Knee Injection

Knee pain and stiffness can be debilitating and difficult to treat. Lifestyle-limiting knee conditions may negatively affect body image and emotional well-being. Weight management, exercises/strengthening programs, physical therapy, physical modalities, orthotics, medications, intra-articular knee injections, and surgery are some of the approaches used to treat knee pain. The most common type of intra-articular knee injection is with corticosteroids, but other agents have been used, including infliximab, hyaluronic acid, botulinum neurotoxin, and platelet-rich plasma (PRP).[1, 2, 3, 4, 5]

Knee pain can be broadly categorized. It can result from an intra-articular process such as a ligamentous or meniscal injury or fracture. Knee pain can also result from cartilage loss due to osteoarthritis or synovitis. Tendinopathies and bursitis can cause knee pain, along with inflammatory insults such as inflammatory arthritis or septic arthritis. Knee pain can be caused by patellar malalignment or dysfunction and referred pain from other areas, such as the spine or hip.

Knee osteoarthritis can be diagnosed on the basis of clinical presentation and radiographic signs.[6]  Baker cysts can be diagnosed on the basis of clinical history and examination and confirmed with ultrasonography (US).[7] A clinical presentation consistent with osteoarthritis includes knee joint pain (typically symmetric bilaterally) and morning joint stiffness that resolves within 30-60 minutes and worsens with weightbearing. Physical examination signs include bony joint enlargement, crepitus and pain upon motion, and limited range of motion. Radiographic signs of osteoarthritis include joint-space narrowing, osteophyte formation, subchondral pseudocysts, and increased subchondral bone density.[6]

Indications for the various agents used for knee injections are discussed below.

Steroid injections have been shown to relieve pain and inflammation in individuals with osteoarthritis (including osteoarthritis complicated by Baker cysts), juvenile idiopathic arthritis, psoriatic arthritis, acute monoarticular gout, pseudogout, and rheumatoid arthritic knees.[6, 7, 8, 9, 10, 11, 12, 13, 14, 15]  However, a 2017 randomized study found intra-articular triamcinolone to be less effective for pain relief in this setting than previous studies had.[16]

Intra-articular infliximab can be used to treat refractory knee monoarthritis/synovitis in patients with rheumatoid arthritis, Behçet disease, and spondyloarthropathy (eg, ankylosing spondylitis) that is resistant to systemic treatment.[5]

Intra-articular knee injections of hyaluronic acid have been shown to provide functional and perceived benefits in knee osteoarthritis for up to 5-6 months.[17] Such injections have also been shown to be helpful in patient with knees that are both rheumatoid arthritic and osteoarthritic.

Intra-articular hyaluronic acid injection into a rheumatoid arthritic knee can modulate inflammatory changes, though the exact mechanism or mechanisms are unclear. In knee osteoarthritis, hyaluronic acid can ameliorate the activities of proinflammatory mediators and pain-producing neuropeptides released by activated synovial cells. Hyaluronic acid may work by affecting the number and distribution of the lining synovial cells to trigger reparative processes of osteoarthritis. Hyaluronic acid may help reduce pain in knee osteoarthritis by decreasing the ongoing nerve activities at rest and with movement, thereby modulating nerve impulses and sensitivities.[4]

Intra-articular injection of botulinum neurotoxin A into the knee joint may provide therapeutic pain relief in patients with advanced knee osteoarthritis. The mechanism of pain reduction via botulinum neurotoxin A may be neurotransmitter-mediated inhibition of sensory neurons, rather than via neuromuscular junction blockade. According to a preliminary study, pain and stiffness significantly improved and lasted about 3 months following intra-articular knee joint botulinum toxin A injection, though physical function did not significantly improve based on the Western Ontario McMaster Universities Osteoarthritis Index.[4]

