Intravenous lipid emulsion for levobupivacaine intoxication in acidotic and hypoxaemic pigs.

Intravenous lipid emulsion is, in some countries, the recommended treatment for local anaesthetic toxicity. Systemic local anaesthetic toxicity results in hypoxaemia and acidosis, and whether this influences the effects of lipid therapy on drug concentrations and cardiovascular recovery is currently unknown. Twenty anaesthetised pigs were given a 3-mg/kg bolus of levobupivacaine followed by a five minute phase of hypoventilation and 1 mmol/kg of lactic acid in one minute. After lactic acid infusion, pigs were treated, in randomised order, with either 20% lipid emulsion or Ringer's acetate for 30 min: a 1.5-ml/kg bolus followed by a 0.25-ml/kg/minute infusion. Haemodynamic parameters were recorded and blood samples were collected for pharmacokinetic analysis. There was no difference between the groups in the area under the plasma levobupivacaine concentration-time curve (AUC) or between that and AUC of unentrapped levobupivacaine in the Lipid group, or in the plasma half-lives. The cardiovascular outcome and normalisation of the electrocardiogram were similar in both groups. Five pigs developed marked hypotension: one in both groups died, while two in the Lipid group and one in the Ringer group needed adrenaline. Administration of lipid emulsion did not improve cardiovascular recovery from levobupivacaine toxicity exacerbated by acidosis and hypoxaemia. Lipid emulsion did not entrap levobupivacaine or affect levobupivacaine pharmacokinetics.

[Effects of pretreatment of electroacupuncture on bupivacaine poisoning in rats].

OBJECTIVE: To observe the effects of electroacupuncture (EA) pretreatment at different times for heart arrest induced by bupivacaine poisoning in rats. METHODS: With a randomized, blind, control study, 24 SD rats were divided into a control group, a EA for 60 min (EA 60) group and a EA for 30 min (EA 30) group, 8 cases in each one. Rats in the EA 60 group and EA 30 groups were treated with EA at bilateral "Neiguan" (PC 6), "Zusanli" (ST 36) and "Fenglong" (ST 40) for 60 min and 30 min respectively. While no treatment was given in the control group. Then rats were monitored by leadⅡelectrocardiograph; catheters were inserted into the femoral vein to open the vein access and into the carotis to monitor the arterial pressure. Three hours after EA, 10 mg/kg bupivacaine was injected through femoral vein. The mean arterial pressure (MAP) and heart rate (HR) were automatically recorded by PowerLab system. The time points when QRS widened by 20 percent and cardiac arrest and the survival rates were observed. RESULTS: After the injection of bupivacaine, five rats in the EA 60 group caught cardiac arrest,while all the rats in the other two groups caught it. The survival rates were not statistically significant among the three groups (P>0.05). The time of QRS widening by 20 percent in the EA 60 group was (87.4±14.8) s,which was longer than (63.6±14.2) s in the EA 30 group and (51.2±12.4) s in the control group (both P<0.05). From injection of bupivacaine to cardiac arrest, the time of (375.3±23.7) s in the EA 60 group and that of (328.3±47.7)s in the EA 30 group were more than (235.5±91.5) s in the control group (both P<0.05). After the injection, MAP and HR in the EA 60 group were higher than those in the EA 30 group and control group at most time points (all P<0.05). CONCLUSIONS: EA pretreatment apparently decreases the vulnerability of bupivacaine-induced heart arrest, with better protective effect of 60 min pretreatment than that of 30 min.

Case discussion and root cause analysis: bupivacaine overdose in an infant leading to ventricular tachycardia.

An otherwise healthy 11-month-old, 8-kg infant presented for an elective circumcision. After a penile block with an excessive dose of 0.5% bupivacaine, the patient progressed to ventricular tachycardia. He was resuscitated with intralipid and had an uneventful recovery. The case was classified as a serious safety event, and a team was created to perform a root cause analysis. A sequence of events was constructed from gathered data, and policies and procedures were reviewed. Proximate cause was determined to be the failure of the surgeon, anesthesiologist, nurse, and scrub technician to communicate about the maximum dose of local anesthetic allowed before the medication being drawn up. Interventions were developed to target the proximate and contributing causes.

Successful Resuscitation With Intralipid After Marcaine Overdose.

