Adding bupivacaine to high-potassium cardioplegia improves function and reduces cellular damage of rat isolated hearts after prolonged, cold storage

BACKGROUND: Bupivacaine retards myocardial acidosis during ischemia. The authors measured function of rat isolated hearts after prolonged storage to determine whether bupivacaine improves cardiac protection compared with standard cardioplegia alone. METHODS: After measuring cardiac function on a Langendorff apparatus, hearts were perfused with cardioplegia alone (controls), cardioplegia containing 500 microm bupivacaine, or cardioplegia containing 2 mm lidocaine; were stored at 4 degrees C for 12 h; and were then reperfused. Heart rate and left ventricular developed pressures were measured for 60 min. Maximum positive rate of change in ventricular pressure, oxygen consumption, and lactate dehydrogenase release were also measured. RESULTS: All bupivacaine-treated, four of five lidocaine-treated, and no control hearts beat throughout the 60-min recovery period. Mean values of heart rate, left ventricular developed pressure, maximum positive rate of change in ventricular pressure, rate-pressure product, and efficiency in bupivacaine-treated hearts exceeded those of the control group (P < 0.001 at 60 min for all). Mean values of the lidocaine group were intermediate. Oxygen consumption of the control group exceeded the other groups early in recovery, but not at later times. Lactate dehydrogenase release from the bupivacaine group was less than that from the control group (P < 0.001) but did not differ from baseline. CONCLUSIONS: Adding bupivacaine to a depolarizing cardioplegia solution reduces cell damage and improves cardiac function after prolonged storage. Metabolic inhibition may contribute to this phenomenon, which is not entirely explained by sodium channel blockade.     

肾上腺素复苏布比卡因所致大鼠离体心脏停跳的能力研究

目的 研究肾上腺素复苏布比卡因所致大鼠离体心脏停跳的能力. 方法 成年雄性SD大鼠24只,按照随机数字法分为B40组、EB40组、B50组和EB50组(每组6只).制作Langendorff离体心脏灌流模型,以100 μmol/L布比卡因诱导心脏停跳后继续灌注3 min,造模成功.B40组,含40 μmol/L布比卡因的K-H液灌流20 min;EB40组,含40 μmol/L布比卡因和0.15 mg/L肾上腺素的K-H液灌流20 min;B50组,含50 μmol/L布比卡因的K-H液灌流20 min;EB50组,含50 μmol/L布比卡因和0.15 mg/L肾上腺素的K-H液灌流10 min,复跳后继续灌流,如未复跳则增加肾上腺素浓度为0.3 mg/L继续灌流10 min.比较各组复跳情况以及复灌20 min内离体心脏心功能参数,包括HR、左室发展压(left ventricular developed pressure,LvdevP)、HR和左室发展压乘积(rate-pressure product,RPP)及冠状动脉流量(coronary flow,CF). 结果 EB40组复跳率100％明显高于其他3组复跳率(0)(P＜0.01);EB40组离体心脏的复跳时间为(35±9)s,复跳后再发停跳时间为(568±182)s;增加肾上腺素浓度为0.3 mg/L后,EB50组离体心脏仍未复跳.复灌20 min期间,EB40组和EB50组的CF高于B40组和B50组(P＜0.01).结论 肾上腺素复苏布比卡因所致大鼠离体心脏停跳的能力与布比卡因浓度有关,布比卡因浓度为40～50 μmol/L时,肾上腺素的复苏能力可能无法显示.     

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).     

