Avascular Necrosis of Femoral Head

                Avascular Necrosis of Femoral Head

                                       Dr. KS Dhillon

Introduction

Avascular necrosis of the femoral head is also known as osteonecrosis or aseptic necrosis of the femoral head. Osteonecrosis (ON), is characterized by bone cell death that follows an impairment of the blood flow to the bone from a traumatic or non-traumatic cause. 

Avascular necrosis of the femoral head (AVNFH) is a progressive, multifactorial and challenging clinical problem that is on the rise and it mostly affects the middle-aged male population in the most productive age group of 25–50 years. 

The loss of blood supply results in osteocyte death and progressive collapse of the articular surface followed by degenerative arthritis of the hip joint.

There are approximately 20,000 to 30,000 new cases reported each year in the United States [1]. The traumatic causes include fractures and dislocations. The non-traumatic causes include chronic steroid use, chronic alcohol use, coagulopathy, congenital causes, among many others. 

Avascular necrosis of the femoral head is a debilitating disease.

Most of the blood supply to the femoral head comes from the medial and lateral circumflex branches of the profunda femoris, which is a branch of the femoral artery (Fig 1). The two circumflex femoral arteries anastomose to form a ring around the neck of the femur, from which many small arteries branch off to supply the femoral head. Another source of blood supply is from the foveal artery, which is also known as the artery of the ligamentum teres. The foveal artery runs within the ligament. Its contribution is only significant in pediatric populations [2]. 

There are 2 important anastomoses that provide collateral blood flow (though limited) to the femoral head. One is the cruciate anastomosis,  between the inferior gluteal artery and the medial circumflex femoral artery. The other is the trochanteric anastomosis, between the superior gluteal artery and medial/lateral circumflex femoral arteries. Both the superior and inferior gluteal arteries are branches of the internal iliac artery. The internal iliac artery is a branch of the common iliac artery, which arises from the aorta. The acetabular blood supply comes mainly from the acetabular branch of the obturator artery, along with some contributions from pubic branches of the obturator artery, and deep branches of the superior gluteal artery [3].

               

 Fig 1- Blood supply of femoral head

Etiology

There are many different etiologies that can cause this condition. One of the most common traumatic causes is femoral neck fracture or dislocation of the femoral head from the acetabulum. When these types of trauma occur, the blood supply to the head of the femur can be disrupted, leading to avascular necrosis. Osteonecrosis occurs in 15% to 50% of fractures of the neck of the femur and 10% to 25% of hip dislocations [4]. 

The AVN rates of specific traumatic injuries are as follows:

• Femoral head fracture: 75-100%
• Basicervical fracture: 50%
• Cervicotrochanteric fracture: 25%
• Hip dislocation: 2-40% (2-10% if reduced within 6 hours of injury)
• Intertrochanteric fracture: rare

About 80% of the non-traumatic avascular necrosis is caused by chronic steroid use and excessive alcohol consumption. Excessive steroid use represents the second most common cause of osteonecrosis after trauma. How exactly steroid use produces osteonecrosis is not clear. It is probably multifactorial. Factors that are involved include fat emboli, fat cell hypertrophy leading to increased intraosseous pressure, endothelial dysfunction, hyperlipidemia, and abnormality of the stem cell pool of the bone marrow. All of these factors contribute to ischemia and subsequent necrosis [5]. In alcohol-induced osteonecrosis also factors such as bone marrow fat cell hypertrophy and proliferation, serum lipid level changes, blood vessel occlusion, and increased intraosseous pressure are involved [6]. 

In Sickle cell disease, the rigid red blood cells impede blood flow leading to ischemia and bony infarction [7]. Autoimmune and chronic inflammatory disorders such as systemic lupus erythematosus (SLE), are also known to be associated with osteonecrosis of the femoral head. In these diseases, prolonged use of steroids contributes to the risk of avascular necrosis though there are reports of cases in whom steroids were not used [8].

In Legg-Calve-Perthes disease avascular necrosis of the femoral head can also occur [9]. Cytotoxic agents and vascular disease secondary to diabetes have also been implicated in the development of femoral head osteonecrosis [10].

The disease progresses through four stages [10,11]:

• Necrosis – when blood supply gets disrupted, and necrosis begins
• Fragmentation – when the body resorbs the necrotic bone and replaces it with woven bone that is weak and prone to breaking and collapse
• Reossification – when stronger bone develops
• Healed/Remodeling – when bone regrowth is complete, and shape becomes finalized (whether normal or abnormal, depending on the damage done during the fragmentation phase)

Epidemiology

The incidence of avascular necrosis of the femoral head in the USA is estimated to occur at a rate of between 20,000 to 30,000 new cases each year. The AVNFH contributes to 10% of the approximately 250,000 total hip arthroplasties performed annually in the USA [1]. There is no association of AVNFH with race, except regarding cases associated with sickle cell disease, which is more prevalent in patients of African descent. This condition is more prevalent in men than women, with studies estimating ratios from 3 to 1 and 5 to 1 [12,13]. The average age of the patients at the time of treatment is 33 to 38 years [1].

Pathophysiology

The exact pathophysiology of avascular necrosis of the femoral head is not always clear. It is generally regarded as being multifactorial [14].  Regardless of the underlying cause, the outcome is essentially the death of osteocytes and bone marrow that results from insufficient blood flow to the subchondral bone of the femoral head [4]. The cell death inevitably leads to the collapse of the femoral head and subsequent osteoarthritis, if the loss of blood supply is not treated effectively in the early stages.

History and Physical Examination

In the early phase of the disease patients are often asymptomatic. When the disease becomes symptomatic, the patient complains of hip pain that may radiate to the groin and/or thigh. The pain is aggravated by activities such as walking and climbing stairs and alleviated by rest. Later in the disease phase, the pain can be present, even in the absence of movement. Physical exam shows limitation of hip movements, pain on hip abduction and internal rotation, muscle wasting, and tenderness in the hip region [15].

Diagnostic Evaluation

The outcome can be significantly affected by early identification of the disease. Appropriate imaging is required when the clinical presentation points to the possibility of AVNFH. Imaging can include x-rays, radionuclide bone scanning, as well as magnetic resonance imaging (MRI). 

X-rays are the 1st line of investigation if AVNFH is suspected. Anterior posterior view and the frog-leg lateral view x-rays are obtained. The radiographs may show subchondral radiolucency, which is known as “crescent sign”. A crescent sign indicates subchondral collapse. 

A Technetium-99m scan will show a “donut sign,” which is a ring of increased uptake around a cold center. This sign represents accelerated bone turnover at the demarcation, where the ring of reactive bone meets the cold centre of dead bone [1]. 

MRI is the gold standard for diagnosis for osteonecrosis. MRI is reliable at showing evidence of disease progression in the early stages. MRI can show bone marrow changes, size and location of the necrotic area, the effect on acetabular cartilage, and depth of collapse of the head [14]. 

Once adequate imaging has been obtained, the extent of necrosis can be classified. The most commonly used staging system is the one by Steinberg. It identifies seven stages as follows:

0. Normal radiograph, bone scan, and MRI

I. Normal radiograph, abnormal bone scan and or magnetic resonance imaging

  IA Mild (involves less than 15% of the femoral head).