Intra-articular knee injections of homologous platelet-rich plasma (PRP) have been shown to improve function and quality of life in patients with degenerative lesions of the knee cartilage and osteoarthritis at 6 months post injection.[2]  Chondrocytes treated with autologous plasma rich in growth factors (PRGF) have shown a significant increase in proteoglycan and collagen synthesis.[18] Additionally, PRP injections have shown greater and longer efficacy than hyaluronic acid injections in reducing pain and symptoms and improved articular function.[19]

Intra-articular steroid knee injections are contraindicated in patients with bacteremia, sepsis, periarticular or intra-articular infections (eg, septic arthritis, periarticular cellulitis, and osteomyelitis), significant skin breakdown at the target site, known hypersensitivity to the steroid injection, intraarticular or osteochondral fracture at the target site, severe joint destruction, joint prosthesis, or uncontrolled coagulopathy.[20, 9, 8]

Absolute contraindications for PRP knee injections include the following:

• Critical thrombocytopenia
• Hemodynamic instability or septicemia
• Septic arthritis, overlying cellulitis, or adjacent osteomyelitis
• Platelet dysfunction syndrome

Relative contraindications to PRP knee injections include the following:

• Regular nonsteroidal anti-inflammatory drug (NSAID) use within 48 hours of the procedure
• Corticosteroid injection of the knee within 1 month or systemic corticosteroid use within 2 weeks
• Recent fever or illness
• Cancer, particularly of bone or blood
• Anemia, with a hemoglobin level lower than 10 g/dL
• Thrombocytopenia, with a platelet count lower than 10 ⁵/μL

Anatomy

The knee is a large complex articulating joint that is highly susceptible to injury. The knee joint consists of three main compartments: medial tibiofemoral, lateral tibiofemoral, and patellofemoral. These share a common synovial cavity. The space between the bones is occupied by the meniscal cartilage, and together they are covered by the synovial membrane and the collateral ligaments.

Procedural planning

A thorough physical evaluation of the knee is imperative for a correct diagnosis and therefore for prescribing a joint injection. Numerous provocative knee tests can be performed to assist in obtaining the correct diagnosis. Plain radiography should also be obtained as part of the diagnostic evaluation. For considerations concerning the various agents used for knee injections, see Indications above and Medication.

Complication prevention

A careful history, physical examination, review of medications and allergies, use of sterile measures, and proper selection of patients, equipment, and medications, along with proper positioning and injection approach, may minimize complications. Care should be taken to avoid injecting too much volume into the knee joint. US or fluoroscopic guidance may be used to improve the accuracy of injection into the knee joint.

In a systematic review and meta-analysis of high-quality randomized controlled trials with a low risk of bias, Richette et al found that intra-articular hyaluronic acid had a moderate but real beneficial effect in patients with knee osteoarthritis.[21]

A 2015 Cochrane review assessing the use of intra-articular corticosteroid injections for knee osteoarthritis suggested that the effects of this modality decreased over time and was unable to document remaining effects 6 months after injection.[22]

A systematic review by Meheux found that in patients with symptomatic knee osteoarthritis, intra-articular injection of PRP yielded significant clinical improvements for as long as 12 months.[23] At 3-12 months post injection, PRP was associated with significantly better clinical outcomes and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores than hyaluronic acid was.

In a 2017 randomized study of 119 patients (average age, 58 years) who had symptomatic knee osteoarthritis with synovitis identified through US, McAlindon et al found that those who underwent quarterly intra-articular injection of 40 mg of triamcinolone experienced significantly greater loss of cartilage volume than those who underwent intra-articular saline injection and that there was no significant difference in knee pain between the two groups.[16]

Prior to knee injection, informed consents must be obtained, and the physician should clearly explain to the patient the steps to be carried out, the expected benefits, and the risks and potential complications of the procedure. Patients are encouraged to ask questions and express understanding of the purpose and possible outcomes of the procedure.

The use of ultrasonography (US) to guide intra-articular knee injections may improve accuracy and the likelihood of directing medication into the joint space.