脂肪乳剂、肾上腺素及脂肪乳剂复合肾上腺素对布比卡因诱导离体大鼠心脏停搏的复苏作用比较

背景目前对于脂肪乳剂复合肾上腺素治疗布比卡因的心脏毒性是否优于单纯脂肪乳剂或肾上腺素尚不清楚。我们比较了在治疗布比卡因引起的离体大鼠心脏停搏中脂肪乳剂、肾上腺素及复合物的作用。同时也测定了脂肪乳剂、肾上腺素及其复合物对布比卡因在心脏组织中浓度的影响。方法从Sprague—Dawley雄性大鼠游离出心脏并进行再灌注建立Langendofrr离体心脏灌注模型。以100μmol／L布比卡因诱导心脏停搏后继续灌注3分钟。脂肪乳剂组含2％脂肪乳剂复合30μmol／L布比卡因;肾上腺素组含0．15μg／ml肾上腺素复合30μmol／L布比卡因;脂肪乳剂复合肾上腺素组含2％脂肪乳剂复合0．15μg／ml肾上腺素及30μmol／L布比卡因;单独以30μmol／L布比卡因灌注为对照组。心脏复跳的定义为有自主规则的心律,恢复后心率血压乘积（rate．pressureproduct,RPP）值〉基础值的10％且持续1分钟以上。我们比较每组100μmol／L布比卡因输注结束至心脏复跳的时间。复跳后对心功能变化继续观察40分钟。4组中能复跳的心脏于试验末截取心尖心肌采用高效液相色谱法测定心肌组织中布比卡因的浓度。结果脂肪乳剂组和复合组的心脏复跳时间（Trecovery）显著短于肾上腺素组和对照组（P〈0．001）,肾上腺素组的T短于对照组（P〈0．）。心脏复跳后分钟内4组平均值从高到低依次排序为复合组〉脂肪乳剂组、肾上腺素组〉对照组（P〈0．01）。心脏复跳过程中RPP的最大值（RPPmaximum）、RPPmaximum与基础值之比（RPPmaximum／RPPbaselinc）从最高到最低的依次排序为复合组〉脂肪乳剂组、肾上腺素组〉对照组（P〈0．01）。RPPmaximum 、RPPmaximum／RPPbaseline在脂肪乳剂组和肾上腺素组之间无显著差异。肾上腺素组和对照组中的心肌组织中布比卡因的浓度高于脂肪乳剂组和复合组（P〈0．001）。结论脂肪乳剂复合肾上腺素治疗布比卡因诱导的离体大鼠心脏停搏,较单纯使用脂肪乳剂或肾上腺素能更好地改善复苏后的心脏功能。     

Effect of intravenous lipid emulsion on bupivacaine plasma concentration in humans

Intravenous lipid emulsion is the recommended treatment for severe local anaesthetic intoxication. Lipid emulsion may entrap lipid soluble drugs by functioning as a 'lipid sink', but its effect on bupivacaine pharmacokinetics remains unknown. In this randomised, double-blind, crossover study, eight healthy male volunteers were infused bupivacaine 0.5mg.kg(-1) intravenously over 20 min, followed by an infusion of either intravenous lipid emulsion or Hartmann's solution for 30 min. At 20 and 30 min after the start of the infusion, the total plasma bupivacaine concentration was lower while receiving lipid emulsion than Hartmann's solution (mean difference 111 (95% CI 55-167) μg.l(-1) and 75 (95% CI 26-124 μg.l(-1) at 20 and 30 min, respectively; p<0.02). However, there were no differences in un-entrapped (non-lipid bound) or free (non-protein bound) bupivacaine plasma concentrations during the infusion. Intravenous lipid emulsion infusion reduced the context-sensitive half-life of total plasma bupivacaine from 45 (95% CI 32-76)min to 25 (95% CI 20-33)min; p=0.01. We observed no significant adverse effects of lipid emulsion. In conclusion, lipid emulsion may slightly increase the rate of bupivacaine tissue distribution. No 'lipid sink' effect was observed with the non-toxic dose of bupivacaine used.     

Effects of clonidine pre-treatment on bupivacaine and ropivacaine cardiotoxicity in rats

