Lipid Sink Research Articles

An in vitro evaluation of intravenous lipid emulsion on three common canine toxicants.

To determine whether intravenous lipid emulsion (ILE) therapy significantly reduces the concentration of baclofen, ibuprofen, and/or bromethalin in canine whole blood over time. Seven 500 mL bags of canine DEA 1.1 negative blood were divided into aliquots of 125 mL and randomly assigned to one of three treatment groups (baclofen, ibuprofen, bromethalin) or four control groups (a positive control for each treatment group and a negative control group). Injectable ibuprofen (200 mg/kg), baclofen (8 mg/kg), or bromethalin (3 mg/kg) was apportioned into 125 mL aliquots of canine whole blood and incubated for 30 min at 38.5°C. ILE (12.4 mL, Intralipid® ) was added to each sample and the solution vortexed [215 rpm for 15 min at 37°C (98.6°F)]. Samples were obtained at designated time points (0, 15, 30, 60, 180, 360 min), centrifuged, and separated into serum and RBC fractions. Serum samples were ultracentrifuged (22,000 g for 10 min at 37°C) to separate lipid rich and poor fractions. Samples were stored at -80°C prior to analysis. A significant decrease in total drug concentration was established for bromethalin and its metabolite desmethylbromethalin compared to positive controls. ILE significantly reduced desmethylbromethalin at the 30-and 360-min time points. The remainder of the desmethylbromethalin time points did not reach significance. Bromethalin concentration was significantly reduced at all time points compared to positive controls. Neither baclofen nor ibuprofen had significant changes in concentration. ILE therapy was effective at reducing the total drug concentration of bromethalin and its metabolite desmethylbromethalin supporting the lipid sink theory. As a single compartment in vitro study, this study does not evaluate other proposed mechanisms of action of ILE therapy. ILE therapy may have other means of significantly decreasing lipophilic drug concentration in cases of toxicosis.

Evaluation of Lipid Emulsion-Mediated Sequestration and Redistribution of the Highly Lipophilic Carbamazepine in the Plasma of Rats

Aim: The idea that intravenous lipid emulsion (ILE) may serve as a "reservoir" for lipophilic drugs has emerged in research as an intravascular "lipid sink" effect. Carbamazepine (CBZ) is a widely used anticonvulsant. This compound has a neutral and highly lipophilic structure and can easily cross body membranes. In this study, our hypothesis focused on the potential efficacy of ILE in modulating blood carbamazepine concentrations. Material and Methods: 22 adult Sprague-Dawley rats were divided into four groups. All groups received CBZ at a dose of 20 mg/kg orogastrically. The first group was the control group. In the second group (activated charcoal group), activated charcoal (AC) was administered orogastrically at a dose of 1 g/kg five minutes after orogastric administration of carbamazepine. The third group (lipid group) received ILE at a dose of 3 ml/kg/min at the fifth minute. The fourth group was the saline group, in which 16 ml/kg of 0.9% NaCl was infused at the fifth minute. Blood samples of 0.5 ml were collected at 0, 4, 8, and 24 hours. Plasma was separated by centrifugation (4000 rpm, 10 minutes) and stored at -80oC for determination of CBZ concentrations. An Agilent 6410B HP-1200 LC series (USA) liquid chromatography system was used for analysis. Quantitative analysis was performed in the multiple reaction mode with electrospray positive ionization (ES+). Results: At the 8th hour of orogastric CBZ administration, CBZ concentration was significantly lower in the activated charcoal group than in the lipid and saline groups (p: 0.021; p: 0.023; p<0.05, respectively). There was no significant difference in CBZ concentrations between the other groups at 8 hours (p>0.05). In the lipid group, the increase in CBZ plasma concentrations was statistically significant at 4 and 8 hours compared to 0 hours (p: 0.005; p: 0.005, respectively). Conclusion: In the lipid group, plasma CBZ concentrations increased at 4 and 8 hours in plasma samples from which lipids were separated by differential centrifugation. In the lipid group, no effects favoring drug-lipid sequestration on the plasma distribution of CBZ were observed.

The expression of genes encoding novel Sesame oleosin variants facilitates enhanced triacylglycerol accumulation in Arabidopsis leaves and seeds.

Triacylglycerols (TAG), accumulate within lipid droplets (LD), predominantly surrounded by OLEOSINs (OLE), that protect TAG from hydrolysis. We tested the hypothesis that identifying and removing degradation signals from OLE would promote its abundance, preventing TAG degradation and enhancing TAG accumulation. We tested whether mutating potential ubiquitin-conjugation sites in a previously reported improved Sesamum indicum OLE (SiO) variant, o3-3 Cys-OLE (SiCO herein), would stabilize it and increase its lipogenic potential. SiCOv1 was created by replacing all five lysines in SiCO with arginines. Separately, six cysteine residues within SiCO were deleted to create SiCOv2. SiCOv1 and SiCOv2 mutations were combined to create SiCOv3. Transient expression of SiCOv3 in Nicotiana benthamiana increased TAG by two-fold relative to SiCO. Constitutive expression of SiCOv3 or SiCOv5, containing the five predominant TAG-increasing mutations from SiCOv3, in Arabidopsis along with mouse DGAT2 (mD) increased TAG accumulation by 54% in leaves and 13% in seeds compared with control lines coexpressing SiCO and mD. Lipid synthesis rates increased, consistent with an increase in lipid sink strength that sequesters newly synthesized TAG, thereby relieving the constitutive BADC-dependent inhibition of ACCase reported for WT Arabidopsis. These OLE variants represent novel factors for potentially increasing TAG accumulation in a variety of oil crops.

