An intra-articular injection of local anesthetics is a common procedure for diagnostic and therapeutic purposes. It has been shown that these agents are toxic to articular cartilage and synovial tissue in a dose- and time-dependent fashion, and in some cases, they may lead to postarthroscopic glenohumeral chondrolysis (PAGCL). However, the role of apoptosis in cell death is still unclear, and the potential role of apoptosis inhibition in minimizing chondrocyte and synovial cell death has not been reported.
Purpose:
(1) To quantify the degree of apoptotic cell death in chondrocytes and synovial cells exposed to local anesthetics, and (2) to determine whether caspase inhibition could reduce cell death.
Study Design:
Controlled laboratory study.
Methods:
Human chondrocytes and synovial cells were expanded in vitro and exposed to normal saline, 0.5% bupivacaine, 0.5% ropivacaine, 1% lidocaine, or 1:1000 epinephrine for 90 minutes. Apoptosis was then detected at 1, 3, 5, and 7 days after exposure using terminal deoxynucleotidyl transferase (TdT)–mediated dUTP nick-end labeling (TUNEL) and immunohistochemistry. Apoptosis was then inhibited using the pan-caspase inhibitor z-vad-fmk. Results were normalized to normal saline controls and analyzed by generalized regression models and pairwise confidence intervals.
Results:
Analysis of cumulative chondrocyte apoptosis relative to controls after anesthetic exposure demonstrated more than 60% cell death with 0.5% bupivacaine and 1:1000 epinephrine. The greatest chondroprotective effect of caspase inhibition occurred with 0.5% ropivacaine. Similarly, in synovial cells, epinephrine was also very cytotoxic; however, 1% lidocaine induced the most apoptosis. Synovial cells exposed to 0.5% ropivacaine were again most sensitive to protective caspase inhibition.
Conclusion:
Local anesthetics induce chondrocyte and synovial cell apoptosis in a time-dependent fashion, with peak apoptosis occurring 5 days after exposure. Both chondrocytes and synovial cells are most sensitive to caspase inhibition after exposure to 0.5% ropivacaine.
Clinical Relevance:
Apoptosis inhibition may be an effective strategy in minimizing chondrocyte and synovial cell death after exposure to anesthetics. Further investigation is clinically warranted.
AnakwenzeOAHosalkarHHuffmanGR. Case reports: two cases of glenohumeral chondrolysis after intraarticular pain pumps. Clin Orthop Relat Res. 2010;468(9):2545-2549.
2.
AndersonSLBuchkoJZTaillonMRErnstMA. Chondrolysis of the glenohumeral joint after infusion of bupivacaine through an intra-articular pain pump catheter: a report of 18 cases. Arthroscopy. 2010;26(4):451-461.
3.
AnzASmithMJStokerA. The effect of bupivacaine and morphine in a coculture model of diarthrodial joints. Arthroscopy. 2009;25(3):225-231.
4.
BusfieldBTRomeroDM. Pain pump use after shoulder arthroscopy as a cause of glenohumeral chondrolysis. Arthroscopy. 2009;25(6):647-652.
5.
ChaparroEErassoDQuirogaC. Repetitive intraperitoneal caspase-3 inhibitor and anesthesia reduces neuronal damage [published online December 3, 2012]. J Enzyme Inhib Med Chem. doi:10.3109/14756366.2012.740478.
6.
ChuCRCoyleCHChuCT. In vivo effects of single intra-articular injection of 0.5% bupivacaine on articular cartilage. J Bone Joint Surg Am. 2010;92(3):599-608.
7.
ChuCRIzzoNJCoyleCHPapasNELogarA. The in vitro effects of bupivacaine on articular chondrocytes. J Bone Joint Surg Br. 2008;90(6):814-820.
8.
ChuCRIzzoNJPapasNEFuFH. In vitro exposure to 0.5% bupivacaine is cytotoxic to bovine articular chondrocytes. Arthroscopy. 2006;22(7):693-699.
9.
CostourosJGDangACKimHT. Inhibition of chondrocyte apoptosis in vivo following acute osteochondral injury. Osteoarthritis Cartilage. 2003;11(10):756-759.
10.
CostourosJGKimHT. Preventing chondrocyte programmed cell death caused by iatrogenic injury. Knee. 2007;14(2):107-111.
11.
DangACKimHT. Chondrocyte apoptosis after simulated intraarticular fracture: a comparison of histologic detection methods. Clin Orthop Relat Res. 2009;467(7):1877-1884.
12.
