Lipid Rescue Research Articles

A ferroptosis-targeting ceria anchored halloysite as orally drug delivery system for radiation colitis therapy

Radiation colitis is the leading cause of diarrhea and hematochezia in pelvic radiotherapy patients. This work advances the pathogenesis of radiation colitis from the perspective of ferroptosis. An oral Pickering emulsion is stabilized with halloysite clay nanotubes to alleviate radiation colitis by inhibiting ferroptosis. Ceria nanozyme grown in situ on nanotubes can scavenge reactive oxygen species, and deferiprone was loaded into the lumen of nanotubes to relieve iron stress. These two strategies effectively inhibit lipid peroxidation and rescue ferroptosis in the intestinal microenvironment. The clay nanotubes play a critical role as either a medicine to alleviate colitis, a nanocarrier that targets the inflamed colon by electrostatic adsorption, or an interfacial stabilizer for emulsions. This ferroptosis-based strategy was effective in vitro and in vivo, providing a prospective candidate for radiotherapy protection via rational regulation of specific oxidative stress.

Побочные эффекты лидокаина в амбулаторной педиатрии

Lidocaine poisoning with parenteral administration, accompanied by systemic toxic effects, is quite rare in pediatric practice, but even single cases may cause the development of critical conditions that require treatment in the intensive care unit. Objective. To demonstrate a clinical case of severe lidocaine poisoning in two children and the main measures to stabilize the condition of patients with overdoses of local anesthetics. The article presents the basic historical data on the creation of lidocaine, its pharmacokinetics and pharmacodynamics in children. The maximum single dose was indicated based on the patient's weight. The main principles of intensive therapy for lidocaine poisoning in children were considered, and the algorithm of actions in the development of a life-threatening state was provided. Special attention was paid to the use of the «lipid rescue protocol» in hemodynamic disorders and cardiac arrest. Conclusion. When prescribing local anesthetics in children, one should take into account the anatomical and physiological characteristics of the child, the age characteristics of the pharmacological effects of the drugs, and the maximum permissible single dose, which will prevent the occurrence of iatrogenic life-threatening complications. Key words: lidocaine, poisoning, systemic toxic effects, intensive care, pediatric

Cardio Protective Effects of Lipid Emulsion against Ropivacaine-Induced Local Anesthetic Systemic Toxicity-An Experimental Study.

Inadvertent intravascular injection of local anesthetics (LA) during regional anesthesia causes Local Anesthetic Systemic Toxicity (LAST). Theories of lipid rescue in the case of LAST proved that the administration of lipids in LAST has beneficial effects. One possible mechanism of action is based on the lipophilic properties of LA which allow plasma-free LA to be bound by the molecules of Lipid Emulsion (LE). The association LA–LE is shuttled towards organs such as liver and the kidneys, and the half-life of LA is shortened. The main objective of this experimental study was to assess the possible cardio-prophylactic effect of LE administration before the induction of LAST by intravenous administration of Ropivacaine. This was an experimental, interventional, prospective, and non-randomized study. The subjects were divided into groups and received, under general anesthesia, LE 20% first 0.3–0.4 mL, followed by 0.1 mL Ropivacaine 2 mg/mL, or Ropivacaine alone. At the end of the experiment, the subjects were sacrificed, and tissue samples of kidney, heart and liver were harvested for histopathological examination. LE, when administered as prophylaxis in Ropivacaine-induced LAST, had protective cardiac effects in rats. The LE known side effects were not produced if the substance was administered in the low doses used for LAST prophylaxis.

Двадцать лет «серебряной пули» против интоксикации местными анестетиками

Местные анестетики (МА), как и все другие медикаменты, могут вызвать нежелательные явления. В отличие от крайне редких (приблизительно 1 : 1 000 000) аллергических реакций на МА интоксикация местными анестетиками (ИМА) значительно более вероятна (инцидентность приблизительно 1 : 1000), особенно с относительно высокими дозами, применяемыми для эпидуральных или больших блокад нервов. Лечение тяжелой ИМА от современных анестетиков мощного и длительного действия (например, бупивакаины) было очень трудным и почти безнадежным до успешного «липидного спасения» довольно высокими внутривенными дозами липидной эмульсии у крыс в 1998 году, затем у пациентов в 2006 году. Этот революционный метод (20% липидная эмульсия болюсом 100 мл в течение 2–3 минут, затем инфузией 200–250 мл в течение 15–20 хвилин, если не восстановится стабильность гемодинамики — рассмотреть повторный болюс или ускорение инфузии), образно названный «серебряной пулей» против ИМА, сначала рекомендовался лишь как средство отчаяния в случае безуспешной реанимации. Однако рекомендации Американского общества региональной анестезии 2010, 2012 и 2017 годов последовательно становились все менее консервативными, и теперь «липидное спасение» рекомендуется при первых признаках серьезной ИМА, сразу после обеспечения проходимости дыхательных путей. Вывод: один литр 20% липидной эмульсии должен находиться на каждом рабочем месте, где выполняют эпидуральную анестезию или большие блокады нервов высокими дозами МА.

