both normal and diabetic rats by intravenous bolus injection of a medium-chain triglyceride: fish oil emulsion

The bolus intravenous injection of a novel medium-chain triglyceride:fish oil emulsion (MCT:FO) was recently proposed as a tool to provoke a rapid and sustained increase of cell phospholipid content in long-chain polyunsaturated omega3 fatty acids, for instance in selected subjects prior to anesthesia and surgery. In this study, therefore, the possible protective effect of MCT:FO upon aortic endothelial function was investigated in both normal and diabetic rats. The animals were injected intravenously 20 h before sacrifice with 1.0 ml of either saline, MCT:FO or a control medium-chain triglyceride:long-chain triglyceride emulsion. The vasomotor response of isolated aortic rings was then explored by assessing the relaxation provoked by increasing concentrations of acetylcholine in rings contracted with phenylephrine. Such measurements were performed before and after exposure of the aortic rings to suitable concentrations of oxidized LDL. In both normal and diabetic rats, the prior injection of the MCT:FO emulsion protected the aortic rings against the deleterious effect of oxidized LDL. In the diabetic rats, a beneficial effect of the MCT:FO emulsion was even observed prior to exposure of the aortic rings to oxidized LDL. These findings support the view that this novel procedure is indeed appropriate to protect endothelial function against oxidative stress.