Bupivacaine

Cardiovascular

Bupivacaine-induced cardiotoxicity, notably after epidural use, is a matter of concern and controversy [ ]. The risk can be greatly reduced or eliminated by careful dosage and/or the use of lower concentrations [ ].

All studies of the cardiotoxic effects of local anesthetics on the isolated heart published from 1981 to 2001 have been reviewed [ ]. Thirteen studies were identified, all of which studied bupivacaine, either alone or compared with other local anesthetics. The general conclusions were:

• Highly lipid-soluble, extensively protein-bound, highly potent local anesthetics, such as tetracaine, bupivacaine, and etidocaine, are much more cardiotoxic than less lipid-soluble, protein-bound, and potent local anesthetics, such as lidocaine and prilocaine.

• Bupivacaine has a potent depressant effect on electrical conduction in the heart, primarily via an action on voltage-gated sodium channels that govern the initial rapid depolarization of the cardiac action potential.

• The S(−) isomer of bupivacaine is less cardiotoxic than the R (+) form.

• Bupivacaine predisposes the heart to re-entrant dysrhythmias.

• The actions of bupivacaine on channels other than voltage-gated sodium channels probably contribute to the dose-dependent cardiotoxic effects of bupivacaine.

The recommended safe upper dose limit for bupivacaine is commonly 2–2.5 mg/kg. However, some authors recommend a lower dose of 1.25 mg/kg as the safe upper limit in dental practice [ ].

Hyperkalemia, acidosis, severe hypoxia, and myocardial ischemia increase the cardiovascular depressive effects of bupivacaine.

There has been a report of T wave changes on the electrocardiogram during caudal administration of local anesthetics [ ].

• A 4.2 kg 2-month-old baby was given a caudal injection under general anesthesia for an inguinal hernia repair. A mixture of 1% lidocaine 2 ml and 0.25% bupivacaine 2 ml was injected. Every 1 ml was preceded by an aspiration test and followed by observation for 20 seconds for electrocardiographic changes. On administration of the third 1 ml dose, there was a significant increase in T wave amplitude. The aspiration test was repeated and was positive for blood. The caudal injection was stopped and the electrocardiogram returned to normal after 35 seconds. The patient remained cardiovascularly stable with no postoperative sequelae.

Previous reports have suggested that an increase in T wave amplitude could result from inadvertent intravascular administration of adrenaline-containing local anesthetics. This is the first case report of local anesthetics alone causing significant T wave changes.

Bradycardia has been reported very occasionally [ ].

Bupivacaine can cause ventricular extra beats [ ]. Ventricular dysrhythmias and seizures were reported in a patient who received 0.5% bupivacaine 30 ml with adrenaline 5 micrograms/ml for lumbar plexus block, after a negative aspiration test [ ]. The patient developed ventricular fibrillation and required advanced cardiac life support for 1 hour, including 15 defibrillations, and adrenaline 40 mg before sinus rhythm could be restored. There were no neurological sequelae.

Infusions of 0.25% bupivacaine into pig coronary arteries caused ventricular fibrillation at lower rates of infusion than 0.25% bupivacaine with 1% lidocaine [ ]. The lidocaine/bupivacaine mixture did not have a greater myocardial depressant effect than bupivacaine alone. The authors suggested that when regional anesthesia requires high doses of local anesthetics, bupivacaine should not be used alone but in a mixture with lidocaine, and that lidocaine should be useful in the management of bupivacaine-induced ventricular fibrillation.

Bupivacaine cardiac toxicity mimicking an acute non-ST segment elevation myocardial infarction has been reported [ ].

• A healthy young woman was given a spinal anesthetic with bupivacaine 6 mg for hemorrhoidectomy and immediately developed hypotension and an accelerated idioventricular rhythm, with ST segment depression. Transthoracic echocardiography showed a reduced left ventricle systolic ejection fraction (about 27%), regional wall motion abnormality of the left ventricle, and increased cardiac markers. The presentation mimicked a non-ST segment elevation myocardial infarction. She improved gradually and 7 days later had normal cardiac function and normal coronary angiography.

The authors assumed that a direct effect of bupivacaine on the myocardium had caused this presentation, although this seems extremely unlikely after a dose of 6 mg given intrathecally.

An animal study of the mechanism of bupivacaine-induced dysrhythmias has shown that bupivacaine facilitates early after-depolarization in rabbit sinoatrial nodal cells by blocking the delayed rectifier potassium current [ ].

Cardiac toxicity is a well-recognized complication of bupivacaine overdose. However, a recent report has shown that bupivacaine can have significant prodysrhythmic effects in patients at risk, even in usual therapeutic doses [ ].