The effect of intravenous lipid emulsion (ILE) on the pharmacokinetic/toxicokinetic dispositions of ivermectin and carprofen in rabbits.

Intravenous lipid emulsion (ILE) has been widely used as an effective antidote in both veterinary and human medicine for the treatment of acute intoxications caused by drugs and pesticides with high lipid solubility. This study was conducted to investigate the effect of ILE co-administration on the kinetic dispositions of ivermectin (IVM) and carprofen (CRP) following intravenous bolus administration at subtoxic doses in rabbits.Twenty-four male New Zealand rabbits weighing 2.78 ± 0.2kg were used in this study. Rabbits were divided into four groups (Group 1: IVM and Group 2: IVM + ILE or Group 3: CRP and Group 4: CRP + ILE), each group consisting of 6 animals. In the IVM study, Group 1 received IVM (0.6mg/kg) alone while Group 2 received IVM (0.6mg/kg) and ILE (2.5ml/kg). In the CRP study, Group 3 received CRP (12mg/kg) alone while Group 4 received CRP (12mg/kg) and ILE (2.5ml/kg). In both drug groups, ILE was administered 3 times as an i.v. bolus at the 10th min and repeated 4th and 8th h after the drug administration. Blood samples were collected from the auricular vein at various times after drug administration. The drug concentrations in plasma samples were determined by high-pressure liquid chromatography. Kinetic parameters were calculated using a non-compartmental model for both CRP and IVM.The C0 and area under the concentration-time curve from zero up to ∞ (AUC0-∞) values were significantly greater with ILE co-administration (2136ng/ml and 360.84ng.d/ml) compared to the IVM alone (1340.63ng/ml and 206ng.d/ml), respectively. Moreover, the volume of distribution (Vdss) and clearance (Cl) of IVM were reduced by approximately 42% and 46% with ILE co-administration compared to IVM alone resulting in a reduction of the distribution and slower elimination, respectively. Similar differences in C0, and Vdss values were also observed in CRP with ILE co-administration compared to CRP alone. ILE co-administration changed significantly the kinetic profile of both IVM and CRP in rabbits, supporting the lipid sink theory in which highly lipid-soluble compounds are absorbed into the lipid phase of plasma from peripheral organs such as the heart and brain affected by the acute toxicity of the compounds.

Lipid emulsion therapy during management of the critically-ill poisoned patient: a prospective cohort study

Background Despite conflicting data, intravenous lipid emulsion has emerged as a potential antidote. The “lipid sink” theory suggests that following intravenous administration of lipid, lipophilic drugs are sequestered in the vascular compartment, thereby reducing their tissue concentrations. This study sought to determine if survival is associated with the intoxicant’s degree of lipophilicity. Methods We reviewed all cases in the Toxicology Investigators Consortium’s lipid sub-registry between May 2012 through December 2018. Information collected included demographics, exposure circumstances, clinical course, management, disposition, and outcome. The primary outcome was survival after lipid emulsion therapy. Survival was stratified by the log of the intoxicant’s octanol-water partition coefficient. We also assessed the association between intoxicant lipophilicity and an increase in systolic blood pressure after lipid emulsion administration. Results We identified 134 patients, including 81 (60.4%) females. The median age was 40 years (interquartile range 21-75). One hundred and eight (80.6%) patients survived, including 45 (33.6%) with cardiac arrest during their intoxication. Eighty-two (61.2%) were hypotensive, and 98 (73.1%) received mechanical ventilation. There was no relationship between survival and the log of the partition coefficient of the intoxicant on linear analysis (P = 0.89) or polynomial model (P = 0.10). Systolic blood pressure increased in both groups. The median (interquartile range) systolic blood pressure before lipid administration was 68 (60-78) mmHg for those intoxicants with a log partition coefficient < 3.6 compared with 89 (76-104) mmHg after lipid administration. Among those drugs with a log partition coefficient > 3.6, the median (interquartile range) was 69 (60-84) mmHg before lipid and 89 (80-96) mmHg after lipid administration. Conclusion Most patients in this cohort survived. Lipophilicity was not correlated with survival or the observed changes in blood pressure. The study did not address the efficacy of lipid emulsion.

Lipid Emulsion to Treat Acute Poisonings: Mechanisms of Action, Indications, and Controversies.

