Intraosseous Regional Antibiotics and Analgesia in TKA: Pharmacokinetic Optimization in Arthroplasty

Simon W. Young, MD, FRACS, NEW ZEALAND Michael Matthew Decker, MD, MSc, UNITED STATES

ISAKOS eNewsletters   Current Perspective 2026   Not yet rated

The efficacy of perioperative pharmacotherapy in total knee arthroplasty (TKA) is fundamentally dependent on achieving therapeutic concentrations within the target end-organ tissues. Historically, orthopaedic surgeons have relied on systemic intravenous (IV) administration, based on the assumption that serum concentrations are a reliable surrogate for tissue concentrations. However, recent pharmacokinetic data have challenged this assumption in TKA¹. Systemic delivery relies on passive diffusion from the central circulation, which creates a concentration gradient. This gradient can fail to penetrate tissue at a high-enough concentration to create the desired effect in the tissues within the operative field^1,2. Alternatively, it may require high systemic doses that can create undesirable systemic side effects such as renal toxicity¹.

Intraosseous regional administration (IORA) addresses these pharmacokinetic challenges by decoupling local tissue concentration from systemic exposure. By administering medication through the venous sinusoids of the metaphyseal bone, distal to an inflated tourniquet, IORA effectively isolates the operative limb. The technique results in the concentration of medication within the surgical field³, exploiting the nature of the intraosseous vascular networks to deliver high-volume, high-concentration boluses directly to the local tissues. This approach results in higher local tissue concentrations, typically not achievable through intravenous administration, with negligible systemic peak levels, thereby maximizing efficacy while minimizing systemic toxicity.

Surgical Technique

The IORA technique is efficiently integrated into most surgeons’ standard TKA workflow following surgical limb exsanguination and tourniquet inflation. The sequestration provided by the tourniquet is critical for creating high local tissue concentrations of the administered medication and for preventing rapid systemic bolus effects.¹

The optimal site for intraosseous needle placement during TKA is the medial proximal tibial metaphysis, approximately 2 to 3 cm distal to the joint line and medial to the tibial tubercle. At this anatomic landmark, the cortex is thin, and the underlying cancellous bone is highly vascular, facilitating manual needle insertion and rapid fluid distribution. We recommend creating a small perforation in the adhesive drapes prior to insertion to prevent the entrainment of adhesive material into the medullary canal³ (Fig 1).

For primary TKA, a manual needle is cost-effective and sufficient (Fig 2). Insertion is achieved via a controlled twisting motion perpendicular to the cortex. In revision scenarios in which the proximal tibia is compromised by stems, cement, or sclerosis, the medial malleolus is a reliable alternative access point (Fig 3). The distal femur is avoided because placing the needle correctly in this area is more technically challenging, and the flow rates are slower. Injection of the desired medication occurs over the span of a few minutes, after which the needle is removed, and a dressing is applied to maintain local pressure^3,4.

IORA for Antibiotic Prophylaxis

The utilization of IORA for antibiotic prophylaxis optimization has predominantly focused on addressing the limitations of systemic vancomycin delivery. With the increasing prevalence of resistant strains of Staphylococcus aureus and coagulase-negative Staphylococcus (CoNS), vancomycin administration as an adjunct to cephalosporins is also increasing. However, systemic administration has numerous potentially harmful side effects, including nephrotoxicity, ototoxicity, and “vancomycin infusion reaction,” a histamine-induced vasodilation. To reduce the likelihood of these side effects, vancomycin is infused over long periods of time (1–2 hours), often leading to suboptimal administration relative to surgical start times. This can result in “optimal” prophylaxis timing relative to incision in only approximately 20% of cases⁴. IORA circumvents these logistical and physiological barriers. The standard protocol utilizes 500 mg of vancomycin diluted in normal saline to a total volume of 120 mL. This volume is important to ensure adequate distribution throughout the vascular circulation of the limb, below the inflated tourniquet³.

