Prophylaxis And Treatment Of Ropivacaine-induced Cardiotoxicity With Different Lipid Emulsion

BackgroundNeuraxon anesthesia is becoming more and more popular in clinical practice. The worst complication associated with the administration of local anesthetics is local anesthetic systemic toxicity (LAST). These agents always have the profound and potentially lethal effect on cardiac conduction and function. LipidRescueTM resuscitation refers to the use of an intravascular infusion of a lipid emulsion to treat LAST. More recently, LipidRescueTM has been proposed (in articles in the ER literature and elsewhere) as a treatment modality for poisoning or overdose by lipophilic agents in general. The hope is that LipidRescue will be equally effective in treating toxin-induced cardiac arrest by a variety of causes. The method is of milestone meaning for treatment of lipophilic agents overdose.In 1928 Mayer firstly reported LAST. Nearly fifty years later, an editorial by Albright indicated several cases of fatal cardiac toxicity associated with use of the long acting lipophilic local anesthetics, bupivacaine and etidocaine. The Albright's editorial attracted the interest of anesthesiologists in the world. From then on, lots of anesthesiologists paid close attention to LAST. The observation of local anaesthetic cardiotoxicity also provided the impetus for considerable research efforts directed both to understand the mechanisms of this toxicity and evaluate possible methods for its treatment.Evidence for a beneficial effect of lipid infusion in LAST was first published by Weinberg more than a decade ago in a rat model of bupivacaine-induced asystole. Subsequent studies in dogs confirmed the efficacy of lipid in reversing severe bupivacaine cardiac toxicity. In 2006 Rosenblatt et al. published the first clinical report of lipid emulsion administered to reverse cardiac arrest in the setting of local anesthetic toxicity—a translational milestone that bridged laboratory experience to the clinic. Since then, there have been multiple reports of the successful use of lipid in treating not only cardiovascular collapse but also central nervous system symptoms caused by local anesthetic. And it appears that this effect is not related to the brand of lipid.The mechanism of LipidRescue remains unknown. The use of a lipid emulsion to treat toxicity due to a highly lipophilic drug suggests the possibility of a'lipid sink' mechanism, where the offending agent is removed from affected tissues by partitioning into a plasma lipid phase created by the infusion. Experiments in isolated heart from rat suggested that underlying mechanisms may also involve metabolic effects. Other possible mechanisms have not been excluded.There are no randomized controlled trials (RCTs) evaluating serious human LAST. In future RCTs are unlikely because of the rarity of these complications and the associated difficulty of obtaining informed consent for medical interventions in critical illness. Common strength-of-evidence schemas that are based on RCT-level evidence are therefore inappropriate for the topic of human LAST but are appropriate for animal studies.Although a few researches are skeptical about LipidRescue, the majority of anesthesiologists have agreed with its use. The Association of Anesthetists of Great Britain & Ireland recommends this method in its guidelines for the management of severe local anesthetic toxicity.Because of lower cardiotoxicity, the separation of sensation and motion, long half time, ropivacaine is widely used in clinical as long-acting amino-amide local anesthetics. Ropivacaine is similar to bupivacaine in structure so attention should be drawn to its potential toxicity. More and more elderly patients who need to tolerate an operation are performed under neuraxonanesthesia because they often have some complications in spite of primary disease. There will have increasingly possibility for incidence of LAST. So the prophylaxis and treatment to LAST in aging people should be emphasized.In most of the investigations about LipidRescue, adult animals were observed the effects of lipid emulsion in treating LAST and the lipid emulsions were often long chain fat emulsion. There are only a few literatures in which medium and long chain fat emulsion were used. No report was available for using different lipid emulsion on ropivacaine's cardiotoxicity prophylaxis and treatment.Based on previous studies, we hypothesized that the lipid emulsion can prevent and treat ropivacaine-induced cardiac arrest. The aim of the