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Bupivacaine drug-induced liver injury: a case series and brief review of the literature
Journal of Clinical Anesthesia (2016) 32, 137–141
Case report
Bupivacaine drug-induced liver injury: a case series and brief review of the literature☆ Preethi Chintamaneni MD (Fellow)a,⁎, Heather L. Stevenson MD, PhD (Assistant Professor)b , Shahid M. Malik MD (Clinical Assistant Professor of Medicine)a a
Department of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Division of Liver and Transplantation Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
b
Received 6 October 2014; revised 8 January 2016; accepted 21 January 2016
Keywords: Analgesics; Cholestasis; Bupivacaine; Drug induced liver injury
Abstract Bupivacaine is an established and efficacious anesthetic that has become increasingly popular in postoperative pain management. However, there is limited literature regarding the potential for bupivacaine-induced delayed liver toxicity. Describe cholestasis as a potential adverse reaction of bupivacaine infusion into a surgical wound. Retrospective review of patients' medical records. We report the cases of 3 patients with new onset of cholestatic injury after receiving bupivacaine infusion for postoperative herniorrhaphy pain management. All patients had negative serologic workups for other causes of liver injury. All patients achieved eventual resolution of their liver injury. Bupivacaineinduced liver injury should be on the differential of individuals presenting with jaundice and cholestasis within a month of infusion via a surgically placed catheter of this commonly used anesthetic. © 2016 Elsevier Inc. All rights reserved.
1. Introduction A wide variety of drugs have the potential to cause drug-induced liver injury (DILI). With an estimated incidence between 1/10,000 and 14/100,000, DILI is the number one cause of acute liver failure in the United States [1,2]. The most common causative agents are acetaminophen, antibiotics, and
☆
Statements: No funding institution; no pharmaceutical or industry support; not presented at any meetings; no conflict of interest exists for the authors; the authors have nothing to disclose. ⁎ Correspondence: Preethi Chintamaneni, MD, Department of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Montefiore Hospital, 200 Lothrop Street, PUH, M2, C Wing, Pittsburgh, PA 15213. Tel.: + 1 412 648 9115; fax: + 1 412 648 9378. E-mail addresses: [email protected], [email protected] (P. Chintamaneni). http://dx.doi.org/10.1016/j.jclinane.2016.01.035 0952-8180/© 2016 Elsevier Inc. All rights reserved.
nonsteroidal anti-inflammatory drugs. The mechanism of liver injury can be a direct hepatotoxic effect, a hypersensitivity reaction, or an autoimmune-induced type injury. DILI may occur as an idiosyncratic reaction and is not necessarily related to dose, duration, or route of administration. The injury may not improve with drug withdrawal or be reproducible with drug rechallenge [3]. Bupivacaine is an established and efficacious anesthetic in reducing postoperative pain and is increasingly used in a variety of surgical specialties [4]. The safe dosage of bupivacaine for epidural administration is generally accepted as no more than 400 mg per 24 hours [5]. However, there has been little characterization of the safety of locally infused bupivacaine preparations. Double-blind placebo trials have indicated that bupivacaine infusion of 240 mg or more in 24 hours is safe and efficacious in managing pain status postinguinal herniorrhaphy [4,6]. In general, elastomeric
138
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bupivacaine infusion pumps contain 0.5% bupivacaine and are infused at a rate of 2 mL/h over a period of 24 to 48 hours. There is little literature in regard to delayed liver toxicity induced by bupivacaine [7,8]. In 1993, Billström et al [9] described cholestasis in 3 of 10 patients who underwent intrapleural bupivacaine infusion to treat upper limb pain secondary to reflex sympathetic dystrophy. All patients received 6 to 7 administrations of 30 mL of 0.5% bupivacaine with epinephrine through an indwelling pleural catheter over a period of 2 weeks. Three of the 10 patients developed biochemical abnormalities, and subsequent liver biopsies were consistent with cholestasis. Each of these patients had resolution of biochemical abnormalities within 2 months. In 2003, Yokoyama et al [10] described 4 cases of acute cholestasis 3 weeks after continuous epidural bupivacaine infusion for back pain. Each of these patients received 0.25% bupivacaine over a 2-week period, with a total bupivacaine dose ranging from 0.5 to 2.0 g. The authors attributed the liver injury to bupivacaine and switched from bupivacaine to lidocaine for pain treatment in all 4 patients, with resolution of biochemical abnormalities within 1 to 2 months. In this case series, we describe severe cholestasis as a potential adverse reaction of bupivacaine infusion into a surgical wound.