Biodetoxification using intravenous lipid emulsion (ILE) in acute poisoning is of growing interest. As well as for local anesthetics, ILE is currently used to reverse toxicity caused by a broad-spectrum of lipophilic drugs. Both pharmacokinetic and pharmacodynamic mechanisms have been postulated to explain its possible benefits, mainly combining a scavenging effect called "lipid sink" and cardiotonic activity. Additional mechanisms based on ILE-attributed vasoactive and cytoprotective properties are still under investigation. Here, we present a narrative review on lipid resuscitation, focusing on the recent literature with advances in understanding ILE-attributed mechanisms of action and evaluating the evidence supporting ILE administration that enabled the international recommendations. Many practical aspects are still controversial, including the optimal dose, the optimal administration timing, and the optimal duration of infusion for clinical efficacy, as well as the threshold dose for adverse effects. Present evidence supports the use of ILE as first-line therapy to reverse local anesthetic-related systemic toxicity and as adjunct therapy in lipophilic non-local anesthetic drug overdoses refractory to well-established antidotes and supportive care. However, the level of evidence is low to very low, as for most other commonly used antidotes. Our review presents the internationally accepted recommendations according to the clinical poisoning scenario and provides the precautions of use to optimize the expected efficacy of ILE and limit the inconveniences of its futile administration. Based on their absorptive properties, the next generation of scavenging agents is additionally presented. Although emerging research shows great potential, several challenges need to be overcome before parenteral detoxifying agents could be considered as an established treatment for severe poisonings.

Comment on lipid emulsion for xenobiotic overdose

We read with interest the assessment of Drs Fettiplace and Weinberg concerning antidotal use of intravenous lipid emulsion.1 While the authors suggest that lipophilicity of the toxicant is not likely to be a useful predictor of clinical benefit of intravenous lipid emulsion in a poisoned patient, French et al. convincingly disagree.2 Further, if the mechanism of action of intravenous lipid emulsion includes the lipid sink or lipid shuttle, it is likely that lipophilicity (measured by the octanol/water partition coefficient or log P) would be one explanatory variable for apparent effect (or lack thereof) after lipid emulsion. An example is organophosphate poisoning, which continues to be a major cause of poisoning morbidity and mortality, with estimates of 3 000 000 organophosphate poisonings and 300 000 organophosphate poisoning deaths worldwide.3, 4 A recent case report described successful lipid emulsion treatment of poisoning by chlorpyrifos (log P = 4.96).5 A pilot study of intravenous lipid emulsion in organophosphate poisoning in India indicated that lipid emulsion may be a safe therapeutic intervention in organophosphate poisoning, but the study lacked the power needed to evaluate for efficacy.6 The same research group recently published an open-label, randomized control trial of lipid emulsion for organophosphate poisoning. They again found lipid emulsion to be safe, but they did not detect benefit.7 Regarding the 2019 pilot study,6 Mullins et al. pointed out that the identified organophosphates varied widely in lipophilicity and recommended stratifying patients by the ingested organophosphate.8 In both the pilot study and the randomized controlled trial,6, 7 at least half of the patients had ingested unknown organophosphates (Table 1), so inferences about outcomes are difficult. In both studies, the most frequently identified organophosphate was chlorpyrifos (log P = 4.96), and the second most frequently identified organophosphate was dichlorvos (log P = 1.43). If log P does predict efficacy as previously suggested,2 chlorpyrifos should achieve concentrations in the lipid phase over 2000 times greater than dichlorvos would reach. It is likely that the unknown category includes chlorpyrifos and dichlorvos. If an outcome difference exists, the dichlorvos cases in the unknown category would probably obscure the possibly better outcomes among the chlorpyrifos cases. A new randomized, controlled trial of intravenous lipid emulsion for organophosphate poisoning is launching in Egypt.9 We recommend that these researchers report the log P values for all identified organophosphates and include subgroup analysis by organophosphate. Knowing both the toxicant and the treatment assignment for each organophosphate-poisoned patient is necessary to understand the results more clearly.

Administration of lipid emulsion reduced the hypnotic potency of propofol more than that of thiamylal in mice.

Administration in a lipid emulsion can modify the pharmacodynamics of drugs via a process known as lipid resuscitation. However, the detailed mechanism remains unclear. We studied the volume and another pharmacodynamic effect, the lipid sink, using propofol and thiamylal. Male adult mice (ddY) were intravenously administered 10 ml/kg propofol or thiamylal diluted with physiological saline, 10% soybean oil, or 20% soybean oil. The 50% effective dose (ED50) for achieving hypnosis was calculated using probit analysis. To investigate the volume effect, 0, 10, or 20 ml/kg of saline or soybean oil was administered, either simultaneously or beforehand. Next, a two- or three-fold dose of the anesthetics was administered and the durations of anesthesia were measured. Finally, at 30 s after the first injection, supplemental soybean oil was administered. The mean (± SE) ED50 values of propofol and thiamylal were 5.79 mg/kg (0.61) and 8.83 mg/kg (0.84), respectively. Lipid dilution increased the ED50 values of both anesthetics. After injection of a dose two-fold the ED50 value, the respective mean (± SD) durations of anesthesia were 125 ± 35 s and 102 ± 38 s. Supplemental administration of soybean oil significantly shortened the duration of anesthesia of propofol, but not that of thiamylal. The results indicate that administration of a lipid emulsion vitiated the anesthetic effect of propofol by reducing the non-emulsified free fraction in the aqueous phase, which may elucidate the lipid resuscitation likely caused by the lipid sink mechanism.