BACKGROUND AND OBJECTIVE: Clonidine has cardiac and systemic effects that can modify the potentially lethal cardiovascular effects of local anaesthetics. We evaluated the effects of clonidine pre-treatment on cardiotoxicity induced by an infusion of bupivacaine or ropivacaine and the success rate of resuscitation in anaesthetized rats. METHODS: Thirty-two Sprague-Dawley rats (250-300 g) were anaesthetized with thiopental and ketamine. Lung ventilation was maintained mechanically, and the electrocardiograph and invasive blood pressure were recorded continuously. Two separate groups of rats were treated with intravenous clonidine 5 microg kg(-1) (n = 16) or saline (n = 16) in a randomized fashion. Fifteen minutes later, each group was randomly subdivided into two equal groups and an infusion of bupivacaine or ropivacaine, 3 mg kg(-1) min(-1), was given until cardiac arrest (asystole) occurred. The times when the cardiotoxic events (25%, 50% and 75% reduction of arterial pressure and heart rate, first dysrhythmia and asystole, respectively), induced by the local anaesthetic, occurred and the resuscitation outcome scores were recorded. RESULTS: Clonidine reduced heart rate and arterial pressure (P < 0.01). Clonidine did not alter cardiotoxicity or the success rate of resuscitation in bupivacaine-treated rats. In the ropivacaine group, clonidine increased the 25%, 50% and 75% reduction times of arterial pressure and the 50% and 75% reduction times of heart rate, times to first dysrhythmia and asystole (P < 0.05). Clonidine also increased the success rate of resuscitation in ropivacaine-treated rats (P < 0.05). CONCLUSIONS: Although pre-treatment with clonidine protects the effects of ropivacaine cardiotoxicity and increases the success rate of resuscitation, it does not affect bupivacaine toxicity.     

The effect of amrinone on recovery from severe bupivacaine intoxication in pigs.

Cardiovascular collapse following intravascular bupivacaine may be resistant to treatment. The effect of amrinone on recovery from bupivacaine-induced severe cardiovascular depression was evaluated in 20 pigs (13-26 kg) in a placebo-controlled randomized double-blind study. Under 0.7% isoflurane anesthesia at FIO2 0.21, 0.5% bupivacaine 2 mg.kg-1.min-1 was infused until mean arterial pressure was 40% of the baseline. Cardiac output and heart rate decreased 75% and 50% from the baseline, respectively. The total dose of bupivacaine was 17 +/- 6 (SD) mg.kg-1 in the control and 19 +/- 5 mg.kg-1 in the amrinone group, resulting in mean plasma concentrations of 42 +/- 6 and 53 +/- 19 micrograms.ml-1, respectively. A bolus of amrinone 4 mg.kg-1 (n = 10) was given immediately after cardiovascular depression, followed by an infusion of 0.6 mg.kg-1.min-1. The control animals received corresponding volumes of physiologic saline (n = 10). After cardiovascular depression, the lungs were ventilated with FIO2 1.0 without anaesthetics or sympathomimetic support. Electric activity of the heart ceased in all control animals in 3.9 +/- 2 min after cardiovascular depression despite atropine and external cardiac compression. All animals in the control group and 5 of 10 animals in the amrinone group were given atropine (P less than 0.01). The animals receiving amrinone survived without cardiac compression (P less than 0.0001). During bupivacaine infusion, all animals developed burst suppression in the electroencephalogram. At the time of cardiovascular depression, in 8 of 10 control and in 6 of 10 amrinone animals, the electroencephalogram was isoelectric.(ABSTRACT TRUNCATED AT 250 WORDS)     

Adding Bupivacaine to High-potassium Cardioplegia Improves Function and Reduces Cellular Damage of Rat Isolated Hearts after Prolonged, Cold Storage

Background: Bupivacaine retards myocardial acidosis during ischemia. The authors measured function of rat isolated hearts after prolonged storage to determine whether bupivacaine improves cardiac protection compared with standard cardioplegia alone.

Methods: After measuring cardiac function on a Langendorff apparatus, hearts were perfused with cardioplegia alone (controls), cardioplegia containing 500 [mu]m bupivacaine, or cardioplegia containing 2 mm lidocaine; were stored at 4[degrees]C for 12 h; and were then reperfused. Heart rate and left ventricular developed pressures were measured for 60 min. Maximum positive rate of change in ventricular pressure, oxygen consumption, and lactate dehydrogenase release were also measured.

Results: All bupivacaine-treated, four of five lidocaine-treated, and no control hearts beat throughout the 60-min recovery period. Mean values of heart rate, left ventricular developed pressure, maximum positive rate of change in ventricular pressure, rate-pressure product, and efficiency in bupivacaine-treated hearts exceeded those of the control group (P < 0.001 at 60 min for all). Mean values of the lidocaine group were intermediate. Oxygen consumption of the control group exceeded the other groups early in recovery, but not at later times. Lactate dehydrogenase release from the bupivacaine group was less than that from the control group (P < 0.001) but did not differ from baseline.     

