Guy Weinberg

Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats.

Background The authors sought to confirm a chance observation that intravenous lipid treatment increases the dose of bupivacaine required to produce asystole in rats. The authors also measured the partitioning of bupivacaine between the lipid and aqueous phases of a plasma‐lipid emulsion mixture. Methods Anesthetized Sprague‐Dawley rats were used in pretreatment (protocol 1) and resuscitation (protocol 2) experiments. In protocol 1, animals were pretreated with saline or 10%, 20%, or 30% Intralipid (n = 6 for all groups), then received 0.75% bupivacaine hydrochloride at a rate of 10 ml [center dot] kg [center dot] min sup ‐1 to asystole. In protocol 2, mortality was compared over a range of bolus doses of bupivacaine after resuscitation with either saline or 30% Intralipid (n = 6 for all groups). The lipid:aqueous partitioning of bupivacaine in a mixture of plasma and Intralipid was measured using radiolabeled bupivacaine. Results Median doses of bupivacaine (in milligrams per kilogram) producing asystole in protocol I were for 17.7 for saline, 27.6 for 10% Intralipid, 49.7 for 20% Intralipid, and 82.0 for 30% Intralipid (P <0.001 for differences between all groups). Differences in mean +/‐ SE concentrations of bupivacaine in plasma (in micrograms per milliliter) were significant (P < 0.05) for the difference between saline (93.3 +/‐ 7.6) and 30% Intralipid (212 +/‐ 45). In protocol 2, lipid infusion increased the dose of bupivacaine required to cause death in 50% of animals by 48%, from 12.5 to 18.5 mg/kg. The mean lipid:aqueous ratio of concentrations of bupivacaine in a plasma‐Intralipid mixture was 11.9 +/‐ 1.77 (n = 3). Conclusions Lipid infusion shifts the dose‐response to bupivacaine‐induced asystole in rats. Partitioning of bupivacaine into the newly created lipid phase may partially explain this effect. These results suggest a potential application for lipid infusion in treating cardiotoxicity resulting from bupivacaine.

Lipid Emulsion Infusion Rescues Dogs From Bupivacaine-Induced Cardiac Toxicity

Background and Objectives We previously demonstrated in rats that intravenous infusion of a lipid emulsion increases survival in resuscitation from severe bupivacaine cardiac toxicity. The present studies were undertaken to determine if this method is similarly effective in a non-rodent model using a larger animal. Methods Bupivacaine, 10 mg/kg, was administered intravenously over 10 seconds to fasted dogs under isoflurane general anesthesia. Resuscitation included 10 minutes of internal cardiac massage followed with either saline or 20% lipid infusion, administered as a 4-mL/kg bolus followed by continuous infusion at 0.5 mL/kg/min for 10 minutes. Electrocardiogram (EKG), arterial blood pressure (BP), and myocardial pH (pHm) and pO2 (pmO2) were continuously measured. Results Survival after 10 minutes of unsuccessful cardiac massage was successful for all lipid-treated dogs (n = 6), but with no survivors in the saline controls (n = 6) (P < .01). Hemodynamics, PmO2, and pHm were improved during resuscitation with lipid compared with saline treatment in which dogs did not recover. Conclusions We found that infusing a lipid emulsion during resuscitation from bupivacaine-induced cardiac toxicity substantially improved hemodynamics, pmO2, and pHm and increased survival in dogs.

ASRA practice advisory on local anesthetic systemic toxicity.

The American Society of Regional Anesthesia and Pain Medicine Practice Advisory on Local Anesthetic Systemic Toxicity assimilates and summarizes current knowledge regarding the prevention, diagnosis, and treatment of this potentially fatal complication. It offers evidence-based and/or expert opinion-based recommendations for all physicians and advanced practitioners who routinely administer local anesthetics in potentially toxic doses. The advisory does not address issues related to local anesthetic-related neurotoxicity, allergy, or methemoglobinemia. Recommendations are based primarily on animal and human experimental trials, case series, and case reports. When objective evidence is lacking or incomplete, recommendations are supplemented by expert opinion from the Practice Advisory Panel plus input from other experts, medical specialty groups, and open forum. Specific recommendations are offered for the prevention, diagnosis, and treatment of local anesthetic systemic toxicity.

Peroxisome proliferator-activated receptor-γ agonists prevent experimental autoimmune encephalomyelitis

The development of clinical symptoms in multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE) involves T‐cell activation and migration into the central nervous system, production of glial‐derived inflammatory molecules, and demyelination and axonal damage. Ligands of the peroxisome proliferator‐activated receptor (PPAR) exert anti‐inflammatory effects on glial cells, reduce proliferation and activation of T cells, and induce myelin gene expression. We demonstrate in two models of EAE that orally administered PPARγ ligand pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein. Pioglitazone also reduced clinical signs when it was provided after disease onset. Clinical symptoms were reduced by two other PPARγ agonists, suggesting a role for PPARγ activation in protective effects. The suppression of clinical signs was paralleled by decreased lymphocyte infiltration, lessened demyelination, reduced chemokine and cytokine expression, and increased inhibitor of kappa B (IkB) expression in the brain. Pioglitazone also reduced the antigen‐dependent interferon‐γ production from EAE‐derived T cells. These results suggest that orally administered PPARγ agonists could provide therapeutic benefit in demyelinating disease.

