Musculoskeletal Corticosteroid Administration: Current Concepts

Canadian Association of Radiologists Journal 70 (2019) 29e36 www.carjonline.org

Musculoskeletal Radiology / Radiologies musculo-squelettique

Musculoskeletal Corticosteroid Administration: Current Concepts Amit Shah, FRCRa, Davina Mak, FRCRb, A. Mark Davies, FRCRb, S.L. James, FRCRb, Rajesh Botchu, FRCRb,* a Department of Radiology, University Hospitals of Leicester, Leicester, United Kingdom Department of Musculoskeletal Radiology, Royal Orthopaedic Hospital, Birmingham, United Kingdom

b

Abstract Numerous corticosteroid preparations are available, but the type and dose administered is frequently at the discretion of the clinician. This is often based on anecdotal evidence and experience rather than formal clinical guidelines. In order to better understand current practice, we anonymously surveyed 100 members of the British Society of Skeletal Radiologists. The results of the survey demonstrated the arbitrary use of all types of steroid preparation at different anatomical locations. In this article, we review the commonly used corticosteroids and propose a guideline to help practitioners decide on the type and dose of steroid depending on the treatment location. R
esum
e De nombreuses pr
eparations de corticost
ero€ıdes sont disponibles. Cependant, le type et la dose administr
es sont souvent d
etermin
es a la discr
etion du clinicien, souvent en fonction de l’exp
erience et d’observations empiriques et non sur la base de recommandations cliniques officielles. Afin de mieux comprendre la pratique actuelle, les auteurs ont proc
ed
e a un sondage anonyme sur 100 membres de la British Society of Skeletal Radiologists. Les r
esultats ont permis de mettre en
evidence une utilisation arbitraire de l’ensemble des types de pr
eparations st
ero€ıdiennes, en diff
erents sites anatomiques. Cet article est une synthese des corticost
ero€ıdes les plus fr
equemment utilis
es et propose une recommandation visant a aider les praticiens a s
electionner le type et la dose de st
ero€ıdes a administrer en fonction de la zone trait
ee. Crown Copyright Ó 2018 Published by Elsevier Inc. on behalf of Canadian Association of Radiologists. All rights reserved. Key Words: Intra-articular injections; Corticosteroids; Evidence-based; Guidelines

It is common practice to use intra-articular (IA) corticosteroids for the treatment of musculoskeletal conditions, and it is one of the commonest drugs administered within a radiology department [1,2]. Injections are performed by various medical and allied health professionals and include IA, bursal, tendon sheath, enthesis, epidural, and soft tissue locations. Evidence supports the use of corticosteroid injection, as its anti-inflammatory properties can provide patients with pain relief, with the aim of improving function [2,3]. Steroid injections into affected joints can allow dose reduction of systemic steroids, as well as orally administered analgesics and anti-inflammatories. Corticosteroid injections may temporise the need for surgery or provide relief when surgery is contraindicated for medical reasons. The * Address for correspondence: Rajesh Botchu, FRCR, Department of Musculoskeletal Radiology, Royal Orthopaedic Hospital, Birmingham, United Kingdom. E-mail address: [email protected] (R. Botchu).

therapeutic effects of corticosteroids are, however, often temporary, with some studies suggesting no long-term difference between corticosteroids and placebo [4]. This is not a consistent and universal finding, with results varying with different anatomical sites and indications. To date, no formal evidence-based guidelines exist to guide clinicians in deciding which steroid to inject. There is a lack of evidence and robust studies looking at the comparable safety and efficacy of available agents and the long-term outcomes of corticosteroid injection. Corticosteroids are often combined with a local anaesthetic (LA), which acts as the solvent for the corticosteroids, provides volume for the injectate to distribute in the joint, and provides immediate analgesia. This LA phase can allow further clinical assessment regarding symptomatic relief, often giving diagnostic information relating to a potential pain source. Commonly used LAs are lidocaine, bupivacaine, and ropivacaine; the latter two are longer-acting. Although it is beyond the scope of this review article to discuss in detail the

0846-5371/$ - see front matter Crown Copyright Ó 2018 Published by Elsevier Inc. on behalf of Canadian Association of Radiologists. All rights reserved. https://doi.org/10.1016/j.carj.2018.11.002

30

A. Shah et al. / Canadian Association of Radiologists Journal 70 (2019) 29e36

Figure 1. A graph demonstrating the responses received by 100 members of the British Society of Skeletal Radiologists for the type of steroid used in different anatomical locations. All responses were anonymous and sections without a response were not counted. ‘‘Other’’ includes use of hydrocortisone, betamethasone, and plasma-rich platelets. This figure is available in colour online at http://carjonline.org/.