Evaluation of the Association of Anaesthetists of Great Britain and Ireland lipid infusion protocol in bupivacaine induced cardiac arrest in rabbits

Infusion of lipid emulsion has been demonstrated to facilitate return of spontaneous circulation in animal models and human cases of local anaesthetic induced cardiac arrest. Guidelines for lipid application exist; however, experimental evidence of efficacy at recommended dosing is lacking. In 20 sedated, mechanically ventilated, and invasively monitored New Zealand White rabbits, asystole was induced via bolus bupivacaine injection. Animals were randomised to receive either 20% Intralipid administered according to Association of Anaesthetists of Great Britain and Ireland guidelines, or identical volumes of 0.9% saline solution, in addition to standard Advanced Cardiac Life Support resuscitative measures. Seven lipid treated rabbits developed return of spontaneous circulation vs four saline treated animals (p = 0.370). A trend toward sooner return of spontaneous circulation in the lipid treated group was observed (2.4 (0.53) vs 3.8 (1.7) min; p = 0.082). Five animals in the lipid treated group survived to protocol termination vs nil animals from the saline treated group (p = 0.033). The current Association of Anaesthestists of Great Britain and Ireland lipid infusion protocol provides a useful beginning for lipid emulsion administration.     

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.     

The relative toxicity of amitriptyline,bupivacaine, and levobupivacaine administered as rapid infusions in rats

Intravascular injection of local anesthetics carries the risk of cardiovascular (CV) and central nervous system (CNS) toxicity. Amitriptyline, a tricyclic antidepressant, has local anesthetic potency that is more than that of bupivacaine. In this study, we compared the CV and CNS toxicity of the local anesthetics bupivacaine and levobupivacaine with that of amitriptyline. Twenty-nine Sprague-Dawley rats had their right external jugular vein and carotid artery cannulated under general anesthesia. On Day 2, rats were sedated with midazolam (0.375 mg/kg intraperitoneally) and received rapid infusions of either 1) bupivacaine, levobupivacaine, or amitriptyline at 2 mg x kg(-1) x min(-1) (5 mg/mL concentration) or 2) normal saline (400 micro L x kg(-1) x min(-1)) through an external jugular vein cannula. Electrocardiogram and arterial blood pressure were measured until the dose to cause impending death was reached (heart rate 50 bpm/asystole or apnea for >30 s). The mean dose required to cause apnea and impending death was significantly larger for amitriptyline (74.0 +/- 21 mg/kg and 74.5 +/- 21 mg/kg, respectively) than for levobupivacaine (32.2 +/- 20 mg/kg and 33.9 +/- 22 mg/kg, respectively) or bupivacaine (21.5 +/- 7 mg/kg and 22.7 +/- 7 mg/kg, respectively) (P < 0.05). A significantly larger dose of amitriptyline, given by rapid infusion, is required to cause CV and CNS toxicity in rats, when compared with bupivacaine and levobupivacaine. IMPLICATIONS:Amitriptyline, a tricyclic antidepressant, has local anesthetic properties and is more potent than bupivacaine. Significantly larger doses of amitriptyline, given by rapid infusion, are required to cause cardiovascular and central nervous system toxicity in rats, when compared with bupivacaine and levobupivacaine.     

Acute cardiovascular and central nervous system toxicity of bupivacaine and desbutylbupivacaine in the rat

Desbutylbupivacaine, a major metabolite of bupivacaine, is known to accumulate during long-term continuous infusion blocks in man. Its acute toxicity in comparison with that of bupivacaine has not been studied. In a lightly anaesthetized rat model, bupivacaine (2 mg/kg/min, N = 10) or desbutylbupivacaine (4 mg/kg/min, N = 10) was infused i.v. until asystole. Arterial blood pressure, ECG and EEG were continuously recorded. The mean doses of bupivacaine producing cardiac toxicity, i.e. arrhythmia (12.4 mg/kg) and asystole (24.0 mg/kg), were approximately half of those of desbutylbupivacaine. Seizure activity on the EEG was observed in only one of the desbutylbupivacaine-infused rats while all rats receiving bupivacaine developed seizures (mean dose 5.2 mg/kg). Desbutylbupivacaine infusion caused a decrease in arterial blood pressure greater than that resulting from bupivacaine infusion. When desbutylbupivacaine 0.67 mg/kg/min was coinfused with bupivacaine 2 mg/kg/min, the cardiovascular toxicity of bupivacaine was clearly potentiated. The EEG parameters were affected in a similar fashion as when bupivacaine alone was infused. In this rat model, desbutylbupivacaine was about half as toxic as bupivacaine judged by cardiac parameters, and clearly less toxic to the central nervous system than bupivacaine.     