Lipid infusion accelerates removal of bupivacaine and recovery from bupivacaine toxicity in the isolated rat heart.

Background and Objectives: Infusion of a lipid emulsion has been advocated for treatment of severe bupivacaine cardiac toxicity. The mechanism of lipid rescue is unknown. These studies address the possibility that lipid infusion reduces cardiac bupivacaine content in the context of cardiac toxicity. Methods: We compared the effects of a 1% lipid emulsion with standard Krebs buffer after inducing asystole in isolated rat heart with 500 μmol/L bupivacaine. We compared times to first heart beat and recovery of 90% of baseline rate pressure product (RPP = heart rate × [left ventricular systolic pressure − left ventricular diastolic pressure]) between controls and hearts receiving 1% lipid immediately after bupivacaine. We also used minibiopsies to compare control bupivacaine tissue content with hearts getting lipid immediately after an infusion of radiolabeled bupivacaine. We then compared bupivacaine efflux from hearts with and without lipid infusion started 75 seconds after radiolabeled bupivacaine was administered. Results: Infusion of lipid resulted in more rapid return of spontaneous contractions and full recovery of cardiac function. Average (± SEM) times to first beat and to 90% recovery of rate pressure product were 44.6 ± 3.5 versus 63.8 ± 4.3 seconds (P < .01) and 124.7 ± 12.4 versus 219.8 ± 25.6 seconds (P < .01) for lipid and controls, respectively. Lipid treatment resulted in more rapid loss of bupivacaine from heart tissue (P < .0016). Late lipid infusion, 75 seconds after bupivacaine infusion ended, increased the release of bupivacaine measured in effluent for the first 15-second interval compared with controls (183 vs. 121 nmol, n = 5 for both groups, P < .008). Conclusions: Lipid emulsion speeds loss of bupivacaine from cardiac tissue while accelerating recovery from bupivacaine-induced asystole. These findings are consistent with the hypothesis that bupivacaine partitions into the emulsion and supports the concept of a “lipid sink.” However, the data do not exclude other possible mechanisms of action.

Resuscitation with Lipid versus Epinephrine in a Rat Model of Bupivacaine Overdose

Background:Lipid emulsion infusion reverses cardiovascular compromise due to local anesthetic overdose in laboratory and clinical settings. The authors compared resuscitation with lipid, epinephrine, and saline control in a rat model of bupivacaine-induced cardiac toxicity to determine whether lipid provides a benefit over epinephrine. Methods:Bupivacaine, 20 mg/kg, was infused in rats anesthetized with isoflurane, producing asystole in all subjects. Ventilation with 100% oxygen and chest compressions were begun immediately, along with intravenous treatment with 30% lipid emulsion or saline (5-ml/kg bolus plus continuous infusion at 0.5 ml · kg−1 · min−1) or epinephrine (30 &mgr;g/kg). Chest compressions were continued and boluses were repeated at 2.5 and 5 min until the native rate–pressure product was greater than 20% baseline. Electrocardiogram and arterial pressure were monitored continuously and at 10 min, arterial blood gas, central venous oxygen saturation, and blood lactate were measured. Effect size (Cohen d) was determined for comparisons at 10 min. Results:Lipid infusion resulted in higher rate–pressure product (P < 0.001, d = 3.84), pH (P < 0.01, d = 3.78), arterial oxygen tension (P < 0.05, d = 2.8), and central venous oxygen saturation (P < 0.001, d = 4.9) at 10 min than did epinephrine. Epinephrine treatment caused higher lactate (P < 0.01, d = 1.48), persistent ventricular ectopy in all subjects, pulmonary edema in four of five rats, hypoxemia, and a mixed metabolic and respiratory acidosis by 10 min. Conclusions:Hemodynamic and metabolic metrics during resuscitation with lipid surpassed those with epinephrine, which were no better than those seen in the saline control group. Further studies are required to optimize the clinical management of systemic local anesthetic toxicity.