present study was to investigate the pretreatment and resuscitation effects of different lipid emulsion on cardiovascular toxicity induced by ropivacaine in aged rats and to determine whether change of ropivacaine plasma concentration and analgesia role would be related to the pretreatment of lipid emulsion during epidural anesthesia in adults undergoing lower limb operations.Objectives1. To investigate the pretreatment effects of different lipid emulsion on cardiovascular toxicity induced by ropivacaine in aged rats.2. To investigate the treatment effects of different lipid emulsion on cardiac arrest induced by ropivacaine in aged rats.3. To determine whether change of ropivacaine plasma concentrations and analgesia role would be related to the pretreatment of lipid emulsion during epidural anesthesia in adults undergoing lower limb operations.MethodsPartⅠ:Protective effects of different lipid emulsion pretreatment on ropivacaine-induced cardiovascular toxicity in elderly ratsTwenty-four healthy elderly male SD rats, aged 18 months, were randomized into three groups (n=8):control group (NS group); long chain fat emulsion group (LLE group); and medium and long chain fat emulsion group (MLE group). Rats were anesthetized with intraperitoneal (i.p.) injection of ketamine (100 mg·kg-1). Then right jugular vein and carotid artery were cannulated for drug administration and blood pressure (BP) monitoring. The trachea was separated and punctured with a 16G cannula needle, and connected to the small animal anesthesia machine. All animals were allowed to stabilize for 10 min at air with mechanical ventilation. NS group received 0.9% saline, LLE group received 20% LLE and MLE group received 20% MLE. The fluids were given at a rate of 3 ml·kg-1·min-1 for 5 minutes, and then 0.75 % ropivacaine was injected at 10 mg·kg-1·min-1 through right jugular vein. The accumulated doses of ropivacaine were recorded at the time of cardiac dysrhythmia, BP decreased 20% and cardiac arrest.PartⅡ:Treatment effects of different lipid emulsion on cardiac arrest induced by ropivacaine in aged ratsHealthy elderly male SD rats, aged 19 months, were anesthetized with i.p. injection of ketamine (100 mg·kg-1). Then right jugular vein and carotid artery were cannulated for drug administration and blood pressure (BP) monitoring. The trachea was separated and punctured with a 16G cannula needle, and connected to the small animal anesthesia machine. All animals were allowed to stabilize for 10 min at air with mechanical ventilation.0.75% ropivacaine was injected at 30 mg·kg-1 through right jugular vein. Advanced cardiac life support was initiated 1 min after cardiac arrest had occurred (defined as the electrocardiogram showing heart rate decreasing to 10 beats per minute, and systolic blood pressure decreasing to 30 mmHg). Chest compressions were started and delivered until return of spontaneous circulation (ROSC was defined as a rate-pressure product [RPP]= systolic blood pressurexheart rate, greater than 20% of the baseline values). After 2 min of BLS CPR, animals who displayed ROSC were excluded from the study and animals failing to achieve ROSC were randomized into four groups (n=8):control group (NS group); long chain fat emulsion group (LLE group); medium and long chain fat emulsion group (MLE group); and epinephrine group (E group). NS group received 0.9% saline, LLE group received 20% LLE and MLE group received 20% MLE as a 5 ml·kg-1 bolus over 10 seconds followed by a continuous infusion of 0.5 ml·kg-1·min-1; E group received epinephrine as a 30μg·kg-1 follow by a continuous infusion of 0.5 ml·kg-1·min-1 with 0.9% saline. Bolus treatment in all groups was repeated at 2.5 and 5 minutes for RPP < 20% of baseline value. Hemodynamic parameters were measured at 0 minute,2.5 minutes,5 minutes,7.5 minutes,10 minutes after first bolus. Survival rates at 10 minutes after first bolus were recorded. Mechanical ventilation with air was continued throughout the experiment.PartⅢ:Effects of different lipid emulsion pretreatment on pharmacodynamics of ropivacaine during epidural anesthesia in adults undergoing lower limb operationsTwenty-nine adult patients aged 18 to 65 years, American Society of Anesthesiologists physical statusⅠandⅡ, scheduled for elective lower limb operations under epidural anesthesia, were invited to participate in the study. Exclusion criteria included any hesitation on the part of the patient to participate in the study despite thorough briefing; fever; a history of severe cardiovascular, hepatic, renal, neurological, psychiatric, or