FIGURE 3- - uploaded by Artur Udelsmann
Content may be subject to copyright.
Source publication
To evaluate the hemodynamic changes following SMOFlipid emulsion therapy with after bupivacaine intoxication in swines.
Large White pigs were anesthetized with thiopental, tracheal intubation was performed and mechanical ventilation was instituted. Hemodynamic variables were recorded with invasive pressure monitoring and pulmonary artery catheteriz...
Context in source publication
Context 1
... seen in Figure 3, there was an increase in values in both groups, in SMOF they were higher than CTRL until T 20 (p<0.001). In both groups the results did not return to levels similar at rest until the end of the experiment, although in SMOF results were successively different from previous values (p<0.001). ...
Citations
... Three pig studies indicated that, whereas ILE increases blood pressure during LAST, it does not alter cardiac index or ejection fraction. [94][95][96] These authors instead report that increased vascular resistance moderates the improvements in pressure. Interpreting these studies warrants a few caveats. ...
The experimental use of lipid emulsion for local anesthetic toxicity was originally identified in 1998. It was then translated to clinical practice in 2006 and expanded to drugs other than local anesthetics in 2008. Our understanding of lipid resuscitation therapy has progressed considerably since the previous update from the American Society of Regional Anesthesia and Pain Medicine, and the scientific evidence has coalesced around specific discrete mechanisms. Intravenous lipid emulsion therapy provides a multimodal resuscitation benefit that includes both scavenging (eg, the lipid shuttle) and nonscavenging components. The intravascular lipid compartment scavenges drug from organs susceptible to toxicity and accelerates redistribution to organs where drug (eg, bupivacaine) is stored, detoxified, and later excreted. In addition, lipid exerts nonscavenging effects that include postconditioning (via activation of prosurvival kinases) along with cardiotonic and vasoconstrictive benefits. These effects protect tissue from ischemic damage and increase tissue perfusion during recovery from toxicity. Other mechanisms have diminished in favor based on lack of evidence; these include direct effects on channel currents (eg, calcium) and mass-effect overpowering a block in mitochondrial metabolism. In this narrative review, we discuss these proposed mechanisms and address questions left to answer in the field. Further work is needed, but the field has made considerable strides towards understanding the mechanisms.
... Of the remaining 13 publications, 10 used study designs not intended to evaluate survival benefit. Of these 10, six indicated that ILE exerted benefits on hemodynamics [5,10,12,13], pharmacokinetics [25] or resolution of electrocardiogram abnormalities [8]. We could not analyze the remaining four for benefit because of lack of a control group [20,27], intentional dosing to death [6], or lack of comparison [30]. ...
Introduction: The Lipid Emulsion Therapy workgroup, organized by the American Academy of Clinical Toxicology, recently conducted a systematic review, which subjectively evaluated lipid emulsion as a treatment for local anesthetic toxicity. We re-extracted data and conducted a meta-analysis of survival in animal models.
Methods: We extracted survival data from 26 publications and conducted a random-effect meta-analysis based on odds ratio weighted by inverse variance. We assessed the benefit of lipid emulsion as an independent variable in resuscitative models (16 studies). We measured Cochran’s Q for heterogeneity and I² to determine variance contributed by heterogeneity. Finally, we conducted a funnel plot analysis and Egger’s test to assess for publication bias in studies.
Results: Lipid emulsion reduced the odds of death in resuscitative models (OR =0.24; 95%CI: 0.1–0.56, p = .0012). Heterogeneity analysis indicated a homogenous distribution. Funnel plot analysis did not indicate publication bias in experimental models.
Discussion: Meta-analysis of animal data supports the use of lipid emulsion (in combination with other resuscitative measures) for the treatment of local anesthetic toxicity, specifically from bupivacaine. Our conclusion differed from the original review. Analysis of outliers reinforced the need for good life support measures (securement of airway and chest compressions) along with prompt treatment with lipid.
... [102,104] ILE was superior in one study (4% of the animal RCS) comparing ILE with vasopressin alone or epinephrine + vasopressin. [92] Lipid infusion was compared to crystalloids, either saline [17,[85][86][87]90,91,94,96,97,[106][107][108][109][110][111] or Ringer's acetate [101] in 15 of the 29 randomized controlled studies (Table 3). Nine (31% of the animal RCS) studies showed therapeutic benefit [85,87,90,91,94,97,106,109,110] and six (21%) no benefit if ILE. [17,86,96,101,107,111] In one study comparing ILE and saline, the control groups were different (electrically initiated ventricular fibrillation versus LA induced venticular fibrillation); this study was therefore considered not useful for evaluating the efficacy of ILE. ...