Ten pump was implanted at the surgical site for 1 day, which infused 0.5% of bupivacaine at a rate of 2 mg/h. Total bupivacaine dose was 98 mg. The patient felt well until 14 days postoperatively when he developed low-grade fevers, fatigue, dark urine, and pruritus. He sought medical attention 1 week later with the onset of painless jaundice. The patient's medical history was significant only for a history of Parkinson disease. There was no family history of liver, biliary, or pancreatic disease. He endorsed occasional social alcohol consumption. Physical examination was notable only for icteric sclera and jaundice without any stigmata of chronic liver disease. Complete blood count was notable for an 8% eosinophilia. LFTs were elevated on arrival (Table). Testing for viral serologies including Hepatitis A, Hepatitis B, Hepatitis C, Herpes Simplex Virus, Epstein-Barr Virus, and Cytomegalovirus were negative. Autoimmune testing, celiac panel, ceruloplasmin, and α1-antitrypsin levels were unrevealing. Magnetic resonance cholangiopancreatography was performed and showed smooth tapering of the common bile duct with no evidence of intrahepatic ductal dilation. The patient received symptomatic treatment, and his LFTs began to down trend after 1 week. A liver biopsy was deemed unnecessary, and patient was discharged to home with follow-up. The patient's LFTs normalized 4 weeks after his hospitalization.
2. Materials and methods
3.2. Case 2 W.P. was a 51-year-old man with normal baseline LFTs who underwent a left inguinal herniorrhaphy. Perioperative antibiotics were limited to cefazolin. The patient underwent general anesthesia for sedation. The patient was injected with 5 mL of bupivacaine 0.5% intraoperatively, and an OnQ Pain pump was placed after repair of the hernia with infusion of 0.5% bupivacaine at a rate of 2 mg/h for 2 days. Total bupivacaine dose was 121 mg. He recovered well from surgery without any complications and felt well until 3 weeks postoperatively when he developed fatigue, mild nausea, and low-grade fevers to 100°F for a few days. He then noticed dark urine, pale stools, jaundice, and pruritus. The patient's medical history was notable for mild osteoarthritis and hyperlipidemia. He did not have a family history of liver or biliary diseases. He had a 40-year pack smoking history and averaged approximately 10 beers per
We report 3 cases of new-onset cholestatic jaundice that developed after receiving bupivacaine infusion for postoperative herniorrhaphy pain management.
3. Results 3.1. Case 1 G.J. was a 66-year-old man with normal baseline liver function tests (LFTs) that underwent a right inguinal herniorrhaphy. Preoperative antibiotics were limited to cefazolin. The patient underwent general anesthesia for sedation, and 10 mL of bupivacaine 0.5% was injected intraoperatively. After the procedure, an elastomeric OnQ
Table
Patient demographics, laboratory test results, and durations.
Patient initials
G.J. W.P. R.F.
Age
66 51 58
Sex
M M M
Peak laboratory values Eos (%)
ALT
AST
ALP
Tb
Cb
8% 9% 7%
305 491 237
160 262 102
585 378 365
11.1 9.5 5.5
6.8 7.4 2.3
Time post–hernia repair to symptoms
Time from initial evaluation to resolution of LFTs
14 d 21 d 15 d
30 d 25 d 30 d
Eos = eosinophils (reference range, 1%-4%); ALT = alanine transaminase (reference range, 30-65 IU/L); AST = aspartate transaminase (reference range, 15-37 IU/L); ALP = alkaline phosphatase (reference range, 50-136 IU/L); Tb = total bilirubin (reference range, 0.3-1.9 mg/dL); Cb = conjugated bilirubin (reference range, 0-0.3 mg/dL).
Bupivacaine Drug Induced Liver Injury: A Case Series week. He was taking simvastatin for hyperlipidemia as well as aspirin and acetaminophen as needed within the recommend dosages. On admission, physical examination was notable only for scleral icterus and jaundice. There were no stigmata of chronic liver disease. The patient's complete blood count was notable for a 9% eosinophilia. LFTs peaked during this hospitalization (Table). The patient's entire serological workup for other causes of liver injury (see testing performed in case 1) was negative. Right upper quadrant ultrasound and computed tomography of the abdomen with contrast showed a normal-appearing liver, gallbladder, pancreas, and biliary tree with no evidence of an obstructive process. Simvastatin was discontinued upon admission, and symptomatic treatment was initiated for management of his pruritus. Peak laboratory values (Table) showed a mixed cholestatic and hepatocellular pattern of injury. Liver biopsy revealed mixed mild portal inflammation and low-grade ductular reaction as well as hepatocanalicular cholestasis with mild portal and periportal fibrosis consistent with a cholestatic adverse drug reaction (Figs. 1 and 2). The portal tracts contained a mixed inflammatory infiltrate composed primarily of lymphocytes with occasional eosinophils and neutrophils. The histopathologic evidence of biliary injury included reactive biliary epithelial cells, a low-grade bile ductular reaction, mild peribiliary edema with inflammation, and hepatocanalicular cholestasis. Although the biopsy was not taken during the peak period of liver injury (based on the laboratory studies), focal aggregates of ceroid-laden macrophages were present, suggesting recent hepatocyte injury. The liver enzymes normalized approximately 4 weeks after hospitalization.