Abstract 13357: From Junctional Rhythm to Slow Vt: Flecainide Poisoning

Introduction: Flecainide is a class IC anti-arrhythmic used to treat atrial fibrillation. Toxicity can cause bradycardia, QRS prolongation, and ventricular tachyarrhythmia (VT) due to blockade of sodium channels. Although most metabolism occurs through the liver, up to 30% excretion is renal but not dialyzable. The case here represents two arrhythmogenic challenges associated with flecainide treated with alkalization and lipid emulsion. Case: A 75-year-old woman with atrial fibrillation initially presented with syncope and hematemesis. Initial ECG showed junctional bradycardia with narrow escape in HR 30s. Labs notable for creatinine 2.55 (nl &lt;1.2 mg/dl) and potassium 4.8 (3.5-5.0 mmol/L). pH was 7.28 with bicarbonate 18 (22-31 mmol/L). She was treated with glucagon and atropine for suspected B-blocker toxicity but quickly went into shock. Rhythm then changed to a wide complex tachycardia (Fig) with wide QRS 280ms, VT rates in 100s. Due to development of this slow VT, flecainide toxicity was highly suspected, and a bicarbonate drip was started to maintain pH&gt;7.50 in addition to intralipid infusion. In the span of 12 hours, she was able to wean off her vasopressor support. On hospital day 3, she started metoprolol and remained in sinus bradycardia at the time of discharge. Discussion: This case represented acute renal failure secondary to flecainide toxicity and gastrointestinal bleed. Toxicity led to QRS widening and slow VT, which diminished contractility. Serum alkalization and sodium load works to displace flecainide from its channel receptor; intralipid sequesters lipophilic toxin in a “lipid sink” mechanism. In extreme cases, ECMO and overdrive pacing are used. Conclusions: Early recognition of flecainide-related arrhythmias is key. The subsequent approach to flecainide toxicity includes reducing absorption (charcoal, lipid emulsion), antagonizing drug effect (alkalization), and proving hemodynamic support (phenylephrine, vasopressin).

Low-dose lipid emulsion for pediatric vasoplegic shock due to quetiapine and fluvoxamine overdose: a case report

Background: Intravenous lipid emulsion (ILE) therapy was originally used for treatment of for local anesthetic systemic toxicity. Over the last decade, it has been successfully used to treat severe toxicity of numerous lipophilic substances. The mechanism by which ILE therapy treats lipophilic drug toxicity was originally purported to be due to the lipid sink mechanism; however, further research suggests that several other factors likely play more substantial roles, including free fatty acid provision to cardiomyocytes, positive inotropic effect, ion channel modulation, and nitric oxide synthase inhibition. No standardized dosing recommendation exists for ILE treatment of pediatric lipophilic drug toxicity. Several case reports have documented successful resuscitation of such overdoses using much lower dosages of ILE than are used for local anesthetic toxicity.

106 Lipid Emulsion Therapy During Resuscitation of the Critically-Ill Poisoned Patient: A Prospective Cohort Study

Intravenous lipid emulsion (ILE) has emerged as a potential antidote for treatment of intoxication by lipophilic drugs. Despite conflicting pre-clinical (animal) data, its use continues to expand. The “lipid sink” theory, which is the prevailing theory on ILE mechanism of action, suggests that ILE generates a flux of drugs from the periphery into the vascular compartment, thereby reducing the target organ exposure and toxicity of lipophilic drugs. The primary aim of this pragmatic, real-life prospective cohort study was to compare efficacy (measured by patient survival to hospital discharge) of ILE during resuscitation of critically-ill poisoned patients intoxicated by xenobiotics with wide spectrum of lipophilicities (determined by the octanol water partition coefficient (Log P).

Is thermogenesis really needed for brown adipose tissue-mediated metabolic benefit?

Brown adipose tissue (BAT) dissipates energy in the form of heat and functions as a metabolic sink for lipids, glucose, and branched-chain amino acids. Enhanced BAT thermogenesis is thought to tightly couple with beneficial energy metabolism. However, in this issue of the JCI, Huang et al. report a mouse model in which BAT thermogenesis was impaired, yet systemic glucose and lipid homeostasis were improved, on a high-fat diet compared with what occurred in control mice. The authors showed that BAT-specific deletion of mitochondrial thioredoxin-2 (TRX2) impaired adaptive thermogenesis through elevated mitochondrial reactive oxygen species (ROS) and cytosolic efflux of mitochondrial DNA. On the other hand, TRX2 loss enhanced lipid uptake in the BAT and protected mice from obesity, hypertriglyceridemia, and insulin resistance. This study provides a unique model in which BAT does not require thermogenesis per se to function as a lipid sink that leads to metabolic benefits in vivo.