benefits and risks of the types of LAs available, the most controversial observation in recent studies is that LAs may be associated with chondrotoxicity [5e7]. There is, however, a lack of randomised control trials, with large numbers based on in vitro observations regarding this potential adverse effect [8]. Currently, there is no convincing clinical or in vivo data to contraindicate the use of LA with single injections. This review will focus on steroid injections in the adult population only.

what I was taught’’ principle. This practise does not appear to be isolated to the UK, with similar practice in the United States [9]. During a recent British Society of Skeletal Table 1 The comparative dose equivalents for the different steroids and particle size compared to a maximum 7.5 mm for erythrocyte [2,41]

Steroid

Current UK Practice In our opinion, the choice of corticosteroid and dose is often based on anecdotal evidence and the ‘‘because that is

Methylprednisolone acetate (Depo-Medrone) Triamcinolone acetonide (Kenalog) Bethamethasone acetate (Celestone) Dexamethasone sodium

Equivalent dose to 40 mg triamcinolone acetonide (mg)

% of particles >10 mm

40

45

40 6 1.5

45 35 0

Musculoskeletal corticosteroid administration / Canadian Association of Radiologists Journal 70 (2019) 29e36 Table 2 Common indications (2a) and contraindications (2b) for corticosteroid injection [2,10] a) Indications Inflammatory arthropathy Degenerative arthropathy Soft tissue/bursal inflammation Transforaminal/epidural b) Absolute contraindication Local or intra-articular sepsis Broken skin or at site of injection Fracture or joint instability Allergy to constituents of injectate Joint destruction Unstable coagulopathy Relative contraindication Prosthetic joint Sever juxta-articular osteoporosis Injection three times within the preceding year or less than 2 weeks

Radiology members meeting, we anonymously surveyed 100 British Society of Skeletal Radiology members on the type of steroid used whilst injecting various anatomical locations. Members were asked to indicate if they used Kenalog (triamcinolone acenotide), Depo-Medrone (methylprednisolone acetate), dexamethasone, or other preparation for 21 different procedures ranging from superficial (small) and deep (large) joints in relation to the skin surface, tendinopathy, soft tissue/bursal injections, and nerve root block (NRB). Members attending the meeting were from across the UK. Fifty-four percent of members responded with 94% of consultant grade. There was no predominant type of steroid used for any particular procedure (Figure 1). Whilst this data is limited by the relatively low response rate, it provides an important insight into current practice within the UK. It confirms that there is apparently arbitrary use of particulate (Kenalog and Depo-Medrone) and nonparticulate (dexamethasone) steroids. Of particular interest was the fact that 33% of the surveyed radiologists are still using particulate steroids for cervical NRB. This will be discussed in detail later in this review. IA CorticosteroidsdMechanism of Actions and Pharmacokinetics The most commonly used corticosteroids are triamcinolone acenotide (Kenalog-40), methylprednisolone acetate (Depo-Medrone), and dexamethasone (Decadron). Other steroids used in internationally include triamcinolone hexacenotide (Aristopan), betamethasone acetate (Celestone), and hydrocortisone [2]. The comparative efficacy for the different steroids is shown in (Table 1). Dexamethasone and hydrocortisone are non-particulate steroids. Particulate steroids, such as methylprednisolone acetate and triamcinolone acenotide, have a varying degree of aqueous solubility and are composed of microcrystals ranging from 3e15x the size of erythrocytes (Table 1). Anti-inflammatory and analgesic

31

mechanisms include synovial blood flow reduction, synovial fluid composition alteration, gene suppression of leukocytes, protease and cytokine production, and altered collagen synthesis [1,10,11]. These effects are more potent in corticosteroids with branched esterification, as they are less soluble. Microcrystalline agents remain at the injection site longer resulting in a longer therapeutic duration, reported up to 21.1 days with triamcinolone acenotide, which is the least soluble steroid [10,11]. More soluble steroids are more rapidly absorbed from the joint, with half-life as short as a few hours [1,11]. Once absorbed from the joint, they are metabolised by the liver and excreted by the kidney. Indications and contraindications for the use of corticosteroid injections are summarized in Tables 2a and b, respectively. Corticosteroid InjectiondPotential Adverse Effects Steroid-induced arthropathy Radiographic follow-up of patients post IA steroid injection has shown worsening and progression of joint arthropathy. Initial reports suggested this might be steroid induced secondary to repeated IA injections. Early studies hypothesised that the proteolytic enzymes in the exudate of corticosteroid-induced synovitis had a chondrotoxic effect and repeated steroids injections in animal models demonstrate deleterious effects on cartilage [11]. These hypotheses have not been clinically substantiated, and some authors have suggested the radiographic deterioration can be attributed to increase joint use post injection due to the steroid-induced pain relief. Furthermore, the overall effect of steroids is potentially protective to cartilage from the more destructive process of inflammation [11]. In addition, animal and human

