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Intra-articular injections of local anesthetics: How much is too much?

Issue: November 2008

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Douglas W. Jackson, MD, asks Constance R. Chu, MD, 4 Questions about the effects of local intra-articular anesthesia injections on cartilage.

Most of us routinely use intra-articular injections of anesthesia in our office practices and following arthroscopic procedures. We have little information available on the potential chondrotoxicity and long-term sequelae of these injections. After reading some of Dr Constance R. Chu’s research, I felt it would be beneficial to our readers for her to share some of her laboratory findings and insight into this subject with Orthopedics Today.

Douglas W. Jackson, MD
Chief Medical Editor

Douglas W. Jackson, MD: The local intra-articular injection of anesthetic agents is a widespread practice following arthroscopic surgery. Which local anesthetic agent did you recently study? How does your investigation correlate with the range of doses and time of exposure in a single joint injection following arthroscopy?

Constance R. Chu, MD: I have studied the effects of commonly used agents for intra-articular injections to include lidocaine, bupivacaine, and the combined effects of lidocaine and Depo-Medrol (methylprednisolone acetate, Pfizer) on articular chondrocytes in vitro. We have found dose- and time-dependent toxic effects of all these agents on articular chondrocytes.

In the most recent publication in the Journal of Bone and Joint Surgery, we used preservative-free formulations of bupivacaine at concentrations routinely used clinically. The study showed that 0.5% bupivacaine was highly toxic to human chondrocytes and human articular cartilage in vitro while the chondrotoxicity of 0.25% bupivacaine increased proportional to both the duration of bupivacaine exposure and to time after bupivacaine exposure. Chondrotoxicity was not observed following exposure to 0.125% bupivacaine. The range of doses and time of bupivacaine exposure to chondrocytes after a single joint injection following arthroscopy would depend on amount of fluid in the joint, volume and concentration of the injected bupivacaine, systemic absorption, bleeding, articular cartilage integrity, joint volume, and other variables. While in vitro studies cannot be directly extrapolated to a clinical situation, they can provide information on concentrations of bupivacaine that may be potentially chondrotoxic.

Clinically, factors such as effusion, hemarthrosis, lateral release, intact cartilage and large joint volume would likely reduce the effective concentration following a small volume single injection of 0.5% bupivacaine to a less toxic 0.25% or to a more benign 0.125% level relatively quickly. Conversely, this process would be slower in a small, noncompliant joint space with no effusion and minimal bleeding following a larger volume single injection of 0.5% bupivacaine.

Jackson: What was your experimental design and study model and how did you define toxic effects?

Chu: This was an in vitro study examining viability of human and bovine articular chondrocytes and osteochondral tissues following exposure to bupivacaine. Toxicity was defined by using flow cytometry, time-lapse confocal microscopy, and three-dimensional volumetric imaging to count fluorescently stained live and dead cells at varying time points after exposure to different concentrations of bupivacaine for durations ranging from 15 to 60 minutes.

Several models of exposure were used: intermittent exposure, continuous exposure, and in situ exposure within cartilage with and without intact articular surfaces. Chondrocyte viability following defined exposure was measured using flow cytometry. Time-lapse confocal microscopy was used to quantify chondrocyte death during continuous exposure. Three-dimensional volumetric imaging was used for in situ assessment of chondrocyte viability within articular cartilage after bupivacaine exposure.

Jackson: You were careful to say that low-dose injections on an infrequent basis may not be a clinical problem. In a joint with the volume of the knee, what range do you feel indicates a low-dose injection and do we have any indication of the time necessary within an intact joint to initiate a deleterious response?

Chu: Intra-articular knee injections typically range from 30 cc to 60 cc for local anesthesia before arthroscopic surgery to 5 cc to 10 cc in the office. I consider the 5-cc to 10-cc injections to be low-volume injections and 30 cc to 60 cc injections to be higher-volume injections within a joint with the volume of the knee.

Chondrocyte death can be observed in the laboratory within minutes after exposing articular cartilage to a toxic agent by using appropriate dyes and fluorescent microscopy. We are currently analyzing data from an in vivo study following single injection of potentially chondrotoxic agents.

Preliminary unpublished results are consistent with the premise that chondrocyte loss leads to cartilage degeneration and that the severity of the resulting arthritis is proportional to the number of chondrocytes killed.

The deleterious changes after 0.5% bupivacaine single injection have been subtle, appearing about 6 months after exposure in our small animal model. The observed changes represent some of the earliest pathologic changes implicated in the pathogenesis of osteoarthritis (OA) and include chondrocyte drop-out and compromised metabolism of the remaining chondrocytes. Assuming similar changes in humans, any descent to clinically appreciable chondrosis or arthritis possibly related to chondrocyte morbidity following single injection of 0.5% bupivacaine would likely take years, even a decade or more.

Jackson: What recommendations regarding the local use of anesthetics do you make to the residents and fellows during discussions at your institution?