Does the use of fish oil-based lipid emulsion in the clinical setting of total parenteral nutrition and lipid rescue therapy interfere with common laboratory analytes on Roche Cobas 6000?

Lipaemic interference on automated analysers has been widely studied using soy-based emulsion such as Intralipid. Due to the greater adoption of fish oil-based lipid emulsion for total parenteral nutrition in view of improved clinical outcomes, we seek to characterize the optical properties of SMOFlipid 20% (Fresenius Kabi, Bad Homburg, Germany), a fish oil-based emulsion, on the Roche Cobas 6000 chemistry analyser (Roche Diagnostic, Basel, Switzerland). Various amounts of SMOFlipid were spiked into pooled serums. We plotted Roche Cobas Serum Index Gen.2 Lipaemia Index (L-index) against the amount of SMOFlipid added. We then studied the interference thresholds for aspartate aminotransferase, alanine aminotransferase, albumin and renal panel analytes using SMOFlipid. We subjected five levels of spiked lipaemia to high-speed centrifugation and analysed the specimens pre- and post-centrifugation. To postulate whether fish oil-based lipid emulsion interferes with laboratory results in the clinical setting, we calculated concentrations of SMOFlipid post-lipid rescue therapy and steady-state concentration of a typical total parenteral nutrition regime using pharmacokinetic principles. SMOFlipid optical behaviour is similar to Intralipid using the Serum Index Gen.2 L-index, with 1 mg/dL of SMOFlipid representing 1 unit of L-index. Manufacturer-stated interference thresholds are accurate for alanine aminotransferase, aspartate aminotransferase, albumin, urea and creatinine. High-speed centrifugation at 60 min 21,100g facilitates the removal of fish oil-based SMOFlipid. Based on the interference thresholds we verified and pharmacokinetics parameters provided by SMOFlipid manufacturer, total parenteral nutrition may not interfere with chemistry analytes given sufficient clearance, but lipid rescue therapy will interfere. Further studies assessing lipaemic interference on immunoassays are needed.

Knowledge of Dentistry Students on Local Anesthetic Systemic Toxicity and Intravenous Lipid Rescue Therapy: A Cross-Sectional Questionnaire-Based Study

Knowledge of Dentistry Students on Local Anesthetic Systemic Toxicity and Intravenous Lipid Rescue Therapy: A Cross-Sectional Questionnaire-Based Study

