Chondrolysis: Risk-Benefit Analysis of “Caine” Local Anesthetics for Anterior Cruciate Ligament Reconstruction

Abstract

Intra-articular local anesthetic injections are commonly utilized to improve analgesia and decrease opioid consumption which subsequently may result in less narcotic-related side effects (i.e. nausea, vomiting, drowsiness, and confusion). Additional potential benefit includes reduced overall cost of care. However, both basic science and clinical studies have shown chondrotoxic effect of local anesthetic on articular cartilage. These detrimental effects appear to demonstrate a dose- and time-dependent relationship between exposure to local anesthetic and chondrocyte viability. Certain local anesthetics—such as bupivacaine—have been observed to exert more chondrotoxicity than others. As adult chondrocytes have minimal to no significant capacity to regenerate, the damage is irreversible, and often leads to devastating effects on quality of life. While the clinical implications of laboratory studies cannot be overstated, the long-term sequelae of single intra-articular injections remain unclear and require further studies.

Keywords

Bupivacaine, cartilage, Chondrolysis, infusion pump, local anesthetic, pain pump

Keywords

Bupivacaine, cartilage, Chondrolysis, infusion pump, local anesthetic, pain pump

Introduction

Intra-articular local anesthetic injections are frequently performed by orthopaedic surgeons in perioperative and ambulatory settings. In the office, local anesthetics combined with corticosteroids are routinely injected into knees to minimize pain and inflammation. Postoperatively, single injections and continuous intra-articular pain pumps have been utilized at the end of arthroscopic procedures, including anterior cruciate ligament reconstructions (ACLRs) to improve pain control and reduce narcotic use. In the past decade, basic science and clinical studies have demonstrated a significant association between local anesthetics and chondrocyte toxicity. Despite in vitro studies showing that exposure to higher concentrations of local anesthetics for prolonged periods are chondrotoxic, the clinical sequelae of single intra-articular injections are unclear and require additional research.

Benefits of Local Anesthetics

Although providing analgesia and pain relief, narcotic consumption can cause respiratory depression, sedation, constipation, nausea, and vomiting. Such narcotic-related side effects may result in delayed time to discharge and possible readmission after being discharged. As the healthcare system transitions toward value-based care and outpatient ACL surgery, there is an increased emphasis on eliminating even temporary complications which are associated with increased cost of care.

To facilitate maximum pain control and decrease narcotic utilization, local anesthetics can be injected alone or as part of multimodal drug protocols either intra- and/or periarticularly into the knee at the end of the operative procedure. In the early postoperative period, both single and continuous intra-articular injection of local anesthetics have been shown to improve pain management as well as reduce narcotic use and its related side effects. Despite the theoretical risk of systemic toxicities of the central nervous system (tinnitus, disorientation, and seizures) and cardiovascular system (hypotension, dysrhythmias, and cardiac arrest), the overall systemic distribution is small—making these risks exceedingly rare.

Despite the anesthesia literature reporting a high systemic safety profile for local anesthetics, their effects on articular cartilage have recently undergone rigorous investigation. Several groups have reported on the cytotoxic effect of bupivacaine, lidocaine, and ropivacaine when applied to animal and human articular chondrocytes. Clinically, local anesthetics have been administered widely as a single intra-articular injection for decades. Given the widespread practice of intra-articular injections, it is important to determine and understand the implications of exposing healthy cartilage to a potentially chondrotoxic substance.

Basic Science Studies

Chondrocyte dysfunction and death is a key pathologic process of articular cartilage loss. On a molecular level, there is evidence to suggest that toxicity of local anesthetics is secondary to mitochondrial deoxyribonucleic acid (DNA) damage, which subsequently results in mitochondrial dysfunction and apoptosis in cultured human chondrocytes. Grishko et al. found that when human articular chondrocytes were exposed for 1 hour to 0.5%, 1%, and 2% lidocaine; 0.25% and 0.5% bupivacaine; or 0.25% and 0.5% ropivacaine and analyzed 120 hours later, cellular apoptosis and mitochondrial DNA damage was observed with all local anesthetics and concentrations.

In a series of critical basic science studies, Chu et al. investigated the effects of local anesthetics on articular chondrocyte function, viability, and cartilage integrity. In 2008 they showed greater than 95% cellular death after exposure to 0.5% bupivacaine for 30 minutes. They also noted a time-dependent relationship where chondrocytes exposed to 0.25% bupivacaine for longer times resulted in greater reduction in viability. However, at 0.125% bupivacaine, even after 60 minutes of exposure, chondrocyte viability was similar to that of the saline control group. In a similar study, the group demonstrated decreased chondrocyte viability after just 15 minutes of exposure to 1% lidocaine. Chondrotoxicity was greater in 2% lidocaine, and longer exposures further reduced chondrocyte viability. The authors concluded that while lidocaine chondrotoxicity was less than that reported with bupivacaine, these observations suggest that local anesthetics—as a class of drugs—negatively affect articular cartilage in a dose- and time-dependent manner. Others, including Lo et al., have derived similar conclusions and also showed that ropivacaine has a detrimental effect on chondrocyte viability.