  IB Moderate (involves 15% to 30% of the femoral head)

  IC Severe (involves over 30% of the femoral head)

II.  Cystic and sclerotic change of the femoral head

 IIA Mild (involves less than 15% of the femoral head)

 IIB Moderate (involves 15% to 30% of the femoral head)

 IIC Severe (involves more than than 30% of the femoral head)

III. Subchondral collapse (crescent sign) without flattening of the femoral head

 IIIA Mild (involves under 15% of the femoral head)

 IIIB Moderate (involves 15% to 30% of the femoral head) 

 IIIC Severe (involves over 30% of the femoral head)

IV. Flattening of the femoral head/femoral head collapse

  IVA Mild (involves under 15% of the femoral head)

  IVB Moderate (involves 15% to 30% of the femoral head)

  IVC Severe (involves greater than 30% of the femoral head)

V. Joint space narrowing and/or acetabular changes

   VA Mild

   VB Moderate

   VC Severe

VI. Advanced degenerative joint disease

Other causes of hip pain should be ruled out by a laboratory workup. The workup can also help assessment for comorbid factors. A workup can include a complete blood count (CBC), lipid panel, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), antinuclear antibody (ANA), anti-cyclic citrullinated peptide (anti-CCP), and hemoglobin electrophoresis. 

Elevated ANA and/or RF would indicate an active autoimmune process and elevated ESR and CRP wound indicate an inflammatory process but all four are non-specific. Elevated anti-CCP antibodies would indicate the presence of rheumatoid arthritis. Hemoglobin electrophoresis showing HbS with a low concentration of HbF would indicate the presence of sickle cell disease [16,17].  A CBC showing evidence of normocytic or microcytic anemia with an elevated reticulocyte count would also indicate the presence of sickle cell disease. Rheumatoid arthritis and sickle cell disease can cause osteonecrosis of the femoral head.

A biopsy is usually not necessary, since the diagnosis can be made accurately based on imaging. If a biopsy is done, the characteristic histological findings will be trabecular necrosis with necrotic hematopoietic marrow [18]. Similarly, angiography studies are not routinely performed, though they do provide good visualization of the vasculature. 

Management of Avascular Necrosis

The management of avascular necrosis of the femoral head can be either conservative or invasive. 

The therapy given will be dependent upon several factors, and each patient must have their case evaluated individually for optimal treatment. Factors such as age of the patient, degree of pain/discomfort, location and extent of necrosis, comorbidities, and any collapse of the articular surface, have to be taken into consideration. 

(A) Conservative treatment

Conservative management of AVNFH includes restricted weight-bearing, pharmacological agents and biophysical modalities of treatment. The aim of drug treatment in the precollapse stage is to improve hip function, provide pain relief, prevent progression to subchondral fracture and collapse, and to allow healing of the necrotic lesions [19,20,21].

Non-weight bearing

Restricted weight-bearing using cane, crutches or a walker is effective in Stage-I and II disease when the osteonecrotic lesion is less than 15% and is located far from the weight-bearing dome (medial lesions) [21]. Mont et al [22] reviewed 21 studies with a total of 819 patients who were treated with restricted weight-bearing. They found that the clinical results were satisfactory (no further surgery) in 22% patients after 34 months. Radiological progression was seen in 74% of the patients. They found that there was no difference in outcomes among patients who were on full, partial, and nonweight-bearing regimens. 

Mont et al [23] in a systematic review found that 59% (394 of 664 hips) of asymptomatic hips had onset of symptoms or disease progression to collapse after 7 years (range, 0.2-20 years). The investigators found that there was an increased risk of collapse in patients with sickle cell disease (73%; 29 of 40 hips) and minimal risk of collapse in patients with SLE (17%; 10 of 59 hips). In 32% of patients with small or medium-sized lesions (<50% of head involvement) progression to symptoms or collapse occurs.

In patients with large lesions, there is an 84% chance of progression. 

Progression to advanced-stage disease depends largely on location, size of the lesion and etiology. Small size lesions often show spontaneous regression [24]. 

This modality of treatment cannot be accepted as a standard isolated modality of treatment. It is usually used together with medical or surgical management.

Bisphosphonates

Bisphosphonate inhibits osteoclastic activity in osteonecrotic lesions in the femoral head and thus promotes bone healing. It prevents subchondral fracture or collapse of the femoral head in early stages of osteonecrosis of the femoral head. In advanced stages of the disease when collapse has occurred it delays the need for total hip replacement (THR) surgery [25,26,27]. Agarwala et al have reported the benefits of alendronate (10 mg/day or 70 mg/week) in patients with osteonecrosis of the femoral head at less than 1-year, 4 years and 10 years follow-up [25,26,27]. 

At an average follow-up of 4 years, Agarwala et al [26] reported radiographic progression to collapse in 12.6% of hips in Stage-I and 55.8% of hips in Stage-II. Radiological progression was seen in 46% of hips in Stage-I, 54% of Stage-II hips and 20% of Stage-III hips. The proportions of hips requiring joint replacement were 2%, 8% and 33% for Stage-I, -II and -III disease. 

Agarwala and Saha [27] published the results of treatment of 40 patients (53 hips) who had precollapse-stage osteonecrosis with alendronate 70 mg weekly for 3 years. The patients were followed up for 10 years. They found a 29% collapse rate. They concluded that the natural history of untreated osteonecrosis with more than 70% collapse rate was favorably altered by alendronate use.

In a level II, prospective comparative study, Nishii et al [28] also found a lower rate of collapse and lesser hip pain after 1-year in patients (14 patients with 20 hips) with osteonecrosis who received alendronate (5 mg daily) for a year as compared to patients who did not receive alendronate. Lai et al [29] reported similar efficacy of alendronate in the treatment of non-traumatic early-stage osteonecrosis (Steinberg Stage-II or III). In their randomized control trial, the authors found 2 of 29 femoral heads collapse in the alendronate group and 19 of 25 heads collapse in the control group at 2 years. There was radiographic progression in 14% of the patients in the treatment group compared with 80% in the placebo group. Only one hip in the alendronate group underwent total hip arthroplasty, whereas 16 hips

in the control group needed a total hip replacement (P < 0.001).

A study by Chen et al [30] provided conflicting evidence about bisphosphonate treatment in osteonecrosis of the femoral head. In this prospective, randomized, double-blinded, placebo-controlled

trial (level I evidence), there were 65 hips in Stage-IIC and IIIC disease. They did not find any significant difference in radiographic disease progression, quality-of-life improvement, and prevention of total hip replacement between the alendronate and the placebo groups after 2 years. The study was, however, underpowered to detect statistical significance.

Although the efficacy of alendronate has been shown in early-stages of osteonecrosis of the femoral head, the doses required and duration of therapy is yet to be established. There are reports of jaw necrosis and subtrochanteric fractures in patients who had long term treatment with bisphosphonate [31]. Most of the studies on the efficacy of alendronate in treatment of osteonecrosis of the femoral head are underpowered and without a control group. With the current evidence, alendronate in patients with osteonecrosis of the femoral head can be used in a dose of 70 mg weekly for 3 years in Stage-I, II and III (Steinberg classification) disease [31].