Table 3 Our proposed guideline on the steroid preparation and the dose to select based on generic anatomical locations Location Small joints Hand Wrist Elbow Acromioclavicular Sternoclavicular Fore and midfoot Large joints Glenohumeral Hip Knee Tibiotalar Subtalar Superficial bursa/soft tissue Deep bursa/soft tissue Tendons-superficial Tendons-deep Transforaminal Cervical Lumbosacral

Dexamethasone (mg)

Depo-Medrone (mg)

Triamcinolone (mg)

-

10e20 40 40 20e40 20e40 20e40

-

20e40

40 40 40 40 40

-

40

40 40

4 4

-

32

A. Shah et al. / Canadian Association of Radiologists Journal 70 (2019) 29e36

cartilage are not identical biochemically, physiologically, or histologically and respond differently to chemical agents and trauma [11]. The potential link between chondrotoxicity and local anaesthetic use makes conclusion regarding progressive arthropathy even more difficult, but some authors have indicated an incidence of steroid-induced arthropathy is 0.8% [10].

can leave the skin fragile, susceptible to minor trauma and infection, easy bruising, and sensitive to touch. Particulate steroids have greater dermal and subcutaneous tissue atrophy [11]. Triamcinolone has a greater risk for dermal changes compared to methylprednisolone due to its increased crystal size and is typically recommended only for IA or deep injection therapy [2].

Septic arthritis Septic arthritis can be a catastrophic but rare complication following IA injections. Frequencies of joint infection after IA injection range from 1 in 3000 to 1 in 100,000 [10,12]. It is best practice to adhere to an aseptic technique. A traumatic procedure or the presence of IA steroid can leave a joint susceptible to infection by haematogenous spread, particularly in the presence of local or systemic infection. As corticosteroids can cause immunosuppression, steroid injection should be avoided if patients are on antibiotic treatment or have bacteraemia [13]. IA injection should not be carried out in the presence of active infection in or near joints. [14].

Tendon rupture The incidence of tendon rupture is less than 1% [10]. The exact cause for steroid-mediated tendon rupture is unknown. Excessive exertion, degenerative, and inflammatory tendinous attrition can lead to tendon rupture. Steroids may exert a deleterious effect on tendon strength, repair and reduce tensile strength [11,16]. Reduced mobility/joint function or inflammation/synovitis can have a ‘‘protective mechanism’’ for diseased tendons, which can be removed by the therapeutic effects of steroids.

Systemic effects Facial flushing has been reported with an incidence of less than 1% [10]. Facial, neck, and torso flushing are reported systemic effects seen more frequently with triamcinolone acenotide. Symptoms can last from several minutes to days, but generally resolve with conservative management [10,11]. Vasovagal reaction can occur due to systemic absorption of the steroid or local anaesthetic or patient anxiety to the procedure itself with incidences reported between 0%-20% [10,15]. Gray et al reported doses of 150e300 mg reducing inflammation of joints distant to the injected site and causing eosinopenia, a sign of systemic steroid absorption [11]; however, in current clinical practice, injected doses of steroids rarely exceed 80 mg. IA doses up to 80 mg can be given without undue adverse systemic effects, although doses greater than 50 mg triamcinolone acenotide have been shown to decrease serum cortisol, confirming suppression of the hypothalamic-pituitary-adrenal axis [11]. Systemic effects can be minimised by limiting the number and dose and increasing the interval between IA injections and ensuring intravascular needle placement or injection is avoided. One must be aware of steroid induced hyperglycaemia and consent diabetic patients appropriately [11]. Hyperglycaemia can last for up to 3 weeks. Cutaneous effects Corticosteroids may cause dermal/subcutaneous tissue atrophy, hypopigmentation, and fat necrosis [11], with a reported incidence of less than 1% [10]. The presence of corticosteroid crystals can lead to the disintegration of the cellular elements and physiochemical changes in connective tissue. The resultant dermal and/or subdermal changes may form depressions in the skin at the injection site. These changes may be irreversible. The injection site is at risk if corticosteroids leak along the needle track, which can occur if injections are placed superficially. The effects of steroids