Lipid emulsion mitigates intravenous amiodarone toxicity in a rat model

Introduction Our study investigated whether lipid emulsion therapy could act as an antidote for intravenous amiodarone toxicity in a rat model. Methods 20 rats were randomised to receive lipid emulsion (ILE) or saline. Rats were infused with amiodarone at 1 mg/kg/min for 20 min. ILE rats then received 6 mL/kg of IV 20% ILE, with controls receiving saline. Amiodarone infusion then recommenced at 0.25 mg/kg/minute for 15 min. Heart rate and mean arterial pressure (MAP) were recorded at the commencement and end of the first amiodarone infusion, and every 5 min during the second amiodarone infusion until experiment termination. Blood was sampled for amiodarone concentration at the conclusion of each infusion. Results At experiment termination MAP was greater for the ILE group (85 vs 60 mmHg, p = 0.01), with no difference in heart rate between groups (224 vs 232 bpm, p = 0.19). Amiodarone concentration decreased after saline treatment and was stable after ILE (change −6.4 micromol/L saline, 0.11 micromol/L lipid p < 0.001) Conclusions ILE therapy mitigated intravenous amiodarone-induced hypotension in this rat model. While amiodarone was retained in lipid treated blood the quantum of this increase did not support the “lipid sink” hypothesis. Further research is required to evaluate the clinical relevance of these findings.

Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study

ABSTRACT Non-fasting lipidemia (nFL), mainly contributed by postprandial lipidemia (PL), has recently been recognized as an important cardiovascular disease (CVD) risk as fasting lipidemia (FL). PL serves as a common feature of dyslipidemia in Type 2 Diabetes (T2D), albeit effective therapies targeting on PL were limited. In this study, we aimed to evaluate whether the therapy combining probiotics (Prob) and berberine (BBR), a proven antidiabetic and hypolipidemic regimen via altering gut microbiome, could effectively reduce PL in T2D and to explore the underlying mechanism. Blood PL (120 min after taking 100 g standard carbohydrate meal) was examined in 365 participants with T2D from the Probiotics and BBR on the Efficacy and Change of Gut Microbiota in Patients with Newly Diagnosed Type 2 Diabetes (PREMOTE study), a random, placebo-controlled, and multicenter clinical trial. Prob+BBR was superior to BBR or Prob alone in improving postprandial total cholesterol (pTC) and low-density lipoprotein cholesterol (pLDLc) levels with decrement of multiple species of postprandial lipidomic metabolites after 3 months follow-up. This effect was linked to the changes of fecal Bifidobacterium breve level responding to BBR alone or Prob+BBR treatment. Four fadD genes encoding long-chain acyl-CoA synthetase were identified in the genome of this B. breve strain, and transcriptionally activated by BBR. In vitro BBR treatment further decreased the concentration of FFA in the culture medium of B. breve compared to vehicle. Thus, the activation of fadD by BBR could enhance FFA import and mobilization in B. breve and diliminish the intraluminal lipids for absorption to mediate the effect of Prob+BBR on PL. Our study confirmed that BBR and Prob (B. breve) could exert a synergistic hypolipidemic effect on PL, acting as a gut lipid sink to achieve better lipidemia and CVD risk control in T2D.