Anticoagulants, statins and other vasodilators

One of the major and common etiological factor for osteonecrosis is hypofibrinolysis and thrombophilia which leads to venous stasis and reduced arterial flow, and this causes an increase in intraosseous pressure and hypoxic bone death [32,33]. 

Systemic anticoagulation therapy started early before collapse of the femoral head may arrest or reverse the process of osteonecrosis. 

Glueck et al [34] in a prospective study reported the outcome of enoxaparin therapy in Stage-I or II osteonecrosis of the hip after 2 years of follow-up (range, 2-4 years). They included patients with either hypofibrinolytic or thrombophilic or combined disorders. They found that in 95% of hips (19 of 20 hips) with primary ON and 20% (3 of 15 hips) of patients with secondary ON (secondary to corticosteroid use) there was no progression of the disease after enoxaparin treatment (60 mg/day for 3 months). They also found that 80% of the hips with secondary osteonecrosis progressed to Stages III and IV osteonecrosis. They concluded that Enoxaparin may prevent progression of primary hip osteonecrosis and decrease the incidence of total hip replacement.

Chotanaphuti et al [35] in a retrospective study of 36 patients with bilateral idiopathic osteonecrosis having at least one hip in the precollapsed stage observed no evidence of radiographic progression in 57.7% (15 of 26 hips) of hips in patients receiving enoxaparin therapy (6000 units 3 months) compared to 21.7% (5 of 23 hips) of hips in patients who did not receive any treatment at the end of 2 years. Seven patients (14 hips, 38.9%) had coagulation disorder in the enoxaparin group compared to 5 patients (10 hips, 27.8%) in the control group.

In these two studies, anticoagulant therapy has shown clear benefit and has prevented the progression of osteonecrosis from precollapsed stage to advanced-stage in idiopathic ON and/or corticosteroid-induced osteonecrosis.

Lipid lowering agents have also been found to be helpful in AVNFH particularly in steroid-induced osteonecrosis [36]. Excessive use of steroids causes hyperlipidemia which increases the fat content of the femoral head [37]. The increase in fat content increases intracortical pressure and lead to sinusoidal collapse and osteonecrosis. Statins help to dramatically reduce lipid levels in blood and tissues.

Pritchett [38] in a study found that after a mean followup of 7.5 years, only 1% of patients taking high-doses of corticosteroids and statin drugs developed AVNFH whereas the prevalence was 3-20% in patients receiving high-dose corticosteroids without statins. 

Ajmal et al [39], however, did not find any significant reduction in osteonecrosis between patients taking steroids and statins versus steroids without statin (4.4% vs. 7%).

Another vasodilator named Iloprost (a prostacyclin derivative) has shown benefit after 1 year of treatment in patients with osteonecrosis and bone marrow edema [40].

Extracorporeal shock wave therapy (EWST)

The exact mechanism of action of how ESWT benefits patients with AVNFH remains unknown. Researchers believe that EWST enhances neovascularization by stimulating the expression of angiogenic growth factors.

Wang et al [41] in a randomized clinical trial, compared one episode of ESWT therapy in 23 patients with 29 hips to core decompression (CD) with non vascularized fibular grafting in 25 patients with 29 hips in early-stages of AVNFH. They found that there was a significant improvement in pain, as well as hip function and a nonsignificant (P = 0.04) but definite decrease in  size of the lesion in the ESWT group as compared to the CD and fibular graft group at the end of 2 years. Seventy nine percent of patients in the ESWT group improved whereas only 29% of patients had improvement in the bone-grafting group.

Wang et al [42] in another study reported the long term outcome (mean, 8.5 years; range, 7.7-8.8 years) of the above two groups of patients. They reported that patients with ESWT had significantly better clinical outcomes and decreased need for hip replacement compared with the surgery group. MRI also revealed a significant decrease in size of the lesion and bone marrow edema in the ESWT group compared to the surgery group.

In another randomized clinical study, Wang et al [43] compared ESWT alone (25 patients, 30 hips) to combined ESWT and alendronate therapy 23 patients, 30 hips). They found that there was significant but statistically similar improvement in pain, function and lesion size in both the groups at the end of 1 year. The authors concluded that the addition of alendronate to ESWT did not provide additional benefits to the patients.

Ludwig et al [44] in a study of 22 patients reported significant improvement in pain, function and lesion size after 1-year of ESWT in Stage-I to Stage-III AVNFH. 

Hsu et al [45] in a prospective randomized study of 98 early osteonecrosis hips compared ESWT to a cocktail regimen consisting of ESWT, hyperbaric oxygen, and alendronate. At 2 years follow-up (range, 1.5-4 years), the overall results showed that 74% improved, 16% remained unchanged and 10% worsened in the cocktail group. In the ESWT 79.2% improved, 10.4% unchanged and 10.4% worsened. Total hip replacement was performed for 10% of the cocktail group and 10.4% of the ESWT group. MRI showed a significant reduction in bone marrow edema and a trend of decrease in the size of the lesions in both groups. Overall there was no difference between the two groups. 

Pulsed electromagnetic therapy

Pulsed electromagnetic therapy favorably affects early-stage osteonecrosis through stimulation of osteogenesis and angiogenesis just as ESWT does [46-49]. Massari et al [50] in a retrospective analysis of 76 hips treated with electromagnetic field stimulation in Ficat Stage-I to III, reported that 94% of hips in Stage-I and II avoided the need for a total hip replacement (THR) at a mean follow up of 2 years. However, a significantly higher proportion of hips in Stage-III progressed to THR at a mean followup of 2 years. At present, evidence in favor of electromagnetic stimulation is limited. 

Hyperbaric oxygen (HBO)

Hyperbaric oxygen improves oxygenation, causes vasoconstriction which reduces edema, and it also induces angioneogenesis; leading to a reduction in intra osseous pressure and improvement in microcirculation [51-53]. Reis et al [51] carried out a study involving 12 patients who suffered from Steinberg stage-I AVN of the head of the femur (four bilateral) whose lesions were 4 mm or more thick and/or 12.5 mm or more long on MRI. They were given daily HBO therapy for 100 days. They found that  81% of patients who received HBO therapy showed a return to normal on MRI as compared with 17% in the untreated group. They concluded that hyperbaric oxygen is effective in the treatment of stage-I AVNFM.

Camporesi et al [52] also reported clinical improvement at 7 years follow-up in 19 patients randomized to receive 30 treatment doses of either hyperbaric oxygen or hyperbaric air for a period of 6 weeks. They found that none of the patients in the hyperbaric oxygen group needed THR at the time of last follow up. The use of hyperbaric oxygen in patients with AVNFH remains controversial due to the limited data available.

(B) Operative treatment

Surgical treatment for precollapsed stage AVNFH involves hip preserving procedures such as core decompression (CD), nonvascularized bone-graft, and vascularized bone-graft. Prosthetic hip surgery is reserved for advanced stage collapse of the head and arthritic hip.