Steroid flare A post-injection, self-limited synovitis can occur in approximately 1%e10% of cases following IA injection [11]. Symptoms of joint pain and swelling can be observed several hours post injection and generally subsides within 48 hours [11]. Microcrystalline steroids share common physical properties with monosodium urate (gout), and calcium pyrophosphate dehydrate (pseudogout) crystals and have been implicated in causing a crystal-induced arthritis; however, other studies have shown post steroid-injection flare was similar in cases of IA injection with and without triamcinolone [11]. Steroid microcrystals can be seen in joints more than a month post injection. Perceived ‘‘worsening of symptoms’’ can also be seen once the local anaesthetic wears off, and it is important to adequately consent and counsel patients to warn them of this. Miscellaneous effects Peri-articular joint capsule calcification can occur as a late complication, with a reported incidence of up to 43% [10,11]. Although, we do not have a definite incidence rate, this level is not seen in our clinical practice. There have been rare reports of drug hypersensitivity to additives or the local anaesthetic within the injectate [11]. Severe joint destruction with osteonecrosis may occur with prolonged repeated IA injections. Corticosteroid use should be carefully considered during pregnancy, and as with all medication, fully informed consent with risks and benefits to the mother and child should be discussed and documented. Although corticosteroids are excreted in small amounts into breast milk, the small dose used intra-articularly, with even smaller systemic absorption, will mean a relatively insignificant amount in breast milk. Furthermore, there is negligible gut absorption from the baby, and so there is no significant risk of hypothalamus-pituitary-adrenal axis suppression. There are, however, documented cases of lactation suppression secondary to triamcinolone injection [17,18]. Corticosteroids are a substrate of the enzyme CYP3A4, which is targeted and

Musculoskeletal corticosteroid administration / Canadian Association of Radiologists Journal 70 (2019) 29e36

blocked by many anti-retrovirals (ritonavir), anti-fungals, calcium-channel blockers (diltiazem), and the oral contraceptive pill, to name a few. Caution is advised when using corticosteroids with such drugs, as it can result in excess systemic steroid levels and lead to Cushing’s syndrome and adrenal suppression [14,19]. No such interaction has been reported with a reduced dose of methylprednisolone and should be used as an alternative to triamcinolone. Also, corticosteroids may induce the metabolism of HIV-protease inhibitors resulting in reduced plasma concentrations. It is, therefore, vital referrers provide detailed and relevant clinical information when referring patients for corticosteroid injections. It is best practice to seek the advice of the infectious diseases clinicians prior to proceeding with a steroid injection [20,21]. A number of resources are available online [22]. It is also advised to be familiar with potential drugs interactions with corticosteroids and pharmacy advice should be sought as required. An under-reported side effect is persistent hiccoughs following corticosteroid injection [23e27]. The onset of hiccoughs typical occurs hours after steroid injection and has been reported to last up to 2 weeks [27]. The incidence is unknown and a number of mechanisms have been postulated, including cerebrospinal fluid volume imbalance following epidural injections, mixture with bupivacaine, sympathetic pathway blockade, steroid activation of the hiccough reflex arc, and alteration in neurotransmitters in the brainstem [23e27].

Who, What, When, Where, and Why of Musculoskeletal Corticosteroid Injections Who Corticosteroid injection is indicated when there is a need to reduce inflammation and improve function in a variety of musculoskeletal conditions. This may be secondary to an inflammatory, traumatic or degenerative process. Steroids should not be used to alleviate arthropathy secondary to infection or in unstable joints. Corticosteroid injections are a useful adjunct to systemic treatment particularly targeting severely affected joints. Combined with appropriate multi-modality therapy, steroid injections can help reduce doses of systemic drugs and potential adverse reactions, reduce reliance on analgesia, and improve quality of life associated with pain reduction and increased function. What The costs, potency, duration of action, and steroid-related reactions vary with the different available preparations. Particulate steroids have greater potency with greater prolonged therapeutic effects but have greater dermal and subcutaneous tissue atrophy [11]. The smallest dose should be used as infrequently as clinically appropriate.

