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Commentary and Perspective   |    
The Balancing Act of the Inflammatory Cascade After Bilateral Total Knee ArthroplastyCommentary on an article by Kethy M. Jules-Elysee, MD, et al.: “Steroid Modulation of Cytokine Release and Desmosine Levels in Bilateral Total Knee Replacement. A Prospective, Double-Blind, Randomized Controlled Trial”
Kamran Sadr, MD, MS1; Richard H. Walker, MD1
1 Scripps Clinic, La Jolla, California
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This article was chosen to appear electronically on October 24, 2012, in advance of publication in a regularly scheduled issue.



Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. None of the authors, or their institution(s), have had any financial relationship, in the thirty-six months prior to submission of this work, with any entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Also, no author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.

Copyright © 2012 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2012 Dec 05;94(23):e179 1-2. doi: 10.2106/JBJS.L.01169
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The surgical community does not fully understand the effects of the inflammatory cascade that follow any major surgery, including total knee arthroplasty. Greater surgical insults, such as bilateral total knee arthroplasty, can shift an initial reparative process into a catabolic cascade with ensuing negative clinical sequelae. High levels of inflammatory markers such as interleukin-6 (IL-6) have been associated with extreme reactions, such as fat embolism syndrome and acute respiratory distress syndrome. Management of this inflammatory cascade and its sequelae has already altered current treatment practices, for example, within orthopaedic traumatology. This well-designed study and its prequel were performed to quantitate, and further our understanding of, the physiologic effects of perioperative systemic corticosteroids on the inflammatory response and recovery after bilateral total knee arthroplasty.
The safety profile of bilateral total knee arthroplasty remains an unresolved topic of continued investigation. A higher risk of cardiac and pulmonary complications and increased mortality have been cited after bilateral total knee arthroplasty performed during a single anesthetic session, which understandably has been shown to markedly increase the amount of marrow contents that shower the lungs intraoperatively. Restrepo et al. demonstrated, in a meta-analysis of 44,684 knee arthroplasties, that simultaneous bilateral total knee arthroplasty had an increased odds ratio of 1.82 for pulmonary embolism, 2.49 for cardiac complications, and 2.24 for mortality compared with unilateral knee arthroplasty1. Despite these concerns, there are benefits to both the patient and the medical system that drive the increasing prevalence of bilateral total knee arthroplasty performed during a single anesthetic session2.
In this investigation by Jules-Elysee et al., the cytokine IL-6 is used as a surrogate for monitoring the inflammatory cascade after bilateral total knee arthroplasty performed during a single anesthetic session. They confirmed the findings in their prior study3 that perioperative systemic corticosteroids lowered IL-6 postoperatively and further demonstrated that prolonging the duration of administration prolonged the effect of lowered IL-6. As well, desmosine, a marker for lung injury, was used as a surrogate for pulmonary stress and was also shown to be lowered by prophylactic perioperative systemic corticosteroid administration.
We enjoyed the report of this novel method for investigating the corticosteroid end effect after bilateral total knee arthroplasty, which clearly demonstrated decreases in these two surrogates for inflammatory response and pulmonary injury. However, the study was not powered to define the clinical benefit regarding such potentially related secondary systemic complications as symptomatic pulmonary embolism, fat embolism syndrome, acute respiratory distress syndrome, or mortality, and thus we can only infer that by giving perioperative corticosteroids we are protecting against these serious complications.
Although designed to evaluate IL-6 levels, and not powered to differentiate clinical findings, this study did demonstrate an association between perioperative corticosteroids and in-hospital clinical findings, including decreased postoperative pain levels (visual analog scale scores and patient-controlled anesthesia consumption), decreased incidence of fever, and increased knee range of motion. However, patient satisfaction was not different between the control and study groups six months postoperatively. In this study, perioperative corticosteroid administration was accompanied by a so-called multimodal analgesia protocol. Inclusion of corticosteroids in multimodal analgesia protocols has been supported widely in the surgical and orthopaedic literature4. As an example, a recent study by Stewart et al. found that dexamethasone significantly decreased pain in a double-blinded prospective study of 200 patients undergoing tonsillectomy5.
Concerns with prophylactic corticosteroid use in the operative arena include its contribution to weakening the immune response and raising the risk of infection as well as altering glycemic control and increasing the risk of hyperglycemia. Even though Jules-Elysee et al. reported no increased rate of infection after corticosteroid administration, they did report elevated glucose levels in the corticosteroid study group. Larger randomized studies would be needed to investigate these end points further.
We applaud Jules-Elysee et al. for their excellent investigation of the physiologic effects, and for providing a better understanding of the clinical effects, of perioperative corticosteroid administration after bilateral total knee arthroplasty. We envision further study regarding the effects of perioperative corticosteroid dose and duration, including tapering the dosage, on IL-6, desmosine, and other inflammatory markers, as well as on postoperative glycemic control. We also envision larger studies regarding postoperative clinical effects and long-term outcomes (e.g., deep vein thrombosis and/or pulmonary embolism, fat embolism syndrome, wound-healing, infection, rate of recovery, and functional outcome) to afford a more complete understanding of the use of perioperative corticosteroids.
Restrepo  C;  Parvizi  J;  Dietrich  T;  Einhorn  TA. Safety of simultaneous bilateral total knee arthroplasty. A meta-analysis. J Bone Joint Surg Am.  2007 Jun;89(  6):1220-6.[CrossRef]
 