UNLABELLED: The authors present the case of a 32-year-old woman who underwent concomitant abdominoplasty and mastopexy. Before discharge from the recovery room, she experienced cardiac arrest and seizures resulting from an accidental overdose of Marcaine, caused by failure of an intramuscular pain pump. The anesthesiologist initiated a rescue protocol with an Intralipid 20% bolus (1.5 mg/kg), followed by continuous intravenous infusion of 0.25 mg/kg for 60 minutes. The Intralipid intervention resulted in a successful outcome. This case emphasizes the importance of ensuring the availability of Intralipid 20% infusion in the operating room. Plastic surgeons who place postoperative pain pumps must be aware of this method of resuscitation and its effectiveness in treating possible cases of local anesthetic overdose or toxicity. LEVEL OF EVIDENCE: 5.

Lipid rescue 911: Are poison centers recommending intravenous fat emulsion therapy for severe poisoning?

Intravenous fat emulsion (IFE) therapy is a novel treatment that has been used to reverse the acute toxicity of some xenobiotics with varied success. We sought to determine how US Poison Control Centers (PCCs) have incorporated IFE as a treatment strategy for poisoning. A closed-format multiple-choice survey instrument was developed, piloted, revised, and then sent electronically to every medical director of an accredited US PCC in March 2011. Addresses were obtained from the American Association of Poison Control Centers listserv, and participation was voluntary and remained anonymous. Data were analyzed using descriptive statistics. The majority of PCC medical directors completed the survey (45 out of 57; 79 %). Of the 45 respondents, all felt that IFE therapy played a role in the acute overdose setting. Most PCCs (30 out of 45; 67 %) have a protocol for IFE therapy. In a scenario with "cardiac arrest" due to a single xenobiotic, directors stated that their center would "always" or "often" recommend IFE after overdose of bupivacaine (43 out of 45; 96 %), verapamil (36 out of 45; 80 %), amitriptyline (31 out of 45; 69 %), or an unknown xenobiotic (12 out of 45; 27 %). In a scenario with "shock" due to a single xenobiotic, directors stated that their PCC would "always" or "often" recommend IFE after overdose of bupivacaine (40 out of 45; 89 %), verapamil (28 out of 45; 62 %), amitriptyline (25 out of 45; 56 %), or an unknown xenobiotic (8 out of 45; 18 %). IFE therapy is being recommended by US PCCs; protocols and dosing regimens are nearly uniform. Most directors feel that IFE is safe but are more likely to recommend IFE in patients with cardiac arrest than in patients with severe hemodynamic compromise.

Local anesthetic systemic toxicity: a historical perspective.

The most feared complication associated with the administration of local anesthetics is the profound and potentially lethal effect that these agents can have on cardiac conduction and function. This review traces the evolution of local anesthetic systemic toxicity beginning with the early deaths associated with the introduction of cocaine into clinical practice. The development of bupivacaine is discussed, with particular emphasis on the delayed recognition and acceptance of its inherent cardiotoxicity. Finally, the origins of lipid resuscitation are reviewed with respect to their theoretical foundation, as well as the confluence of events and experimental investigations that delivered this therapy into clinical practice.

A physiologically based pharmacokinetic (PBPK) model for predicting the efficacy of drug overdose treatment with liposomes in man.

Physiologically based pharmacokinetic (PBPK) models were developed for design and optimization of liposome therapy for treatment of overdoses of tricyclic antidepressants and local anesthetics. In vitro drug-binding data for pegylated, anionic liposomes and published mechanistic equations for partition coefficients were used to develop the models. The models were proven reliable through comparisons to intravenous data. The liposomes were predicted to be highly effective at treating amitriptyline overdoses, with reductions in the area under the concentration versus time curves (AUC) of 64% for the heart and brain. Peak heart and brain drug concentrations were predicted to drop by 20%. Bupivacaine AUC and peak concentration reductions were lower at 15.4% and 17.3%, respectively, for the heart and brain. The predicted pharmacokinetic profiles following liposome administration agreed well with data from clinical studies where protein fragments were administered to patients for overdose treatment. Published data on local cardiac function were used to relate the predicted concentrations in the body to local pharmacodynamic effects in the heart. While the results offer encouragement for future liposome therapies geared toward overdose, it is imperative to point out that animal experiments and phase I clinical trials are the next steps to ensuring the efficacy of the treatment.