Core decompression

Core decompression is the most commonly performed surgical procedure for treatment of early AVNFH. It decreases the intraosseous pressure in the femoral head and increases blood flow to the necrotic area, thus promoting new bone formation. It is the only cost-effective surgical procedure for AVNFH [54,55]. The success of CD is largely dependent on the etiology of the osteonecrosis and radiographic parameters such as size of the lesion , location and extent of collapse of the lesion. The overall success rate of the procedure as defined by the need for further surgery varies between 40%

and 80% at 2-7 year follow up [31].

Conventional core decompression (CD) was performed using 8-10 mm cannula or trephine. This technique, however, had the  potential to cause a subtrochanteric fracture and penetrate the hip joint.

But the technique has now improved overtime [56,57]. Core decompression is now done by multiple small drillings. 

Kim et al [58] compared the results of the efficacy of two decompressive methods i.e multiple drilling (MD) vs. conventional CD for the treatment of precollapse AVNFH in a consecutive series of 54 patients. They found that radiographically and clinically, high failure was significantly related to the larger size and laterally located lesion in both groups. The average preoperative and the last Harris Hip Score (HHS) was 73.7-86.7 in single CD and 74.6-87.0 in MD group. The group who had undergone multiple drilling had significantly longer time before the collapse (mean 42.3 months vs. 22.6 months, P = 0.011) and the lower rate of collapse within 3 years after operation (55.0% vs. 85.7%). 

In a systematic review, Marker et al [59] compared the outcome of the recent technique of CD to that of old conventional technique. They found that the recent technique of CD had a better outcome as compared to the old conventional technique. In this review there were 1,337 hips treated before 1992 and 1,268 hips between 1992 and 2007. The proportion of patients without additional surgery increased from 59% (range, 29-85%) in the earlier studies to 70% (range, 39-100%) in the more recent reports. The radiographic success also increased from 56% (range, 0-94%) for the earlier cohort to 63% (range, 22-90%). CD is an effective procedure for early AVNFH mainly in Ficat stage I and II. 

The new technique of CD involves MD of the necrotic lesion of femur head which is an easy, simple and also safe procedure. 

A study by Al Omran [60] also reported similar observations as made by Marker et al in their review. In Omran’s series, 61 patients underwent a classical 8 mm drilling and 33 patients underwent 3.2 mm diameter multiple drilling. They found that there was significant improvement in outcome in both groups. There was no difference in the outcome between the groups at the end of 2 years.  

Song et al [61] in a retrospective study reported the outcome of MD in 163 hips as a treatment for Ficat stage I to III osteonecrosis. They defined clinical success as HHS >75 and no need for additional surgery. They reported clinical success in 79% (31 of 39 hips) of Stage-I hips and 77% (62 of 89 hips) of Stage-II hips. Eighty eight percent (52 of 59 hips) of the hips with small to medium-sized lesions required no additional surgical procedure at a mean followup of 7.2 years.

Mont et al [56] reported a 71% successful outcome following MD (2-3 perforations) with 3 mm steinmann pin. They also observed better outcome in small and medium size lesions of Stage-I compared with large lesions and Stage-II disease. 

The current recommendation is that CD should be carried out with a 3.2 mm drill bit with multiple perforation (at least 3). This has now become the established modality of treatment for early-stage AVNFH. This procedure can be safely performed under image intensifier with percutaneous method with minimal risk of complications.

Nonvascularized bone graft

Nonvascularized tibial autografts, fibular autografts or allografts are used to support subchondral bone and articular cartilage after removal of the necrotic lesion from the femoral head. Osteoconductive and osteoinductive properties of bone-grafts help in healing of the osteonecrotic lesion. 

This modality of treatment is successful in precollapse, and early postcollapse (<2 mm collapse) AVNFH when the articular cartilage is relatively undamaged. The surgeons usually carry out this procedure in patients with Ficat stage I and II AVNFH when CD fails [62].

Three techniques of bone-grafting have been described. These include Phemister technique (grafting through CD track), trap door (grafting through a window created in the femoral head) and the light bulb procedure (grafting through a window created in femoral neck or femoral neck-head junction). 

These modalities of treatment are rarely used nowadays as an isolated procedure. Many now use these techniques in combination with growth factors and various bone-graft substitutes [62].

The position of bone-graft within the necrotic lesion or at the transition zone between necrotic lesion and normal does not make a difference in the outcome but the type of graft does make a difference. Tibial autograft is better than the fibular graft and has a definite impact on the outcome [63-65]. 

Findings of finite-element analysis recommend that the graft be placed as close as possible to the subchondral bone, and in the lateral part of the head [66].

Although many studies have reported encouraging results with the use of nonvascularized bone-graft (70-90% excellent result at 2-7 years followup) [66-72] but there are a few studies that have shown a high rate of radiological progression [73,74].

Seyler et al [75] reported 83% survivorship in stage I and II AVN and 78% survivorship at a minimum follow up of 2 years in 39 hips using the light bulb procedure.

Keizer et al [64] in a retrospective study (80 hips in 65 patients), used tibial autograft and fibular allograft in 18 and 62 patients of AVNFH respectively. Seventy eight hips were available for evaluation. Forty two patients (54%) had clinical failure (secondary surgery or a poor Merle d’Aubigné and Postel score <8 points) at a mean of 4.5 years. Kaplan–Meier survivorship

analysis with clinical and radiological end-point showed a mean survival rate of 55% at 5 years and a mean of 33% at 10 years. Survivorship analysis with revision surgery as an end-point showed a mean survival rate of 66% at 5 years and of 52% at 10 years. 

On comparative evaluation, tibial autograft showed a significantly better survival than fibular graft. At 6 year follow up, the survival rate for tibial graft was 75% compared to fibular allograft which showed a mean survival rate of 42%.

The effect of autologous nonvasculairized fibular graft in combination with BMP-7 has been evaluated by several investigators [76,77]. Use of cancellous chips admixed with BMP-7 during nonvascularized grafting via a trapdoor technique avoids the need for a secondary procedure in 80% of stage II and III AVNFH [78,79].

Vascularized bone graft

Vascularized bone-grafting is recommended for the treatment of early AVNFH (stage I to III) [80-82]. The vascularised graft (eg., vascularized iliac crest graft, vascularized fibula graft) provides a viable structural support and prevents joint collapse. The graft has inherent osteogenic potential, hence it augments bony healing in the necrotic lesion site. The clinical outcome is not so good in patients with large lesions where the involvement is more than 50% of the femoral head, and the collapse is more than 2 mm. Such grafting procedure is generally not recommended for patients with a history of smoking, alcoholism, peripheral vascular disease or other risk factors [31]. The major problem with this procedure is its surgical complexity and the surgery takes a long time to do.

Muscle pedicle bone graft

Meyers [80] in 1978 first reported the use of muscle pedicle bone-graft for treatment of AVNFH. He found good results in all patients with Stage I and II disease but only in 33% patients in advanced disease (Stage III and IV disease) at 6 months to 2 years follow up. 

Lee and Rehmatullah [83] reported a 70% success rate with muscle pedicle bone-graft in idiopathic AVNFH. 

Baksi [84] in 1991 reported the outcome of muscle pedicle bone grafting in 68 hips (61 patients) at 3-12 years followup. 

Of the several types of muscle pedicle bone-grafts he used, he preferred the tensor fascia lata anteriorly, and the quadratus femoris posteriorly.  About 83% of his patients had good or excellent results.

