Total knee arthroplasty is one of the most successful operations performed. Multiple modalities are utilized for pain management in the perioperative period. Regional anesthesia is a common, effective method associated with high patient satisfaction. It typically provides exceptional local pain control without the systemic side effects that have been associated with oral or parenteral narcotics. Alleviation of pain allows for earlier mobilization and potentially shorter hospital stays. However, continuous infusion of a long-acting local anesthetic is not without risk. Case reports of severe complications such as hypotension, arrhythmia, seizure, and cardiovascular collapse have been reported, but all involved intra-articular injections or a single injection of a large dose of anesthetic medication to attain a regional block1-6. We found no reports of arrhythmia in association with an indwelling catheter in patients who were receiving regional anesthesia.
We present the case of a patient in whom a third-degree heart block developed in association with a continuous bupivacaine infusion through an indwelling femoral catheter. The patient was informed that data concerning the case would be submitted for publication, and she consented.
A seventy-eight-year-old woman who weighed 59 kg had a five-year history of progressive, debilitating, left knee pain that was most severe with walking, stair-climbing, and arising from a seated position. As nonoperative treatment had failed to provide relief, the decision was made to perform a total knee replacement. Her medical history included osteoarthritis of both knees, peptic ulcer disease, a cerebrovascular accident in 1993, and cirrhosis of the liver secondary to alcohol abuse. The patient had previously undergone a right total knee arthroplasty with no complications. Physical examination of the left lower extremity demonstrated a 20° valgus deformity and an arc of knee motion from 15° to 115°. Due to the known fact that the patient had liver disease, liver-function testing was obtained, the results of which revealed the following serum levels: aspartate aminotransferase, 57 U/L (laboratory normal value, <40 U/L), alanine aminotransferase, 42 U/L (laboratory normal value, <60 U/L), total bilirubin 0.7 mg/dL (11.97 μmol/L) (laboratory normal value, <1.4 mg/dL [23.94 μmol/L]), albumin 3.4 g/dL (34 g/L) (laboratory normal range, 3.5 to 4.0 g/dL [35 to 40 g/L]), and an international normalized ratio of 1.4 (laboratory normal range, 0.9 to 1.1). She had normal cognitive function, no asterixis, and no ascites. Assessment of the patient's chronic liver disease, with use of the modified Child-Pugh classification system, resulted in a score of 5 points (grade A), indicating well-compensated liver disease and a one-year survival rate of 100%7,8. The patient had no known history of hypertension, myocardial infarction, or cardiac arrhythmia. A preoperative electrocardiogram demonstrated normal sinus rhythm.
A left total knee arthroplasty was performed without complication. Prior to surgery, the anesthesia team, using a Stimuplex needle (B. Braun Medical, Bethlehem, Pennsylvania), placed a femoral nerve catheter without difficulty or complication. A femoral nerve block was established with the administration of 30 mL of 0.50% bupivacaine, and the catheter was left in place. No additional bupivacaine was infused during the surgery. The surgery was performed with the patient under general anesthesia. Following surgery, the patient was transferred to the postoperative anesthesia care unit, where laboratory studies and radiographs were obtained and the bupivacaine infusion was initiated (0.25% bupivacaine at 8 mL per hour). Postoperative laboratory studies revealed a hematocrit of 34% (laboratory normal range, 40% to 52%), a serum calcium level of 7.9 mg/dL (1.98 mmol/L) (laboratory normal range, 8.5 to 10 mg/dL [2.13 to 2.50 mmol/L]), and a serum magnesium level of 0.9 mg/dL (0.37 mmol/L) (laboratory normal range, 1.8 to 2.4 mg/dL [0.74 to 0.99 mmol/L]), with all other values within normal limits. Intravenous calcium gluconate and magnesium sulfate were given to correct the electrolyte imbalance. She was transferred to the surgical floor when her condition became stable.
On the evening of surgery, approximately six hours after the initiation of the bupivacaine infusion (nine hours after placement of the catheter and establishment of the nerve block), the heart rate of the patient was 38 beats per minute. The patient was alert and oriented but drowsy. Blood tests revealed a hematocrit of 32.5%, no electrolyte abnormalities, and normal levels of cardiac enzymes. Abnormal values included a serum albumin level of 2.8 g/dL (28 g/L) and an international normalized ratio of 1.6. An electrocardiogram (Fig. 1) demonstrated complete atrioventricular heart block (third degree). Cardiology and intensive care unit teams evaluated the patient, and a diagnosis of asymptomatic complete heart block with no discernible etiology was made. The femoral nerve catheter was discontinued by the orthopaedic team, and the patient was transferred to the coronary care unit for evaluation and monitoring. Within six hours following cessation of the bupivacaine infusion, the patient's heart returned to a normal sinus rhythm. The patient was transferred out of the coronary care unit forty-eight hours later and had no further episodes of heart block, conduction abnormality, or arrhythmia during the period of hospitalization. She was discharged home on the fourth postoperative day with no further complications. Additional cardiology workup on an outpatient basis was negative for any etiology of the heart block; the patient was therefore not started on any cardiac medications and was discharged from the cardiology clinic.
The efficacy of pain relief from regional anesthesia is well established. Salinas et al. performed a prospective randomized study comparing single femoral nerve blockade with continuous femoral nerve blockade during total knee arthroplasty9. The group that received the continuous block demonstrated significantly lower overall consumption of parenteral narcotics (p ≤ 0.0001 on postoperative day 1; p = 0.0004 on postoperative day 2) and had significantly lower pain scores at rest (p = 0.002 on postoperative day 1; p < 0.0001 on postoperative day 2) and during physical therapy (p = 0.01 on postoperative day 1; p = 0.0005 on postoperative day 2).