LIPID EMULSION THERAPY FOR LIFE-THREATENING FLECAINIDE TOXICITY

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: We present a case of flecainide (FLC) toxicity secondary to renal failure treated with intravenous lipid emulsion (ILE) therapy. CASE PRESENTATION: The patient is a 63 year old female with a history of stage IVB uterine carcinosarcoma, chronic kidney disease and supraventricular tachycardia (SVT) on FLC. She was admitted with intra-abdominal hemorrhagic metastases. A rapid response was called due to hypotension, and she was noted to be oliguric for the previous 24 hours with a serum creatinine 2.5 mg/dL (baseline 1.3 mg/dL) and hyponatremic (126 mmol/L). EKG showed a new wide complex rhythm, at 78bpm, QRS widening to 280ms, and prolonged QTc of 631. She subsequently suffered a wide complex tachyarrhythmic cardiac arrest (CA), refractory to two shocks, with return of spontaneous circulation after treatment with sodium bicarbonate (NaHCO3). FLC was discontinued and the patient was started on a hypertonic NaHCO3 drip, but frequent NaHCO3 pushes were required to correct widening of the QRS complex. The hypotension progressed requiring high dose infusions of epinephrine (15 mcg/min) and norepinephrine (90 mcg/min). ILE infusion was started, 20% lipid 1.5 mL/kg administered over 5 minutes, followed by an infusion of 0.25 mL/kg/minute over two hours. A serum FLC level was drawn during ILE infusion and came back elevated at 1.35 mcg/mL (therapeutic level 0.20-1.0 mcg/mL). In the 48 hours following ILE, there was resolution of the wide complex arrhythmias, and vasopressor requirements were reduced by more than 50% DISCUSSION: FLC is a class 1C antiarrhythmic that inhibits Na+ channels and is used for prevention of SVT. It has a narrow therapeutic range and about 30% is renally excreted making acute kidney injury a risk for toxicity. Other risk factors for toxicity are hyponatremia and hypokalemia. Characteristic signs of toxicity include hypotension, lethargy and EKG changes such as QRS widening and PR prolongation. These changes can progress to wide complex brady or tachyarrhythmic CA as seen in our patient. Standard of care is administration of hypertonic NaHCO3 which acts both as a Na+ load to compete with FLC for binding at Na+ channels and as an alkalinizing agent which decreases the ionized receptor-binding form of FLC. However, when NaHCO3 treatment fails, there are few other well studied options. One is VA-ECMO for which our patient was not a candidate. The other is lipid emulsion therapy, which is hypothesized to work by creating a lipid sink to sequester the drug and also has some positive ionotropy. CONCLUSIONS: In our patient, administration of ILE resulted in significant clinical improvement. Unfortunately, the clinical improvement did not sustain after several days and due to overall poor prognosis, the patient was eventually transitioned to comfort measures. REFERENCE #1: Subedi R, Dean R, Chaudhary A. Flecainide toxicity in renal failure. Proc (Bayl Univ Med Cent). 2018 May 9;3(3):328-330. REFERENCE #2: Ghataoura R, Patil S. Flecainide toxicity: a presentation to the emergency department with literature review. BMJ Case Rep. 2020 Feb 28;13(2):e232691. doi: 10.1136/bcr-2019-232691. PMID: 32114494; PMCID: PMC7050315. REFERENCE #3: Valentino MA, Panakos A, Ragupathi L, Williams J, Pavri BB. Flecainide Toxicity: A Case Report and Systematic Review of its Electrocardiographic Patterns and Management. Cardiovasc Toxicol. 2017 Jul;17(3):260-266. doi: 10.1007/s12012-016-9380-0. PMID: 27435408. DISCLOSURES: No relevant relationships by Rebecca Fieles, source=Web Response No relevant relationships by David Gerber, source=Web Response No relevant relationships by Brian Park, source=Web Response No relevant relationships by Harry Rockower, source=Web Response No relevant relationships by Diana Solomon, source=Web Response No relevant relationships by Yanika Wolfe, source=Web Response

Phosphatidylinositol Stabilizes Fluid-Phase Liposomes Loaded with a Melphalan Lipophilic Prodrug.

Previously, a liposomal formulation of a chemotherapeutic agent melphalan (Mlph) incorporated in a fluid lipid bilayer of natural phospholipids in the form of dioleoylglyceride ester (MlphDG) was developed and the antitumor effect was confirmed in mouse models. The formulation composed of egg phosphatidylcholine (ePC), soybean phosphatidylinositol (PI), and MlphDG (8:1:1, by mol) showed stability in human serum for at least 4–5 h. On the contrary, replacing PI with pegylation of the liposomes, promoted fast dissociation of the components from the bilayer. In this work, interactions of MlphDG-liposomes with the most abundant plasma protein—albumin—in function of the presence of PI in the formulation were explored using Fourier transform infrared spectroscopy. The release of MlphDG from the liposomes was studied by asymmetrical flow field-flow fractionation (AF4) using micelles formed by a polyethylene glycol conjugate with phosphatidylethanolamine to mimic the physiological lipid sink like lipoproteins. Our results show that PI actually protects the membrane of MlphDG-liposomes from the protein penetration, presumably due to pairing between the positively charged MlphDG and negatively charged PI, which compensates for the heterogeneity of the lipid bilayer. The AF4 technique also evidences high stability of the formulation as a drug carrier.

Changes in Leaf-Level Nitrogen Partitioning and Mesophyll Conductance Deliver Increased Photosynthesis for Lolium perenne Leaves Engineered to Accumulate Lipid Carbon Sinks.