Vascularized iliac crest graft

Vascularized iliac crest grafting method is recommended for treatment of stage II and early-stage III AVN, when necrosis does not yet involve the complete femoral head.

Iwato et al [85] had a 74% success rate (17 of 23 hips) with vascularized iliac crest graft use in AVNFH. Three Stage II joints and three Stage III joints continue to have significant problems on follow up.

Eisenschenk et al [86] reported stable disease after 5 years of follow up in 56% of AVNFH patients treated with iliac crest graft perfused by the circumflex ilium profunda artery.

Matsusaki et al [87] used vascularized iliac bone-graft combined with trans-trochanteric anterior rotational osteotomy in patients with extensive necrosis of the femoral head where the necrotic area occupied more than two-thirds of the weight-bearing zone of the femoral head. There was a significant clinical improvement and no disease progression in 12 of 17 hips (71%) after a mean followup of 50.7 months. They concluded that a vascularized iliac bone-graft combined with trans-trochanteric anterior rotational osteotomy to treat AVNFH is a good procedure for joint preservation. 

In a retrospective study, Babhulkar [88] reported only one progression to collapse of the femoral head in 31 patients after treatment with CD and vascularized iliac crest graft. His study included patients with nontraumatic ANFH in stage IIB and IIIC only and the patients were followed up for 5-8 years.

Vascularized fibular graft

Fang et al [89] carried out a systematic review of the literature on the use of vascularized fibular graft (VFG) in the treatment of AVNFH. In this review there were six studies with a total of 984 patients. There were 122 conversions to THR (16.5%) from 740 patients who were treated with VFG. In the remaining 244 patients treated with other methods such as CD, non-VFG, and vascularized iliac graft, there were 104 conversions to THA (42.6%). Hence, VFG can achieve a lower conversion rate than the other three methods. Three of the studies evaluated 122 patients with radiographs for progression to collapse. A total of 14 hips out of the 84 hips (16.7%) treated with VFG collapsed, and a total of 56 of 88 (63.6%) hips treated with non-VFG collapsed. The results were in favor of vascularized grafting more than nonvascularized grafting. In the precollapse phase (Steinberg I and II), VFG had better hip salvage than the other three methods. Out of the 270 hips, a total of 16 of 163 (9.8%) hips treated with VFG failed, and a total of 43 of 107 (40.2%) hips treated with non-VFG failed.

In precollapse and early postcollapse phase (Steinberg II and III) 116 of 705 (16.5%) hips treated with VFG failed, and a total of 83 of 194 (42.8%) hips treated with non-VFG failed. There were 30 complications (23.8%) in 126 patients who were treated with VFG and there were 13 complications (8.9%) in 146 patients treated with CD, and vascularized iliac graft. In the weighted test for overall effect, this difference did not reach significance. 

Urbaniak et al [90] studied the outcome of 103 hips treated with vascularized fibula graft. They reported a 91% survivorship in stage II and 77% survivorship in stage III disease at a final follow up of 5 years. 

Yoo et al [91] also reported excellent results, with a 89% survivorship in 124 hips with stage II and III disease at a minimum of 10 years’ followup (mean, 13.9 years; range 10-23.7 years). 

Eward et al [92] reported the long-term follow up data (mean, 14.4 years; 10.5-26 years) of 65 hips with precollapse-stage AVN treated with vascularized fibula grafting. Seventy-five percent of the hips survived without the need for THR at a minimum of 10 year followup. The investigators found that demographic and radiographic factors were not associated with changes in graft survivorship.

Proximal femoral osteotomy

The underlying principle of the proximal femoral osteotomy in ONFH is to rotate the necrotic femur head away from the load-bearing area and replace it with the uninvolved healthy portion. The osteotomy also reduces the intraosseous venous pressure and improves vascularity. 

There are two types of osteotomy that have been described, namely the  trans-trochanteric rotational osteotomy and intertrochanteric varus or valgus osteotomy (combined with flexion or extension). The success rates for these osteotomies have been reported to vary between 70% and 93% [93-97]. 

Jacobs et al [98] reported a 73% success rate at 5.3 years follow up after intertrochanteric osteotomy in AVNFH.

Maistrelli et al [99] reported satisfactory results in 71% of hips after 2 years of intertrochanteric varus/valgus osteotomy and the figure dropped to 58% at 8.2 years. 

Gallinaro and Masse [100] observed success rate in 62.5% of cases after flexion osteotomy at 10.2 years follow up. 

Scher et al [101] found a survival rate of 87% following flexion valgus osteotomy with autogenous bone-grafting at 10 years follow up.

Jacobs et al [98] reported a 78% success rate of rotational osteotomy at 3-16 years followup.

 Zhao et al [102] reported the outcome of curved trans-trochanteric varus osteotomy in 73 hips at a mean followup of 12.4 years (range, 5-31 years). They found that 91.8% (67 of 73 hips) of the hips remained intact and did not need conversion to a THR. There was a significant improvement in HHS after surgery. 

Sakano et al [103] similarly reported that 90% (18 hips) of their 20 hips did not collapse or require conversion to a THR following trans-trochanteric varus osteotomy at a mean follow up of 4 years (range, 0.7- 4.1 years). 

Ito et al [94] reported the long term results of varus half wedge osteotomy in 34 hips at a mean followup of 18.1 years (range, 10.5-26 years). They found that 74% (25 hips) of the hips had satisfactory results with a mean HHS of more than 80 points despite having a mean limb length discrepancy of 19 mm (range, 8-36 mm).

The authors concluded that the varus osteotomy of the proximal femur provides favorable long term outcomes in the presence of more than one-third of normal superolateral bone in the femoral head.

The main reason for limited acceptance for the above osteotomy technique is because of its technical complexity.

Osteotomies are best carried out in patients who are not being treated with long term steroids, and who have minimal osteoarthritic changes, with no loss of joint space, no acetabular involvement and small combined necrotic angle (Kerboul’s angle <200).

Arthroplasty

Patients with AVNFH need a THR when all other modalities of treatment have failed, or when the joint is arthritic secondary to advanced collapse (more than 2 mm) of the head. The victims of AVNFH are usually young adults, hence THR is considered as a last resort of treatment. The functional demands of young adults is high and there is a high possibility of the need of revision arthroplasty in such patients. Wear of the polyethylene and osteolysis leading to aseptic loosening are major concerns. 

In patients with AVNFH who had a hip replacement, the reported incidence of aseptic loosening is between 8-37% [104]. 

Bipolar arthroplasty is no more an acceptable mode of treatment in patients with AVNFH. Young patients with bipolar arthroplasty have a high incidence of protrusio acetabuli, increased rate of loosening. Revision rates of between 13.9% to 27.6% have been reported with bipolar hemiarthroplasty in AVNFH after an average followup of more than 5 years [105-108].

In patients with femoral head collapse of more then 2 mm with no damage to the acetabulum, limited femoral resurfacing arthroplasty is also a treatment. There are a few recent studies which show that the outcome of this procedure is not so predictable.

Adili et al [109] showed an overall hip survivorship 75.9% at 3 years, after resurfacing.