3.3. Case 3 R.F. was a 58-year-old man with normal baseline LFTs who underwent a left inguinal herniorrhaphy. Perioperative
Fig. 1 Low power image of hematoxylin and eosin–stained liver tissue showing ductular reaction with low-grade edema and focal periductular neutrophils (arrows) as well as hepatocanalicular cholestasis (arrowhead) with mild portal and periportal fibrosis, all findings consistent with cholestatic liver injury.
139
Fig. 2 High-power image of hematoxylin and eosin stain of liver tissue showing ductular reaction with arrows showing low-grade edema and focal periductular neutrophils.
antibiotics included 1 dose of ciprofloxacin 400 mg and 1 dose of metronidazole 500 mg. The patient underwent general anesthesia for sedation. The patient was injected with 15 mL of 0.5% bupivacaine intraoperatively, and an OnQ Pain pump was implanted at the surgical site. The elastomeric pump contained 0.5% bupivacaine and infused medication at 2 mg/h for 2 days. Total bupivacaine dose was 171 mg. The patient was discharged home without complications. Five days postoperatively, however, the patient developed fevers, abdominal pain, nausea, vomiting, arthralgias, and myalgias. His fevers resolved, but he continued to have persistent nausea and vomiting. He subsequently developed dark urine and acholic stools. At postoperative day 20, the patient presented to his primary care physician for further evaluation. The patient's medical history was notable for hyperlipidemia, atrial tachycardia, and coronary artery disease. He did not endorse a family history of pancreatic, biliary, or liver disease. He denied any tobacco, recreational drug, or alcohol use. His home medications included low-dose aspirin and simvastatin 40 mg daily, but this was discontinued preoperatively (for unclear reasons). Physical examination revealed a man in no distress with mild jaundice and scleral icterus, but no stigmata of chronic liver disease. Laboratory work was notable for no leukocytosis but a mild peripheral eosinophilia (7%). LFTs are listed in the Table. As in cases 1 and 2, the entire serological workup for other causes of liver injury and infectious workup were unrevealing. These findings prompted further evaluation including right upper quadrant ultrasound and computed tomography of the abdomen with contrast. Both studies showed normal-appearing liver, gallbladder, pancreas, and biliary system. The patient was treated conservatively, and with
140 spontaneous downtrending laboratory test results, a liver biopsy was not pursued. Liver function enzymes and total bilirubin normalized within 1 month after his initial presentation.
4. Discussion Bupivacaine is one of the more commonly used anesthetics for the management of postoperative pain. This is the first case series linking bupivacaine administered via a pain pump post– hernia repair to the development of jaundice and cholestasis. In accordance with the parameters set by International DILI Expert Working Group, the biochemical profiles of all 3 patients satisfied the diagnostic threshold for DILI, each with a cholestatic pattern of injury that would be classified as moderate in severity. An extensive serological and radiologic investigation for alternative causes of liver injury was performed in all 3 cases and was unrevealing. Simvastatin is part of a class of drugs reported to be associated with LFT elevations; however, unlike with bupivacaine, simvastatin is associated with a hepatocellular DILI [7]. Cephalosporin antibiotics are known to cause hepatitis and transient elevations of alkaline phosphatase and transaminases; however, there are few reports of cholestatic jaundice [8]. The immunologic mechanism by which bupivacaine elicits cholestatic liver injury remains unclear. Yokoyama et al [10] postulated that bupivacaine-induced liver injury may occur via an allergic reaction or the generation of toxic metabolites. In our case series, we found that all 3 patients demonstrated delayed onset of symptoms with fever and both peripheral and biopsy eosinophilia strongly favoring an immune-mediated reaction to bupivacaine resulting in liver injury. In our study and prior studies, there is no clear evidence of a dose-dependent relationship or association with duration of administration. Immune-mediated drug reactions, unlike drugs with direct hepatic toxicity, are usually host-dependent reactions that are not dose related. Although Billström et al [9] and Yokoyama et al [10] observed liver injury in patients receiving longer durations (2 weeks) of bupivacaine administration, we found cases of liver injury with only 48 hours of bupivacaine administration. These findings suggest that the duration of administration may not have a direct effect on toxicity. In addition, Yokoyama et al [10] and Billström et al [9] used higher total dosages of bupivacaine (500-2000 mg and 900-1050 mg, respectively), whereas our study used significantly lower total dosages (98-171 mg), thus suggesting that there may not be a dose-dependent relationship. Given the limited incidence of bupivacaine-induced liver injury, further studies are needed to better elucidate whether there is a dose-dependent relationship or if the duration of administration increases the risk of bupivacaine-induced liver injury. However, the fact that the current studies related to bupivacaine toxicity do not show a dose-dependent relationship further supports the hypothesis that its mechanism of injury is immune mediated. Although we have demonstrated several instances of bupivacaine-induced liver injury, the true incidence of
