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To compare the hemodynamic changes following two different lipid emulsion therapies after bupivacaine intoxication in swines.
Large White pigs were anesthetized with thiopental, tracheal intubation performed and mechanical ventilation instituted. Hemodynamic variables were recorded with invasive pressure monitoring and pulmonary artery catheterizat...
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... The majority of the animal studies used bupivacaine. In the controlled animal studies, approximately half of the studies favored ILE while the other half favored vasopressors or a combination of ILA and vasopressors [22][23][24][25][26][27][28][29][30][31][32]. The animal studies were not generalizable to human settings because of limited observation of test subjects and that conclusions on efficacy were based on cardiovascular variables only, not including effect on neurologic symptoms as the animals were anesthetized. ...
Purpose of review:
The decision to provide intravenous lipid emulsion (ILE) therapy as a treatment modality for the reversal of various drug toxicity was discovered in the last decade. Numerous publications, in both human and animals attested to its clinical use, but current supporting evidence supporting inconsistent.
Recent findings:
A recent systematic review reported evidence for benefit of ILE in bupivacaine toxicity. Human randomized trials and large observational studies as well as animal models of orogastric poisoning failed to report a clear benefit of ILE for nonlocal anesthetics poisoning.
Summary:
ILE can be used to resuscitate local anesthetics especially bupivacaine. The impact of ILE on oral overdoses is controversial and clear evidence on benefit is lacking. A thorough risk benefit assessment with consideration of alternative options is warranted to minimize the risk of adverse effects. Evidence supports using bolus doses of ILE, while infusion rates are still debatable.
... We deliberately chose to use a larger dose of lipid emulsion than that recommended in guidelines of regional anesthesia societies, 3 since in animal experiments on local anesthetic toxicity, larger lipid doses have been required for a rescue effect. 11,17 Materials and methods ...
Local anesthetic toxicity is thought to be mediated partly by inhibition of cardiac mitochondrial function. Intravenous (i.v.) lipid emulsion may overcome this energy depletion, but doses larger than currently recommended may be needed for rescue effect. In this randomized study with anesthetized pigs, we compared the effect of a large dose, 4 mL/kg, of i.v. 20% Intralipid® (n = 7) with Ringer’s acetate (n = 6) on cardiovascular recovery after a cardiotoxic dose of bupivacaine. We also examined mitochondrial respiratory function in myocardial cell homogenates analyzed promptly after needle biopsies from the animals. Bupivacaine plasma concentrations were quantified from plasma samples. Arterial blood pressure recovered faster and systemic vascular resistance rose more rapidly after Intralipid than Ringer’s acetate administration (p < 0.0001), but Intralipid did not increase cardiac index or left ventricular ejection fraction. The lipid-based mitochondrial respiration was stimulated by approximately 30% after Intralipid (p < 0.05) but unaffected by Ringer’s acetate. The mean (standard deviation) area under the concentration–time curve (AUC) of total bupivacaine was greater after Intralipid (105.2 (13.6) mg·min/L) than after Ringer’s acetate (88.1 (7.1) mg·min/L) (p = 0.019). After Intralipid, the AUC of the lipid-un-entrapped bupivacaine portion (97.0 (14.5) mg·min/L) was 8% lower than that of total bupivacaine (p < 0.0001). To conclude, 4 mL/kg of Intralipid expedited cardiovascular recovery from bupivacaine cardiotoxicity mainly by increasing systemic vascular resistance. The increased myocardial mitochondrial respiration and bupivacaine entrapment after Intralipid did not improve cardiac function.
... Weinberg et al. reported the Intravenous Lipid Emulsion (ILE) therapy given after severe bupivacaine intoxication to be effective in resuscitation in intact rats [1]. Since then, it was shown that lipid emulsions are effective in the treatment of accidental or intentional drug intoxications in many case reports and animal studies [2][3][4][5][6][7]. ...