DangACWarrenAPKimHT. Beneficial effects of intra-articular caspase inhibition therapy following osteochondral injury. Osteoarthritis Cartilage. 2006;14(6):526-532.
13.
D’LimaDHermidaJHashimotoSColwellCLotzM. Caspase inhibitors reduce severity of cartilage lesions in experimental osteoarthritis. Arthritis Rheum. 2006;54(6):1814-1821.
14.
D’LimaDDHashimotoSChenPCColwellCWJrLotzMK. Human chondrocyte apoptosis in response to mechanical injury. Osteoarthritis Cartilage. 2001;9(8):712-719.
D’LimaDDHashimotoSChenPCLotzMKColwellCWJr.Prevention of chondrocyte apoptosis. J Bone Joint Surg Am. 2001;83Suppl 2(Pt 1):25-26.
17.
D’LimaDDKuhnKLotzMK. Detection of apoptosis in cartilage in situ and in isolated chondrocytes. Methods Mol Med. 2004;100:275-290.
18.
DragooJLBraunHJKimHJPhanHDGolishSR. The in vitro chondrotoxicity of single-dose local anesthetics. Am J Sports Med. 2012;40(4):794-799.
19.
DragooJLKorotkovaTKanwarRWoodB. The effect of local anesthetics administered via pain pump on chondrocyte viability. Am J Sports Med. 2008;36(8):1484-1488.
20.
DragooJLKorotkovaTKimHJJagadishA. Chondrotoxicity of low pH, epinephrine, and preservatives found in local anesthetics containing epinephrine. Am J Sports Med. 2010;38(6):1154-1159.
21.
ElserFBraunSDewingCBMillettPJ. Glenohumeral joint preservation: current options for managing articular cartilage lesions in young, active patients. Arthroscopy. 2010;26(5):685-696.
22.
FarkasBKvellKCzompolyTIllesTBardosT. Increased chondrocyte death after steroid and local anesthetic combination. Clin Orthop Relat Res. 2010;468(11):3112-3120.
23.
FengLBalakirRPrechtPHortonWEJr.Bcl-2 regulates chondrocyte morphology and aggrecan gene expression independent of caspase activation and full apoptosis. J Cell Biochem. 1999;74(4):576-586.
24.
FischerUSchulze-OsthoffK. Apoptosis-based therapies and drug targets. Cell Death Differ. 2005;12Suppl 1:942-961.
25.
GomollAHKangRWWilliamsJMBachBRColeBJ. Chondrolysis after continuous intra-articular bupivacaine infusion: an experimental model investigating chondrotoxicity in the rabbit shoulder. Arthroscopy. 2006;22(8):813-819.
26.
GrishkoVXuMWilsonGPearsallAW4th. Apoptosis and mitochondrial dysfunction in human chondrocytes following exposure to lidocaine, bupivacaine, and ropivacaine. J Bone Joint Surg Am. 2010;92(3):609-618.
27.
HansenBPBeckCLBeckEPTownsleyRW. Postarthroscopic glenohumeral chondrolysis. Am J Sports Med. 2007;35(10):1628-1634.
28.
HashimotoKHamplKFNakamuraYBollenAWFeinerJDrasnerK. Epinephrine increases the neurotoxic potential of intrathecally administered lidocaine in the rat. Anesthesiology. 2001;94(5):876-881.
29.
KimHTLoMYPillarisettyR. Chondrocyte apoptosis following intraarticular fracture in humans. Osteoarthritis Cartilage. 2002;10(9):747-749.
30.
LeeDLongSAAdamsJL. Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality. J Biol Chem. 2000;275(21):16007-16014.
31.
LevyJCViraniNAFrankleMACuffDPupelloDRHamelinJA. Young patients with shoulder chondrolysis following arthroscopic shoulder surgery treated with total shoulder arthroplasty. J Shoulder Elbow Surg. 2008;17(3):380-388.
32.
LoIKSciorePChungM. Local anesthetics induce chondrocyte death in bovine articular cartilage disks in a dose- and duration-dependent manner. Arthroscopy. 2009;25(7):707-715.
33.
LoMYKimHT. Chondrocyte apoptosis induced by collagen degradation: inhibition by caspase inhibitors and IGF-1. J Orthop Res. 2004;22(1):140-144.
34.
LoMYKimHT. Chondrocyte apoptosis induced by hydrogen peroxide requires caspase activation but not mitochondrial pore transition. J Orthop Res. 2004;22(5):1120-1125.
35.