P. Chintamaneni et al. bupivacaine-induced liver injury has not yet been clearly established. Without knowing the true incidence of bupivacaineinduced liver injury, we recommend adherence to the current preoperative guidelines that do not recommend routine testing in healthy patients undergoing low-risk, elective surgery [11]. In otherwise healthy patients, the American College of Gastroenterology [12] does not recommend routine postoperative screening of liver function unless there are clinical signs or symptoms of acute liver injury. In those patients who do develop symptoms of acute liver injury with suspected DILI, the American College of Gastroenterology clinical guidelines recommend that patients undergo extensive chronic liver disease workup (viral hepatitis serologies, autoimmune workup, and infectious workup) and workup to exclude biliary tract pathologies [12]. Given the extensive nature of this evaluation, we feel that referral to a hepatologist is warranted in any patients who develop signs of symptoms of acute liver injury. In addition, there have been no case reports of bupivacaineinduced hepatotoxicity in patients with underlying liver disease; thus, the effect of bupivacaine in patients with preexisting liver disease remains unknown. As a result, we cannot comment on the risks of bupivacaine use in patients with preexisting liver disease. In this scenario, routine preoperative liver function testing might be used to help establish a baseline assessment of liver function to better interpret any laboratory results obtained after administration of bupivacaine. In those patients with a prior history of liver disease, close monitoring for evidence of hepatoxicity every 4 to 6 weeks for a period of 6 months is reasonable after administration of any potential hepatotoxic agent [12]. Bupivacaine is a member of the amide class of long-acting local anesthetics. There has not been any literature to suggest that liver injury is associated with amide-type long-acting anesthetics other than bupivacaine and a single case report with lidocaine. Uematsu et al [13] described a case of lidocaine-associated liver toxicity in a 67-year-old woman receiving thoracic epidural nerve blocks with 10 mL of lidocaine 3 to 4 times a week for herpes zoster pain that, after 2 weeks, developed acute liver injury. Although we have described several cases of bupivacaine-induced liver injury, there is little literature suggesting that other amide-type long-acting local anesthetics can cause liver injury. Thus, we recommend that, in patients with preexisting liver disease, the use of other amide-type long-acting anesthetics should be considered instead of bupivacaine.
5. Conclusion Bupivacaine elastomeric pumps are becoming an increasingly popular device for postoperative pain management. The current series adds 3 additional cases of a moderately severe cholestatic injury presenting in 3 male patients approximately 3 weeks after administration of bupivacaine at the time of an inguinal hernia repair. Fortunately (as in the previously reported cases in the literature), all 3 patients recovered without any specific therapy. Bupivacaine-induced liver injury
Bupivacaine Drug Induced Liver Injury: A Case Series should be on the differential of individuals presenting with jaundice and cholestasis within a month of infusion via a surgically placed catheter of this commonly used anesthetic. In addition, we recommend that surgeons and anesthesiologists consider using other long-acting local anesthetics until the risk for drug-induced liver injury with bupivacaine is further investigated.
141
[6]
[7]
[8]
References [1] Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 2002;36(2):451-5. [2] Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SH, et al. U.S. Acute Liver Failure Study Group. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137(12):947-54. [3] Fontana RJ. Approaches to the study of drug-induced liver injury. Clin Pharmacol Ther 2010;88(3):416-9. [4] Schurr MJ, Gordon DB, Pellino TA, Scanlon TA. Continuous local anesthetic infusion for pain management after outpatient inguinal herniorrhaphy. Surgery 2004;136:761-9. [5] Corcoran W, Butterworth J, Weller RS, Beck JC, Gerancher JC, Houle TT, et al. Local anesthetic–induced cardiac toxicity: a survey of contemporary
[9] [10]
[11]
[12]
[13]
practice strategies among academic anesthesiology departments. Anesth Analg 2006;103(5):1322-6. LeBlanc KA, Bellanger D, Rhynes VK, Hausmann M. Evaluation of continuous infusion of 0.5% bupivacaine by elastomeric pump for postoperative pain management after open inguinal hernia repair. J Am Coll Surg 2005;200(2):198-202. Björnsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol 2012;56(2):374-80. Alqahtani SA, Kleiner DE, Ghabril M, Gu J, Hoofnagle JH, Rockey DC, et al. Identification and characterization of cefazolin-induced liver injury. Clin Gastroenterol Hepatol 2014;1542-3565(14):1824-32. Billström R, Blomberg HM. Cholestasis after intrapleural bupivacaine for chronic upper limb pain. Anesth Analg 1993;76:1158-9. Yokoyama M, Ohashi I, Nakatsuka H, Mizobuchi S, Toda Y, Matsumi M, et al. Drug-induced liver disease during continuous epidural block with bupivacaine. Anesthesiology 2001;95(1):259-61. Benarroch-Gampel J, Sheffield KM, Duncan CB, Brown KM, Han Y, Townsend CM Jr, et al. Preoperative laboratory testing in patients undergoing elective, low-risk ambulatory surgery. Ann Surg 2012; 256(3):518. Chalasani N, Hayashi P, Baonkovsky H, Navarro VJ, Lee WM, Fontana RJ, et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2014;109: 950-66. Uematsu H, Hiei K, Kawasaki H. Unknown fever and abnormal liver functions after repeated epidural blocks with lidocaine for management of herpes zoster pain. Masui 1994;43(3):405-8.