Local anesthetic systemic toxicity.

PURPOSE: The practice of regional anesthesia has been revitalized of late with the popularization of ultrasound-guided techniques. Advocates must be vigilant for the effects of unintentionally high blood levels of local anesthetic. Systemic local anesthetic toxicity, though rare, is a potentially devastating occurrence. This narrative review summarizes the effects of local anesthetic toxicity. We highlight how these toxic effects have motivated the search for a safe and long-acting local anesthetic. We outline current prevention and treatment options and appraise an emerging therapy in light of unfolding evidence. SOURCES: A search of the English language literature was conducted using the PubMed database from the National Library of Medicine. Bibliographies of retrieved articles were used to retrieve additional articles. PRINCIPAL FINDINGS: The advent of multiple safety steps has led to a dramatic reduction in the incidence of local anesthetic toxicity over the past 30 years. Rising plasma levels of local anesthetic lead to a progressive spectrum of neurological and cardiac effects. Seizure activity may herald the onset of myocardial depression and ventricular arrhythmias that are often refractory to treatment. In addition to specific measures, such as lipid emulsion therapy, general supportive measures are warranted, for example, Advanced Life Support Guidelines. CONCLUSION: Vigilance during the performance of regional anesthesia and immediate intervention at the earliest sign of toxicity improve the chances of successful treatment.

Preliminary results of the Australasian Regional Anaesthesia Collaboration: a prospective audit of more than 7000 peripheral nerve and plexus blocks for neurologic and other complications.

BACKGROUND AND OBJECTIVES: Peripheral nerve blockade is associated with excellent patient outcomes after surgery; however, neurologic and other complications can be devastating for the patient. This article reports the development and preliminary results of a multicenter audit describing the quality and safety of peripheral nerve blockade. METHODS: From January 2006 to May 2008, patients who received peripheral nerve blockade had data relating to efficacy and complications entered into databases. All patients who received nerve blocks performed by all anesthetists during each hospital's contributing period were included. Patients were followed up by phone to detect potential neurologic complications. The timing of follow-up was either at 7 to 10 days or 6 weeks postoperatively, depending on practice location and time period. Late neurologic deficits were defined as a new onset of sensory and/or motor deficit consistent with a nerve/plexus distribution without other identifiable cause, and one of the following: electrophysiologic evidence of nerve damage, new neurologic signs, new onset of neuropathic pain in a nerve distribution area, paresthesia in relevant nerve/plexus distribution area. RESULTS: A total of 6950 patients received 8189 peripheral nerve or plexus blocks. Of the 6950 patients, 6069 patients were successfully followed up. In these 6069 patients, there were a total of 7156 blocks forming the denominator for late neurologic complications. Thirty patients (0.5%) had clinical features requiring referral for neurologic assessment. Three of the 30 patients had a block-related nerve injury, giving an incidence of 0.4 per 1000 blocks (95% confidence interval, 0.08-1.1:1000). The incidence of systemic local anesthetic toxicity was 0.98 per 1000 blocks (95% confidence interval, 0.42-1.9:1000). CONCLUSIONS: These results indicate that the incidence of serious complications after peripheral nerve blockade is uncommon and that the origin of neurologic symptoms/signs in the postoperative period is most likely to be unrelated to nerve blockade.

[Fatal poisoning with the local anesthetic bupivacaine].

Lethal concentration of bupivacaine was determined based on the examination of a case of poisoning with this local anesthetic agent taken at a dose 5 times the normal value. This study is of special interest taking into consideration the lack of data on toxic and lethal doses of bupivacaine in splanchnic organs and tissues in the literature.

Fatal bupivacaine intoxication following unusual erotic practices.

A fatal drug overdose is described which involved unusual erotic practices. A 54-year-old male was discovered supine on the floor surrounded by sexual paraphernalia, syringes, and medications including three empty bottles of bupivacaine. Acute and chronic injection sites of the external genitalia with contusions, scarring, focal necrosis, and calcification were present at autopsy. Toxicology revealed femoral blood, heart blood, and vitreous bupivacaine concentrations of 3.8, 2.8 and 1.3 mg/L, respectively. The urine bupivacaine concentration was 11.4 mg/L. The cause of death was attributed to bupivacaine intoxication and the manner of death was accidental.