metabolic disease; a known history of allergy or sensitivity to local anesthetics of the amide type; women with pregnancy or during emmenia period or taking contraceptive pills; the existence of an absolute or relative contraindication for the application of the epidural technique such as neuromuscular disease, bleeding diathesis, and local skin infections in the lumbar region; the administration of other drugs that inhibit the metabolism of ropivacaine, for example, fluvoxamine, imipramine, theophylline, verapamil; and unsupination operations.On arrival in the operating theatre, monitoring of arterial pressure, ECG, and SpO2 were instituted, and venous access was secured. The patients were randomized into three groups:control group (NS group, n=11); long chain fat emulsion group (LLE group, n=10); and medium and long chain fat emulsion group(MLE group, n=8).Three groups of patients were pretreated with 0.9% saline,20% LLE or 20% MLE, also at 2 ml·kg-1·h-1 for 30 min via left upper limb vein. A test dose of three milliliters of 1% ropivacaine containing 1:200,000 epinephrines was injected. Five minutes later, if there was no sign of intravascular or subarachnoid injection,2 mg·kg-1 (including the test dose) of ropivacaine containing 1:200,000 epinephrine was injected through the epidural catheter at a rate of 4 ml per 10 seconds.Hemodynamic parameters were recorded during perioperation. Sensory block was determined using a blunt point needle to test for loss of sensation to pinprick. The degree of motor block was determined using a modified Bromage classification. Ropivacaine plasma concentrations were measured from artery plasma samples by high-performance liquid chromatography at 1,5,10,15,30,45,60,90,120 minutes after total ropivacaine was given.ResultsPartⅠ:Protective effects of different lipid emulsion pretreatment on ropivacaine-induced cardiovascular toxicity in elderly ratsCompared with the NS groug, the doses of ropivacaine were significantly higher in the groups LLE and MLE (P< 0.05) when the rats developed to cardiac dysrhythmia, BP decreased 20%, or cardiac arrest. There was no significant difference between the groups LLE and MLE (P> 0.05).PartⅡ:Treatment effects of different lipid emulsion on cardiac arrest induced by ropivacaine in aged ratsCompared with the NS group, HR in the group LLE, MLE and E was higher at 5 and 7.5 minutes (P< 0.05). Rats treated with epinephrine had significantly higher HR than those treated with vehicle at 10 minutes. Systolic blood pressure in the E group was significantly higher than those of the NS and LLE and MLE group at 2.5 minutes. At 7.5 and 10 minutes SBP in the group E, LLE and MLE exceeded those of the NS group. Rats treated with E showed elevated SBP but a descending tendency at the end of the experiment. Lipid-treated animals had a progressive increase in SBP throughout the experiment. Mean RPP in E group rats exceeded those in the NS group at 5,7.5 and 10 minutes. Although there were no differences among the four groups, mean RPP in group E and LE were similar with each other and higher than the NS group.3 of 8 in group MLE,2 of 8 in group LLE,5 of 8 in group E, and 1 of 8 in the NS group achieved ROSC by 10 minutes. There were no significantly differences among the different treatment groups in survival rate at 10 minutes.PartⅢ:Effects of different Iipid emulsion pretreatment on pharmacodynamics of ropivacaine during epidural anesthesia in adults undergoing lower limb operationsNo differences were observed between groups in onset time of sensory and motor block, time to maximum spread of sensory block, the segment of spinal nerve block, persistent time of sensory and motor block. The plasma ropivacaine concentration among all groups had no differences at each time.Conclusions1. The dosage of ropivacaine on cardiovascular toxicity in aged rats was significantly increased with the pretreatment of LLE and MLE, which suggested the prophylactic effects of LE to the local anesthetic toxicity.2. Although epinephrine and different lipid emulsion do not improve the resuscitation rate of ropivacaine induced cardiac arrest in aged rats, it maintains amelioration of hemodynamics indexes which may be beneficial during resuscitation. The evidence is not sufficient that lipid emulsion is superior to epinephrine in the treatment of ropivacaine induced cardiac arrest in aged rats.3. Pretreatment of LLE and MLE had no effect on pharmacodynamics of ropivacaine during epidural anesthesia in adults undergoing lower limb operations.