Case report
Bupivacaine drug-induced liver injury: a case series and brief review of the literature☆ Preethi Chintamaneni MD (Fellow)a,⁎, Heather L. Stevenson MD, PhD (Assistant Professor)b , Shahid M. Malik MD (Clinical Assistant Professor of Medicine)a a
Department of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA Division of Liver and Transplantation Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
b
Received 6 October 2014; revised 8 January 2016; accepted 21 January 2016
Keywords: Analgesics; Cholestasis; Bupivacaine; Drug induced liver injury
Abstract Bupivacaine is an established and efficacious anesthetic that has become increasingly popular in postoperative pain management. However, there is limited literature regarding the potential for bupivacaine-induced delayed liver toxicity. Describe cholestasis as a potential adverse reaction of bupivacaine infusion into a surgical wound. Retrospective review of patients' medical records. We report the cases of 3 patients with new onset of cholestatic injury after receiving bupivacaine infusion for postoperative herniorrhaphy pain management. All patients had negative serologic workups for other causes of liver injury. All patients achieved eventual resolution of their liver injury. Bupivacaineinduced liver injury should be on the differential of individuals presenting with jaundice and cholestasis within a month of infusion via a surgically placed catheter of this commonly used anesthetic. © 2016 Elsevier Inc. All rights reserved.
1. Introduction A wide variety of drugs have the potential to cause drug-induced liver injury (DILI). With an estimated incidence between 1/10,000 and 14/100,000, DILI is the number one cause of acute liver failure in the United States [1,2]. The most common causative agents are acetaminophen, antibiotics, and
☆
Statements: No funding institution; no pharmaceutical or industry support; not presented at any meetings; no conflict of interest exists for the authors; the authors have nothing to disclose. ⁎ Correspondence: Preethi Chintamaneni, MD, Department of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Montefiore Hospital, 200 Lothrop Street, PUH, M2, C Wing, Pittsburgh, PA 15213. Tel.: + 1 412 648 9115; fax: + 1 412 648 9378. E-mail addresses: [email protected], [email protected] (P. Chintamaneni). http://dx.doi.org/10.1016/j.jclinane.2016.01.035 0952-8180/© 2016 Elsevier Inc. All rights reserved.
nonsteroidal anti-inflammatory drugs. The mechanism of liver injury can be a direct hepatotoxic effect, a hypersensitivity reaction, or an autoimmune-induced type injury. DILI may occur as an idiosyncratic reaction and is not necessarily related to dose, duration, or route of administration. The injury may not improve with drug withdrawal or be reproducible with drug rechallenge [3]. Bupivacaine is an established and efficacious anesthetic in reducing postoperative pain and is increasingly used in a variety of surgical specialties [4]. The safe dosage of bupivacaine for epidural administration is generally accepted as no more than 400 mg per 24 hours [5]. However, there has been little characterization of the safety of locally infused bupivacaine preparations. Double-blind placebo trials have indicated that bupivacaine infusion of 240 mg or more in 24 hours is safe and efficacious in managing pain status postinguinal herniorrhaphy [4,6]. In general, elastomeric
138
P. Chintamaneni et al.
bupivacaine infusion pumps contain 0.5% bupivacaine and are infused at a rate of 2 mL/h over a period of 24 to 48 hours. There is little literature in regard to delayed liver toxicity induced by bupivacaine [7,8]. In 1993, Billström et al [9] described cholestasis in 3 of 10 patients who underwent intrapleural bupivacaine infusion to treat upper limb pain secondary to reflex sympathetic dystrophy. All patients received 6 to 7 administrations of 30 mL of 0.5% bupivacaine with epinephrine through an indwelling pleural catheter over a period of 2 weeks. Three of the 10 patients developed biochemical abnormalities, and subsequent liver biopsies were consistent with cholestasis. Each of these patients had resolution of biochemical abnormalities within 2 months. In 2003, Yokoyama et al [10] described 4 cases of acute cholestasis 3 weeks after continuous epidural bupivacaine infusion for back pain. Each of these patients received 0.25% bupivacaine over a 2-week period, with a total bupivacaine dose ranging from 0.5 to 2.0 g. The authors attributed the liver injury to bupivacaine and switched from bupivacaine to lidocaine for pain treatment in all 4 patients, with resolution of biochemical abnormalities within 1 to 2 months. In this case series, we describe severe cholestasis as a potential adverse reaction of bupivacaine infusion into a surgical wound.