To investigate the effects of continuous intra-articular bupivacaine infusions via pain pumps, Gomoll et al. evaluated the continuous infusion of saline, bupivacaine, or bupivacaine with epinephrine over a period of 48 hours into the glenohumeral joint of rabbits. The animals were sacrificed 1 week later, and osteochondral and synovial samples from the shoulder were analyzed with cell assays and conventional histologic analysis. When compared with saline solution, continuous intra-articular infusion of bupivacaine with and without epinephrine led to significant cell death (20%–30%), 50% reduction in cell metabolic activity, and worse histologic scores. Interestingly, the study revealed that the results for bupivacaine with and without epinephrine were not significantly different, suggesting that bupivacaine itself is the chondrotoxic agent. In a follow-up long-term study, Gomoll et al. replicated their previous rabbit glenohumeral infusion model to assess cartilage status 3 months after exposure. While no gross or radiographic changes were observed, statistically significant increase in proteoglycan content was noted in bupivacaine groups compared with saline. The authors explained the findings by postulating that, in this rabbit model, the increase in proteoglycan synthesis could indicate a reparative response to noxious stimulus. The rabbit model also has a significantly higher cell-to-tissue volume ratio, which may partially explain the ability of the rabbit to recover from this initial insult. Also, this study initially evaluated for necrosis, not apoptosis, which could explain the potential for cellular rebound.

In light of concerns about the chondrotoxic effects following continuous infusion of local anesthetic, the question arises whether a single intra-articular injection of local anesthetic has any deleterious consequences to the articular cartilage and whether such injections should be used following arthroscopic surgery as part of multimodal pain management. In 2004 Dogan et al. evaluated the effects of a single intra-articular knee injection of 0.5% bupivacaine in a rabbit model at 10 days. Histopathological analysis demonstrated increased levels of inflammatory changes in articular cartilage and synovial membrane cell hypertrophy. Subsequently, in 2010 Chu et al. injected preservative-free 0.5% bupivacaine into stifle joints of rats in vivo and evaluated articular cartilage up to 6 months after the injection. Live and dead cells were quantified, and gross morphologic and histologic findings were graded. This in vivo study showed that when compared with saline solution–treated knees, the bupivacaine-treated knees at 6 months demonstrated up to a 50% decrease in chondrocyte density. However, on both gross and histological evaluation, the articular surfaces of bupivacaine-injected joints remained intact and did not result in tissue loss or surface damage during the study period. The study authors highlight that the effects of a single intra-articular injection of bupivacaine on articular cartilage are subtle, and that an intact articular surface can mask severe pathologic changes. In vivo, the dose and time of exposure to the toxic agent after a single joint injection is reduced by factors such as bleeding, joint fluid, and systemic absorption. During arthroscopic ACLR the local anesthetic is further diluted by irrigation fluid and hemarthrosis, if present. Nonetheless, the marked reduction in chondrocyte density is cause for concern and may lead to further changes with longer follow-up.

While the safety of single intra-articular local anesthetic injection remains unclear, the clinical implications of these controlled laboratory studies cannot be overstated, as adult chondrocytes have minimal to no significant capacity to regenerate and damage is irreversible, often leading to devastating effects on quality of life.

Clinical Studies: Chondrolysis

As a result of improved surgical techniques, advances in orthopaedic technology, and better recovery from anesthesia, in the United States, outpatient arthroscopic ACLR has become increasingly popular. In 2006, 95% of ACLRs were performed in an outpatient setting, while in 1994 only 43% were performed as outpatient surgery. Intravenous or subcutaneous narcotic use for breakthrough pain in the outpatient setting is impractical. Improved pain management techniques include nonsteroidal antiinflammatory drugs, narcotics, regional anesthesia, peri- and intra-articular injections, and pain pumps.

Continuous knee intra-articular injection of local anesthetics using pain pumps for postoperative ACLR was popularized in the late 1990s and early 2000s. These external devices, which contain local anesthetics, have a catheter exiting the reservoir which is then placed into the joint intraoperatively to provide continuous infusion of local anesthetic. Pumps were originally thought to be safe and effective at relieving pain and decreasing narcotic consumption, such that in 2002 Hoenecke et al. recommended the continuous infusion of bupivacaine for 48 hours after ACLR. In the ensuing years, after initial observation in the glenohumeral and subsequently in the knee joint, cases of rapid loss of articular cartilage associated with postoperative continuous infusion of local anesthetics have been reported. Coined chondrolysis , the etymology of the term is from Greek: “chondros” for cartilage and “lysis” for dissolution. Progression of cartilage loss results in the clinical syndrome of early osteoarthritis: joint pain and loss of joint function. Postarthroscopic chondrolysis is both a clinical and radiologic diagnosis marked by joint-space narrowing and subchondral sclerosis. The absence of osteophyte formation distinguishes chondrolysis from degenerative osteoarthritis ( Fig. 53.1 ). Because of its devastating consequences, often in young active patients where there often is no ideal treatment solution, this relationship has garnered much attention in the orthopaedic community, in the media, and from various medicolegal groups.