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Definition

A post‐injection flare is an acute, non‐septic inflammatory response to the medication [7, 8]. Aside from the discomfort of the patient and the anxiety of the owner, the biggest concern related to a post‐injection flare is differentiating it from septic synovitis. Septic synovitis is an inflammatory response of the synovial cavity associated with infection.

Risk factors

 Substandard aseptic technique

 Post‐injection flares:Injected substance: corticosteroids, local anesthetics, hyaluronate, and polysulfated glycosaminoglycans

 Post‐injection synovial sepsis:In humans: failure of aseptic technique, experience of practitioner, use of multi‐dose vials, injection through infected tissue, concurrent systemic infection, and use of immunosuppressive drugs [9, 10]In horses:Corticosteroids [11–13]Polysulfated glycosaminoglycan or hyaluronic acid [11]Combination of corticosteroid‐polysulfated glycosaminoglycan [13]Dexamethasone had higher risk than betamethasone [12]Treating veterinarian [12, 13], >20 years in practice by the treating veterinarian [14]Technical factors: <7‐minute preparation time, clipping the site, not using gloves, using the same needle to draw up medication and do the injection, and having someone other than the veterinarian performing the procedure preparing the site [14].

Pathogenesis

Post‐injection flare is a chemical synovitis, presumably due to an inflammatory reaction to the medication or substance within the medication. Developing an infection after intra‐synovial injection is related to the amount and type of bacterial contamination and the type of medication being administered. Some intra‐synovial medications potentiate infection to a greater degree than other medications. For example, in an experimental study, injection of 33 colony‐forming units of Staphylococcus aureus with saline resulted in a synovial infection in 1 out of 8 horses, whereas when 33 colony‐forming units of S. aureus was injected with polysulfated glycosaminoglycan, hyaluronic acid, or methylprednisolone acetate, synovial infection developed in 8 out of 8, 4 out of 8, and 3 out of 8 of horses, respectively [11]. In a different study, concurrent injection of 125–250 mg amikacin with polysulfated glycosaminoglycan significantly reduced the risk of infection [15].

It is speculated that these intra‐synovial medications may potentiate infection by interfering with the normal immune defenses of the joint. In two large‐scale equine studies, the risk of septic synovitis after intra‐synovial injection was 1 case per 1,087 injections [13] and 1 case per 1,279 injections [12], which is much higher than the risk of post‐injection septic synovitis in human medicine (1/10,000 to 1/77,300) [9, 16].

Prevention

Strict aseptic technique should be used any time a synovial structure is injected, including aseptic preparation of the site with disinfectant, use of single‐use vials, aseptic handling of medication, and performing the injection with sterile gloves [17]. Research studies have suggested that there is no need to clip hair from synoviocentesis sites [18, 19] and skin preparation times of >2 minutes were recommended [19]; however, a survey of equine veterinarians suggested that not clipping and >7‐minute preparation time was associated with reduced risk of infection [14]. Clipping may be beneficial if the area is soiled. The injection should be performed in a clean, dry, non‐dusty environment that is protected from wind [12].

Concurrent administration of antibiotics with the intra‐synovial medication is used by some veterinarians. Routine use of antibiotics concurrent with intra‐synovial medication has not been shown to statistically alter the risk of infection, likely because the incidence of infection in these studies is low [12, 13]. Concurrent administration of antibiotics is recommended any time polysulfated glycosaminoglycans are injected intra‐synovially [15]. Inclusion of antimicrobial agents should not replace strict aseptic technique, and has the potential to interfere with the efficacy of the primary medication.

Diagnosis

Non‐septic inflammation or joint flare occurs within several hours of the intra‐synovial administration and is characterized by synovial effusion and pain [7, 8]. In general, a post‐injection flare will occur acutely (within hours), will respond rapidly to anti‐inflammatory medication, and does not persist beyond 1–2 days [7, 8]. Signs of septic synovitis include localization of pain, heat, and effusion in the injected synovial structure. Clinical signs of septic synovitis typically occur within 2.5–4 days of injection, but may occur 1–19 days after injection [12, 20]. Intra‐synovial corticosteroid injections may delay recognition of the problem, because the anti‐inflammatory effect of the medication may suppress clinical signs.

Diagnosis should be supported by synoviocentesis with cytology and culture of the synovial fluid. Traditionally, cytological findings of >30,000 total nucleated cells/μl, >80% neutrophils, and >4.0 g/dl total protein is supportive of the diagnosis [21, 22]. If intra‐synovial corticosteroids have been administered, infection may be associated with <10,000 total nucleated cell/μl [8]. Recent studies have used low cut‐off values (<10,000 or even <5,000 cell/μl) as overall definition of sepsis (refer to Chapter 45: Complications of Synovial Endoscopic Surgery, for further information). Other markers of synovial infection, such as serum amyloid A, have recently been investigated (see Chapter 45: Complications of Synovial Endoscopic Surgery). Culture is confirmatory of the diagnosis, but treatment should proceed without waiting for culture results, partially because of the disadvantage of delaying treatment and the low yield in obtaining positive culture results in septic synovitis. In multiple studies, iatrogenic infections of synovial structures appear to have a high prevalence of staphylococci infections [23–25]. Further information about diagnosis and management of synovial sepsis is covered in Chapter 45: Complications of Synovial Endoscopic Surgery.

Treatment

A joint flare reaction is usually self‐limiting but may require systemic or topical anti‐inflammatory treatment [7, 8]. Lavage will hasten resolution of the post‐injection flare by removing inflammatory debris and any residual inciting medication, but adds expense and may reduce effectiveness of the original intra‐synovial medication. However, given the severity of delaying treatment in septic synovitis, it is prudent to proceed with lavage of the affected synovial structure and systemic and intra‐synovial antimicrobial treatment if the two post‐injection complications cannot be differentiated [7]. Septic synovitis of any cause is a life‐threatening problem, and aggressive treatment should be instituted immediately. Mainstays of treatment are local and systemic administration of broad‐spectrum antimicrobial agents and lavage of the synovial structure. It is worth emphasizing that antimicrobial selection should target staphylococci, which often have penicillinases.

Expected outcome

Prognosis for recovery following joint flare reaction is excellent. Prognosis following treatment of post‐injection septic synovitis is guarded, partially because the pre‐existing joint pathology that prompted the intra‐synovial injection may limit full recovery and partially because Staphylococcal infections have been associated with poorer outcomes and lower return to athletic activity than other infections [23, 24].