Cucklere et al [110] showed a 31% failure at a mean followup of 4.5 years (18 failure of 59 hips).

Better implant designs have improved the outcome of THR in AVNFH in recent years. In a systematic review of 67 studies involving 3,277 THR in 2593 patients, Johannson et al [111] reported a mean survivorship of 97% at 6 years follow up in patients who had a THR after 1990. 

There was a higher risk factor of revision in patients with sickle cells disease, Gaucher disease, end-stage kidney disease and in renal transplant patients. The revision rate was lower in patients with SLE, idiopathic AVN and in patients after heart transplant.

In a study by Kim et al [112], ceramic head on polyethylene bearing hip replacements showed a 100% survivorship (excluding infection) at an average 8.5 years follow up. Cup wear or loosening is more common then stem loosening. Kim et al [112] in their study of 148 THRs, reported 98% stem survivorship (cemented and cementless) at 17.3 years follow up. The cementless cup survivorship was 85% after 17.3 years.

The surgeons can sometimes find difficulty in performing a THR in patients with AVNFH because of previous surgery with altered hip biomechanics, presence of hardware, screw tracks, scar, fibrosis around the hip, and bone grafts, may evoke potential problems. 

There are, however, several studies that have reported that the medium term results of THR are not affected by previous surgery in AVNFH [113-116].

Helbig et al [117] reported no complications or component loosening, at a mean followup of 54 months in the series of 15 hips, that were converted to THR following previous CD. 

Kawasaki et al [118] in a study of 15 failed trans-trochanteric rotational osteotomies that were converted to THR, reported no significant differences in implant survivorship, compared with a matching group of 16 primary THRs at a mean followup of 5 years.

Ball et al [119] compared 21 failed hip resurfacings that were converted to a standard THR, with 64 standard THRs in patients with AVNFH and they found no differences in aseptic loosening, dislocations, HHS or other complications between the two groups.

Issa et al [120] evaluated the outcome in 87 patients who had 92 THRs, who had failed prior hip preserving surgery including 35 hips that had previous resurfacing, 9 hips that had a hemi-resurfacing, 29 hips that had a nonvascularized bone-grafting, and 19 that had a CD. These patients were compared with 121 hips in 105 osteonecrosis patients who underwent THR and had no prior surgery. At a mean followup of 75 months, they found no significant differences in survivorship, clinical, and radiological outcomes among the 2 groups.

Even in patients with sickle cell disease, Gaucher disease, end-stage kidney failure and/or posttransplantation, the outcomes of THR have improved over time [121,122]. 

Issa et al [123] evaluated 42 THRs for osteonecrosis in 32 sickle cell patients with a mean age of 37 years compared with 102 THRs in 87 non sickle cell osteonecrosis patients with a mean age of 43 years. At a mean followup of 7 years (3-10.5), they found no significant differences in aseptic implant survivorship, HHS, and SF-36 physical or mental component scores between the two patient cohorts.

Chang et al [124] evaluated 74 hips in 52 patients who underwent THR for AVNFH after kidney transplantation with cementless THRs. They found a 96.6% cumulative implant survivorship at a mean followup of 10.2 years. This is comparable with survivorship due to other causes for THR. 

The outcomes of THR even in high-risk patients are improving, potentially

due to improved medical and surgical management, as well as due to the use of modern prosthetic designs, such as cementless acetabular and femoral fixation.

Hip arthrodesis

In some patients with AVNFH, an arthrodesis of the hip may be indicated. It may be indicated in very young individuals who are not suitable for THR especially those in a labor-intensive occupation. In patients with hip infection following surgical procedures for AVNFH, a hip arthrodesis may also be indicated.

Conclusion

Symptomatic avascular necrosis of the femoral head is a disabling condition. The etiology and pathogenesis is poorly understood. There are several treatment options for AVN of the femoral head including nonoperative modalities, joint preserving procedures, and hip replacement. Non-operative or joint preserving treatment is suitable in patients when the diagnosis is made early before the lesion becomes too large and before the head collapse occurs. The presence of a crescent sign, femoral head flattening, and acetabular involvement indicates a more advanced-stage disease in which joint preserving options are not as effective. In such patients a joint replacement becomes necessary.

Occasionally an arthrodesis of the hip may be necessary.

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Infections associated with orthopaedic implants

           Infections associated with orthopaedic implants

               

                                                 Dr. KS Dhillon

Introduction

The use of implants in most of the orthopaedic procedures is common. The risk of infection can increase dramatically when implants are present in the body [1]. The overall surgical site infection rate following implant surgery is about 3% [2]. Since the number of these surgeries are increasing the number of infections is proportionally increasing.

In the United States, more than 4.4 million people have at least 1 internal fixation device and more than 1.3 million have an artificial joint [3].

In the last several decades sophisticated prevention strategies have been developed to lower the risk of infections in implant surgery. These include laminar airflow with ultraclean air [4], routine antimicrobial prophylaxis [5], short operating time, use of antibiotic-bonded cement [6], and antimicrobial coating [7,8].

The number of orthopedic device-related infections (ODRIs) per institution remains low. This scarcity of infections per institution is the main reason why the treatment of such an infection is poorly standardized. Randomized controlled clinical trials cannot be conducted in most institutions because of the low numbers of such cases. Therefore, many of the studies frequently lack appropriate statistical power because of low number of cases as well as due to the fact that many of the patients are lost to follow-up, changing residence, or dying of underlying diseases [9].

Currently, there are ample standard procedures for the identification of the microbes causing these infections [10]. There are, however, only a few diagnostic tools for rapid diagnosis of ODRIs with varying degrees of sensitivity and specificity available [11,12].

Pathogenesis Of ODRIs

Biofilm formation. 

An understanding of the pathogenesis of biofilm formation facilitates optimal diagnosis and treatment. The formation of biofilm also explains why signs and symptoms are relieved by short-term treatment with antimicrobial agents but reoccur immediately following the withdrawal of treatment [13]. 

Implants undergo physiological changes after they are implanted in the body. The earliest step is a contest between tissue cell integration and bacterial adhesion to the implant surface [14]. The body fluids immediately coat all surfaces of the implant with a layer of the host material, consisting mainly of serum proteins and platelets. Albumin is the major serum component. It is rapidly deposited on the implant and it prevents nonspecific neutrophil activation and deposition of matrix proteins on the surfaces [15]. 

Adhesins, such as fibronectin, fibrin, fibrinogen, collagen, vitronectin, laminin, thrombospondin, bone sialoprotein, elastin, and the matrix-binding protein mediate the adherence of Staphylococcus aureus to bioprosthetic materials. These host proteins promote the attachment of Staphylococcus aureus onto metallic or polymeric surfaces by specific receptors. The adherence progresses to aggregation of microorganisms on the surface of the foreign body, forming a biofilm. 

As the colonies increase in size, sessile bacteria at the periphery detach and disperse as planktonic bacteria. This process can lead to clinically overt infection. 