Comparison of caudal epidural bupivacaine with bupivacaine plus tramadol and bupivacaine plus ketamine for postoperative analgesia in children

This study compared the effect of single-dose caudal epidural bupivacaine, bupivacaine plus ketamine and bupivacaine plus tramadol for postoperative pain management in children having surgery for inguinal hernia. Following ethics committee approval and informed parental consent, 75 children ASA PS I and II, between three and nine years of age and scheduled for elective unilateral inguinal hernia repair with general anaesthesia were recruited. The patients were randomly divided into three groups to receive 0.5 ml/kg caudal bupivacaine 0.25% (group B), bupivacaine 0.25% plus tramadol 1 mg/kg (group BT) or bupivacaine 0.25% plus ketamine 0.5 mg/kg (group BK). The injections were performed under general anaesthesia. Mean arterial pressure, heart rate, pulse oximetry, respiratory rate and sedation and pain scores were recorded at defined intervals following recovery from anaesthesia. The groups were similar in age, weight and duration of operation (P >0.05). No patient experienced hypotension, bradycardia or respiratory depression. Duration of analgesia was (mean+/-SD) 6.5+/-4.1 h in group B, 9.2+/-3.9 h in group BK, and 8.5+/-3.1 h in group BT (P <0.05). More patients in group B required supplementary analgesics in the first 24 h (P <0.05). Sedation scores were comparable in all groups. Incidence of emesis and pruritus was similar in all the groups. Caudally administered 0.5 ml/kg bupivacaine 0.25% plus ketamine or bupivacaine 0.25% plus tramadol 1 mg/kg provided significantly longer duration of analgesia without an increase in the adverse effects when compared to bupivacaine alone.     

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

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.     

Dose-dependent effects of bupivacaine on rat muscle arterioles

The dose-dependent actions of bupivacaine on the microvasculature were evaluated by television microscopy in an in vivo rat cremaster muscle preparation. Animals were anesthetized with chloralose and urethane. Mean arterial pressure was measured via a carotid artery cannula; heart rate was calculated from the phasic pressure trace. The cremaster muscle was suffused with a balanced electrolyte solution that was controlled for temperature, pH, PO2, PCO2, and osmolarity to provide a physiologic environment. Internal diameters of fourth-order arterioles were measured with an electronic vernier displayed on the video monitor. Arteriolar diameters were measured every 30 s during a 10-min control period, a 10-min period of topical application of bupivacaine hydrochloride, and a 30-min recovery period. Bupivacaine 10(-1), 10(0), 10(1), and 10(2) micrograms X ml-1 produced progressive vasoconstriction to 82.7 +/- 2.9%, 75.0 +/- 5.6%, 71.0 +/- 7.0%, and 65.7 +/- 9.4% of control (P less than 0.05 for each), respectively. Bupivacaine, 10(3) and 2.5 X 10(3) micrograms X ml-1, did not alter arteriolar diameters significantly, although there was a tendency for vasodilation. In a second group of animals, arteriolar diameters were measured during intravenous bupivacaine infusion that produced stable plasma concentrations of 2.3 +/- 0.2 micrograms X ml-1. Vasoconstriction of 91.4 +/- 2.2%, of control (P less than 0.01) was observed. These results demonstrate that dose-dependent arteriolar constriction occurs even with blood bupivacaine levels that are at the upper limits of those expected to occur during regional anesthesia.     