A 22-gauge needle is ideal for knee injections with a 5-mL syringe, but any needle size from 22 to 25 gauge may be used. For injections, needle gauge should be based on medication viscosity. A higher-gauge needle may increase the resistance in pushing the medication while minimizing discomfort. For arthrocentesis, a smaller-gauge needle (eg, 18-22 gauge) is preferred. Syringe size should be based on the same principles as mentioned above. (See the images below.)

For sterilization, either iodine or hexachlorodine scrub should be used. For anesthesia, a bleb or lidocaine or an ethyl chloride spray should be used.

In obese patients, it is better to perform the knee injection under fluoroscopic guidance.

Careful initial palpation and marking of the injection site may reduce the need to repalpate an already prepared site. During the initial marking of the intra-articular injection target site, the knee should be flexed 90° to expose the joint space for the anteromedial or anterolateral approach and almost fully or fully extended for the superolateral or superomedial approach. The selected skin site for injection can be marked. Sterile gloves may be used.

Using sterile techniques, skin over the target area may be prepared with iodine disinfectant × 3, allowed to air-dry, and then wiped with alcohol prior to needle placement; alternatively, cyclohexidine may be used for skin preparation in place of iodine plus alcohol.

Any number of the relatively insoluble injectable corticosteroids, including triamcinolone acetonide 10-40 mg, triamcinolone hexacetonide 10-40 mg, or prednisolone acetate 10-25 mg, or slightly soluble corticosteroids, such as methylprednisolone acetate 40-80 mg or triamcinolone diacetate 20-40 mg, may be used.[9, 8]

Anesthesia

A 10- to 15-s stream of ethyl chloride topical anesthetic spray can be steadily directed at the skin area over the target injection site prior to needle advancement. Lidocaine 1-2% can be injected over the target site via a 25-gauge 1.5-in. (3.8-cm) needle after negative aspiration for further numbing effect prior to the steroid injection, or it can be injected directly into the knee joint as a mixture with corticosteroid.

Positioning

For the anterolateral or anteromedial approach, the patient can be in the sitting or supine position, with the knee flexed to 90° to allow easy access to the joint capsule. Knee radiography would show if medial or lateral joint-space narrowing predominates.

For the superolateral or superomedial approach, the knee is almost fully or is fully extended to allow gentle rocking of the patella. The needle is directed under the proximal patella near and parallel to the undersurface of the quadriceps tendon insertion on the patella.[9, 8]

The best approach to a knee injection is the path of least obstruction and maximal access to the synovial cavity, which could be superolateral, superomedial, or anteromedial/anterolateral.

Plain radiography is recommended for better assessment of the bony anatomy of the individual knee joint. The knee injection site can be selected according to the patient’s bony anatomy and can be marked with the tip of a retracted ballpoint pen before sterile preparation (see Periprocedural Care, Patient Preparation).

The superolateral approach into the suprapatellar pouch might provide a better and more reliable route of entry into the knee joint than the superomedial or anteromedial/anterolateral approaches.[9, 8]

Lockman also reported the concept of the triangle with reasonable accuracy, in which one line is drawn from the apex of the patella (the apex of the triangle) to the lateral pole of the patella and another line is drawn from the apex to the medial upper pole of the patella, resulting in an inverted triangle.[20] The base of the triangle forms the upper border of the patella. The lateral line of the triangle is then marked at the midpoint, where the needle can be inserted and directed intra-articularly into the knee joint.

Superolateral approach

For the superolateral approach, the patient lies supine with the knee almost fully or fully extended with a thin pad support underneath the knee to facilitate relaxation. The clinician’s thumb is used to gently rock then stabilize the patella while the needle is inserted underneath the supralateral surface of the patella, aimed toward the center of the patella, and then directed slightly posteriorly and inferomedially into the knee joint.