Costerton et al [16] have defined bacterial biofilms as “structured communities of bacterial cells enclosed in a self-produced polymeric matrix and adherent to an inert or living surface.” Both types of surfaces are usually present in ODRIs. They are present on medical devices and sequestra of dead bone. Biofilms can resist cellular and humoral immune responses and grow slowly [17]. The biofilm bacteria are less susceptible to antimicrobial agents than their planktonic counterparts due to several established mechanisms. Clinically established mechanisms include slime production, adherence of bacteria, and slow rate of bacterial growth. The bacterias become sessile in the biofilm, and their phenotypic features change to a large extent. The two clinically important mechanisms that protect the bacteria are failure of antimicrobial agents to penetrate the biofilm and the stationary phase of growth. 

Some bacteria, such as Staph aureus, form small-colony variants that are characterized by reduced growth rate, diminished exoprotein production, decreased susceptibility to aminoglycosides, and also possible intracellular persistence [18]. Standard antibiotic therapy usually reverses signs and symptoms caused by planktonic bacteria released from the biofilm but fails to kill bacteria that are in the biofilm [16]. To successfully treat ODRIs with retention of the implant the treatment must be against both planktonic and sessile bacteria. The alternative is to kill planktonic bacteria with antimicrobial agents and remove the implants to get rid of sessile bacteria [16].

Slime production

Some microorganisms, such as coagulase-negative staphylococci (CNS),  P. aeruginosa, and Streptococcus mutans, develop slime, which is an amorphous extracellular glycocaliceal substance based on polysaccharides. Slime production is usually triggered by adherence of the bacteria to surfaces. Many strains of CNS have been found to exude slime. The slime extracted from CNS consists of 80% teichoic acid and 20% protein [19]. Glycocalix which is present on bacterial surfaces promotes intercellular adhesion, captures nutrients, and protects microorganisms from the deleterious effects of antimicrobial agents. 

The susceptibility of the microorganisms to antimicrobial agents can be altered by slime that has potent immunomodulatory properties. Slime can also decrease chemotaxis and opsonization of neutrophil granulocytes, increase degranulation, and block the penetration of antibiotics into the bacterial cell [20].

Mode of growth

Bacteria in a biofilm grow slowly. They do not grow exponentially. They exist in a slow-growing or starved state [16]. Studies in animal models confirm the slow-growing or starved state of bacterial growth for S. aureus and Escherichia coli. In ODRIs some cells are dormant or replicating slowly and, consequently, are not killed by antibiotics. 

Much higher concentrations of antibiotics are needed to kill stationary phase bacteria as compared to logarithmically growing bacteria [21,22]. 

Rifampin has been found to be highly effective against stationary-phase gram-positive cocci such as Staph aureus and Staphylococcus epidermidis. The Minimum Bactericidal Concentration (MBC) of rifampin determined for stationary-phase bacteria remained in a range achievable in serum and tissue with a standard dosage of rifampin. The MBCs of ciprofloxacin, on the other hand, increased 200 times when tested with stationary-phase S. epidermidis. Ciprofloxacin has been found to be highly efficacious against stationary-phase Salmonella Dublin and E. coli ATCC 25922. 

The reason why some antimicrobial agents perform better than others against stationary-phase bacteria is poorly understood. The efficacy of β-lactam antibiotics is reduced partly because of their primary mode of action. Their killing of bacteria by β-lactam antibiotics is growth-dependent, and, therefore, slow-growing bacteria in device-related infections are not affected. Slime production can also inhibit antimicrobial activity. Studies show that antimicrobial agents should be bactericidal against slow-growing bacteria for optimal effectiveness [21,23,24]. 

Nomenclature of orthopedic device-related infections

ODRIs can be divided into 3 categories, namely early postoperative infections, late chronic infections, and hematogenous infections.

Early postoperative infections

These infections occur in the immediate postoperative period. The patient usually presents with chills, fever, and sweating. Post-operative pain persists in the early postoperative period and does not decline as it does in noninfected patients. The wound is often tender, erythematous, swollen, and fluctuant. The distinction between a superficial infection and a deep infection around the implant is usually a diagnostic challenge. 

Empirical treatment with antibiotics is not recommended because antibiotics may mitigate signs or symptoms of infection but will ultimately result in chronic infection. Therefore, such patients usually require a rapid workup for suspected early infection and implant salvage may be done if the following criteria are met [25]:

• Acute infection with signs and symptoms of less than 14-28 days
• Implant stable with no signs of loosening
• Clearly established diagnosis by isolating a single microorganism
• Positive histopathologic result
• Pathogen susceptible to oral bactericidal drug
• Patient willing to undergo long term antimicrobial therapy

Late chronic infection

Chronic infections originate at the time of surgery and are caused by a very low inoculum or a low-virulence pathogen such as CNS. Low virulence pathogens delay the onset of clinically apparent infection and do not trigger symptoms of acute infection. The onset of this type of infection is usually between 16 months and 2 years [26]. The hallmark of such infections is a gradual deterioration of function and intensifying pain. Premature early loosening of the implant may be the only symptom of chronic infection in patients who have a joint prosthesis. In some cases, it may be difficult to differentiate between aseptic loosening of a prosthesis and low-grade chronic infection. Such infections usually respond poorly to treatment with antimicrobial agents with retention of the device, despite extensive debridement.

Hematogenous infection

In this type of infection, there is a sudden, rapid deterioration in the function of an implant that was functioning well for a long time following the surgery [26]. Almost exclusively this type of infection is seen in patients with joint prostheses. Most hematogenous infections are seen more than 2 years after the surgery. The patients present with signs and symptoms similar to early postoperative infection. Hematogenous seeding can be triggered by catheter-associated urinary tract infection, dental manipulations, urosepsis, and remote infections. Streptococci are most frequently isolated in this type of infection. Immunosuppressed and transplant patients are at risk for hematogenous seeding. 

Microorganisms In ODRIs

In patients with ODRIs, staphylococci are the most frequently encountered microorganisms isolated, accounting for about 50% of the cases [27]. Polymicrobial are seen in 14 to 19%, Gram-negative bacilli in 8 to 11%, streptococci 8 to 10%, anaerobes 6 to 10%, enterococci in 3%, and others in 10% of the cases.

Multiple specimens for culture should be taken from the infection site, and the samples should be put in transport media for anaerobic microorganisms. Results of multiple specimens will facilitate the interpretation of culture results. A single positive result may signify contamination, whereas the presence of an organism in all 3 specimens, indicates infection. 

Workup for Diagnosis

There are no preoperative tests that are consistently sensitive and specific for infection in patients who require a revision arthroplasty. Investigative test interpretation is easier for internal fixation devices than for joint prostheses. Diagnosis based solely on history and physical findings can prove to be inaccurate. A careful history and risk assessment is mandatory for all patients suspected to have ODRI. 

Several risk factors for the development of ODRI in patients with prosthetic joints have been established. The most important is postoperative surgical site infection [28] followed by a high NNIS (National Nosocomial Infections Surveillance) system score, systemic malignancy, and prior joint arthroplasty [29]. Knee arthroplasties have a higher risk of infection (2%) as compared to hip arthroplasties (1.3%) [30]. Revision arthroplasty is also associated with a higher risk of infection (9%) [31]. 

Pain at the site of implant is the only consistent clinical finding in ODRIs. The presence of a sinus tract communicating with the implant indicates the presence of infection. 