Diacylglycerol acyl-transferase (DGAT) and cysteine oleosin (CO) expression confers a novel carbon sink (of encapsulated lipid droplets) in leaves of Lolium perenne and has been shown to increase photosynthesis and biomass. However, the physiological mechanism by which DGAT + CO increases photosynthesis remains unresolved. To evaluate the relationship between sink strength and photosynthesis, we examined fatty acids (FA), water-soluble carbohydrates (WSC), gas exchange parameters and leaf nitrogen for multiple DGAT + CO lines varying in transgene accumulation. To identify the physiological traits which deliver increased photosynthesis, we assessed two important determinants of photosynthetic efficiency, CO2 conductance from atmosphere to chloroplast, and nitrogen partitioning between different photosynthetic and non-photosynthetic pools. We found that DGAT + CO accumulation increased FA at the expense of WSC in leaves of L. perenne and for those lines with a significant reduction in WSC, we also observed an increase in photosynthesis and photosynthetic nitrogen use efficiency. DGAT + CO L. perenne displayed no change in rubisco content or Vcmax but did exhibit a significant increase in specific leaf area (SLA), stomatal and mesophyll conductance, and leaf nitrogen allocated to photosynthetic electron transport. Collectively, we showed that increased carbon demand via DGAT+CO lipid sink accumulation can induce leaf-level changes in L. perenne which deliver increased rates of photosynthesis and growth. Carbon sinks engineered within photosynthetic cells provide a promising new strategy for increasing photosynthesis and crop productivity.

Intravenous lipid emulsion as an antidote in clinical toxicology: a systematic review.

Intravenous lipid emulsions (ILE) were developed many decades ago to supply nutritional requirements to patients unable to obtain adequate enteral nutrition. The utility of ILE was extended to therapeutics, facilitating the delivery of drugs. More recently, the potential for ILE to act as an antidote for inversion of drug toxicity has been recognized. This review aims to summarize the literature on ILE therapy as an antidote. Suggested mechanisms of action, safety profile, and recommendations on the administration of ILE in cases of drug intoxication are highlighted. A complete literature survey was performed using the PubMed database search to collect available information regarding mechanisms of ILE action as an antidote, ILE administration for drug toxicity, and presentation of adverse events. A total of 102 studies met the selection criteria for inclusion in the review. Mainly used for local anesthetics toxicity, ILE therapy has been expanded in clinical toxicology involving overdose treatment of drugs other than local anesthetics. Partitioning in a lipid phase of fat droplets is a mechanism named the lipid sink phenomenon that has primarily been described to explain this action of ILE and remains the most widely accepted. At the same time, recent research has also revealed several molecular mechanisms that may contribute to ILE efficacy. ILE therapy comprises a recognized approach in clinical toxicology. Due to the lack of randomized clinical trials, recommendations on administration are based on animal studies and published cases. Thus, the constantly increased knowledge about ILE therapy supports the need for a detailed appraisal.

Treatment of Bupropion Toxicity with Lipid Emulsion

We have read with interest the case report, “Successful Management of Adolescent Bupropion Overdose with Intravenous Lipid Emulsion Therapy,” recently published in the Journal of Pediatric Intensive Care.[1] Lipid emulsion is effective in the treatment of acute toxicity induced by local anesthetics or nonlocal anesthetic drugs, including amitriptyline, bupropion, and verapamil, in pediatric patients.[2] A previous in vitro study reported that the magnitude of the reduction of the serum concentration of bupropion, which is a highly lipid-soluble antidepressant (log [octanol/water partition coefficient]: 3.2), was 46 by 2% lipid emulsion (Intralipid).[3] In addition, the magnitude of the sequestration of drugs with varied lipid solubility by lipid emulsion is dependent mainly on the lipid partition coefficient and partially on the volume of distribution, which appears to account for 88% of variations in the reduction of drug serum concentration by lipid emulsion.[3] As suggested by Bornstein et al, the lipid sink theory, which is considered the mechanism underlying the effect of lipid emulsion as a nonspecific antidote, states that lipid emulsion absorbs highly lipid-soluble drugs, such as bupivacaine (log [octanol/water partition coefficient]: 3.41), from the heart.[1] [4] However, the following comments should be considered to understand this case report well. First, the first administration of lipid emulsion improved the mental status of the patient.[1] On day 3, the second administration of lipid emulsion was performed due to the recurrence of an altered mental status.[1] The elimination half-life of bupropion is 29 ± 9 hours.[5] In addition, the absorption of a toxic dose following oral administration (enteral route) is more prolonged than that following intravenous administration, leading to extended toxicity.[6] In contrast, Intralipid has a very short half-life (13.7 ± 5.2 minutes).[7] Considering previous reports, the lipid phase of lipid emulsion appears to absorb highly lipid-soluble bupropion from the heart and brain for a very short period following lipid emulsion administration.[3] [7] Furthermore, 1% of plasma triglyceride concentration, which provides lipemic plasma without fat overload, is sufficient to exert scavenging and cardiotonic effects on the toxicity induced by an enteral overdose.[6] Thus, the altered mental status on day 3 following a marked improvement after the first administration of lipid emulsion may be ascribed to a greatly reduced concentration of Intralipid.[1] A previous report recommends the following lipid emulsion regimen to treat toxicity induced by enteral overdose: bolus administration of Intralipid 1.5 mL/kg for 1 minute and subsequently 0.25 mL/kg/min for an additional 3 minutes, followed by intravenous infusion of 0.025 mL/kg/min (up to 6.5 hours) to theoretically maintain a 1% plasma triglyceride concentration.[6] This regimen, as an adjuvant, can be used with supportive care in cases of toxicity induced by oral overdose.[6] However, further research in an in vivo model on the optimal dosing regimen of lipid emulsion for the treatment of toxicity following oral overdose of bupropion is needed because the pharmacokinetics of an oral overdose are different from those of intravenous overdose (e.g., local anesthetic systemic toxicity). Second, initially, lipid sink was widely accepted as the underlying mechanism of lipid emulsion treatment.[4] However, a previous study using a physiologically based pharmacokinetic model reported that lipid emulsion decreased only 11 and 18% bupivacaine concentrations in the heart and brain, respectively.[8] The free bupivacaine concentration was not significantly different between the control and lipid emulsion groups in an in vivo study after administration of a nontoxic dose of bupivacaine in humans.[9] Thus, lipid shuttle has recently been widely accepted as the mechanism of lipid emulsion treatment; it states that lipid emulsion absorbs lipid-soluble drugs, such as bupivacaine, from the heart and then the lipid emulsion, containing the sequestered lipid-soluble drug (e.g., bupivacaine), is transported to the liver and muscle for detoxification and storage, leading to enhanced redistribution.[4] We believe that this case report contributes valuable data on the efficacy of lipid emulsion treatment in bupropion toxicity and emphasizes the need for continuous infusion of lipid emulsion following the initial bolus administration in lipid emulsion treatment.