Beta2-adrenoceptor agonist fenoterol enhances functional repair of regenerating rat skeletal muscle after injury.

Beta(2)-adrenoceptor agonists such as fenoterol are anabolic in skeletal muscle, and because they promote hypertrophy and improve force-producing capacity, they have potential application for enhancing muscle repair after injury. No previous studies have measured the beta(2)-adrenoceptor population in regenerating skeletal muscle or determined whether fenoterol can improve functional recovery in regenerating muscle after myotoxic injury. In the present study, the extensor digitorum longus (EDL) muscle of the right hindlimb of deeply anesthetized rats was injected with bupivacaine hydrochloride, which caused complete degeneration of all muscle fibers. The EDL muscle of the left hindlimb served as the uninjured control. Rats received either fenoterol (1.4 mg x kg(-1) x day(-1)) or an equal volume of saline for 2, 7, 14, or 21 days. Radioligand binding assays identified a approximately 3.5-fold increase in beta(2)-adrenoceptor density in regenerating muscle at 2 days postinjury. Isometric contractile properties of rat EDL muscles were measured in vitro. At 14 and 21 days postinjury, maximum force production (P(o)) of injured muscles from fenoterol-treated rats was 19 and 18% greater than from saline-treated rats, respectively, indicating more rapid restoration of function after injury. The increase in P(o) in fenoterol-treated rats was due to increases in muscle mass, fiber cross-sectional area, and protein content. These findings suggest a physiological role for beta(2)-adrenoceptor-mediated mechanisms in muscle regeneration and show clearly that fenoterol hastens recovery after injury, indicating its potential therapeutic application.

Blood pressure is maintained despite profound myocardial depression during acute bupivacaine overdose in pigs.

UNLABELLED: Bupivacaine-induced cardiovascular collapse is a feared complication because of the difficulty in restoring stable circulation (1). Early recognition is important so that the injection of bupivacaine can be discontinued. We used an animal model of near-cardiac arrest from bupivacaine infusion to identify the sequence of hemodynamic events that precedes bupivacaine-induced cardiovascular collapse. Twelve pigs (23-25 kg) were sedated with ketamine and anesthetized with halothane. Arterial blood pressure and cardiac output were measured. Bupivacaine (3.75 mg/mL) was administered at a rate of 5.73 mL/min (approximately 1 mg x kg(-1) x min(-1)) through a central venous catheter until severe ventricular arrhythmia occurred. Blood pressure and heart rate were unchanged, but cardiac output decreased by 40% with increasing doses of bupivacaine. Calculated peripheral resistance increased by 54%. The QRS complex of the surface electrocardiogram widened, and the R-wave amplitude decreased 80%, together with the decrease in cardiac output. T-wave amplitude increased initially but returned toward baseline at the largest bupivacaine doses. The plasma concentration of bupivacaine after the infusion was 16+/-6.8 microg/mL. IMPLICATIONS: The increase in vascular resistance that accompanies acute bupivacaine overdose maintains blood pressure but masks severe myocardial depression.

The safety of continuous pleural lignocaine after thoracotomy in children and adolescents.

Several studies have proven pleural bupivacaine effectively provides postthoracotomy analgesia for both children and adults. When 0.25% bupivacaine is administered as a continuous infusion or repeated bolus, serum bupivacaine levels frequently approach the toxic range. The hazards of bupivacaine toxicity are more difficult to monitor, especially in children who may not report symptoms of local anaesthetic toxicity. Because of this concern, we initiated the use of pleural lignocaine to provide postthoracotomy analgesia for paediatric patients. The records of all patients receiving pleural lignocaine from January 1991 to December 1992 were reviewed. A total of 98 pleural catheters were inserted in 96 patients ranging in age from five months to 20 years. Seven patients had lignocaine levels that exceeded 5 micrograms.ml-1 and no patient manifested symptoms of systemic toxicity. This study shows that the administration of pleural lignocaine is a safe method of providing postthoracotomy analgesia. Lignocaine infusions in the dosage range of 20 to 40 micrograms.kg-1.min-1 rarely produce toxic levels, and monitoring of lignocaine levels every 12 h is an effective method of screening for toxicity.