Early versus delayed postoperative adductor canal block in total knee arthroplasty.

Background: We hypothesized that patients who received an adductor canal block (ACB) in the operating room following unilateral total knee arthroplasty would have a lower oral morphine milligram equivalent (MME) consumption during the postanesthesia care unit (PACU) phase 1 recovery period compared to patients who received an ACB in the PACU. Methods: This was a retrospective cohort study of patients who underwent robotic-assisted unilateral total knee arthroplasty under general anesthesia between March 1, 2020, and February 28, 2021, and received postoperative ACB either in the operating room or the PACU. Results: A total of 36 and 178 patients received postoperative ACB in the operating room and PACU, respectively, and had median and interquartile range MME consumption in the PACU of 22.5 (20-40) mg and 30.0 (20-40) mg (P = 0.76), respectively. Patients who had an ACB performed in the operating room and PACU had median and interquartile ranges of time spent in the PACU of 101 (75-178) minutes and 186 (125-272) minutes (P < 0.01), respectively. Conclusion: Patients who received an ACB in the operating room did not have a lower OME consumption than patients who received an ACB in the PACU but did have a shorter PACU length of stay.

Lipid emulsion for xenobiotic overdose: PRO.

Infusion of lipid emulsion for drug overdose arose as a treatment for local anaesthetic systemic toxicity (LAST) initially based on laboratory results in animal models with the subsequent support of favourable case reports. Following successful translation to the clinic, practitioners also incorporated lipid emulsion as a treatment for non-local anaesthetic toxicities but without formal clinical trials. Recent clinical trials demonstrate a benefit of lipid emulsion in antipsychotic, pesticide, metoprolol and tramadol overdoses. Formal trials of lipid emulsion in LAST may never occur, but alternative analytic tools indicate strong support for its efficacy in this indication; for example, lipid emulsion has obviated the need for cardiopulmonary bypass in most cases of LAST. Herein, we describe the pre-clinical support for lipid emulsion, evaluate the most recent clinical studies of lipid emulsion for toxicity, identify a possible dose-based requirement for efficacy and discuss the limitations to uncontrolled studies in the field.

Heterogeneity and bias in animal models of lipid emulsion therapy: a systematic review and meta-analysis.

INTRODUCTION: Clinicians utilize lipid emulsion to treat local anesthetic toxicity and non-local anesthetic toxicities, a practice supported by animal experimentation and clinical experience. Prior meta-analysis confirmed a mortality benefit of lipid emulsion in animal models of local anesthetic toxicity but the benefit of lipid emulsion in models of non-local anesthetic toxicity remains unanswered. Further, swine suffer an anaphylactoid reaction from lipid emulsions calling into question their role as a model system to study lipid, so we examined swine and non-swine dependent outcomes in models of intravenous lipid emulsion. METHODS: We conducted a systematic review and meta-analysis examining the use of lipid emulsion therapy in animal models of cardiac toxicity. We quantified mortality using a random-effects odds-ratio method. Secondary outcomes included survival in the following subgroups: local-anesthetic systemic toxicity, non-local anesthetic toxicity, swine-based models, and non-swine models (e.g., rat, rabbit and dog). We assessed for heterogeneity with Cochran's Q and I2. We examined bias with Egger's test & funnel plot analysis. RESULTS: Of 2784 references screened, 58 met criteria for inclusion. Treatment with lipid emulsion reduced chance of death in all models of toxicity with an odds ratio of death of 0.26 (95% CI 0.16-0.44, Z-5.21, p < 0.00001, Cohen's-d = 0.72, n = 60). Secondary outcomes confirmed a reduced chance of death in models of local anesthetic toxicity (OR 0.16 {95% CI 0.1-0.33}) and non-local anesthetic toxicity (OR 0.43 {95% CI 0.22-0.83}). Heterogeneity (Cochran's Q 132 {df = 59, p < 0.01}, I 2 = 0.55) arose primarily from animal-model and disappeared (I 2 < = 0.12) when we analyzed swine and non-swine subgroups independently. Swine only benefited in models of local anesthetic toxicity (OR 0.28 {95% CI 0.11-0.7}, p = 0.0033) whereas non-swine models experienced a homogeneous benefit across all toxins (OR 0.1 {95% CI 0.06-0.16}, p < 0.00001). Egger's test identified risk of bias with outliers on funnel plot analysis. DISCUSSION: Lipid emulsion therapy reduces mortality in animal models of toxicity. Heterogeneity arises from the animal-model used. Swine only benefit in models of local anesthetic toxicity, potentially due to lipid dose, experimental design or swine's anaphylactoid reaction to lipid. Outlier analysis reinforced the need for appropriate dosing of lipid emulsion along with airway management and chest compressions in the setting of cardiac arrest.