Concern regarding the cardiotoxicity of bupivacaine arose as early as 1979, after the report of six cases of sudden cardiovascular collapse associated with its use5. This prompted intense research and debate into the cardiotoxic effects of bupivacaine5. While delayed resuscitative efforts were blamed by some, others proposed a specific selective cardiotoxicity of bupivacaine10. These concerns drove the commercial development of ropivacaine as a safer, less cardiotoxic alternative for regional anesthesia.
In 2002, Heavner reviewed the literature with regard to bupivacaine toxicity. His review concluded that bupivacaine is an exceptionally potent depressant of electrical conduction of the heart and that it predisposes the heart to arrhythmias, is stereoselective, and acts through voltage-gated sodium channels and, to a lesser degree, other voltage-gated ion channels11. However, no study that we reviewed demonstrated a dose of bupivacaine that caused cardiovascular symptoms or side effects (e.g., arrhythmia, conduction abnormality, or myocardial infarction) before the onset of central nervous system symptoms or side effects (e.g., seizure or a change in mental status).
In the clinical setting, single-dose bupivacaine has been used extensively with few cardiotoxic side effects. The cases of 25,697 patients at the Mayo Clinic who received a brachial plexus, epidural, or caudal block were analyzed with regard to four demographic axes, the experience of the anesthesiologist, and the drug that was used6. Of patients who received bupivacaine, seventeen had a subsequent seizure. Of these, sixteen were from the group of 3762 patients who had a brachial plexus block, none were from the group of 154 patients who had a caudal block, and one was from the group of 9416 who had an epidural block. None of the patients had associated cardiovascular complications.
Our patient had no history of cardiac disease, no perioperative ischemic event, no laboratory abnormalities, and no discernible etiology for complete heart block after evaluation by the acute response teams of both the cardiology division and the intensive care unit. The electrocardiograms did demonstrate complete heart block twelve hours after initiation of the bupivacaine continuous femoral nerve block and complete resolution six hours after cessation of the block. Bupivacaine is protein-bound intravascularly. It is then metabolized by the p450 enzyme pathway in the liver, specifically CYP3A12. It is well established that this enzyme pathway is impaired by 25% to 50% in patients with advanced liver disease13. While our patient did not have advanced liver disease (Child-Pugh class A), it is probable that she had some impairment of this metabolic pathway. The low serum albumin level and probable metabolic dysfunction likely led to a transient increase in the serum concentration of free bupivacaine. To date, an extensive cardiac workup has been normal and the patient has had no other cardiac events, arrhythmias, or similar episodes. The mechanism of action of bupivacaine, its known cardiotoxic effects, and the temporal association with the placement and removal of the continuous femoral nerve block lead us to believe that our patient's development of third-degree heart block was due to the bupivacaine. Surgeons and anesthesiologists alike must be cognizant of potential complications that may arise from regional anesthesia.
Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.
Investigation performed at the Department of Orthopaedic Surgery, Stanford University, Stanford, California
1. Liguori GA, Chimento GF, Borow L, Figgie M. Possible bupivacaine toxicity after intraarticular injection for postarthroscopic analgesia of the knee: implications of the surgical procedure. Anesth Analg. 2002;94:1010-3, table of contents.
2. Favier JC, Da Conceiçao M, Fassassi M, Allanic L, Steiner T, Pitti R. Successful resuscitation of serious bupivacaine intoxication in a patient with pre-existing heart failure. Can J Anaesth. 2003;50:62-6.
3. Soltesz EG, van Pelt F, Byrne JG. Emergent cardiopulmonary bypass for bupivacaine cardiotoxicity. J Cardiothorac Vasc Anesth. 2003;17:357-8.
4. Auroy Y, Narchi P, Messiah A, Litt L, Rouvier B, Samii K. Serious complications related to regional anesthesia: results of a prospective survey in France. Anesthesiology. 1997;87:479-86.
5. Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology. 1979;51:285-7.
6. Brown DL, Ransom DM, Hall JA, Leicht CH, Schroeder DR, Offord KP. Regional anesthesia and local anesthetic-induced systemic toxicity: seizure frequency and accompanying cardiovascular changes. Anesth Analg. 1995;81:321-8.
7. Millwala F, Nguyen GC, Thuluvath PJ. Outcomes of patients with cirrhosis undergoing non-hepatic surgery: risk assessment and management. World J Gastroenterol. 2007;13:4056-63.
8. Ziser A, Plevak DJ, Wiesner RH, Rakela J, Offord KP, Brown DL. Morbidity and mortality in cirrhotic patients undergoing anesthesia and surgery. Anesthesiology. 1999;90:42-53.
9. Salinas FV, Liu SS, Mulroy MF. The effect of single-injection femoral nerve block versus continuous femoral nerve block after total knee arthroplasty on hospital length of stay and long-term functional recovery within an established clinical pathway. Anesth Analg. 2006;102:1234-9.
10. Marx GF. Cardiotoxicity of local anesthetics—the plot thickens. Anesthesiology. 1984;60:3-5.
11. Heavner JE. Cardiac toxicity of local anesthetics in the intact isolated heart model: a review. Reg Anesth Pain Med. 2002;27:545-55.
12. Gantenbein M, Attolini L, Bruguerolle B, Villard PH, Puyoou F, Durand A, Lacarelle B, Hardwigsen J, Le-Treut YP. Oxidative metabolism of bupivacaine into pipecolylxylidine in humans is mainly catalyzed by CYP3A. Drug Metab Dispos. 2000;28:383-5.
13. Villeneuve JP, Pichette V. Cytochrome P450 and liver diseases. Curr Drug Metab. 2004;5:273-82.