TREATMENT OF ACUTE BUPROPRIONE TOXICITY WITH LIPID INFUSION AND PLASMAPHERESIS

SESSION TITLE: Plasmapheresis to the Rescue SESSION TYPE: Fellow Case Reports PRESENTED ON: 10/21/2019 3:15 PM - 4:15 PM INTRODUCTION: Bupropion is an atypical antidepressant used to treat major depressive disorder and other psychiatric conditions. The toxic side effects of bupropion include seizures, tachycardia, arrhythmias, and death. These side effects are dose and formulary dependent. We describe a case of acute bupropion toxicity from a suicide attempt with symptoms, which was treated with Intralipid infusion along with serial plasmapheresis. CASE PRESENTATION: A 19-year-old male was transferred from an outside hospital for suicide attempt with ingestion of 40 tablets of 150 mg sustained released (SR) bupropion for a total dose of 9 gm. He was not a candidate for any activated charcoal. The patient developed tonic-clonic seizures and the decision was made to initiate a bolus of 140 mL of 20% Intralipid before and during transport. On admission to our hospital he developed status epilepticus and had QTc prolongation (467 and 487). He was started on 800 mL lipid infusion immediately followed by serial plasmapheresis. The triglyceride levels were closely monitored. The patient received a total of 940 mL (140 mL bolus plus 800 mL continuous infusion) of intralipid along with 3 sessions of plasmapheresis. He remained seizure free and his QTc normalized and was successfully extubated. DISCUSSION: Bupropion is a highly lipid soluble and protein-bound medication. Mild toxicity includes dry mouth, nausea, insomnia, dizziness. Life-threatening toxicities include seizure and arrhythmias. Seizures are generally seen with an overdose of bupropion. Ingestion of 4.5-9 g of bupropion increases the likelihood of seizures. Treatment is mostly symptomatic and with benzodiazepines. Lipid infusions can be used as lipid rescue therapy for acute cardiovascular collapses. The mechanism is the same as the use of lipid infusion as rescue therapy in case of local anesthetic, tricyclic antidepressants or serotonin-specific reuptake inhibitor toxicities. The proposed mechanism involves lipids from the infusion binding to the offending drug and pulling it from the target tissue preventing its accumulation and minimizing the toxic effects. Despite several reports there seem to be increased risks and compilations associated with lipid infusions like acute respiratory distress syndrome, hypertriglyceridemia, pancreatitis, and cardiac toxicity. There are not many reports of the use of plasmapheresis in a timely manner (depending on the half-life of the drug) for an SR drug after lipid infusion to promote removal of all the lipid molecules including those bound to the offending drug thereby preventing toxicity from the drug and lipid infusion as well. In our case combination of both helped in stabilizing and treating the patient. CONCLUSIONS: Use of lipid infusion in conjugation with plasmapheresis for the treatment of acute bupropion toxicity with symptoms allows safe use of lipid infusion and ensures complete removal of offending drug. Reference #1: Tolentino Stephanie; Gharpure, Varsha; Tsifansky, Michael Critical Care Medicine: December 2013 Reference #2: Intravenous lipid emulsion in clinical toxicology Leelach Rothschild,corresponding author1 Sarah Bern,1 Sarah Oswald,1 and Guy Weinbergcorresponding author1,2 DISCLOSURES: No relevant relationships by Praful Tewari, source=Web Response

Opposite effects of vitamin C and vitamin E on the antifungal activity of honokiol.

The aim of the present study was to evaluate the effects of two well-known natural antioxidants vitamin C (VC) and vitamin E (VE) on the antifungal activity of honokiol against Candida albicans. The broth microdilution method was employed to test the antifungal activities of honokiol with or without antioxidants in the medium against C. albicans strain. Intracellular reactive oxygen species (ROS) and lipid peroxidation were determined by fluorescence staining assay. Mitochondrial dysfunction was assessed by detecting the mitochondrial DNA and the mitochondrial membrane potential. We observed that VC could significantly potentiate the antifungal activities of honokiol while VE reduced the effectiveness of honokiol against C. albicans. In addition, VC accelerated honokiol-induced mitochondrial dysfunction and inhibited glycolysis leading to a decrease in cellular ATP. However, VE could protect against mitochondrial membrane lipid peroxidation and rescue mitochondrial function after honokiol treatment. Our research provides new insight into the understanding of the action mechanism of honokiol and VC combination against C. albicans.

Effect of Intralipid on the Dose of Ropivacaine or Levobupivacaine Tolerated by Volunteers: A Clinical and Pharmacokinetic Study

(Anesthesiology. 2016;125(3):474–483) On the basis of case reports since 2006 and laboratory studies dating back to 1998, rapid intravenous administration of lipid emulsion—“lipid rescue”—has become standard treatment for local anesthetic systemic toxicity (LAST). Hence, the purpose of this crossover study in volunteers was to determine the effect of Intralipid (Fresenius, Paris, France) administration on the time to neurologic symptoms during local anesthetic systemic toxicity (eg, convulsions; severe arrhythmias).

Oestrogen inhibition reverses pulmonary arterial hypertension and associated metabolic defects.

Increased oestrogen is a strong epidemiological risk factor for development of pulmonary arterial hypertension (PAH) in patients, associated with metabolic defects. In addition, oestrogens drive penetrance in mice carrying mutations in bone morphogenetic protein receptor type II (BMPR2), the cause of most heritable PAH. The goal of the present study was to determine whether inhibition of oestrogens was effective in the treatment of PAH in these mice.The oestrogen inhibitors fulvestrant and anastrozole were used in a prevention and treatment paradigm in BMPR2 mutant mice, and tamoxifen was used for treatment. In addition, BMPR2 mutant mice were crossed onto oestrogen receptor (ESR)1 and ESR2 knockout backgrounds to assess receptor specificity. Haemodynamic and metabolic outcomes were measured.Oestrogen inhibition both prevented and treated PAH in BMPR2 mutant mice. This was associated with reduction in metabolic defects including oxidised lipid formation, insulin resistance and rescue of peroxisome proliferator-activated receptor-γ and CD36. The effect was mediated primarily through ESR2, but partially through ESR1.Our data suggest that trials of oestrogen inhibition in human PAH are warranted, and may improve pulmonary vascular disease through amelioration of metabolic defects. Although fulvestrant and anastrozole were more effective than tamoxifen, tamoxifen may be useful in premenopausal females, because of a reduced risk of induction of menopause.