... [92] Lipid infusion was compared to crystalloids, either saline [17,[85][86][87]90,91,94,96,97,[106][107][108][109][110][111] or Ringer's acetate [101] in 15 of the 29 randomized controlled studies (Table 3). Nine (31% of the animal RCS) studies showed therapeutic benefit [85,87,90,91,94,97,106,109,110] and six (21%) no benefit if ILE. [17,86,96,101,107,111] In one study comparing ILE and saline, the control groups were different (electrically initiated ventricular fibrillation versus LA induced venticular fibrillation); this study was therefore considered not useful for evaluating the efficacy of ILE. [108] Various LA doses were evaluated in the included studies, and these doses were provided in varying units. ...
... Resuscitation treatments were generally initiated immediately or within 3 min of the termination of LA administration (Table 3). Intravenous lipid emulsion was initiated immediately or within one minute in 19 studies [17,85,87,90,92,94,96,98,[100][101][102][103][104]106,110,[116][117][118][119] or less commonly up to 3 min (two studies), [97,105] 4 min (one study), [86] 10 min (two studies), [109,111] or 20 min (one study) [108] after termination of LA administration. The timings of administration of study treatments were not reported in three studies (10%). ...
Background:
Following national and regional recommendations, intravenous lipid emulsion (ILE) has become established in clinical practice as a treatment for acute local anesthetic (LA) toxicity, although evidence of efficacy is limited to animal studies and human case reports. A collaborative lipid emulsion workgroup was therefore established by the American Academy of Clinical Toxicology to review the evidence on the effect of ILE for LA toxicity.
Methods:
We performed a systematic review of the literature published through 15 December 2014. Relevant articles were determined based on pre-defined inclusion and exclusion criteria. Pre-treatment experiments, pharmacokinetic studies not involving toxicity and studies that did not address antidotal use of ILE were excluded.
Results:
We included 113 studies and reports. Of these, 76 were human and 38 animal studies. One publication included both a human case report and an animal study. Human studies included one randomized controlled crossover trial involving 16 healthy volunteers. The subclinical LA toxicity design did not show a difference in the effects of ILE versus saline. There was one case series and 73 case reports of ILE use in the context of toxicity (83 patients) including CNS depression or agitation (n = 45, 54%), seizures (n = 49, 59%), hypotension, hypertension, EKG changes, arrhythmias (n = 39, 47%), cardiac arrest (n = 18, 22%), cardiopulmonary resuscitation, and/or requirement for endotracheal intubation and/or mechanical ventilation (n = 35, 42%). There were 81 (98%) survivors including 63 (76%) with no reported sequelae from the LA poisoning or ILE, although the presence or absence of sequelae was not reported in 15 (18%) cases. Animal studies included 29 randomized controlled studies, three observational studies, five case series, and one case report; bupivacaine was used in 29 of these reports (76%). Of 14 controlled experiments in animals, eight showed improved survival or time to return of spontaneous circulation and five no benefit of ILE versus saline or non-ILE treatments. Combining ILE with epinephrine improved survival in five of the six controlled animal experiments that studied this intervention. The studies were heterogeneous in the formulations and doses of ILE used as well as the doses of LA. The body of the literature identified by this systematic review yielded only a very low quality of evidence.
Conclusion:
ILE appears to be effective for reversal of cardiovascular or neurological features in some cases of LA toxicity, but there is currently no convincing evidence showing that ILE is more effective than vasopressors or to indicate which treatment should be instituted as first line therapy in severe LA toxicity.
... Cardiac index.Systemic vascular resistance index (SVRI)Figure 7shows that bolus injection of lipid solution had no repercussions on SVRI in T 1. However, after starting lipid pump infusion, and after T 20 , all values were higher than at T 0 and T 1 , in addition toT10 <T 20 until T 50 (p=0.0001). No differences between infusion rates were noticed. ...
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.