33

Triamcinolone acetonide Kenalog contains triamcinolone acetonide 40 mg/mL of sterile aqueous suspension and is a microcrystalline corticosteroid shown to have the greatest potency. In the UK, it is licenced for IM/IA injection only [14]. Kenalog is not licenced for use in children under 6. Particles of triamcinolone vary greatly in size and are densely packed. Triamcinolone has particle sizes ranging from 15e60 mm compared to methylprednisolone of 0.5e26 mm, bethamethasone of 10e 20 mm, and erythrocytes of 2.5e7.5 mm [11]. When diluted with bupivacaine, triamcinolone may coalesce into large (>100 mm) aggregates causing clouding of the solution. The dose of Kenalog should be adjusted according to the proposed injection location and clinical scenario with up to 40 mg. A total of 80 mg per procedure (multiple sites), have been given without undue reactions. Kenalog should ideally be used for large joints (eg, tibiotalar, hip or glenohumeral joints) or deep soft tissue targets that are deep to muscle/ tendon (eg, subacromial subdeltoid or trochanteric bursa). This will minimise the risk of subcutaneous fat atrophy or dermal hypopigmentation. Methylprednisolone acetate Depo-Medrone is an aqueous suspension of microcrystalline methylprednisolone acetate 40 mg/mL. Methylprednisolone acetate is a synthetic glucocorticoid with greater anti-inflammatory potency than prednisolone. Methylprednisolone acetate has uniformly sized, densely packed particles with <5% of particles >50 mm in diameter and do not form many aggregations [28]. Depo-Medrone is licensed for IM, IA, intrabursal, intralesional, or into the tendon sheath [14]. Based on the recommendations by the National Institute for Health and Care Excellence, methylprednisolone is suggested for small joints and methylprednisolone or triamcinolone for medium or large joints [29]. Methylprednisolone is suggested for superficial soft tissue injections and triamcinolone for deeper sites. Doses vary upon the clinical scenario, and we propose up to 40 mg is used for large joints (knee, ankle, shoulder) and bursae and 5e20 mg for superficial soft tissue or small joints (metacarpophalangeal, interphalangeal, sternoclavicular, acromioclavicular) [14]. Medicine and Healthcare Products Regulatory Agency, UK, have recently issued a drug safety alert that Solu-Medrone 40 mg (a methylprednisolone preparation) contains lactose produced from cows’ milk as an excipient and may contain trace amounts of milk proteins; other strengths of SoluMedrone do not contain lactose [30]. Other injectable methylprednisolone preparations (ie, Depo-Medrone, DepoMedrone with lidocaine) do not contain milk proteins. SoluMedrone 40 mg will be reformulated to remove any trace of milk proteins. Dexamethasone Dexamethasone 3.3 mg/mL vials are solutions for injection. Each mL of solution contains 3.3 mg dexamethasone (as sodium phosphate), which is equivalent to 4 mg dexamethasone phosphate or 4.3 mg dexamethasone sodium

34

A. Shah et al. / Canadian Association of Radiologists Journal 70 (2019) 29e36

phosphate. Dexamethasone 3.3 mg/mL solution for injection may be administered by IM, IA, or direct intravenous (IV) injection, IV infusion, or epidural/transforaminal infiltration. It is a clear, colourless solution, essentially free from particulate matter [14]. Dexamethasone sodium phosphate has particulate size <5 mm with the lowest density and the least tendency to aggregation among all the steroid preparations. Theoretically, dexamethasone should have minimal neurologic sequelae and a short duration of action compared to particulate steroids [31]. Dexamethasone sodium phosphate injection has a rapid onset but short duration of action when compared with less soluble preparations, as it does not remain at the target site as long. Dexamethasone sodium phosphate has a higher anti-inflammatory and potency compared to other steroids but affects can be transient as it is rapidly absorbed [28]. When and Why Because of transient and temporary benefit, steroid injections may need to be repeated. Repeat injections should not be given within short intervals to minimise the risks described earlier, though these are relatively insignificant and infrequent. Approximate duration of action of steroids are between 1-2 weeks depending on the type of steroid preparation [10]. A 2- to 3-week interval is suggested if a second corticosteroid injection is required, and a minimum of a 6week interval if a repeat injection into the same location is performed [11]. The National Institute for Health and Care Excellence recommends the same joint is not injected more than 3 times a year [29]. Weight-bearing joints and tendons subject to sudden strain (eg, Achilles tendon, ankle tendons) should be rested and protected (eg, air boot) post injection with avoidance of excessive use. The length of time is often locally agreed in conjunction with the foot and ankle surgeons. Therapeutic management should be reconsidered after 3 steroid injections into a single site. This, of course, is dependent on the clinical situation, and other management options such as surgery may not possible, leaving steroid injections the only clinically viable therapy. Epidural Steroid Injections Controversy exists on the effectiveness of epidural steroid injections (ESI) and the use of particulate steroid is on an offlabel basis [32]. There has been a particular focus on the use of epidural steroid injection in the recent literature. Radiologists perform transforaminal selective NRB and generally use longer acting particulate steroids (triamcinolone, methylprednisolone, or betamethasone) [33]. Numerous studies have shown a significant therapeutic benefit in terms of pain relief, disability, and activity levels compared to a control group or dexamethasone [28,34]. However, evidence has shown that steroids can have neuro-toxic effects, and rare serious adverse events, such as brainstem and cord infarction, have been reported [32]. The risk is greater for particulates like triamcinolone and negligible for dexamethasone [35].