Ten pump was implanted at the surgical site for 1 day, which infused 0.5% of bupivacaine at a rate of 2 mg/h. Total bupivacaine dose was 98 mg. The patient felt well until 14 days postoperatively when he developed low-grade fevers, fatigue, dark urine, and pruritus. He sought medical attention 1 week later with the onset of painless jaundice. The patient's medical history was significant only for a history of Parkinson disease. There was no family history of liver, biliary, or pancreatic disease. He endorsed occasional social alcohol consumption. Physical examination was notable only for icteric sclera and jaundice without any stigmata of chronic liver disease. Complete blood count was notable for an 8% eosinophilia. LFTs were elevated on arrival (Table). Testing for viral serologies including Hepatitis A, Hepatitis B, Hepatitis C, Herpes Simplex Virus, Epstein-Barr Virus, and Cytomegalovirus were negative. Autoimmune testing, celiac panel, ceruloplasmin, and α1-antitrypsin levels were unrevealing. Magnetic resonance cholangiopancreatography was performed and showed smooth tapering of the common bile duct with no evidence of intrahepatic ductal dilation. The patient received symptomatic treatment, and his LFTs began to down trend after 1 week. A liver biopsy was deemed unnecessary, and patient was discharged to home with follow-up. The patient's LFTs normalized 4 weeks after his hospitalization.
2. Materials and methods
3.2. Case 2 W.P. was a 51-year-old man with normal baseline LFTs who underwent a left inguinal herniorrhaphy. Perioperative antibiotics were limited to cefazolin. The patient underwent general anesthesia for sedation. The patient was injected with 5 mL of bupivacaine 0.5% intraoperatively, and an OnQ Pain pump was placed after repair of the hernia with infusion of 0.5% bupivacaine at a rate of 2 mg/h for 2 days. Total bupivacaine dose was 121 mg. He recovered well from surgery without any complications and felt well until 3 weeks postoperatively when he developed fatigue, mild nausea, and low-grade fevers to 100°F for a few days. He then noticed dark urine, pale stools, jaundice, and pruritus. The patient's medical history was notable for mild osteoarthritis and hyperlipidemia. He did not have a family history of liver or biliary diseases. He had a 40-year pack smoking history and averaged approximately 10 beers per
We report 3 cases of new-onset cholestatic jaundice that developed after receiving bupivacaine infusion for postoperative herniorrhaphy pain management.
3. Results 3.1. Case 1 G.J. was a 66-year-old man with normal baseline liver function tests (LFTs) that underwent a right inguinal herniorrhaphy. Preoperative antibiotics were limited to cefazolin. The patient underwent general anesthesia for sedation, and 10 mL of bupivacaine 0.5% was injected intraoperatively. After the procedure, an elastomeric OnQ
Table
Patient demographics, laboratory test results, and durations.
Patient initials
G.J. W.P. R.F.
Age
66 51 58
Sex
M M M
Peak laboratory values Eos (%)
ALT
AST
ALP
Tb
Cb
8% 9% 7%
305 491 237
160 262 102
585 378 365
11.1 9.5 5.5
6.8 7.4 2.3
Time post–hernia repair to symptoms
Time from initial evaluation to resolution of LFTs
14 d 21 d 15 d
30 d 25 d 30 d
Eos = eosinophils (reference range, 1%-4%); ALT = alanine transaminase (reference range, 30-65 IU/L); AST = aspartate transaminase (reference range, 15-37 IU/L); ALP = alkaline phosphatase (reference range, 50-136 IU/L); Tb = total bilirubin (reference range, 0.3-1.9 mg/dL); Cb = conjugated bilirubin (reference range, 0-0.3 mg/dL).
Bupivacaine Drug Induced Liver Injury: A Case Series week. He was taking simvastatin for hyperlipidemia as well as aspirin and acetaminophen as needed within the recommend dosages. On admission, physical examination was notable only for scleral icterus and jaundice. There were no stigmata of chronic liver disease. The patient's complete blood count was notable for a 9% eosinophilia. LFTs peaked during this hospitalization (Table). The patient's entire serological workup for other causes of liver injury (see testing performed in case 1) was negative. Right upper quadrant ultrasound and computed tomography of the abdomen with contrast showed a normal-appearing liver, gallbladder, pancreas, and biliary tree with no evidence of an obstructive process. Simvastatin was discontinued upon admission, and symptomatic treatment was initiated for management of his pruritus. Peak laboratory values (Table) showed a mixed cholestatic and hepatocellular pattern of injury. Liver biopsy revealed mixed mild portal inflammation and low-grade ductular reaction as well as hepatocanalicular cholestasis with mild portal and periportal fibrosis consistent with a cholestatic adverse drug reaction (Figs. 1 and 2). The portal tracts contained a mixed inflammatory infiltrate composed primarily of lymphocytes with occasional eosinophils and neutrophils. The histopathologic evidence of biliary injury included reactive biliary epithelial cells, a low-grade bile ductular reaction, mild peribiliary edema with inflammation, and hepatocanalicular cholestasis. Although the biopsy was not taken during the peak period of liver injury (based on the laboratory studies), focal aggregates of ceroid-laden macrophages were present, suggesting recent hepatocyte injury. The liver enzymes normalized approximately 4 weeks after hospitalization.
3.3. Case 3 R.F. was a 58-year-old man with normal baseline LFTs who underwent a left inguinal herniorrhaphy. Perioperative
Fig. 1 Low power image of hematoxylin and eosin–stained liver tissue showing ductular reaction with low-grade edema and focal periductular neutrophils (arrows) as well as hepatocanalicular cholestasis (arrowhead) with mild portal and periportal fibrosis, all findings consistent with cholestatic liver injury.