Objective: Although the action mechanism of intravenous lipid emulsion has not been fully elucidated yet, its use in liposoluble drugs intoxications. In this study, we examined the lipophilic features of causative agents and the success of the treatment ILE therapy in intoxication cases. Methods: We reviewed 765 cases published in PubMed between 1966 and June, 2015. After applying exclusion criteria, totally 141 cases ingested single substance and received ILE therapy with 20% ILE solution were included in present study. Amount of lipid solutions given and the results were recorded. Success rate was statistically assessed according to log p values of the substances taken and the amount of lipid emulsion used. Results: 141 patients were involved in this study; log p values were calculated for all drugs regardless of the success of ILE therapy. ILE therapy under the amount of 100 ml failed to achieve successful outcome. ALOGPS and ChemAxon log P values were higher in cases, which received ILE therapy ≤ 500 ml and showed successful results. It was found that log p value had no contribution to the treatment success in the group received ILE therapy>500 ml. Conclusions: It was found that ILE therapy<500 ml was successful in drugs with higher lipophilicity while success rate was higher in ILE therapy>500 ml and that liposolubility had no significant contribution to treatment success.
Introduction:
Ropivacaine is considered to have a wider margin of cardiovascular safety. However, several reports of ventricular arrhythmias (VA) due to ropivacaine toxicity have been documented. Intravenous lipid emulsions (ILEs) have recently been used successfully in the treatment of local anesthetic intoxication. The main objective of the present study was to evaluate the efficacy of the ILEs in the prevention of pacing-induced-VA and electrophysiological alterations in an animal model of ropivacaine toxicity.
Methods:
Nineteen pigs were anesthetized and instrumentalized. A baseline programmed electrical ventricular stimulation protocol (PEVSP) to induce VA was performed. Ropivacaine (5 mg·kg-1 + 100 μg·kg-1·min-1) followed by normal saline infusion (control group n = 8) or intralipid 20% (1.5 mL·kg-1 + 0.25 mL·kg-1·min-1) for the ILE group (n = 8), were administered three minutes after the ropivacaine bolus. PEVSP was repeated 25 min after the onset of ropivacaine infusion. Pacing-induced VA and electrophysiological abnormalities were assessed in both groups. A sham-control group (n = 3) without ropivacaine infusion was included.
Results:
Most of the electrophysiological parameters evaluated were affected by ropivacaine: PR interval by 28% (p = 0.001), AV interval by 40% (p = 0.001), sinus QRS by 101% (p = 0.001), paced QRS at a rate of 150 bpm by 258% (p = 0.001), and at 120 bpm by 241% (p = 0.001). Seven animals (87.5%) in the control group and eight animals (100%) in the ILE group developed sustained-VA (p = 0.30). Successful resuscitation occurred in 100% of animals in the ILE group vs. 57% of animals in the control group, p = 0.038. Pacing-induced-VA terminated at the first defibrillation attempt in 75% of the animals in the ILE group vs. 0% in the control group, p = 0.01.
Conclusion:
Ropivacaine strongly altered the parameters of ventricular conduction, thus facilitating the induction of VA. ILEs did not prevent pacing-induced VA. However, facilitated resuscitation and termination of VA were delivered at the first defibrillation attempt compared to the control group.
Background:
Although intravenous lipid emulsion (ILE) was first used to treat life-threatening local anesthetic (LA) toxicity, its use has expanded to include both non-local anesthetic (non-LA) poisoning and less severe manifestations of toxicity. A collaborative workgroup appraised the literature and provides evidence-based recommendations for the use of ILE in poisoning.
Methods:
Following a systematic review of the literature, data were summarized in four publications: LA and non-LA poisoning efficacy, adverse effects, and analytical interferences. Twenty-two toxins or toxin categories and three clinical situations were selected for voting. Voting statements were proposed using a predetermined format. A two-round modified Delphi method was used to reach consensus on the voting statements. Disagreement was quantified using RAND/UCLA Appropriateness Method.
Results:
For the management of cardiac arrest, we recommend using ILE with bupivacaine toxicity, while our recommendations are neutral regarding its use for all other toxins. For the management of life-threatening toxicity, (1) as first line therapy, we suggest not to use ILE with toxicity from amitriptyline, non-lipid soluble beta receptor antagonists, bupropion, calcium channel blockers, cocaine, diphenhydramine, lamotrigine, malathion but are neutral for other toxins, (2) as part of treatment modalities, we suggest using ILE in bupivacaine toxicity if other therapies fail, but are neutral for other toxins, (3) if other therapies fail, we recommend ILE for bupivacaine toxicity and we suggest using ILE for toxicity due to other LAs, amitriptyline, and bupropion, but our recommendations are neutral for all other toxins. In the treatment of non-life-threatening toxicity, recommendations are variable according to the balance of expected risks and benefits for each toxin. For LA-toxicity we suggest the use of Intralipid(®) 20% as it is the formulation the most often reported. There is no evidence to support a recommendation for the best formulation of ILE for non-LAs. The voting panel is neutral regarding ILE dosing and infusion duration due to insufficient data for non-LAs. All recommendations were based on very low quality of evidence.