Pharmacokinetic studies have demonstrated that this low-dose regional administration achieves tissue concentrations in bone and subcutaneous fat that are orders of magnitude higher than those achieved with standard systemic doses. One randomized trial compared the mean tissue concentrations of vancomycin in subcutaneous fat and bone among three groups: 250 mg IORA vancomycin, 500 mg IORA vancomycin and 1 g IV vancomycin. In subcutaneous fat, mean concentrations were 14 µg/g in the 250 mg IO group, 44 µg/g in the 500 mg IO group, and only 3.2 µg/g in the IV group. In bone, the mean concentrations were 16 µg/g in the 250 mg IO group, 38 µg/g in the 500 mg IO group, and only 4.0 µg/g in the IV group³. In a follow-up study in which 500 mg IO was compared to 1 g IV vancomycin in patients with high BMI, similar concentration differentials persisted, with the IO group demonstrating 9-fold and 5-fold higher vancomycin levels in subcutaneous fat and bone, respectively³. Additional trials focusing on aseptic revision TKA cases demonstrated an even more profound differential, with the IO administration group demonstrating 13-fold and 12-fold higher vancomycin levels in the subcutaneous fat and bone, respectively³. These high tissue concentrations are important when considering that the pharmacokinetic-pharmacodynamic parameter with the greatest predictive value for the efficacy of vancomycin is the area under the concentration (AUC) time curve¹.

These improved pharmacodynamics have shown promise in enhancing infection control in large retrospective comparative studies. One study comparing 725 IORA (725 patients) with IV (1,181 patients) showed a one-year PJI rate of 0.1% in the IORA group versus 1.4% in the IV group⁴. Another comparative study showed 90-day PJI rates of 0.22% for IORA versus 1.46% for IV prophylaxis⁴. A recent meta-analysis combining data from six studies reinforced these findings, showing a weighted mean PJI incidence of 0.25% for IORA, compared to 1.1% for IV prophylaxis⁴. Additionally, IORA has been used as an adjunct in patients undergoing debridement, antibiotics, and implant retention (DAIR) for early PJI, with a 92.3% success rate in a small retrospective series². Given the potential value of achieving antibiotic MBEC (minimum biofilm eradication concentration) in DAIR procedures, and the reported higher soft-tissue and bone concentrations of vancomycin when administered via IORA as compared to IV, further investigation is warranted.

The safety profile of IORA is noteworthy. The regional sequestration of the drug prevents high systemic peak levels, virtually eliminating the risk of systemic adverse events. Studies reviewing the use of IO vancomycin have shown no cases of red man syndrome, acute kidney injury, or other common vancomycin-associated side effects, even when the tourniquet was deflated earlier than expected. For surgeons utilizing reduced tourniquet protocols, maintaining inflation for just 10 minutes post-injection allows sufficient tissue binding to retain therapeutic levels⁴.

IORA for Regional Analgesia

The principles of IORA have recently been applied to multimodal analgesia to maximize local efficacy while minimizing systemic side effects. Systemic non-steroidal anti-inflammatory drugs (NSAIDs) are effective but carry risks of renal and gastrointestinal toxicity. IORA delivery of NSAIDs creates a “depot effect,” generating high local concentrations in the synovial fluid and joint capsule to inhibit local COX-2 activity while potentially downregulating peripheral nociceptors5. A recent prospective, double-blinded, randomized controlled trial evaluated the efficacy of 75 mg of Diclofenac administered via IORA immediately prior to incision5. The intervention group demonstrated a statistically significant reduction in visual analog scale (VAS) pain scores at 1, 12, and 24 hours postoperatively compared with the systemic IV control group. This enhanced analgesia resulted in a significant reduction in postoperative opioid consumption. Day-of-surgery opioid consumption was nearly halved in the IORA group compared with the systemic group. This effect endured out to postoperative day 3, equating to approximately 2 fewer morphine doses per day. This reduction in opioid burden was associated with accelerated functional recovery, including improved sleep quality and reduced pain interference with gait. By two weeks post-surgery, patients receiving IO diclofenac demonstrated superior functional outcomes as measured with the KOOS Jr. and QoR-15 scores. Importantly, no renal or local complications were observed, validating the safety profile of this regional delivery method5. Like IORA vancomycin, the systemic impacts of IORA diclofenac were mitigated while taking advantage of the benefits of higher local tissue concentrations. There remains great opportunity for further investigation of intraosseous administration of other medications involved in multimodal analgesia for improved early recovery after TKA.