Bupivacaine Inhibits Acylcarnitine Exchange in Cardiac Mitochondria

Background The authors previously reported that secondary carnitine deficiency may sensitize the heart to bupivacaine-induced arrhythmias. In this study, the authors tested whether bupivacaine inhibits carnitine metabolism in cardiac mitochondria. Methods Rat cardiac interfibrillar mitochondria were prepared using a differential centrifugation technique. Rates of adenosine diphosphate–stimulated (state III) and adenosine diphosphate–limited (state IV) oxygen consumption were measured using a Clark electrode, using lipid or nonlipid substrates with varying concentrations of a local anesthetic. Results State III respiration supported by the nonlipid substrate pyruvate (plus malate) is minimally affected by bupivacaine concentrations up to 2 mM. Lower concentrations of bupivacaine inhibited respiration when the available substrates were palmitoylcarnitine or acetylcarnitine; bupivacaine concentration causing 50% reduction in respiration (IC50 ± SD) was 0.78 ± 0.17 mM and 0.37 ± 0.03 mM for palmitoylcarnitine and acetylcarnitine, respectively. Respiration was equally inhibited by bupivacaine when the substrates were palmitoylcarnitine alone, or palmitoyl–CoA plus carnitine. Bupivacaine (IC50 = 0.26 ± 0.06 mM) and etidocaine (IC50 = 0.30 ± 0.12 mM) inhibit carnitine-stimulated pyruvate oxidation similarly, whereas the lidocaine IC50 is greater by a factor of roughly 5, (IC50 = 1.4 ± 0.26 mM), and ropivacaine is intermediate, IC50 = 0.5 ± 0.28 mM. Conclusions Bupivacaine inhibits mitochondrial state III respiration when acylcarnitines are the available substrate. The substrate specificity of this effect rules out bupivacaine inhibition of carnitine palmitoyl transferases I and II, carnitine acetyl- transferase, and fatty acid &bgr;-oxidation. The authors hypothesize that differential inhibition of carnitine-stimulated pyruvate oxidation by various local anesthetics supports the clinical relevance of inhibition of carnitine–acylcarnitine translocase by local anesthetics with a cardiotoxic profile.

Noradrenergic regulation of inflammatory gene expression in brain.

It is now well accepted that inflammatory events contribute to the pathogenesis of numerous neurological disorders, including multiple sclerosis (MS), Alzheimers disease (AD), Parkinsons disease, and AIDs dementia. Whereas inflammation in the periphery is subject to rapid down regulation by increases in anti-inflammatory molecules and the presence of scavenging soluble cytokine receptors, the presence of an intact blood-brain barrier may limit a similar autoregulation from occurring in brain. Mechanisms intrinsic to the brain may provide additional immunomodulatory functions, and whose dysregulation could contribute to increased inflammation in disease. The findings that noradrenaline (NA) reduces cytokine expression in microglial, astroglial, and brain endothelial cells in vitro, and that modification of the noradrenergic signaling system occurs in some brain diseases having an inflammatory component, suggests that NA could act as an endogenous immunomodulator in brain. Furthermore, accumulating studies indicate that modification of the noradrenergic signaling system occurs in some neurodiseases. In this article, we will briefly review the evidence that NA can modulate inflammatory gene expression in vitro, summarize data supporting a similar immunomodulatory role in brain, and present recent data implicating a role for NA in attenuating the cortical inflammatory response to beta amyloid protein.

Lipid emulsion infusion: Resuscitation for local anesthetic and other drug overdose

It seems implausible that an injection of a simple, off-the-shelf, intravenous nutritional solution could be acutely life-saving for a patient with severe drug overdose. Yet, dozens of published case reports support this observation, first made more than a decade ago in a rodent model of bupivacaine toxicity. It is even more surprising that such a simple formulation can rapidly reverse severe clinical toxicity from a variety of vastly disparate medications with distinct pharmacodynamics and mechanisms of action. This review will focus on the clinical application of lipid emulsion therapy in resuscitation from drug-related toxicity and provide an introduction to the development of the method, guidelines for its use and insights into potential controversies and future applications.

Clinical presentation of local anesthetic systemic toxicity: a review of published cases, 1979 to 2009.

The classic description of local anesthetic systemic toxicity (LAST) generally described in textbooks includes a series of progressively worsening neurologic symptoms and signs occurring shortly after the injection of local anesthetic and paralleling progressive increases in blood local anesthetic concentration, culminating in seizures and coma. In extreme cases, signs of hemodynamic instability follow and can lead to cardiovascular collapse. To characterize the clinical spectrum of LAST and compare it to the classic picture described above, we reviewed published reports of LAST during a 30-year period from 1979 to 2009. Ninety-three cases were identified and analyzed with respect to onset of toxicity and the spectrum of signs and symptoms. Sixty percent of cases followed the classic pattern of presentation. However, in the remainder of cases, symptoms were substantially delayed after the injection of local anesthetic, or involved only signs of cardiovascular compromise, with no evidence of central nervous system toxicity. Although information gained from retrospective case review cannot establish incidence, outcomes, or comparative efficacies of treatment, it can improve awareness of the clinical spectrum of LAST and, theoretically, the diagnosis and treatment of affected patients. The analytic limitations of our method make a strong case for developing a prospective, global registry of LAST as a robust alternative for educating practitioners and optimizing management of LAST.