Local Anesthetic Systemic Toxicity: A Narrative Literature Review and Clinical Update on Prevention, Diagnosis, and Management.

BACKGROUND: The objective of this narrative review of local anesthetic systemic toxicity is to provide an update on its prevention, diagnosis, and management. METHODS: The authors used a MEDLINE search of human studies, animal studies, and case reports and summarize findings following the American Society of Regional Anesthesia and Pain Medicine practice advisories on local anesthetic systemic toxicity. RESULTS: Between March of 2014 and November of 2016, there were 47 cases of systemic toxicity described. Twenty-two patients (47 percent) were treated with intravenous lipid emulsion and two patients (4.3 percent) died. Seizures were the most common presentation. The spectrum of presenting neurologic and cardiovascular symptoms and signs are broad and can be obscured by perioperative processes. Local anesthetic type, dosage, and volume; site of injection; and patient comorbidities influence the rate of absorption from the site of injection and biodegradation of local anesthetics. Consider discussing appropriate dosages as a component of the surgical "time-out." A large-volume depot of dilute local anesthetic can take hours before reaching peak plasma levels. Oxygenation, ventilation, and advanced cardiac life support are the first priorities in treatment. Lipid emulsion therapy should be given at the first sign of serious systemic toxicity with an initial bolus dose of 100 ml for adults weighing greater than 70 kg and 1.5 ml/kg for adults weighing less than 70 kg or for children. CONCLUSION: All physicians who administer local anesthetics should be educated regarding the nature of systemic toxicity and contemporary management algorithms that include lipid emulsion therapy.

The Third American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity: Executive Summary 2017.

The American Society of Regional Anesthesia and Pain Medicine's Third Practice Advisory on local anesthetic systemic toxicity is an interim update from its 2010 advisory. The advisory focuses on new information regarding the mechanisms of lipid resuscitation, updated frequency estimates, the preventative role of ultrasound guidance, changes to case presentation patterns, and limited information related to local infiltration anesthesia and liposomal bupivacaine. In addition to emerging information, the advisory updates recommendations pertaining to prevention, recognition, and treatment of local anesthetic systemic toxicity. WHAT'S NEW IN THIS UPDATE?: This interim update summarizes recent scientific findings that have enhanced our understanding of the mechanisms that lead to lipid emulsion reversal of LAST, including rapid partitioning, direct inotropy, and post-conditioning. Since the previous practice advisory, epidemiological data have emerged that suggest a lower frequency of LAST as reported by single institutions and some registries, nevertheless a considerable number of events still occur within the general community. Contemporary case reports suggest a trend toward delayed presentation, which may mirror the increased use of ultrasound guidance (fewer intravascular injections), local infiltration techniques (slower systemic uptake), and continuous local anesthetic infusions. Small patient size and sarcopenia are additional factors that increase potential risk for LAST. An increasing number of reported events occur outside of the traditional hospital setting and involve non-anesthesiologists.

The Mechanisms Underlying Lipid Resuscitation Therapy.

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.

Lipid emulsion improves survival in animal models of local anesthetic toxicity: a meta-analysis.