139
Fig. 2 High-power image of hematoxylin and eosin stain of liver tissue showing ductular reaction with arrows showing low-grade edema and focal periductular neutrophils.
antibiotics included 1 dose of ciprofloxacin 400 mg and 1 dose of metronidazole 500 mg. The patient underwent general anesthesia for sedation. The patient was injected with 15 mL of 0.5% bupivacaine intraoperatively, and an OnQ Pain pump was implanted at the surgical site. The elastomeric pump contained 0.5% bupivacaine and infused medication at 2 mg/h for 2 days. Total bupivacaine dose was 171 mg. The patient was discharged home without complications. Five days postoperatively, however, the patient developed fevers, abdominal pain, nausea, vomiting, arthralgias, and myalgias. His fevers resolved, but he continued to have persistent nausea and vomiting. He subsequently developed dark urine and acholic stools. At postoperative day 20, the patient presented to his primary care physician for further evaluation. The patient's medical history was notable for hyperlipidemia, atrial tachycardia, and coronary artery disease. He did not endorse a family history of pancreatic, biliary, or liver disease. He denied any tobacco, recreational drug, or alcohol use. His home medications included low-dose aspirin and simvastatin 40 mg daily, but this was discontinued preoperatively (for unclear reasons). Physical examination revealed a man in no distress with mild jaundice and scleral icterus, but no stigmata of chronic liver disease. Laboratory work was notable for no leukocytosis but a mild peripheral eosinophilia (7%). LFTs are listed in the Table. As in cases 1 and 2, the entire serological workup for other causes of liver injury and infectious workup were unrevealing. These findings prompted further evaluation including right upper quadrant ultrasound and computed tomography of the abdomen with contrast. Both studies showed normal-appearing liver, gallbladder, pancreas, and biliary system. The patient was treated conservatively, and with
140 spontaneous downtrending laboratory test results, a liver biopsy was not pursued. Liver function enzymes and total bilirubin normalized within 1 month after his initial presentation.
4. Discussion Bupivacaine is one of the more commonly used anesthetics for the management of postoperative pain. This is the first case series linking bupivacaine administered via a pain pump post– hernia repair to the development of jaundice and cholestasis. In accordance with the parameters set by International DILI Expert Working Group, the biochemical profiles of all 3 patients satisfied the diagnostic threshold for DILI, each with a cholestatic pattern of injury that would be classified as moderate in severity. An extensive serological and radiologic investigation for alternative causes of liver injury was performed in all 3 cases and was unrevealing. Simvastatin is part of a class of drugs reported to be associated with LFT elevations; however, unlike with bupivacaine, simvastatin is associated with a hepatocellular DILI [7]. Cephalosporin antibiotics are known to cause hepatitis and transient elevations of alkaline phosphatase and transaminases; however, there are few reports of cholestatic jaundice [8]. The immunologic mechanism by which bupivacaine elicits cholestatic liver injury remains unclear. Yokoyama et al [10] postulated that bupivacaine-induced liver injury may occur via an allergic reaction or the generation of toxic metabolites. In our case series, we found that all 3 patients demonstrated delayed onset of symptoms with fever and both peripheral and biopsy eosinophilia strongly favoring an immune-mediated reaction to bupivacaine resulting in liver injury. In our study and prior studies, there is no clear evidence of a dose-dependent relationship or association with duration of administration. Immune-mediated drug reactions, unlike drugs with direct hepatic toxicity, are usually host-dependent reactions that are not dose related. Although Billström et al [9] and Yokoyama et al [10] observed liver injury in patients receiving longer durations (2 weeks) of bupivacaine administration, we found cases of liver injury with only 48 hours of bupivacaine administration. These findings suggest that the duration of administration may not have a direct effect on toxicity. In addition, Yokoyama et al [10] and Billström et al [9] used higher total dosages of bupivacaine (500-2000 mg and 900-1050 mg, respectively), whereas our study used significantly lower total dosages (98-171 mg), thus suggesting that there may not be a dose-dependent relationship. Given the limited incidence of bupivacaine-induced liver injury, further studies are needed to better elucidate whether there is a dose-dependent relationship or if the duration of administration increases the risk of bupivacaine-induced liver injury. However, the fact that the current studies related to bupivacaine toxicity do not show a dose-dependent relationship further supports the hypothesis that its mechanism of injury is immune mediated. Although we have demonstrated several instances of bupivacaine-induced liver injury, the true incidence of