Chu: The most important recommendation I have made is to avoid continuous intra-articular infusion of local anesthetics. The in vitro data consistently show a dose and time dependent chondrotoxicity of both bupivacaine and lidocaine suggesting this is a class effect of local anesthetics. By counteracting the dilutional effects of systemic absorption and other joint fluids, continuous intra-articular infusion of local anesthetics can be expected to prolong exposure of chondrocytes to potentially toxic levels of these agents. Eventually, the threshold for chondrolysis may be reached, as has been suggested by clinical reports in the shoulder.

In regards to single injection, my recommendation has been to use the lowest dosage for the shortest period of time to achieve the desired clinical effect. For applications such as impingement test, differential joint injections or routine office injections for degenerative knees, I have found that 3 cc to 5 cc of 1% lidocaine is sufficient. Minimizing the frequency of single injections of local anesthetics alone or in combination with corticosteroids remains a sound basic principal. For patients who still have articular cartilage, I choose to avoid intra-articular use of agents such as 0.5% bupivacaine for which we have observed severe chondrotoxicity in the laboratory.

In discussing my rationale, I would like to introduce the concept of “clinically unapparent” as different from “clinically insignificant.” As described earlier, we are observing subtle signs of chondrocyte loss and injury in our 0.5% bupivacaine single injection in vivo study. In osteochondral tissues, we showed that cartilage with compromised articular surfaces is more vulnerable to bupivacaine toxicity. Pre-existing cartilage pathology and injury are common in joints undergoing arthroscopy or needing injections. We also have new, unpublished, in vitro data showing markedly increased chondrocyte toxicity when a local anesthetic was used in combination with a corticosteroid. While readily evident using flow cytometry, advanced microscopy and molecular biology, these changes are undetectable clinically. Put together, these data raise the question that single injection of local anesthetics may result in some degree of chondrocyte morbidity that may accelerate cartilage loss, especially in joints with pre-existing cartilage damage.

Given the demonstrated dose and time dependent chondrotoxicity of these agents, the magnitude of chondrocyte morbidity following a single injection would be far less than a continuous infusion scenario. My opinion is that the theoretical chondrocyte morbidity would range from miniscule following small dose injection into a large joint, to limited with a larger dose injection into a small joint. Because any potential acceleration of cartilage degeneration from relatively limited chondrocyte loss and dysfunction would likely take many years to progress into clinically detectable chondrosis, if it does at all, the eventual development of OA cannot be attributed to any one factor. I am not saying this is what happens after a single intra-articular injection; but if something contributes to development of OA in 5 years instead of 10, or even 15 years instead of 20, I would consider this to be “clinically significant.” I do not think it is feasible or advisable to study these questions clinically. Therefore, given my repeated personal observations of the chondrotoxicity of local anesthetics in the laboratory, I have chosen to err on the side of caution in minimizing the possibility of contributing to “clinically unapparent” cartilage damage.

Medicine is as much art as science. As such, clinical judgment in weighing the known potential risks and benefits for each situation is most important. Intra-articular local anesthetics have and continue to play an important role in the care of patients with joint pathology. For example, if I had to treat a locked meniscus, where for reasons such as patient health, a local anesthetic was recommended, clinical analysis would support administering intra-articular bupivacaine. Following the principle of using the lowest dosage for the shortest period of time to achieve the desired clinical effect, I would use 0.25% bupivacaine instead of 0.5% bupivacaine. We know from clinical experience that 0.25% bupivacaine works well for this purpose and the in vitro study under discussion shows the potential chondrotoxicity of 0.25% bupivacaine to be far less than 0.5% bupivacaine. Continuing the same principle, I would start with a 30-cc injection instead of 60 cc, adding more only if necessary, and I would start scoping as soon as anesthesia was achieved to dilute the remaining bupivacaine.

Other surgeons may have a lower threshold or even routinely use intra-articular bupivacaine for arthroscopic procedures. I would like to stress that I am not aware of any compelling clinical or in vivo data to contraindicate occasional use of local anesthetics as a single injection.

My studies show that the potential chondrotoxicity of local anesthetics is dose and time dependent. While this means more is not necessarily better, it also doesn’t mean none is best. Scientific studies provide incremental knowledge from which clinicians apply their experience and judgment to best serve the patient’s clinical situation.

For more information:

• Constance R. Chu, MD, Associate Professor, Albert Ferguson Endowed Chair Joint Replacement and Sports Medicine, can be reached at the Department of Orthopaedic Surgery, University of Pittsburgh, 3471 Fifth Ave.; Suite 911, Pittsburgh, PA 15213; 412-605-3245; e-mail: chucr@upmc.edu.

Reference

• Chu CR, Izzo NJ, Coyle CH, et al. The in vitro effects of bupivacaine on articular chondrocytes. J Bone Joint Surg (Br). 2008;90(6):814-820.