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.

Insulin Signaling in Bupivacaine-induced Cardiac Toxicity: Sensitization during Recovery and Potentiation by Lipid Emulsion.

BACKGROUND: The impact of local anesthetics on the regulation of glucose homeostasis by protein kinase B (Akt) and 5'-adenosine monophosphate-activated protein kinase (AMPK) is unclear but important because of the implications for both local anesthetic toxicity and its reversal by IV lipid emulsion (ILE). METHODS: Sprague-Dawley rats received 10 mg/kg bupivacaine over 20 s followed by nothing or 10 ml/kg ILE (or ILE without bupivacaine). At key time points, heart and kidney were excised. Glycogen content and phosphorylation levels of Akt, p70 s6 kinase, s6, insulin receptor substrate-1, glycogen synthase kinase-3ß, AMPK, acetyl-CoA carboxylase, and tuberous sclerosis 2 were quantified. Three animals received Wortmannin to irreversibly inhibit phosphoinositide-3-kinase (Pi3k) signaling. Isolated heart studies were conducted with bupivacaine and LY294002-a reversible Pi3K inhibitor. RESULTS: Bupivacaine cardiotoxicity rapidly dephosphorylated Akt at S473 to 63 ± 5% of baseline and phosphorylated AMPK to 151 ± 19%. AMPK activation inhibited targets downstream of mammalian target of rapamycin complex 1 via tuberous sclerosis 2. Feedback dephosphorylation of IRS1 to 31 ± 8% of baseline sensitized Akt signaling in hearts resulting in hyperphosphorylation of Akt at T308 and glycogen synthase kinase-3ß to 390 ± 64% and 293 ± 50% of baseline, respectively. Glycogen accumulated to 142 ± 7% of baseline. Irreversible inhibition of Pi3k upstream of Akt exacerbated bupivacaine cardiotoxicity, whereas pretreating with a reversible inhibitor delayed the onset of toxicity. ILE rapidly phosphorylated Akt at S473 and T308 to 150 ± 23% and 167 ± 10% of baseline, respectively, but did not interfere with AMPK or targets of mammalian target of rapamycin complex 1. CONCLUSION: Glucose handling by Akt and AMPK is integral to recovery from bupivacaine cardiotoxicity and modulation of these pathways by ILE contributes to lipid resuscitation.

Blood Density Is Nearly Equal to Water Density: A Validation Study of the Gravimetric Method of Measuring Intraoperative Blood Loss.

Purpose. The gravimetric method of weighing surgical sponges is used to quantify intraoperative blood loss. The dry mass minus the wet mass of the gauze equals the volume of blood lost. This method assumes that the density of blood is equivalent to water (1 gm/mL). This study's purpose was to validate the assumption that the density of blood is equivalent to water and to correlate density with hematocrit. Methods. 50 µL of whole blood was weighed from eighteen rats. A distilled water control was weighed for each blood sample. The averages of the blood and water were compared utilizing a Student's unpaired, one-tailed t-test. The masses of the blood samples and the hematocrits were compared using a linear regression. Results. The average mass of the eighteen blood samples was 0.0489 g and that of the distilled water controls was 0.0492 g. The t-test showed P = 0.2269 and R (2) = 0.03154. The hematocrit values ranged from 24% to 48%. The linear regression R (2) value was 0.1767. Conclusions. The R (2) value comparing the blood and distilled water masses suggests high correlation between the two populations. Linear regression showed the hematocrit was not proportional to the mass of the blood. The study confirmed that the measured density of blood is similar to water.

Past, Present, and Future of Lipid Resuscitation Therapy.

Lipid resuscitation therapy was identified in 1998 as an effective treatment for local anesthetic systemic toxicity in an animal model. Since the original observation, the field has progressed tremendously with successful clinical translation and expansion of use to treatment of other types of drug overdose. Recent work has expanded our understanding of the mechanism of this novel treatment, one that includes both a dynamic scavenging component and direct cardiotonic effect. In this review, we discuss the past, present, and future of lipid resuscitation therapy with a focus on our understanding of the mechanism and directions that the field is moving, both from a clinical and basic research side.