Memtsoudis  SG;  Besculides  MC;  Reid  S;  Gaber-Baylis  LK;  González Della Valle  A. Trends in bilateral total knee arthroplasties: 153,259 discharges between 1990 and 2004. Clin Orthop Relat Res.  2009 Jun;467(  6):1568-76.  Epub 2008 Nov 11.[CrossRef]
 
Jules-Elysee  KM;  Lipnitsky  JY;  Patel  N;  Anastasian  G;  Wilfred  SE;  Urban  MK;  Sculco  TP. Use of low-dose steroids in decreasing cytokine release during bilateral total knee replacement. Reg Anesth Pain Med.  2011 Jan-Feb;36(  1):36-40.[CrossRef]
 
Salerno  A;  Hermann  R. Efficacy and safety of steroid use for postoperative pain relief. Update and review of the medical literature. J Bone Joint Surg Am.  2006 Jun;88(  6):1361-72.[CrossRef]
 
Stewart  R;  Bill  R;  Ullah  R;  McConaghy  P;  Hall  SJ. Dexamethasone reduces pain after tonsillectomy in adults. Clin Otolaryngol Allied Sci.  2002 Oct;27(  5):321-6.[CrossRef]
 

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References

Restrepo  C;  Parvizi  J;  Dietrich  T;  Einhorn  TA. Safety of simultaneous bilateral total knee arthroplasty. A meta-analysis. J Bone Joint Surg Am.  2007 Jun;89(  6):1220-6.[CrossRef]
 
Memtsoudis  SG;  Besculides  MC;  Reid  S;  Gaber-Baylis  LK;  González Della Valle  A. Trends in bilateral total knee arthroplasties: 153,259 discharges between 1990 and 2004. Clin Orthop Relat Res.  2009 Jun;467(  6):1568-76.  Epub 2008 Nov 11.[CrossRef]
 
Jules-Elysee  KM;  Lipnitsky  JY;  Patel  N;  Anastasian  G;  Wilfred  SE;  Urban  MK;  Sculco  TP. Use of low-dose steroids in decreasing cytokine release during bilateral total knee replacement. Reg Anesth Pain Med.  2011 Jan-Feb;36(  1):36-40.[CrossRef]
 
Salerno  A;  Hermann  R. Efficacy and safety of steroid use for postoperative pain relief. Update and review of the medical literature. J Bone Joint Surg Am.  2006 Jun;88(  6):1361-72.[CrossRef]
 
Stewart  R;  Bill  R;  Ullah  R;  McConaghy  P;  Hall  SJ. Dexamethasone reduces pain after tonsillectomy in adults. Clin Otolaryngol Allied Sci.  2002 Oct;27(  5):321-6.[CrossRef]
 
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