The effects of bupivacaine on the umbilical circulation and placental gas exchange in the fetal lamb

Seven chronically catheterized fetal sheep at 125-140 days gestation were studied in 12 experiments to determine the direct effects of the local anesthetic bupivacaine (infused intravenously to the fetus) on the umbilical circulation and placental gas exchange. Electrocortical activity, umbilical blood flow, heart rate, and umbilical arterial and venous pressures were continuously monitored in experiments comprising a baseline period, a drug infusion period and a recovery period, each of 2 hr duration. Samples of umbilical arterial and venous blood were taken for blood gas analysis, and for bupivacaine assay using high pressure liquid chromatography technique. Fetal plasma bupivacaine levels were 1.3 +/- 0.3 microgram/ml (mean +/- SEM) between 60-120 min of infusion. Heart rate and umbilical blood flow decreased significantly to 89 and 94% of control, respectively, (P less than 0.05) during the infusion and returned to control levels by 2 hr afterwards. Mean umbilical arterial and venous pressures were not significantly altered, and no significant rise in umbilical vascular resistance occurred. No changes occurred in umbilical arterial or venous pH, PO2, or PCO2. In summary, bupivacaine reversibly depressed fetal heart rate and umbilical blood flow without detrimental changes in fetal blood gas or acid-base status.     

Comparison of resuscitation of sheep and dogs after bupivacaine-induced cardiovascular collapse

This study evaluated interspecies sensitivity and ability to resuscitate pentobarbital anesthetized sheep and dogs after cardiovascular toxic doses of bupivacaine. Every minute, 3 mg/kg of bupivacaine was injected into the right atrium over the course of 10 sec until cardiovascular collapse occurred. While the bupivacaine was given, the animals were made apneic for 90 sec and then ventilated with 100% oxygen. After the bupivacaine administration, cardiovascular collapse occurred in the form of electromechanical dissociation progressing to asystole in dogs, whereas in sheep the predominant rhythm was ventricular fibrillation leading to asystole. Resuscitation was performed using open chest heart massage, bretylium for treatment of ventricular tachycardia and fibrillation, and epinephrine with atropine for treatment of electromechanical dissociation or asystole. The initial dose of bupivacaine used to cause cardiovascular collapse was 3.5 +/- 1.2 mg/kg in sheep and 24.6 +/- 8.5 mg/kg in dogs (P less than 0.01). All sheep and dogs were resuscitated from the first cardiovascular collapse. The resuscitation time was 2.1 +/- 1.0 min in dogs and 36.9 +/- 15.4 min in sheep (P less than 0.01). All dogs could be resuscitated after two additional cardiovascular collapses induced by bupivacaine, but no sheep could be resuscitated after a second cardiovascular collapse. Concentrations of bupivacaine in cardiac tissue and serum levels of bupivacaine after the last resuscitation attempt were significantly greater in the dogs than in the sheep. We conclude that sheep are more sensitive to bupivacaine than dogs, but that even sheep can be resuscitated after cardiovascular collapse produced by bupivacaine.     

Optimal myocardial protection during crystalloid cardioplegia. Interrelationship between volume and duration of infusion

There is often a large difference between volumes of crystalloid cardioplegic solution used clinically (2 to 4 ml/gm myocardium) and experimentally (in rat heart preparations, volumes of 30 ml/gm or more are used). In an attempt to reconcile these differences and define the minimum volume and/or duration of infusion of the St. Thomas' Hospital cardioplegic solution consistent with maximal myocardial protection, we have used the isolated working rat heart to characterize the relationships between myocardial protection and (1) the duration of cardioplegic infusion and (2) the volume of cardioplegic infusion. Hearts (n = 6 per group, weighing 0.90 +/- 0.06 gm) were subjected to 0, 5, 10, 15, 30, 45, 60, 120, 180, 240, or 300 seconds of cardioplegic infusion (mean infusion volumes = 0, 1.3 +/- 0.1, 2.0 +/- 0.1, 2.8 +/- 0.2, 5.0 +/- 0.1, 8.3 +/- 0.2, 10.5 +/- 0.8, 21.8 +/- 2.1, 22.7 +/- 1.3, 32.3 +/- 2.1, and 39.1 +/- 1.8 ml per heart, respectively) before 30 minutes of normothermic ischemia. They recovered 3.9% +/- 2.3%, 9.7% +/- 5.0%, 22.8% +/- 5.8%, 34.6% +/- 4.6%, 54.7% +/- 6.6%, 64.0% +/- 5.0%, 67.4% +/- 4.0%, 56.6% +/- 11.1%, 60.0% +/- 5.8%, 51.6% +/- 7.0%, and 68.0% +/- 7.8% of their preischemic cardiac output on reperfusion. Creatine kinase leakage, tissue adenosine triphosphate and creatine phosphate content, and other indices of cardiac function supported this observation. To assess volume of infusion rather than duration, we infused hearts (n = 6 per group) with 1.0, 1.5, or 2.0 ml of cardioplegic solution over 120 seconds. Although recovery of cardiac output with 2.0 ml (56.2% +/- 6.8%) was not significantly different from that (56.6% +/- 11.1%) observed with large volumes of solution (21.9 +/- 2.1 ml), infusion of 1.5 and 1.0 ml resulted in poor recovery of cardiac output (40.1% +/- 4.6% and 21.8% +/- 3.9%, respectively). To assess duration (with low volumes) rather than volume of infusion, we infused hearts (n = 6 per group) with 2.0 ml of cardioplegic solution over 10, 30, 60, or 120 seconds. Maximal protection was observed with 30, 60, and 120 seconds of infusion (recovery of cardiac output = 56.7% +/- 5.9%, 45.1% +/- 7.9%, and 56.2% +/- 6.8%, respectively). Our results suggest that, for maximum myocardial protection, the St. Thomas' Hospital solution should be infused at a rate of not less than 2.0 ml/gm wet weight of heart and that the duration of infusion should be not less than 30 seconds.     