• A 56-year-old man with an essentially normal preoperative electrocardiogram underwent lung reduction surgery for COPD, with epidural bupivacaine and sufentanil for postoperative analgesia. He developed Brugada-like changes on the first day postoperatively, with new right bundle branch block, down-sloping ST elevation in V1–V3, and frequent ventricular extra beats, which quickly evolved into VT, requiring intravenous lidocaine and amiodarone. The electrocardiographic changes and ventricular dysrhythmias persisted until the epidural anesthetic was withdrawn 5 days later. The same pattern of events recurred when a new epidural infusion, again with bupivacaine and sufentanil, was started after surgery to correct an air leak.

This patient was subsequently found to have a genetic mutation consistent with Brugada syndrome, which only became evident on exposure to bupivacaine. The authors concluded that bupivacaine should be added to the list of drugs (including flecainide and procainamide), that can unmask a subclinical form of Brugada syndrome. This is in line with previous similar findings published [ ] and a report with ropivacaine described below.

Inadvertent administration of bupivacaine can lead to fatal cardiovascular collapse that may be refractory to conventional resuscitation. A study in rats has suggested that in addition to its direct cardiotoxic effect, bupivacaine may have a toxic action on the brainstem, and that cardiovascular collapse may result from dysfunction of vital cardiorespiratory control systems [ ].

Conduction disturbances have been attributed to bupivacaine.

• A 60-year-old woman with pre-existing heart failure awaiting surgery for a fractured humerus was accidentally given a mixture of bupivacaine 75 mg and clonidine 15 micrograms intravenously [ ]. She developed a nodal rhythm with extreme bradycardia, severe shock, and convulsions. Seizures were controlled with thiopental, and suxamethonium and adrenaline partially restored the blood pressure to 50/30 mmHg and the heart rate to 60/minute (nodal rhythm). After clonidine 75 micrograms intravenously, her blood pressure rose to 90/70 mmHg and her heart rate to 70/minute. Her cardiac rhythm reverted to sinus rhythm with first degree atrioventricular block.

The authors concluded that clonidine had reversed bupivacaine-induced conduction disturbances.

The effect of a lipid emulsion infusion on bupivacaine- induced cardiac toxicity has been studied in dogs [ ]. Bupivacaine 10 mg/kg was given intravenously over 10 minutes to fasted dogs under general anesthesia. Resuscitation included 10 minutes of internal cardiac massage followed by either saline or 20% lipid infusion, as a 4 mg/kg bolus followed by a continuous infusion of 0.5 ml/kg/minute for 10 minutes. Electrocardiography, arterial blood pressure, myocardial pH, and myocardial PO2 were continuously monitored. All six lipid treated dogs survived after 10 minutes of cardiac massage, but there were no survivors among the six dogs who were given saline. Hemodynamics, PO2, and myocardial pH were also improved in the treatment group. This study supports the need for further investigation of lipid-based resuscitation to treat bupivacaine toxicity in order to determine the optimum dosage regimen.

Longer-acting, more lipophilic local anesthetics, such as bupivacaine, can cause cardiovascular toxicity at serum concentrations that are not much greater than those required to cause nervous system toxicity.

• A 65-year-old man had 15 ml of plain bupivacaine 0.5% infiltrated before a planned radiofrequency ablation of a lumbar sympathetic ganglion [ ]. He immediately developed respiratory arrest with bradycardia and hypotension (54/40 mmHg). Asystolic cardiac arrest was treated successfully but he subsequently developed pulmonary edema after a hypotensive episode. Angiography showed left anterior descending artery ischemia and his electrocardiographic T waves normalized 7 months later.

The authors report this case as bupivacaine-induced cardiovascular collapse with several novel features. Firstly, it developed after the administration of a relatively low dose of bupivacaine, less than 1.1 mg/kg. Secondly, the presentation was that of mixed cardiogenic and vasomotor shock. Finally, he developed an unexplained delayed cardiographic finding of symmetrically inverted anterior T waves. The authors thought that drug-drug interactions may also have contributed; since he was taking amitriptyline and carbamazepine, each of which is potentially cardiotoxic and may have lowered the threshold for bupivacaine toxicity.

Cardiopulmonary bypass has been used to successfully treat bupivacaine-induced cardiovascular collapse [ ].

• A 39-year-old woman (72 kg, 165 cm) with congenital clubfoot presented for total right ankle arthroplasty. She had no history of syncope, seizures, coronary artery disease, or congenital heart disease. After induction of anesthesia she received a popliteal nerve block with 30 ml of 0.5% bupivacaine using a nerve stimulator device. Communication was maintained with the patient throughout the injection, and she denied any neurological symptoms suggestive of intravascular injection. About 30 seconds after the block, she had a generalized tonic–clonic seizure and soon afterwards developed ventricular fibrillation. Advanced cardiac life support was begun. She was given adrenaline 2 mg and bretylium 1000 mg intravenously, as well as six attempts at electrical defibrillation. Bupivacaine cardiotoxicity because of inadvertent intravascular injection was suspected and cardiopulmonary bypass was begun and continued for 30 minutes. She was extubated on the second postoperative day and discharged home on postoperative day 10 with no neurological sequelae.