Local anesthetic toxicity: acute and chronic management.

Local anesthetics are commonly used medicines in clinical settings. They are used for pain management during minor interventional treatments, and for postoperative care after major surgeries. Cocaine is the well‐known origin of local anesthetics, and the drug and related derivatives have long history of clinical usage for more than several centuries. Although illegal use of cocaine and its abuse are social problem in some countries, other local anesthetics are safely and effectively used in clinics and hospitals all over the world. However, still this drug category has several side‐effects and possibilities of rare but serious complications. Acute neurotoxicity and cardiac toxicity are derived from unexpected high serum concentration. Allergic reactions are observed in some cases, especially following the use of ester structure drugs. Chronic toxicity is provoked when nerve fibers are exposed to local anesthetics at a high concentration for a long duration. Adequate treatments for acute toxic reactions can secure complete recovery of patients, and careful use of drugs prevents long‐lasting neurological complications. In addition to respiratory and circulatory management, effectiveness of lipid rescue in the acute toxicity treatment has been certified in many clinical guidelines. Prevention of the use of high concentration of local anesthetics is also validated to be effective to decrease the possibility of nerve fiber damage.

ISMP Medication Error Report Analysis: Betaine Anhydrous Versus Betaine Hydrochloride Look-Alike Generic Names Don't Give Zurampic Without Allopurinol Lantus Overdose Tied to Confusing Vial Label More on Lipid Rescue.

These medication errors have occurred in health care facilities at least once. They will happen again-perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them at your inservice training programs. Your assistance is required to continue this feature. The reports described here were received through the Institute for Safe Medication Practices (ISMP) Medication Errors Reporting Program. Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below. Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMPWeb site (www.ismp.org), by calling 800-FAIL-SAFE, or via e-mail at ismpinfo@ismp.org. ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications.

Lipid emulsion injection-induced reversal of cardiac toxicity and acceleration of emergence from general anesthesia after scalp infiltration of a local anesthetic: a case report

BackgroundA scalp block or wound infiltration of local anesthetic is thought to effectively control post-craniotomy pain. However, it can result in local anesthetic toxicity (LAST), which is difficult to distinguish from brain damage due to the surgical procedure when emergence from general anesthesia is delayed. Lipid rescue (infusion of a lipid emulsion) is a widely accepted treatment for LAST.Case presentationA 64-year-old man underwent surgical resection of a glioma in the brainstem. While still under general anesthesia, and before suturing of the wound, he received a 20-mL scalp infusion of ropivacaine 0.75%. His emergence from anesthesia was delayed, his respiration was suppressed, and premature ventricular contractions occurred; all of which are symptoms of LAST. Injection of a 20% lipid emulsion rapidly alleviated these symptoms. Interestingly, the blood concentration of ropivacaine increased after lipid rescue.ConclusionsThe increase in ropivacaine concentration in the blood after lipid rescue suggests that the intravenously administered lipid emulsion absorbed the ropivacaine from the intoxicated brain and heart tissue. This finding is consistent with the lipid sink theory as a mechanistic explanation of lipid rescue.

Systemic toxicity of local anesthetics

The paper presents characteristics of local anesthetics used in dentistry and maxillofacial surgery taking into account their effectiveness and toxicity. We described the main clinical symptoms of manifestation of systemic toxicity and measures for prevention of local anesthesia complications, as well as the detailed protocol of 'lipid rescue' and resuscitation at manifestation of systemic toxic reaction of local anesthetics with the mechanism of the fatty emulsion action.

Pilot Trial of Intravenous Lipid Emulsion Treatment for Severe Nifedipine-Induced Shock.

