One patient in the 1-g systemic group developed red man syndrome during vancomycin infusion consisting of erythema, pruritis, and hot flushing. The vancomycin infusion was stopped after 700 mg had been given and the symptoms resolved. The patient remained hemodynamically stable and the procedure was carried out as normal. Tissue and blood samples for this patient were not included in the analysis. No clinical signs of red man syndrome were seen in any patient undergoing IORA; in particular, no signs were seen after tourniquet deflation. Minor transient drops in systolic blood pressure (5-30 mm Hg) were seen after tourniquet deflation in six patients in the 250-mg IORA group, five patients in the 500-mg IORA group, and seven patients in the 1-g systemic group. One patient in the 500-mg IORA group developed a deep vein thrombosis in a peroneal calf vein seen on ultrasound scan at Day 3. He was treated with warfarin, and repeat scan at 6 weeks showed resolution of the clot and the warfarin was discontinued. No deep or superficial infections occurred in either group. One patient in the 250-mg IORA group went on to have a TKA performed on his contralateral knee 2 months after his participation in this study. He was given systemic prophylaxis with 1 g cefazolin. He developed a deep infection 4 weeks postoperatively, which eventually required two-stage revision surgery. The infecting organism was CoNS, resistant to cefazolin.
Antibiotic resistance is an increasing problem, and rates of orthopaedic infection due to MRSA or resistant CoNS are rising . This, together with the severe consequences of a deep infection, has led some authors to propose vancomycin as an alternative prophylactic agent in TKA , particularly in centers where MRSA rates are high [30, 39]. However, vancomycin has a number of disadvantages, including systemic side effects such as nephrotoxicity and ototoxicity, concerns about promoting further bacterial resistance, and a prolonged administration time. We previously investigated IORA as a method of maximizing tissue concentrations of cefazolin in TKA . This study explored the use of IORA to give a lower dose of a more toxic drug, potentially minimizing its adverse effects. We hypothesized lower doses of vancomycin via IORA could still achieve tissue concentrations equal or superior to those of systemic administration before TKA.
A limitation of our study is, while we saw no evidence of red man syndrome with IORA vancomycin, the number of patients was small and those with significant cardiac disease were excluded. Red man syndrome is an anaphylactoid reaction caused by the degranulation of mast cells resulting in histamine release. It is not an allergic reaction and is independent of preformed immunoglobulin E. It occurs in 30% to 90% of healthy volunteers given vancomycin , and symptoms are usually mild and alleviated by use of an antihistamine. Incidence is related to both dosage and rate of infusion; Polk et al.  observed the reaction during systemic infusion of 1 g vancomycin in 82% of volunteers, but no reaction occurred when a 500-mg dose was used. Healy et al.  noted symptoms in eight of 10 volunteers (80%) given 1 g vancomycin over 1 hour but in only three of 10 volunteers (30%) given the same dose over 2 hours. The absence of red man syndrome seen with IORA vancomycin in our study is likely due to both the lower doses used and the depot effect of the high tissue concentrations that causes antibiotic to be released gradually into the systemic circulation after tourniquet deflation . However, until data on a larger number of patients are available, we recommend patients receiving IORA vancomycin be monitored closely after tourniquet deflation and an antihistamine be available if required.
A second potential limitation of the IORA technique is the lower systemic concentration once the tourniquet is released. Many surgeons routinely continue antibiotics for 24 hours postoperatively, and further systemic vancomycin doses after IORA would still be required to maintain levels. However, due to the high initial concentrations achieved, vancomycin levels in perioperative tissues are likely to remain elevated for some time. Hoddinott et al. demonstrated persistently elevated antibiotic levels in drain fluid the morning following surgery in TKA patients given prophylactic cefazolin via a regional route . Additionally, a distinction should be drawn between antibiotic use for prophylaxis and that for treatment of an established infection. The goal of prophylaxis is to prevent initial bacterial adherence and colonization during the period the wound is open, when contamination is occurring . The critical period therefore when adequate antibiotic concentrations must be present in the tissues is from the time of incision to the time of closure, an outcome achieved in our study in both IORA groups. Moreover, a number of randomized controlled trials have shown no difference in infection rates between a single preoperative dose and continuing antibiotics for 24 hours [13, 16], implying further doses after IORA may be unnecessary.