Superomedial approach

For the superomedial approach, the patient lies supine with the knee almost fully or fully extended with a thin pad support underneath the knee to facilitate relaxation. The clinician’s thumb is used to gently rock and then stabilize the patella while the needle is inserted underneath the supramedial surface of the patella, aimed toward the center of the patella, and then directed slightly posteriorly and inferolaterally into the knee joint.

Anterolateral and anteromedial approaches

For the anterolateral and anteromedial approaches, the patient can sit or lie supine with the knee flexed 90° to afford better exposure of the intra-articular surface and thus facilitate ease of needle entry into the joint space.

The sterile needle is inserted either lateral to the patellar tendon (for the anterolateral approach) or medial to the tendon (for the anteromedial approach), approximately 1 cm above the tibial plateau, and directed 15-45° from the anterior knee surface vertical midline toward the intra-articular joint space.[20, 9, 8]  (See the images below.)

The postprocedural protocol includes a comparison of preinjection and postinjection pain levels with specific knee examinations and palpation. The effect of lidocaine should be immediate, whereas steroids usually take effect within 1-2 days.

According to an American College of Rheumatology survey, 71% of rheumatologists ask patients to decrease weightbearing, often for 48 hours post injection.

Postinjection flare, characterized by localized pain, may occur within several hours of an intra-articular knee joint steroid injection. It usually resolves within 48 hours. If a flare occurs, the patient should be instructed to ice the area and take nonsteroidal anti-inflammatory drugs (NSAIDs). Rest is also recommended.

Overall, no major safety issues were detected within the constraints of a trial designed by the Cochrane study.[10]

Noninfectious

Tendon rupture and nerve atrophy or necrosis are common complications of joint injections; however, they are uncommon with knee injections. Both result from steroid injections. Other complications, such as skin atrophy, vitiligo, and dystrophic calcification around the joint capsule, may occur but are very uncommon.

Another noninfectious complication of joint injections is steroid toxicity, which manifests as osteoporosis, menstrual irregularity, ecchymoses, and/or accelerated cataract formation. All of these are related to the systemic absorption of steroids. Other systemic metabolic effects of steroids that have been reported include suppression of the hypothalamic-pituitary axis and an increase in blood glucose levels, both of which are self-limited. A rare but clinically significant complication is osteonecrosis, which occurs in 0.1-3% of cases.

Of the above complications, impaired blood glucose control has the most practical significance, particularly in patients with diabetes.

A 2017 study of 119 patients with knee osteoarthritis found that 2 years of quarterly triamcinolone injections led to to increased cartilage loss as compared with intra-articular saline injections.[16]  

Infectious

Of the infectious complications of joint injections, iatrogenic septic arthritis is the most feared. This complication occurs in 1 per 2000-15,000 injections. If septic arthritis is suspected, it must first be distinguished from a postinjection flare, which usually lasts hours rather than days; thus, if a flare persists for longer than 48 hours or begins after 48 hours post injection, an infectious cause should be suspected. If iatrogenic septic arthritis is suspected, immediate repeat arthrocentesis should be performed, along with immediate institution of an antibiotic regimen.

As an initial treatment, repeated arthrocentesis is equal to surgery. When repeated arthrocentesis is performed as an initial treatment and effusion volume fails to decrease substantially over the first 48-72 hours, arthrotomy or arthroscopy should be performed.

Platelet-rich plasma

It is unknown whether platelet-rich plasma (PRP) acts via local paracrine factors to alter pain, via production of new hyaline or fibrocartilage formation, a combination of the two, or another mechanism altogether. However, it is known that PRP contains higher-than-normal levels of cytokines and growth factors, including platelet-derived growth factor (PDGF), insulinlike growth factors (IGFs) 1 and 2, interleukin (IL)-8, keratinocyte growth factor (KGF), epidermal growth factor (EGF), connective tissue growth factor (CTGF), fibroblast growth factor (FGF), and transforming growth factor (TGF).