The prolonged duration of cardiac support needed after refractory drug-induced cardiotoxicity may make cardiopulmonary bypass, although invasive, the best option for successful resuscitation of such patients. Notwithstanding the practical and technical limitations of staff and equipment availability, the authors argued that cardiopulmonary bypass should become first-line therapy after unsuccessful basic resuscitation in such cases.

Methods of mitigating bupivacaine cardiotoxicity have been investigated in animals. Insulin–dextrose–potassium infusion was extremely successful in the treatment of bupivacaine-induced cardiotoxicity in dogs—all those who were treated survived, while the controls all developed irreversible cardiac arrest [ ]. In contrast, clonidine pretreatment did not alter bupivacaine cardiotoxicity or resuscitability in rats [ ].

Death

Fatal bupivacaine toxicity occurred after recreational use by injection into the external genitalia for autoerotic purposes [ ].

Nervous system

Neurological symptoms subsequent to unrecognized intravascular injection are the major complications of bupivacaine: tinnitus, muscle twitching, nystagmus, and convulsions can occur. The use of vasoconstrictors is probably not advisable, as they prolong the duration of action of local anesthetics. Whether the addition of hyperbaric glucose to 0.5% bupivacaine for spinal anesthesia alters the incidence of pain from an orthopedic tourniquet is disputed; some findings suggest that it aggravates the problem [ ].

• A 13-year-old girl developed tonic-clonic seizures followed by ventricular fibrillation after subcutaneous infiltration of extensive skin abrasions with 30 mg (0.5 mg/kg) of bupivacaine over about 1 hour. She was successfully resuscitated with cardiopulmonary resuscitation and intubation, intravenous diazepam, adrenaline, and sodium bicarbonate [ ].

The authors noted that although the anticonvulsant effect of diazepam is significant, some animal studies have shown that diazepam can prolong the half-life of bupivacaine. They stressed the difficulty in treating bupivacaine-induced dysrhythmias and suggested the use of phenytoin as a first-line agent in their management. However, this advice is based on only two case reports.

In seven children (aged 36–52 weeks) given caudal anesthesia with bupivacaine 3.1 mg/kg + adrenaline 5 micrograms/ml, there were significant electroencephalographic signs of central nervous system toxicity in six, and two had clinical signs of possible epileptic activity. The authors stopped the study early because of the high incidence of adverse effects. They felt that these were due to the fact that no sedative or anesthetic drugs that could have masked or alleviated local anesthetic toxicity were given, and also that infants have low concentrations of alpha1 acid glycoprotein, leading to increased unbound plasma concentrations [ ]. However, it should be noted that 2 mg/kg is the usual upper dose limit recommended for bupivacaine. It is hardly surprising that such a high proportion of those studied showed evidence of systemic toxicity after the administration of a much higher dose of bupivacaine to such small children by a route that is known to result in rapid absorption of local anesthetic into the systemic circulation.

Reactions to local anesthetics often occur as a result of inadvertent overdose or accidental intravenous injection.

• A 53-year-old woman received postoperative epidural analgesia by nurse-administered bolus doses after a total knee replacement [ ]. She received her first epidural bolus of 0.25% bupivacaine 6 ml with morphine 2 mg 2 hours after the operation, with good effect. Six hours later she was accidentally given a second top-up dose intravenously. She became distressed and complained of tinnitus, palpitation, and dizziness. She was able to cooperate and was in sinus rhythm with a tachycardia of 120/minute. She was observed overnight on ICU and made a full recovery.

Despite correct epidural placement, this complication arose as a result of human error, and the authors believed that the low concentration and volume of the top-up had protected the patient from more serious sequelae.

Musculoskeletal

Muscular atrophy after intramuscular injection has been documented [ ].

Immunologic

A non-IgE-mediated allergic reaction to bupivacaine has been reported [ ].

• A 69-year-old woman with a history of bronchospasm after NSAID administration had heavy feelings in her arms and itchy eyes, without any change in hemodynamics, 30 minutes after an intradermal injection of bupivacaine. The same symptoms occurred during subsequent retesting 1 month later, with the addition of coughing and sneezing.

There has been a report of delayed type IV hypersensitivity to bupivacaine [ ].

• A 33-year-old woman developed an eczematous reaction 3 days after continuous lumbar epidural analgesia with bupivacaine 0.075% during labor. The skin responded to topical steroids. A patch test 4 months later was positive to bupivacaine.