Animal studies and human case reports show promise in using lipid rescue to treat refractory calcium channel antagonist toxicity. However, the majority of research and clinical experience has focused on non-dihydropyridine agents. Thus, we sought to investigate the value of lipid emulsion (ILE) therapy for dihydropyridine-induced shock. This IACUC-approved study utilized seven swine that were sedated with alpha-chloralose, mechanically ventilated, and instrumented for drug delivery and hemodynamic measures. After stabilization and basal measures, nifedipine (0.01875 mg/kg/min) was infused until imminent cardiac arrest (seizure, end tidal CO2 < 10 mmHg, bradydysrhythmia, or pulseless electrical activity). Animals then received a 7mL/kg bolus of 20% lipid emulsion via central catheter. Lipid circulation was visually confirmed by the presence of fat in peripheral arterial blood. Hemodynamics were continuously monitored until 10 min after lipid bolus. Surviving animals were euthanized. Pre- and post-lipid treatment parameters were analyzed using the Wilxocon signed rank test (p <0.05 significant). Nifedipine toxicity was characterized by vasodilatory hypotension, impaired vascular contractility, and tachycardia with terminal bradycardia. The median time to imminent cardiac arrest from start of nifedipine infusion was 218 min. Lipid treatment did not improve hemodynamics or restore circulation in any animal. There was no benefit from lipid rescue in this model of nifedipine toxicity. Further study of ILE for dihydropyridine toxicity is warranted but initial animal model results are not promising.

Population Semiphysiologic Kinetic Modeling and Simulation of Plasma Triglyceride Levels After Soybean Oil-Based Intravenous Lipid Emulsion Administration in Rats.

Soybean oil-based intravenous lipid emulsion (SO-ILE) has clinical utility as an energy source and in lipid rescue therapy. However, an excessive infusion rate of SO-ILE in routine use and in lipid rescue therapy may cause serious side effects. There is little information about plasma triglyceride (TG) kinetics following SO-ILE administration. The present study aimed to develop a population semiphysiologic kinetic model of TG and to predict the TG kinetics even at extremely high concentrations in rats. TG concentration profiles after intravenous bolus (0.1, 0.25, 0.5, 1.0, 1.5, and 2.0 g/kg) or infusion (3.0 g/kg/h for 1 hour) of SO-ILE to rats were analyzed by a kinetic model constructed with 4 pathways: apolipoprotein acquisitions, zero-order catabolism, first-order uptake to storage sites, and zero-order secretion from storage sites. The developed model was subjected to internal and external validation. Plasma TG concentrations appeared to decline in a biphasic manner with nonlinear TG kinetics. The developed kinetic model was well validated and found to accurately predict the external validation data. The proposed kinetic model accurately described TG concentrations after SO-ILE administration at various infusion rates, including a lipid rescue regimen. The maximum acceptable infusion rate of SO-ILE in routine use should correspond to the maximum velocity of the apolipoprotein acquisition: 0.619 g/kg/h in rats. The prediction of TG kinetics at extremely high concentrations will provide useful information for lipid rescue therapy.

Tricyclic Antidepressant Overdose Treated with Adjunctive Lipid Rescue and Plasmapheresis

Tricyclic antidepressant poisoning remains a major cause of morbidity and mortality, particularly in the setting of suicidal attempts. The current standard of care for treatment is the administration of sodium bicarbonate infusion. Adjunctive lipid emulsion therapy and plasmapheresis have received attention recently. We report an 18-year-old patient who was successfully managed with lipid emulsion and plasmapheresis as adjuncts to sodium bicarbonate treatment and review some of the recent literature.

Lipid Rescue - Efficacy and Safety Still Unproven.

Lipid Rescue - Efficacy and Safety Still Unproven.

Involvement of Opioid Receptors in Lipid Rescue of Bupivacaine-Induced Cardiotoxicity

Surv Anesthesiol 2016;60(2):78–79 Lipid rescue, or lipid emulsion (LE), has been shown to resuscitate patients from cardiac-related effects of local anesthetics and from toxicities caused by a wide range of drugs, such as calcium channel blockers, β-blockers, and psychoactive agents. Using nonselective opioid receptor antagonists (ORAs) and highly selective ORAs, the authors of this study examined whether the rescue action of LE is mediated through central or peripheral opioid receptors.

Foldamer scaffolds suggest distinct structures are associated with alternative gains-of-function in a preamyloid toxin.

An oligoquinoline foldamer library was synthesized and screened for antagonism of lipid bilayer catalysed assembly of islet amyloid polypeptide (IAPP). One tetraquinoline, ADM-116, showed exceptional potency not only in this assay, but also in secondary assays measuring lipid bilayer integrity and rescue of insulin secreting cells from the toxic effects of IAPP. Structure activity studies identified three additional oligoquinolines, closely related to ADM-116, which also have strong activity in the primary, but not the secondary assays. This contrasts work using an oligopyrdyl foldamer scaffold in which all three assays are observed to be correlated. The results suggest that while there is commonality to the structures and pathways of IAPP conformational change, it is nevertheless possible to leverage foldamers to separately affect IAPP's alternative gains-of-function.