P. Chintamaneni et al. bupivacaine-induced liver injury has not yet been clearly established. Without knowing the true incidence of bupivacaineinduced liver injury, we recommend adherence to the current preoperative guidelines that do not recommend routine testing in healthy patients undergoing low-risk, elective surgery [11]. In otherwise healthy patients, the American College of Gastroenterology [12] does not recommend routine postoperative screening of liver function unless there are clinical signs or symptoms of acute liver injury. In those patients who do develop symptoms of acute liver injury with suspected DILI, the American College of Gastroenterology clinical guidelines recommend that patients undergo extensive chronic liver disease workup (viral hepatitis serologies, autoimmune workup, and infectious workup) and workup to exclude biliary tract pathologies [12]. Given the extensive nature of this evaluation, we feel that referral to a hepatologist is warranted in any patients who develop signs of symptoms of acute liver injury. In addition, there have been no case reports of bupivacaineinduced hepatotoxicity in patients with underlying liver disease; thus, the effect of bupivacaine in patients with preexisting liver disease remains unknown. As a result, we cannot comment on the risks of bupivacaine use in patients with preexisting liver disease. In this scenario, routine preoperative liver function testing might be used to help establish a baseline assessment of liver function to better interpret any laboratory results obtained after administration of bupivacaine. In those patients with a prior history of liver disease, close monitoring for evidence of hepatoxicity every 4 to 6 weeks for a period of 6 months is reasonable after administration of any potential hepatotoxic agent [12]. Bupivacaine is a member of the amide class of long-acting local anesthetics. There has not been any literature to suggest that liver injury is associated with amide-type long-acting anesthetics other than bupivacaine and a single case report with lidocaine. Uematsu et al [13] described a case of lidocaine-associated liver toxicity in a 67-year-old woman receiving thoracic epidural nerve blocks with 10 mL of lidocaine 3 to 4 times a week for herpes zoster pain that, after 2 weeks, developed acute liver injury. Although we have described several cases of bupivacaine-induced liver injury, there is little literature suggesting that other amide-type long-acting local anesthetics can cause liver injury. Thus, we recommend that, in patients with preexisting liver disease, the use of other amide-type long-acting anesthetics should be considered instead of bupivacaine.
5. Conclusion Bupivacaine elastomeric pumps are becoming an increasingly popular device for postoperative pain management. The current series adds 3 additional cases of a moderately severe cholestatic injury presenting in 3 male patients approximately 3 weeks after administration of bupivacaine at the time of an inguinal hernia repair. Fortunately (as in the previously reported cases in the literature), all 3 patients recovered without any specific therapy. Bupivacaine-induced liver injury
Bupivacaine Drug Induced Liver Injury: A Case Series should be on the differential of individuals presenting with jaundice and cholestasis within a month of infusion via a surgically placed catheter of this commonly used anesthetic. In addition, we recommend that surgeons and anesthesiologists consider using other long-acting local anesthetics until the risk for drug-induced liver injury with bupivacaine is further investigated.
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[7]
[8]
References [1] Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 2002;36(2):451-5. [2] Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SH, et al. U.S. Acute Liver Failure Study Group. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137(12):947-54. [3] Fontana RJ. Approaches to the study of drug-induced liver injury. Clin Pharmacol Ther 2010;88(3):416-9. [4] Schurr MJ, Gordon DB, Pellino TA, Scanlon TA. Continuous local anesthetic infusion for pain management after outpatient inguinal herniorrhaphy. Surgery 2004;136:761-9. [5] Corcoran W, Butterworth J, Weller RS, Beck JC, Gerancher JC, Houle TT, et al. Local anesthetic–induced cardiac toxicity: a survey of contemporary
[9] [10]
[11]
[12]
[13]
practice strategies among academic anesthesiology departments. Anesth Analg 2006;103(5):1322-6. LeBlanc KA, Bellanger D, Rhynes VK, Hausmann M. Evaluation of continuous infusion of 0.5% bupivacaine by elastomeric pump for postoperative pain management after open inguinal hernia repair. J Am Coll Surg 2005;200(2):198-202. Björnsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol 2012;56(2):374-80. Alqahtani SA, Kleiner DE, Ghabril M, Gu J, Hoofnagle JH, Rockey DC, et al. Identification and characterization of cefazolin-induced liver injury. Clin Gastroenterol Hepatol 2014;1542-3565(14):1824-32. Billström R, Blomberg HM. Cholestasis after intrapleural bupivacaine for chronic upper limb pain. Anesth Analg 1993;76:1158-9. Yokoyama M, Ohashi I, Nakatsuka H, Mizobuchi S, Toda Y, Matsumi M, et al. Drug-induced liver disease during continuous epidural block with bupivacaine. Anesthesiology 2001;95(1):259-61. Benarroch-Gampel J, Sheffield KM, Duncan CB, Brown KM, Han Y, Townsend CM Jr, et al. Preoperative laboratory testing in patients undergoing elective, low-risk ambulatory surgery. Ann Surg 2012; 256(3):518. Chalasani N, Hayashi P, Baonkovsky H, Navarro VJ, Lee WM, Fontana RJ, et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol 2014;109: 950-66. Uematsu H, Hiei K, Kawasaki H. Unknown fever and abnormal liver functions after repeated epidural blocks with lidocaine for management of herpes zoster pain. Masui 1994;43(3):405-8.