There are several methods of preparing the plasma rich in platelet-derived anti-inflammatory and growth factors. Whereas, by definition, the plasma to be used must be enriched to a platelet concentration higher than baseline, the optimal degree of enrichment is currently unknown. Anecdotal evidence has shown that the optimal dose may be at 2.5 times baseline and that high concentrations (5-9 times baseline) may actually have an inhibitory effect, though no clear studies have confirmed this point.

The benefits of white blood cells (WBCs) in the plasma are also unclear. Macrophages work to balance proinflammatory and anti-inflammatory aspects of healing, whereas neutrophils contain over 40 lysogenic enzymes and release free radicals and proteases, which can inhibit healing. However, types of leukocytes cannot be fractionated, so it may be more beneficial overall to include WBCs in the plasma despite any minor damage caused by the neutrophils.

Regardless of specific method used, there are four basic stages. First, the plasma is drawn using sterile technique, often from the antecubital fossa. The plasma is then centrifuged. Afterward, the PRP is separated. Finally, the PRP is injected into the knee joint. The amounts of blood drawn vary according to the procedure selected, but a commonly chosen amount of PRP to be injected is 3-5 mL per injection, with a series of three injections performed.[19, 24, 25]

The clinician should be aware of several details of PRP injection. The plasma is generally anticoagulated, most often with anticoagulant citrate dextrose (ACD), which has a lower pH than is physiologic. In that some growth factors are pH-sensitive, it is generally recommended to buffer the preparation to a physiologic level prior to injection. The number of times the plasma is centrifuged may also have an effect.

Plasma-rich growth factor (PRGF) obtained via a single-spin method and administered in a series of three injections is the most common method used. However, a series of three injections of PRP obtained following two spin cycles has also shown significant benefit, despite greater short-term side effects (eg, pain and swelling).[24]

Given the complexity of the procedure and equipment used to prepare the PRP, it is highly recommended that the practitioner attend a workshop or course on the preparation and use of PRP before performing the procedure in an office setting.

Numerous manufacturers produce equipment for preparation of PRP, and each manufacturer has its own recommendations for the preparation method and quantities of plasma used. Two such devices are the Arthrex ACP and the Biomet GPS III.

The Arthrex ACP Double Syringe Method reduces 10 mL of blood into 3 mL of PRP via a single centrifuge cycle at 1500 rpm for 5 minutes, allowing the top portion of plasma to be drawn up for use. The GPS III Platelet Concentration System reduces 27 mL of blood to 3 mL of PRP via a single centrifuge cycle at 3200 rpm for 15 minutes. The practitioner may also choose to use a double-spin technique—for example, spinning a quantity of blood at 1500 rpm for 5 minutes, separating off the top layer of plasma for a second cycle at 6300 rpm for 20 minutes, and removing half the remaining plasma volume.

Of these three methods, the single cycle of 27 mL at 3200 rpm for 15 minutes produces the highest concentration of platelets and growth factors overall.[25]

Corticosteroids

Corticosteroids used in this setting are listed in Table 1 below.

Table 1. Corticosteroid Agents Used in Knee Injection ^{[26, 27]} (Open Table in a new window)

Class Summary

These agents have anti-inflammatory (glucocorticoid) and salt-retaining (mineralocorticoid) properties. Glucocorticoids have profound and varied metabolic effects. In addition, these drugs modify the body's immune response to diverse stimuli. (See Table 1 in Medication Summary.)

No large trials have evaluated the various preparations of steroids. The most useful study on this subject is from the 1993 survey from the American College of Rheumatology, in which the most notable finding was the geographic variation of steroid preparations used by physicians.

Subsequent small trials/surveys reveal that (1) methylprednisolone (Depo-Medrol) and triamcinolone acetonide (Kenalog) cause less local postinjection flares than longer-acting agents do; (2) triamcinolone acetonide (Kenalog) and triamcinolone hexacetonide (Aristospan) are less soluble and therefore longer-acting; (3) less soft-tissue atrophy and risk of tendon rupture is seen with dilution of the steroid by lidocaine; and (4) precipitation of steroid crystals out of solution occurs with the addition of methylparabens in local anesthetics.