A CASE OF FATAL NEURO-CARDIO TOXICITY WITH BUPROPION OVERDOSAGE

SESSION TITLE: Tuesday Fellows Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/22/2019 01:00 PM - 02:00 PM INTRODUCTION: Bupropion is an atypical antidepressant used to treat severe depression, anxiety, bipolar disorders and smoking cessation. It has structural similarities to amphetamines. Consumption of large quantities of bupropion has shown to cause a wide variety of manifestations including cardiac, neurological and behavioral issues. In our case, the patient overdosed on bupropion along with depakote leading to major cardiac manifestations including refractory hypotension, bradycardia and conduction abnormalities resulting in recurrent cardiac arrests and then death. CASE PRESENTATION: This is a 28 year old male with history of severe depression who was brought to the hospital after consumption of 30 300mg bupropion extended release pills as a part of a suicidal attempt. Unfortunately within minutes of presentation, he had a dramatic and quick neurological and cardiac deterioration that ranged from initially being oriented to completely lethargic and then status epilepticus and cardiac arrest (PEA) requiring Endo-Tracheal intubation. Although depakote consumption was reported, the EKG and cardiac manifestations were consistent with buproprion toxicity. Initial electrocardiogram(EKG) showed normal QRS, QTc intervals which then rapidly progressed to show prolongation of both intervals. Despite the toxicologist recommendations of continuing the bicarbonate drip and lipid emulsion, his medical condition continued to deteriorate and expired within eight hours of presentation. DISCUSSION: Bupropion over dosage has been reported to manifest with symptoms from development of altered mental status to status epilepticus and larger doses have reported to have refractory cardiogenic shock with significant conduction abnormalities. Unfortunately, hemodialysis is not an option and no antidote has been available for treatment. Toxicologists have described two techniques that have been used to combat buproprion toxicity. 1. Serum alkalization with sodium bicarbonate infusion has been used traditionally in the overdose of tricyclic antidepressants and has been used in bupropion overdose, as all of them are known to cause QTc prolongation. Although the mechanism is unclear, it is postulated that an increase in the sodium concentration, change in pH, or a combination of these physiological alterations may be responsible. 2. Intra-venous lipid emulsion therapy with initial bolus dose followed by a continuous infusion has been described in bupropion overdoses. The mechanism is described as a ‘lipid sink’ with the trapping of bupropion which is lipophilic and hence limiting levels of the drug. The duration from ingestion to presentation and the large dose are major reasons why our patient did not respond to aggressive therapy. CONCLUSIONS: We have to emphasize that due to the fatal neuro-cardio toxicity that bupropion overdosage may cause, we need to do more studies to help understanding and preventing this fatality. Reference #1: Florian Morazin, Agnès Lumbroso, Patrick Harry, Marcel Blaise, Alain Turcant, Philippe Montravers & Rémy Gauzit (2007) Cardiogenic shock and status epilepticus after massive bupropion overdose, Clinical Toxicology, 45:7, 794-797, DOI: 10.1080/15563650701665076 Reference #2: Bupropion-Associated QRS Prolongation Unresponsive to Sodium Bicarbonate Therapy Wills, Brandon K DO, MS; Zell-Kanter, Michele PharmD; Aks, Steven E DO American Journal of Therapeutics: March-April 2009 - Volume 16 - Issue 2 - p 193-196 https://doi.org/10.1097/MJT.0b013e3180a5bd83 DISCLOSURES: No relevant relationships by Moayyad Alziadat, source=Web Response No relevant relationships by Mohd Hazem Azzam, source=Web Response No relevant relationships by Anish Samuel, source=Web Response No relevant relationships by Rishitha Yelisetti, source=Web Response