Conclusion:
Clinical recommendations regarding the use of ILE in poisoning were only possible in a small number of scenarios and were based mainly on very low quality of evidence, balance of expected risks and benefits, adverse effects, laboratory interferences as well as related costs and resources. The workgroup emphasizes that dose-finding and controlled studies reflecting human poisoning scenarios are required to advance knowledge of limitations, indications, adverse effects, effectiveness, and best regimen for ILE treatment.
The Side Effects of Drugs Annuals form a series of volumes in which the adverse effects of drugs and adverse reactions to them are surveyed. The series supplements the contents of Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions. This review of relevant publications from January 2015 to December 2015 (with an occasional publication from December 2014 and January 2016 initially publicized in 2015) covers adverse reactions to local anesthetics after transverses abdominis plane (i.e., TAP), epidural, spinal, peripheral nerve, dorsal penile and paravertebral blocks. It also covers blocks for dental, dermatologic and other procedures. Individual local anesthetics covered include benzocaine, bupivacaine, cinchocaine, lidocaine, levobupivacaine, mepivacaine, pramocaine, ropivacaine and tetracaine. Routes of administration covered include neuraxial, regional, peripheral, intra-articular and topical.
Adverse events were most often seen from overdose of drugs and range from neurologic (e.g., seizures) to cardiovascular (e.g., hemodynamic compromise) and to dermatologic (e.g., contact allergy) amongst others. When there were multiple adverse events, they were listed under the more severe adverse event.
PURPOSE:
To evaluate hemodynamic changes caused by sole intravenous infusion of lipid emulsion with doses recommended for treatment of drug-related toxicity.
METHODS:
Large White pigs underwent general anesthesia, tracheal intubation was performed, and mechanical ventilation was instituted. Hemodynamic variables were recorded using invasive blood pressure and pulmonary artery catheterization. Baseline hemodynamic measurements were obtained after a 30-minute stabilization period. An intravenous bolus injection of 20% lipid emulsion at 1.5 ml/kg was administered. Additional hemodynamic measurements were made after 1 minute, followed by a continuous intravenous lipid infusion of 0.25 ml/kg/min. Further measurements were carried out at 10, 20 and 30 minutes, when the infusion was doubled to 0.5 ml/kg/min. Assessment of hemodynamic changes were then made at 40, 50 and 60 minutes.
RESULTS:
Lipid infusion did not influence cardiac output or heart rate, but caused an increase in arterial blood pressure, mainly pulmonary blood pressure due to increased vascular resistance. Ventricular systolic stroke work consequently increased with greater repercussions on the right ventricle.
CONCLUSION:
In doses used for drug-related toxicity, lipid emulsion cause significant hemodynamic changes with hypertension, particularly in the pulmonary circulation and increase in vascular resistance, which is a factor to consider prior to use of these solutions.
Drug overdoses from both pharmaceutical and recreational drugs are a major public health concern. Although some overdoses may be treated with specific antidotes, the most common treatment involves providing supportive care to allow the body to metabolize and excrete the toxicant. In many cases, supportive care is limiting, ineffective, and expensive. There is a clear medical need to improve the effectiveness of detoxification, in particular by developing more specific therapies or antidotes for these overdoses. Intravenous lipid emulsions (ILEs) have been investigated as a potential treatment for overdoses of local anesthetics and other hydrophobic drugs. While ILE therapy has been successful in several cases, its use beyond local anesthetic systemic toxicity is controversial and its mechanism of detoxification remains a subject of debate. ILEs were not originally developed to treat overdose, but clarifying the mechanisms of detoxification observed with ILE may allow us to design more effective future treatments. Liposomes are highly biocompatible and versatile formulations, thus it was a natural step to explore their use for drug overdose therapy as well. Several researchers have designed liposomes using a variety of approaches including surface charge, pH gradients, and inclusion of enzymes in the liposome core to optimize the formulations for detoxification of a specific drug or toxicant. The in vitro results for drug sequestration by liposomes are very promising and animal trials have in some cases shown comparable performance to ILE at reduced lipid dosing. This narrative review summarizes the current status and advances in the use of emulsions and liposomes for detoxification and also suggests several areas in which studies are needed for developing future therapies.
Copyright © 2015. Published by Elsevier B.V.