Methylprednisolone can lead to sodium retention and its preservative, benzyl alcohol, a potentially neuro-toxin increasing the risk of arachnoiditis. Neurologic risks can also be as a result of direct needle injury or needle placement leading to vasospasm and neurologic ischaemia [28]. Particulate embolisation into vessels with resultant ischemia and scarring of the nerves could lead to serious central neural sequelae. Methylprednisolone and triamcinolone may coalesce into large aggregates (>100 mm); however, sporadic particles can even exceed a size of >1000 mm [32]. Based on the dimensions of arterioles of 37 mm, and capillaries of 9 mm, both methylprednisolone and triamcinolone sludge can block these arterial vessels and result in ischemia [28]. Dexamethasone has particulate size 0.5 mm (smaller than erythrocytes) with the least tendency to form aggregates among all the steroid preparations and, therefore, should have minimal neurologic sequelae [28,32]. The U.S. Food and Drug Administration (FDA) have specifically labelled triamcinolone ‘‘not for epidural use,’’ issued safety warnings and list epidural use as a contraindication [32]. Manchikanti et al criticised this in their review article concluding ‘‘the authors request that the FDA modify the warning based on the evidence’’ [33]. Possible mechanisms of spinal cord injury in patients undergoing cervical and lumbar ESI included embolisation of particulate steroids, needle-induced vasospasm, compression from an epidural hematoma, or abscess and mechanical disruption of radiculomedullary arteries [32]. The exact pathophysiology of spinal cord injury remains unclear, particularly in patients after lumbosacral ESI. It is thought that steroids with larger particle sizes have a potential for occlusion of small vessels of the arterial tree as a potential consequence after incidental radiculomedullary artery steroid injection. Derby et al demonstrated that the largest triamcinolone acetonide particles (range 0.5e100 mm) were more than 12 times greater than median-sized erythrocytes (approximately 7.5 mm) compared to dexamethasone particles, which were approximately 10 times smaller [36]. Triamcinolone, methylprednisolone, and betamethasone all form densely packed aggregates, especially when mixed with a local anaesthetic [36]. However, it must be noted in human plasma, there was a significant reduction in size of the steroid aggregates due to the coating effects of albumin [36]. Okubadejo et al compared intra-arterial injection of particulate steroids versus non-particulate steroids during cervical NRB of pigs under general anaesthetic [37]. All 4 pigs injected with methylprednisolone failed to regain consciousness, required mechanical ventilation, and had MRI and histopathologic evidence of cervical cord and brain stem oedema and ischaemic injury. In contrast, pigs injected with dexamethasone had no clinical, MRI, or histopathologic evidence of neurologic injury [37]. Studies have also reported cord infarction several segments cranial to the injected level infarction post lumbar NRB using particulate steroid. However, some of these patients had previous laminectomies and with ESI using an interlaminar approach. These studies speculated that the presence of epidural scar tissue increases

Musculoskeletal corticosteroid administration / Canadian Association of Radiologists Journal 70 (2019) 29e36

the risk of spinal cord injury after lumbar epidural steroid injections [32]. Some studies have demonstrated that symptomatic relief lasts longer following lumbar NRB with particulate steroids (triamcinolone) compared to dexamethasone, whilst others report no statistical difference in the efficacy or duration of symptomatic relief of particulate versus non-particulate steroid (4 mg dexamethasone) [32]. The only statistically significant finding noted is those having dexamethasone lumbar ESI require on average more repeated injections compared to triamcinolone to achieve the same result [38] with similar observations following cervical NRB [32]. As mentioned previously, there are a number of factors implicated in the rare but extremely serious neurologic consequence of ESI. There is a significant paucity of robust prospective studies to be able to provide evidencebased guidance on ESI steroid selection. Current studies vary greatly in the technique, steroid type and dose used, patient selection, and methodology. Correct technique, such as needle position using Kambin’s triangle approach for lumbar ESI is suggested to avoid risks of injuring foraminal arteries [39,40].

