In vitro exposure to 0.5% bupivacaine is cytotoxic to bovine articular chondrocytes

Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
Arthroscopy The Journal of Arthroscopic and Related Surgery (Impact Factor: 3.19). 07/2006; 22(7):693-9. DOI: 10.1016/j.arthro.2006.05.006
Source: PubMed

ABSTRACT Intra-articular use of 0.5% bupivacaine is common in arthroscopic surgery. This study was conducted to test the hypotheses that (1) 0.5% bupivacaine is toxic to articular chondrocytes, and (2) the intact articular surface protects chondrocytes from the effects of short-term exposure to 0.5% bupivacaine.
Freshly isolated bovine articular chondrocytes were prepared into alginate bead cultures and were treated with 0.5% bupivacaine solution or 0.9% saline for 15, 30 or 60 minutes, washed, and returned to growth media. Chondrocytes were recovered from alginate 1 hour, 1 day, and 1 week after bupivacaine exposure; they were fluorescently labeled to identify apoptotic and dead cells and were analyzed by flow cytometry. Twelve osteochondral cores were harvested from bovine knees. The superficial 1 mm of cartilage was removed from 6 cores (top-off). Intact and top-off cores were submerged in 0.9% saline or 0.5% bupivacaine solution for 30 minutes and then maintained in chondrocyte growth media for 24 hours. Live-cell/dead-cell fluorescent imaging was assessed using confocal microscopy.
Greater than 99% chondrocyte death/apoptosis was observed in all bupivacaine-exposed alginate bead cultures compared with 20% cell death in saline-treated controls (P < .05). Osteochondral cores with intact surfaces treated with 0.5% bupivacaine showed 42% dead chondrocytes. When the articular surface was removed, 0.5% bupivacaine resulted in increased cell death, with 75% dead chondrocytes (P < .05).
Results show that 0.5% bupivacaine solution is cytotoxic to bovine articular chondrocytes and articular cartilage in vitro after only 15 to 30 minutes' exposure. The intact bovine articular surface has some chondroprotective effects.
Because healthy chondrocytes are important for maintenance of the cartilage matrix, chondrocyte loss may contribute to cartilage degeneration. This study shows a cytotoxic effect of 0.5% bupivacaine solution on bovine articular chondrocytes in vitro. Although these results cannot be directly extrapolated to the clinical setting, the data suggest that caution should be exercised in the intra-articular use of 0.5% bupivacaine.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Analgesic discography (discoblock) can be used to diagnose or treat discogenic low back pain by injecting a small amount of local anesthetics. However, recent in vitro studies have revealed cytotoxic effects of local anesthetics on intervertebral disc (IVD) cells. Here we aimed to investigate the deteriorative effects of lidocaine and bupivacaine on rabbit IVDs using an organotypic culture model and an in vivo long-term follow-up model. Methods For the organotypic culture model, rabbit IVDs were harvested and cultured for 3 or 7 days after intradiscal injection of local anesthetics (1% lidocaine or 0.5% bupivacaine). Nucleus pulposus (NP) cell death was measured using confocal microscopy. Histological and TUNEL assays were performed. For in vivo study, each local anesthetic was injected into rabbit lumbar IVDs under a fluoroscope. Six or 12 months after the injection, each IVD was prepared for magnetic resonance imaging (MRI) and histological analysis. Results In the organotypic culture model, both anesthetic agents induced time-dependent NP cell death; when compared with injected saline solution, significant effects were detected within 7 days. Compared with the saline group, TUNEL-positive NP cells were significantly increased in the bupivacaine group. In the in vivo study, MRI analysis did not show any significant difference. Histological analysis revealed that IVD degeneration occurred to a significantly level in the saline- and local anesthetics-injected groups compared with the untreated control or puncture-only groups. However, there was no significant difference between the saline and anesthetic agents groups. Conclusions/Significance In the in vivo model using healthy IVDs, there was no strong evidence to suggest that discoblock with local anesthetics has the potential of inducing IVD degeneration other than the initial mechanical damage of the pressurized injection. Further studies should be performed to investigate the deteriorative effects of the local injection of analgesic agents on degenerated IVDs.