Prolonged asystole during intraoperative myocardial reperfusion: an experimental study

It has been observed in a proportion of patients, that clinically cardiac asystole persists for a prolonged period during intraoperative reperfusion. To evaluate this phenomenon, isovolumic functional indices (left ventricular [LV] balloon) and myocardial oxygen consumption (MV02) were compared in 22 canine preparations before and after two different interventions. After 45 minutes of normothermic global ischemia, (1) the control group (N = 11) was maintained on cardiopulmonary bypass with the hearts beating empty and (2) the experimental group (N = 11) was subjected to cardioplegia reperfusion at normothermia for one hour. In contradistinction to the initial hypothesis, functional recovery was better in the experimental group compared with the controls. Significant differences were observed in recovery of LV peak developed pressure (LVPDP) (controls, 66.8 +/- 7.3% [mean +/- standard error of the mean], and experimental group, 99.5 +/- 8.9%; p less than 0.05), maximum rate of rise of LV pressure (controls, 116.6 +/- 16.2%, and experimental group, 147.7 +/- 10.1; p less than 0.05), and maximum fall of LV pressure (controls, 100.3 +/- 15.8%, and experimental group, 143.1 +/- 11.5%; p less than 0.05). Correlation between LVPDP and MVO2 was also better preserved in the experimental group (controls: r = 0.15, N = 74, p = 0.18; experimental group: r = 0.47, N = 75, p less than 0.001). Values for myocardial water content and total creatine kinase in the two groups were similar. It was concluded that prolonged asystole during intraoperative reperfusion is not detrimental; on the contrary, there is enhanced functional recovery of the myocardium similar to that seen after secondary cardioplegia.     

Effect of hypertonic saline on electrocardiography QRS duration in rabbit model of bupivacaine toxicity resuscitated by intravenous lipid

Intravenous lipid emulsion is established therapy for bupivacaine induced cardiotoxicity. The benefit of combined hypertonic saline and lipid treatment is unexplored. In this experiment, sedated rabbits were resuscitated from bupivacaine‐induced asystole with intravenous lipid according to the Association of Anaesthetists of Great Britain and Ireland’s guideline, or by identical lipid dosing with hypertonic saline: 6 mEq.kg^?1 21% sodium chloride. Early electrocardiography QRS prolongation was less with lipid plus hypertonic saline (mean (SD) QRS 0.19 (0.07) s lipid only vs 0.09 (0.01) s lipid plus hypertonic saline; p = 0.003) at 9 min though not different from the lipid only group at 20 min. No difference was observed in rates of circulatory return (7/10 lipid only and 9/10 lipid plus hypertonic saline; p = 0.58) or survival (5/10 lipid only and 6/10 lipid plus hypertonic saline; p = 1.00). Some benefit to cardiac conduction may be afforded by hypertonic saline co‐administered with lipid emulsion in bupivacaine‐induced cardiotoxicity.