Dexamethasone acetate (Baycadron)

This agent decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reducing capillary permeability. Dosage varies with the degree of inflammation and the size of the affected area.

Methylprednisolone acetate (Depo-Medrol, Medrol, Solu-Medrol, A-Methapred)

Methylprednisolone acetate decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Dosage varies with the degree of inflammation and the size of the affected area.

Hydrocortisone acetate (Solu-Cortef, Cortef, A-Hydrocort)

Hydrocortisone acetate decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing increased capillary permeability. Dosage varies with the degree of inflammation and the size of the affected area.

Prednisolone (Millipred, Orapred, Orapred ODT, Prelone)

Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body. Alternative corticosteroids may be used in equivalent dosage.

Betamethasone (Celestone, Celestone Soluspan)

Betamethasone is the drug of choice for intraarticular injections. It does not crystallize if used with paraben-free anesthetic preparations.

Class Summary

Hyaluronic acid helps form the structural integrity of the synovium and cartilage and to lubricate the synovial joint. Hyaluronic acid can interact with proinflammatory mediators and bind to CD44 receptors on the chondrocytes to modulate cell proliferation, migration, and gene expression.

Several hyaluronic acid preparations are available for clinical use. Brand names of various hyaluronic acid derivatives include the following:

-Euflexxa: 2-mL solution of 1% sodium hyaluronate 10 mg/mL into each knee

-Hyalgan: 2-mL solution of sodium hyaluronate 10 mg/mL

-Orthovisc: 2-mL solution of 15 mg/mL

-Supartz: Supplied as a sterile nonpyrogenic solution in 2.5-mL prefilled syringe containing sodium hyaluronate 10 mg/mL

-Synvisc: 2-mL solution of hylan polymers (hylan G-F 20) 8 mg/mL

-Synvisc One: Supplied as a sterile nonpyrogenic solution in a 10-mL glass syringe containing three doses (48 mg) of hylan G-F 20

Hyalgan, Supartz, and Osteoartz contain sodium hyaluronate compounds, with the molecular weight range of 0.5-1.2 × 106 Da, and require three or five injections about 1 week apart. Orthovisc and Euflexxa contain ibid compounds, with a molecular weight range of 1.0-3.6 × 106 Da, and require three or four weekly injections. Synvisc and Synvisc One contain hylan G-F 20, with the molecular weight of 6 × 106 Da, and require three and one injection(s), respectively.

Euflexxa is prepared from bacterial fermentation, whereas all the others are prepared from cockscomb.[28]

Hyaluronate derivatives (Euflexxa, Hyalgan, Orthovisc, Supartz, Synvisc, Synvisc One)

Hyaluronate derivatives function as tissue or joint lubricant, which act to modulate the interactions between adjacent tissues.

Class Summary

An intraarticular botulinum A neurotoxin knee joint injection may provide therapeutic pain relief for patients with advanced knee osteoarthritis. The mechanism of pain reduction by botulinum neurotoxin A may be due to neurotransmitter-mediated inhibition of sensory neurons, rather than via neuromuscular junction blockade.

Preparations of botulinum toxin type A include Botox, Dysport, and Xeomin.[9, 8]

IncobotulinumtoxinA (Xeomin)

IncobotulinumtoxinA is botulinum toxin type A that is free of complexing proteins found in the natural toxin from Clostridium botulinum. This drug is an acetylcholine release inhibitor and neuromuscular blocking agent.

AbobotulinumtoxinA (Dysport)

AbobotulinumtoxinA binds to receptor sites on the motor nerve terminals and, after uptake, inhibits release of acetylcholine, blocking transmission of impulses in neuromuscular tissue.