Potential complications

Intraosseous medication delivery is generally safe, though it carries specific risks, most notably fat embolism, extravasation, and infection. Fat embolism occurs frequently during IO infusions, as animal models demonstrate that fat intravasation from the bone marrow happens across all infusion regimens. The magnitude of this risk is directly influenced by the specific cannulation site, infusion pressure, and flow rate. While experimental models have detected fat emboli in lung specimens—with subclinical pulmonary emboli persisting for up to 24 hours—these events remain almost exclusively subclinical in adult human subjects¹. Extravasation remains the most common complication, occurring in roughly 12% of patients. While usually limited to minor subcutaneous or subperiosteal infiltration, it can lead to rare but serious outcomes such as compartment syndrome. Infection risk, including localized cellulitis (0.7%) and osteomyelitis (0.6%), are very low and compare favorably to standard indwelling vascular catheters. These risks are typically only associated with prolonged catheter placement or use in patients with systemic bacteremia. Current literature assessing the administration of IO medications in orthopaedic surgical cases has demonstrated extremely low clinical complication rates².

Conclusion and future perspectives

Intraosseous regional administration (IORA) offers a robust solution to the pharmacokinetic limitations of systemic perioperative medication administration. By utilizing the metaphyseal venous system and the depot effect created by tourniquet use, surgeons can achieve supraphysiological tissue concentrations of antibiotics and analgesics while simultaneously reducing systemic exposure. The technique appears safe, reproducible, and is supported by a growing body of evidence demonstrating superior tissue levels, reduced infection rates, and enhanced early postoperative recovery.

Looking forward, the clinical utility of IORA is poised to extend beyond primary knee arthroplasty procedures. Future applications could include enhanced prophylaxis in non-arthroplasty lower extremity procedures, such as complex osteotomies and ligament reconstruction, as well as expansion into upper extremity surgery. Furthermore, the ability to deliver high local antibiotic concentrations holds promise as a potent adjunct in the treatment of periprosthetic joint infection (PJI), particularly in the setting of debridement, antibiotics and implant retention (DAIR) procedures. Finally, the continued refinement of enhanced regional pain regimens via intraosseous delivery offers the potential to further minimize perioperative pain and opioid consumption via new multimodal intraosseous medication protocols, thereby accelerating early recovery across a broader spectrum of orthopaedic procedures.

Figure 1. The needle is inserted into the medial proximal tibial metaphysis just proximal to the level of the tibial tubercle, 2-3 cm below the joint line. A small amount of adhesive drape is removed prior to needle insertion to avoid transfer of the drape into the tissue below.

Figure 2. A solution containing 500 mg of vancomycin made up to approximately 120 mL with saline. A manual intraosseous needle is shown (Intraox, BPB medica, Mirandola, Italy).

Figure 3. Placement of the IO needle in the medial malleolus, useful in the setting of revision surgery with a long-stemmed tibial component compromising a proximal tibial insertion. Note the needle orientation to avoid intra-articular placement.

References

1. Young SW, Chen W, Clarke HD, Spangehl MJ. Intraosseous regional prophylaxis in total knee arthroplasty. Bone Joint J. 2023;105-B(11):1135-1139. doi:10.1302/0301-620X.105B11.BJJ-2023-0708
2. Wells Z, Zhu M, Young SW. Intraosseous regional administration of prophylactic antibiotics in total knee arthroplasty. Antibiotics (Basel). 2022;11(5):634. doi:10.3390/antibiotics11050634
3. Holland S, Young SW. Local delivery of antibiotics. In: Hansen E, Kühn KD, eds. Essentials of Cemented Knee Arthroplasty. Springer; 2022:661-671
4. Kawaguchi K, Tay ML, Zhu M, Dewar DC, Young SW. Intraosseous antibiotic prophylaxis for elective total knee arthroplasty. CMI Commun. Published online December 30, 2024. doi:10.1016/j.cmicom.2024.105058
5. Ng JS, van der Werf B, Nicholson L, Farrington W, Young SW. The AAHKS Clinical Research Award: intraosseous regional diclofenac for postoperative pain management in total knee arthroplasty. J Arthroplasty. 2025;40(suppl):S18-S27. doi:10.1016/j.arth.2025.05.013

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