    PLoS ONE 10/2014; 9(10):e109851. DOI:10.1371/journal.pone.0109851 · 3.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Postoperative knee chondrolysis caused by continuous intra-articular pain pumps infusing bupivacaine with epinephrine is a rare but serious complication. PURPOSE: To determine the association between postoperative intra-articular infusion of bupivacaine with epinephrine and the development of knee chondrolysis in patients who have undergone arthroscopic anterior cruciate ligament reconstruction (ACLR). The authors hypothesized that the development of knee chondrolysis after ACLR is associated with postoperative high-dose intra-articular bupivacaine with epinephrine infusion. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: In this retrospective cohort study, the charts of all patients treated with arthroscopic ACLR by a single surgeon between January 1, 2004, and December 31, 2006, were reviewed. Patients with severe articular cartilage damage at the time of the index procedure, with known knee joint infection, inflammatory arthritis, multiligament knee injury, bilateral knee injury, or any previous knee surgery, were excluded. Patients were grouped into 2 cohorts: the exposure group (those who had postoperative infusion of bupivacaine with epinephrine via an intra-articular pain pump [IAPP]) and the nonexposure group (those without postoperative infusion). RESULTS: A total of 105 patients met the inclusion and exclusion criteria. There were 57 male and 48 female patients with a mean age at surgery of 25.5 ± 8.6 years (range, 13-52 years). The exposure group consisted of 46 patients and the control group of 59 patients. Thirteen of 46 patients (28.3%) who received an IAPP developed chondrolysis. There were no cases of chondrolysis in the control group. Of those in the exposure group, 32 patients were exposed to 0.5% bupivacaine with epinephrine and 12 developed chondrolysis (37.5%), while 14 patients were exposed to 0.25% bupivacaine with epinephrine and 1 developed chondrolysis (7.1%). Patients exposed to 0.5% bupivacaine with epinephrine had a significantly higher incidence of chondrolysis compared with those exposed to 0.25% (P = .03). Patients with chondrolysis had severe pain and limitations in daily activity. CONCLUSION: The development of knee chondrolysis was associated with the intra-articular infusion of bupivacaine with epinephrine postoperatively. Furthermore, the presented evidence suggests that this occurs in a dose-dependent manner. The risk of knee chondrolysis might be reduced by avoidance of intra-articular infusion of bupivacaine with epinephrine. We recommend against continuous intra-articular infusion of local anesthetic postoperatively.
    The American Journal of Sports Medicine 11/2014; DOI:10.1177/0363546514555667 · 4.70 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Intra-articular bupivacaine helps alleviate pain in animals receiving joint surgery, but its use has become controversial as ex vivo studies have illuminated the potential for chondrotoxicity. Such studies typically involve cell cultures incubated in solutions containing high bupivacaine concentrations for long durations. The aim of this study was to measure the actual synovial fluid bupivacaine concentrations after intra-articular injection. Eight healthy beagles with normal stifles and 22 large and giant-breed dogs with stifle osteoarthritis (OA) were treated with a single intra-articular injection of bupivacaine (1 mg/kg) into a stifle. Joint fluid samples were taken from the treated stifle immediately after injection and 30 min after injection and analyzed for bupivacaine concentrations. Immediately after injection, the median bupivacaine concentrations in normal and OA stifles were 3.6 and 2.5 mg/mL, respectively. Thirty minutes after injection, bupivacaine concentrations in normal and OA stifles were 0.4 and 0.6 mg/mL, respectively. These results provide insight into the pharmacokinetics of bupivacaine after injection into a joint. Given its immediate dilution and rapid drop in synovial fluid concentration, bupivacaine is unlikely to damage chondrocytes when administered as a single intra-articular injection.
    Journal of Veterinary Pharmacology and Therapeutics 09/2014; 38(1). DOI:10.1111/jvp.12158 · 1.32 Impact Factor