McNickleAGL’HeureuxDRProvencherMTRomeoAAColeBJ. Postsurgical glenohumeral arthritis in young adults. Am J Sports Med. 2009;37(9):1784-1791.
36.
NuttallMENadeauDPFisherPW. Inhibition of caspase-3-like activity prevents apoptosis while retaining functionality of human chondrocytes in vitro. J Orthop Res. 2000;18(3):356-363.
37.
ParkJSutradharBCHongGChoiSHKimG. Comparison of the cytotoxic effects of bupivacaine, lidocaine, and mepivacaine in equine articular chondrocytes. Vet Anaesth Analg. 2011;38(2):127-133.
38.
Perez-CastroRPatelSGaravito-AguilarZV. Cytotoxicity of local anesthetics in human neuronal cells. Anesth Analg. 2009;108(3):997-1007.
39.
PettyDHJazrawiLMEstradaLSAndrewsJR. Glenohumeral chondrolysis after shoulder arthroscopy: case reports and review of the literature. Am J Sports Med. 2004;32(2):509-515.
40.
PiperSLKimHT. Comparison of ropivacaine and bupivacaine toxicity in human articular chondrocytes. J Bone Joint Surg Am. 2008;90(5):986-991.
41.
PiperSLKramerJDKimHTFeeleyBT. Effects of local anesthetics on articular cartilage. Am J Sports Med. 2011;39(10):2245-2253.
42.
PourmandEPBindermanIDotySBKudryashovVBoskeyAL. Chondrocyte apoptosis is not essential for cartilage calcification: evidence from an in vitro avian model. J Cell Biochem. 2007;100(1):43-57.
43.
ProvencherMTNavaieMSolomonDJSmithJCRomeoAAColeBJ. Joint chondrolysis. J Bone Joint Surg Am. 2011;93(21):2033-2044.
44.
RapleyJHBeavisRCBarberFA. Glenohumeral chondrolysis after shoulder arthroscopy associated with continuous bupivacaine infusion. Arthroscopy. 2009;25(12):1367-1373.
45.
RyuJHSavoieFH3rd. Postarthroscopic glenohumeral chondrolysis of the shoulder. Sports Med Arthrosc. 2010;18(3):181-187.
46.
SaltzmanMMercerDBertelsenAWarmeWMatsenF. Postsurgical chondrolysis of the shoulder. Orthopedics. 2009;32(3):215.
47.
SandersTGZlatkinMBParuchuriNBHigginsRW. Chondrolysis of the glenohumeral joint after arthroscopy: findings on radiography and low-field-strength MRI. AJR Am J Roentgenol. 2007;188(4):1094-1098.
48.
ScheffelPTClintonJLynchJRWarmeWJBertelsenALMatsenFA3rd. Glenohumeral chondrolysis: a systematic review of 100 cases from the English language literature. J Shoulder Elbow Surg. 2010;19(6):944-949.
49.
SerratoJAJrFleckensteinCMHasanSS. Glenohumeral chondrolysis associated with use of an intra-articular pain pump delivering local anesthetics following manipulation under anesthesia: a report of four cases. J Bone Joint Surg Am. 2011;93(17):e99(1-8).
50.
SeshadriVCoyleCHChuCR. Lidocaine potentiates the chondrotoxicity of methylprednisolone. Arthroscopy. 2009;25(4):337-347.
51.
SolomonDJNavaieMStedje-LarsenETSmithJCProvencherMT. Glenohumeral chondrolysis after arthroscopy: a systematic review of potential contributors and causal pathways. Arthroscopy. 2009;25(11):1329-1342.
52.
TakahashiTYamamotoHOgawaY. Role of apoptosis inhibition in various chondrocyte culture systems. Int J Mol Med. 2003;11(3):299-303.
53.
WiaterBPNeradilekMBPolissarNLMatsenFA3rd. Risk factors for chondrolysis of the glenohumeral joint: a study of three hundred and seventy-five shoulder arthroscopic procedures in the practice of an individual community surgeon. J Bone Joint Surg Am. 2011;93(7):615-625.
54.
YehPCKharraziFD. Postarthroscopic glenohumeral chondrolysis. J Am Acad Orthop Surg. 2012;20(2):102-112.
55.
ZinkWGrafBM. Local anesthetic myotoxicity. Reg Anesth Pain Med. 2004;29(4):333-340.
56.
ZinkWMisslerGSinnerBMartinEFinkRHGrafBM. Differential effects of bupivacaine and ropivacaine enantiomers on intracellular Ca2+ regulation in murine skeletal muscle fibers. Anesthesiology. 2005;102(4):793-798.