Cardiac depression induced by cocaine or cocaethylene is alleviated by lipid emulsion more effectively than by sulfobutylether-ß-cyclodextrin.

OBJECTIVES: Cocaine intoxication leads to over 500,000 emergency department visits annually in the United States and ethanol cointoxication occurs in 34% of those cases. Cardiotoxicity is an ominous complication of cocaine and cocaethylene overdose for which no specific antidote exists. Because infusion of lipid emulsion (Intralipid) can treat lipophilic local anesthetic toxicity and cocaine is an amphipathic local anesthetic, the authors tested whether lipid emulsion could attenuate cocaine cardiotoxicity in vivo. The effects of lipid emulsion were compared with the metabolically inert sulfobutylether-ß-cyclodextrin (SBE-ß-CD; Captisol) in an isolated heart model of cocaine and cocaethylene toxicity to determine if capture alone could exert similar benefit as lipid emulsion, which exhibits multimodal effects. The authors then tested if cocaine and cocaethylene, like bupivacaine, inhibit lipid-based metabolism in isolated cardiac mitochondria. METHODS: For whole animal experiments, Sprague-Dawley rats were anesthetized, instrumented, and pretreated with lipid emulsion followed by a continuous infusion of cocaine to assess time of onset of cocaine toxicity. For ex vivo experiments, rat hearts were placed onto a nonrecirculating Langendorff system perfused with Krebs-Henseleit solution. Heart rate, left ventricle maximum developed pressure (LVdevP), left ventricle diastolic pressure, maximum rate of contraction (+dP/dtmax), maximum rate of relaxation (-dP/dtmax), rate-pressure product (RPP = heart rate × LVdevP), and line pressure were monitored continuously during the experiment. A dose response to cocaine (10, 30, 50, and 100 µmol/L) and cocaethylene (10, 30, and 50 µmol/L) was generated in the absence or presence of either 0.25% lipid emulsion or SBE-ß-CD. Substrate-specific rates of oxygen consumption were measured in interfibrillar cardiac mitochondria in the presence of cocaine, cocaethylene, ecgonine, and benzoylecgonine. RESULTS: Treatment with lipid emulsion delayed onset of hypotension (140 seconds vs. 279 seconds; p = 0.008) and asystole (369 seconds vs. 607 seconds; p = 0.02) in whole animals. Cocaine and cocaethylene induced dose-dependent decreases in RPP, +dP/dtmax, and -dP/dtmaxabs (p < 0.0001) in Langendorff hearts; line pressure was increased by cocaine and cocaethylene infusion, but not altered by treatment. Lipid emulsion attenuated cocaine- and cocaethylene-induced cardiac depression. SBE-ß-CD alone evoked a mild cardiodepressant effect (p < 0.0001) but attenuated further cocaine- and cocaethylene-induced decrements in cardiac contractility at high concentrations of drug (100 µmol/L; p < 0.001). Finally, both cocaine and cocaethylene, but not ecgonine and benzoylecgonine, inhibited lipid-dependent mitochondrial respiration by blocking carnitine exchange (p < 0.05). CONCLUSIONS: A commercially available lipid emulsion was able to delay progression of cocaine cardiac toxicity in vivo. Further, it improved acute cocaine- and cocaethylene-induced cardiac toxicity in rat isolated heart while SBE-ß-CD was effective only at the highest cocaine concentration. Further, both cocaine and cocaethylene inhibited lipid-dependent mitochondrial respiration. Collectively, this suggests that scavenging-independent effects of lipid emulsion may contribute to reversal of acute cocaine and cocaethylene cardiotoxicity, and the beneficial effects may involve mitochondrial lipid processing.