Conclusion Steroid injections have been shown to improve patient outcomes. It is important to remember that corticosteroid injections should be an adjunctive therapy complemented with conservative therapy and other analgesic or antiinflammatory medication as appropriate. With the current lack of guidance on the steroid use, we have proposed a guideline to help standardise steroid injections. With the current lack of guidance on the steroid use, we have proposed a guideline to help standardise steroid injections (Table 3). We believe a more standardised practice can potentially lead to improved patient outcomes and enable multi-centre data to be studied. References [1] Caldwell JR. Intra-articular corticosteroids. Guide to selection and indications for use. Drugs 1996;52:507e14. [2] MacMahon PJ, Eustace SJ, Kavanagh EC. Injectable corticosteroid and local anesthetic preparations: a review for radiologists. Radiology 2009;252:647e61. [3] National Institute for Health and Care Excellence. Osteoarthritis: Care and managment in adults. Available at: https://www.nice.org.uk/ guidance/cg177; 2014. Accessed January 13, 2018. [4] vanVeen KE, Alblas KC, Alons IM, et al. Corticosteroid injection in patients with ulnar neuropathy at the elbow: a randomized, doubleblind, placebo-controlled trial. Muscle Nerve 2015;52:380e5. [5] Chu CR, Coyle CH, Chu CT, et al. In vivo effects of single intraarticular injection of 0.5% bupivacaine on articular cartilage. J Bone Joint Surg Am 2010;92:599e608. [6] Chu CR, Izzo NJ, Papas NE, Fu FH. In vitro exposure to 0.5% bupivacaine is cytotoxic to bovine articular chondrocytes. Arthroscopy 2006;22:693e9. [7] Piper SL, Kim HT. Comparison of ropivacaine and bupivacaine toxicity in human articular chondrocytes. J Bone Joint Surg Am 2008; 90:986e91.