... 32 Successful lipid rescue has followed local anaesthesia toxicity involving bupivacaine, 30,33 ropivacaine, 34,35 mepivacaine, 35,36 and lignocaine. 35,37 Although Intralipid® has been most commonly used, 31 successful resuscitation from LAST has followed the use of other lipid emulsions such as SMOFlipid in pigs, 38,39 Liposyn III following bupivacaine induced cardiac arrest, 40 and Medialipid. 41 Despite the 20% greater binding efficacy of long-compared with medium-chain triglycerides, 42 Clinoleic® and Intralipid did not bind ropivacaine or bupivacaine differently. ...
Lipid emulsions were introduced into clinical practice more than five decades ago as a calorically dense, non-glucose-based energy source for parenteral nutrition. Recently, intravenous lipid emulsions have been used as rescue for systemic local anaesthetic toxicity. However, the non-nutritive, therapeutic roles of lipid emulsions have recently expanded. This review considers these newer uses of lipid emulsions as drug administration vehicles, for treatment of lipophilic drug toxicity, and as modifiers of ischaemia-reperfusion injury in the anaesthetic and critical care environments. The potential adverse effects of lipid emulsion administration are also succinctly addressed.
Background
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).
Method
Various amounts of SMOFlipid were spiked into pooled seras. We plotted Roche Cobas Serum Indices Lipaemic indices(L-index) against the amount of SMOFlipid added. We then studied the interference thresholds for AST, ALT, 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 TPN regime using pharmacokinetic principles.
Results
SMOFlipid optical behaviour is similar to Intralipid using the Serum indices L-index, with 1mg/dL of SMOFlipid representing 1 unit of L-index. Manufacturer stated interference thresholds are accurate for ALT, AST, albumin, urea and creatinine. High speed centrifugation at 60 min 21100G facilitates the removal of fish-oil based SMOFlipid.
Conclusion
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
Accidental intravascular or high-dose injection of local anesthetics (LA) can result in serious, potentially life-threatening complications. Indeed, adequate supportive measures and the administration of lipid emulsions are required in such complications. The study's objectives were threefold: (i) evaluate the myocardial toxicity of levobupivacaine when administered intravenously; (ii) investigate levobupivacaine toxicity on cardiomyocytes mitochondrial functions and cellular structure; (iii) assess the protective effects of a lipid emulsion in the presence or absence of myocardial ischemia. Domestic pigs randomized into 2 groups of 24 animals each, with either preserved coronary circulation or experimental myocardial ischemia. Six animals from each group received either: a) single IV injection of saline, b) lipid emulsion (Intralipid®), c) levobupivacaine, d) combination levobupivacaine-Intralipid®. Serially measured endpoints included: heart rate, duration of the monophasic action potentials (dMAP), mean arterial pressure, and peak of the time derivative of left ventricular pressure (LV dP/dtmax). In addition, the following cardiomyocytes mitochondrial functions were measured: reactive oxygen species (ROS) production, oxidative phosphorylation and calcium retention capacity (CRC) as well as the consequences of ROS production on lipids, proteins and DNA. IV injection of levobupivacaine induced sinus bradycardia and reduced dMAP and LV dP/dtmax. At the mitochondrial level, oxygen consumption and CRC were decreased. In contrast, ROS production was increased leading to enhanced lipid peroxidation and structural alterations of proteins and DNA. Myocardial ischemia was associated with global worsening of all changes. Intralipid® quickly improved hemodynamics. However, beneficial effects of Intralipid® were less clear after myocardial ischemia.. This article is protected by copyright. All rights reserved.
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 catheterization (Swan-Ganz catheter). After a 30-minute resting period, 5 mg.kg-1 of bupivacaine by intravenous injection was administered and new hemodynamic measures were performed 1 minute later; the animals were than randomly divided into three groups and received 4 ml.kg-1 of one of the two different lipid emulsion with standard long-chaim triglyceride, or mixture of long and medium-chain triglyceride, or saline solution. Hemodynamic changes were then re-evaluated at 5, 10, 15, 20 and 30 minutes.
Bupivacaine intoxication caused fall in arterial blood pressure, cardiac index, ventricular systolic work index mainly and no important changes in vascular resistances. Both emulsion improved arterial blood pressure mainly increasing vascular resistance since the cardiac index had no significant improvement. On the systemic circulation the hemodynamic results were similar with both lipid emulsions.
Both lipid emulsions were efficient and similar options to reverse hypotension in cases of bupivacaine toxicity.