We found tissue concentrations were three to seven times greater in the 250-mg IORA group than in the systemic group, and given the lower risk of toxicity with lower doses, we would recommend 250 mg as the IORA dose for vancomycin. Vancomycin exhibits concentration-independent killing, and once concentrations are four to five times the MIC, further increases do not alter the killing rate [17, 22]. Surveillance studies from US laboratories report the modal vancomycin MIC is 1.0 μg/mL for MRSA isolates and 2.0 μg/mL for CoNS . Tissue concentrations seen in the systemic group were higher than these MICs but were relatively borderline if one considers up to 50% of vancomycin may be protein bound . Inadequate tissue concentrations have been postulated as the reason why vancomycin appears be less effective against methicillin-sensitive strains of S Aureus than cephalosporins [8, 39], a problem likely to be exacerbated if timing of vancomycin administration is suboptimal .
Timing of prophylactic antibiotics is critical to their effectiveness; maximum benefit occurs when given in the 60 minutes before skin incision . As protocols for systemic vancomycin require infusion rates of no greater than 1 g/60 minutes, a prophylactic dose of 1 g needs to be started 1 to 2 hours before surgery . This is difficult to incorporate into operating room protocols , and clinical studies show optimal timing of vancomycin is rarely achieved in practice [1, 39]. An advantage of IORA over systemic is that it ensures appropriate timing of administration, and in our study and a previous IORA study , very high tissue levels of antibiotic were present immediately after skin incision. A disadvantage is that IORA injection occurs after tourniquet inflation, adding 2 to 4 minutes to overall tourniquet time. The intraosseous needles are also an additional cost.
Regional administration of prophylactic antibiotics in TKA has been investigated previously using teicoplanin, a glycopeptide antibiotic currently unavailable in North America with a similar spectrum of activity to vancomycin. de Lalla et al.  compared intravenous regional administration (IVRA) of 400 mg teicoplanin via a foot vein to 800 mg teicoplanin given systemically. IVRA provided tissue concentrations two to 10 times higher than the systemic route. The same authors prospectively evaluated this IVRA protocol in 250 patients undergoing TKA and reported a 0% deep infection rate .
While this is the first study of IORA vancomycin in humans, it is well described in the veterinary literature where regional antibiotic administration is commonly used to treat limb infections. Rubio-Martínez et al.  compared IORA versus IVRA of vancomycin in 12 horses. No complications were reported, and tissue concentrations achieved with the two routes were similar. That study and a number of other animal studies [4, 24, 34] have demonstrated tissue antibiotic concentrations using the IVRA and IORA routes for administration are equivalent. IORA injections also travel directly into the intravascular space, and in TKA, the main advantages over IVRA are reliability and speed of access. Proximal tibial cannulation using modern intraosseous kits is rapid and reproducible  and, in contrast to foot vein cannulation, does not require any changes to standard sterile draping.
Potential complications of intraosseous infusion include fluid extravasation with compartment syndrome related to incorrect needle placement in emergency situations . Needle site infection is rare and correlates with the length of time the needle is left in situ . Fat embolus is a theoretical concern, and subclinical lung microemboli have been seen histologically after intraosseous infusion in some animal studies [14, 28]. However, no measurable effects on ventilation-perfusion performance have been found [20, 28], and other studies report no difference in histologic fat embolus rates between intraosseous and intravenous infusions . To date, no cases of clinical fat emboli associated with intraosseous infusion have been reported in humans .
Accepted indications for vancomycin prophylaxis in TKA include β-lactam allergy and known colonization with MRSA . High institutional MRSA prevalence has also been suggested as an indication , but the prevalence at which routine prophylaxis with vancomycin becomes beneficial is controversial . Promotion of further antibiotic resistance with routine vancomycin prophylaxis remains a significant concern, as prolonged exposure to sublethal concentrations may promote the emergence of resistant organisms . In theory, low-dose IORA may apply less selection pressure than systemic administration by maximizing tissue levels at the site of action and reducing the overall exposure; however, any advantage is difficult to quantify.
While concerns about the routine use of vancomycin for prophylaxis remain, the use of low-dose vancomycin IORA can achieve higher tissue concentrations than systemic administration without prolonged preoperative infusion times. This may optimize the timing of vancomycin administration and reduce the risk of systemic side effects, while providing equal or enhanced prophylaxis in TKA.
We thank Irene Zeng MSc (Hons) for her assistance with statistical analysis and the Awhina Trust for their funding support, and we thank Dr Kelly Vince for his advice and guidance on the project. We also thank Vidacare Corp for supplying the intraosseous needles without charge.
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