35

[8] Gulihar A, Robati S, Twaij H, Salih A, Taylor GJ. Articular cartilage and local anaesthetic: A systematic review of the current literature. J Orthop 2015;12(Suppl 2):S200e10. [9] Centeno LM, Moore ME. Preferred intraarticular corticosteroids and associated practice: a survey of members of the American College of Rheumatology. Arthritis Care Res 1994;7:151e5. [10] Stephens MB, Beutler AI, O’Connor FG. Musculoskeletal injections: a review of the evidence. Am Fam Physician 2008;78:971e6. [11] Gray RG, Tenenbaum J, Gottlieb NL. Local corticosteroid injection treatment in rheumatic disorders. Semin Arthritis Rheum 1981;10: 231e54. [12] Holland C, Jaeger L, Smentkowski U, Weber B, Otto C. Septic and aseptic complications of corticosteroid injections: an assessment of 278 cases reviewed by expert commissions and mediation boards from 2005 to 2009. Dtsch Arztebl Int 2012;109:425e30. [13] Wittich CM, Ficalora RD, Mason TG, Beckman TJ. Musculoskeletal injection. Mayo Clin Proc 2009;84:831e7. [14] The Electronic Medicines Compendium (EMC). Available at: http:// www.medicines.org.uk/emc/. Accessed July 17, 2017. [15] Kennedy DJ, Schneider B, Casey E, et al. Vasovagal rates in fluoroscopically guided interventional procedures: a study of over 8,000 injections. Pain Med 2013;14:1854e9. [16] Nichols AW. Complications associated with the use of corticosteroids in the treatment of athletic injuries. Clin J Sport Med 2005;15:370e5. [17] McGuire E. Sudden loss of milk supply following high-dose triamcinolone (Kenacort) injection. Breastfeed Rev 2012;20:32e4. [18] Babwah TJ, Nunes P, Maharaj RG. An unexpected temporary suppression of lactation after a local corticosteroid injection for tenosynovitis. Eur J Gen Pract 2013;19:248e50. [19] Herold MA, Gunthard HF. Cushing syndrome after steroid-infiltration in two HIV-patients with antiretroviral therapy. Praxis 2010;99:863e5. [20] Maviki M, Cowley P, Marmery H. Injecting epidural and intra-articular triamcinolone in HIV-positive patients on ritonavir: beware of iatrogenic Cushing’s syndrome. Skeletal Radiol 2013;42:313e5. [21] Newton L, Halsema CV, Snowden N. HIV and rheumatology: a practical guide. Arthritis Research UK. Reports on the Rheumatic Diseases Top Rev No 5 2014;7(Autumn):1-9. [22] University of Liverpool. HIV Drug Interactions. Available at: http:// www.hiv-druginteractions.org/checker. Accessed December 4, 2017. [23] Beyaz SG. Persistent hiccup after lumbar epidural steroid injection. J Anaesthesiol Clin Pharmacol 2012;28:418e9. [24] Abbasi A, Roque-Dang CM, Malhotra G. Persistent hiccups after interventional pain procedures: a case series and review. PM & R 2012; 4:144e51. [25] Woelk CJ. Managing hiccups. Can Fam Physician 2011;57:672e5. [26] McAllister RK, McDavid AJ, Meyer TA, Bittenbinder TM. Recurrent persistent hiccups after epidural steroid injection and analgesia with bupivacaine. Anesth Analg 2005;100:1834e6. [27] Habib G, Artul S, Hakim G. Annoying hiccups following intra-articular corticosteroid injection of betamethasone acetate/betamethasone sodium phosphate at the knee joint. Case Rep Rheumatol 2013;2013: 829620. [28] Datta R, Upadhyay K. A Randomized clinical trial of three different steroid agents for treatment of low backache through the caudal route. Med J Armed Forces India 2011;67:25e33. [29] National Institute for Health and Care Excellence. Clinical Knowledge Summaries. Available at: https://cks.nice.org.uk/osteoarthritis#! prescribinginfosub:2. Accessed March 27, 2017. [30] Medicine and Healthcare Products Regulatory Agency. Available at: http://www.gov.uk/drug-safety-update/methylprednisolone-injectablemedicine-containing-lactose-solu-medrone-40-mg-do-not-use-in-patientswith-cows-milk-allergy. Accessed October 29, 2017. [31] Hodler J, Boos N, Schubert M. Must we discontinue selective cervical nerve root blocks? Report of two cases and review of the literature. Eur Spine J 2013;22(Suppl 3):466e70. [32] Dietrich TJ, Sutter R, Froehlich JM, Pfirrmann CWA. Particulate versus non-particulate steroids for lumbar transforaminal or interlaminar epidural steroid injections: an update. Skeletal Radiol 2015;44:149e55.

36

A. Shah et al. / Canadian Association of Radiologists Journal 70 (2019) 29e36

[33] Manchikanti L. Role of neuraxial steroids in interventional pain management. Pain Physician 2002;5:182e99. [34] Bensler S, Sutter R, Pfirrmann CW, Peterson CK. Is there a difference in treatment outcomes between epidural injections with particulate versus non-particulate steroids? Eur Radiol 2017;27:1505e11. [35] Mackinnon SE, Hudson AR, Gentili F, Kline DG, Hunter D. Peripheral nerve injection injury with steroid agents. Plast Reconstr Surg 1982;69: 482e90. [36] Derby R, Lee SH, Date ES, Lee JH, Lee CH. Size and aggregation of corticosteroids used for epidural injections. Pain Med 2008;9: 227e34. [37] Okubadejo GO, Talcott MR, Schmidt RE, et al. Perils of intravascular methylprednisolone injection into the vertebral artery. An animal study. J Bone Joint Surg Am 2008;90:1932e8.

[38] Kennedy DJ, Plastaras C, Casey E, et al. Comparative effectiveness of lumbar transforaminal epidural steroid injections with particulate versus nonparticulate corticosteroids for lumbar radicular pain due to intervertebral disc herniation: a prospective, randomized, double-blind trial. Pain Med 2014;15:548e55. [39] Atluri S, Glaser SE, Shah RV, Sudarshan G. Needle position analysis in cases of paralysis from transforaminal epidurals: consider alternative approaches to traditional technique. Pain Physician 2013;16:321e34. [40] Park JW, Nam HS, Cho SK, et al. Kambin’s triangle approach of lumbar transforaminal epidural injection with spinal stenosis. Ann Rehabil Med 2011;35:833e43. [41] Mager DE, Lin SX, Blum RA, Lates CD, Jusko WJ. Dose equivalency evaluation of major corticosteroids: pharmacokinetics and cell trafficking and cortisol dynamics. J Clin Pharmacol 2003;43:1216e27.