Blood test results, C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR), x-rays, and bone scan results are usually highly variable. The sensitivity of standard microbiological cultures usually does not exceed 70% [32]. A combination of evaluation of clinical signs and symptoms, blood tests, radiography, bone scans, and a microbiological workup can usually provide an accurate diagnosis. 

The presence of a normal ESR and CRP level basically rules out the presence of ODRI. The CRP levels are always elevated following surgery but the levels should return to normal within 2–3 weeks [33]. 

The common workup for ODRI includes testing of WBC, ESR, CRP, plain radiographs, and multiple aspiration specimens for culture. Scintigraphy by means of a technetium scan, gallium citrate scan, or indium labeled leukocyte scan can be helpful in the diagnosis of ODRI. Intraoperative cultures should be combined with histopathology.

Clinical presentation

The clinical presentation of ODRIs is multifaceted and depends on:

(i) the preceding trauma and/or surgical procedures

(ii) the anatomical localization

(iii) the quality of bone and surrounding soft tissue

(iv) the time interval between microbial inoculation (trauma, surgery) and manifestation of infection

(v) the type of microorganism. 

Wound healing disturbances after internal fixation are highly suspicious of early infection. Early postoperative infection (less than 3 weeks) is characterized by erythema, local hyperthermia, a secreting wet wound, and protracted wound healing. The treatment of such infections includes debridement surgery which is both for diagnostic and therapeutic purposes. 

Delayed (3 to 10 weeks) or chronic (more than 10 weeks) infections are usually caused by low-virulence microorganisms such as coagulase-negative staphylococci. Such infections can also result from inadequate treatment of early infection. A short course of antibiotics without wound debridement can lead to a suppressed early infection which will reappear at a later date. Delayed and chronic infections present with persistent pain and signs of local inflammation, such as erythema, swelling, or intermittent drainage of pus from a sinus tract. Radiologically, there can be a pseudoarthrosis with bone sequestrum and soft-tissue calcification. 

Periprosthetic joint infection (PJI) can occur by seeding from the bloodstream by a systemic infection such as sepsis, skin and soft-tissue infection, pneumonia or enterocolitis, and also by contamination during implantation surgery.

The first symptom may be new-onset joint pain, initially without local inflammation. The most common causative agents are S. aureus, haemolytic streptococci, and Gram-negative bacilli. In exogenous staphylococcal infection, a temperature more than 38.3 °C is present in only about one-quarter of the patients, and the sepsis syndrome is present in less than 10% of the patients. In all patients with acute symptoms, regardless of the time after implantation of the orthopedic device, a prompt diagnostic work-up, and prompt treatment is required because the chance of retaining the implant is high if the duration of symptoms is short.

Chronic PJIs present with joint effusion, pain due to inflammation or implant loosening, local erythema and hyperthermia, and sometimes with recurrent or permanent sinus tracts. Routine follow-up markers such as C-reactive protein and/or erythrocyte sedimentation rate do not normalize after surgery and fluctuate within an elevated range.

Treatment

There are several established options for the treatment of ODRIs. The treatment depends on several factors such as [9]: 

• Type of infection (acute vs chronic)
• The isolated pathogen and its susceptibility pattern
• The fixation of the device
• The quality and availability of the bone stock
• The training and experience of the orthopedic surgeon and the infectious diseases physician. 

The treatment options for ODRIs include: 

• Debridement with retention of prosthesis and long term treatment with antibiotics
• Girdlestone arthroplasty
• One stage replacement with or without antimicrobial cement, and with long term antibiotics
• Two-stage replacement with or without antimicrobial cement and with long term antibiotics
• Suppressive antimicrobial therapy
• Arthrodesis
• Amputation

In patients with chronic infections, most authors recommend the removal of the device to eradicate the infection [34-37]. Patients with chronic infections usually do not respond to antimicrobial therapy alone and always implant removal is required [34,38]. A loose prosthesis always has to be removed. 

Early postoperative infection 

Treatment of early postoperative infections should be guided by an orthopedic surgeon and an infectious diseases physician who is trained in the management of ODRIs [39]. A thorough diagnostic workup should be carried out for patients presenting with fever, redness, pain, and drainage early after surgery and they should not be treated with antimicrobial agents before workup has been done. 

In patients with hematoma, extensive and meticulous debridement should be carried out and multiple biopsy samples should be taken from clinically infected tissue around the implant and multiple microbiological samples, including anaerobic cultures, should also be taken. Prophylactic antibiotics should be withheld until accurate specimens for histopathology and culture have been obtained [40]. This debridement must be done immediately following the onset of signs and symptoms of infection to prevent biofilm formation of the infecting pathogen which will lead to antibiotic resistance [13,16]. Preoperative aspiration may be an alternative, but such cultures are often falsely negative.

Patients who meet the criteria below are eligible for treatment with antimicrobial agents and salvage of the prosthesis or implant:

• Acute infection with signs and symptoms of equal to or less than 14 to 28 days
• Stable implant with no loosening
• Clearly established diagnosis by isolating a single organism from multiple cultures
• Positive histopathological results
• Pathogen susceptible to oral, preferably bacteriocidal, antimicrobial agent
• Antimicrobial with proven effectiveness
• Patient willing to undergo prolonged antimicrobial therapy

Initial treatment with antimicrobial agents is always given intravenously. There is no consensus as to how long antibiotics should be given intravenously. Most authors think that the minimum duration should be 2 weeks [23]. Tsukayama et al. [4] recommend 4 weeks and other authors [34] recommend 6 weeks of intravenous antibiotics. The treatment is then changed to oral medications for a minimum of 3 months for internal fixation devices and hip prostheses and for 6 months for total knee prostheses [23, 42,43,44]. 

The choice of antimicrobial therapy will depend on the pathogen isolated and its susceptibility pattern. The dosage of the antimicrobial agents should be as high as clinically possible. 

Rifampin has excellent efficacy against stationary-phase staphylococci and is orally well absorbed. Rifampin should always be included in the treatment regime of staphylococcal ODRIs if the strain is susceptible.

Rifampin monotherapy rapidly leads to the development of resistant strains. 

Therefore, rifampin must always be combined with another antimicrobial agent, preferably a quinolone. Quinolones are effective in preventing resistance to rifampin when given concurrently. The commonly used quinolones are ciprofloxacin or ofloxacin. 

The patient has to be closely monitored during treatment. The clinical signs and symptoms of infection should be recorded. The WBC count, CRP level, ESR, and, less frequently, radiographic examination has to be repeated. Treatment should be continued for a minimum of 3 months for total hip prostheses and internal fixation devices infections or for 6 months for total knee prostheses infections. The treatment should be continued for a maximum of 1 year if clinical or laboratory parameters have not normalized. The patient has to be followed up after completion of antimicrobial therapy so that failure of the treatment can be identified early.

About 80% of early infections will respond to such treatment. Patients with longer intervals from surgery to the onset of infection (1–3 months) might respond to such treatment if the pathogens are of low virulence, such as CNS or Propionibacterium species [35]. The failure rates, however, are likely to be higher compared with immediate removal of the implant and treatment with antimicrobial agents.

Chronic infection

The diagnosis of chronic infection can sometimes be difficult because of the lack of signs and symptoms. It can be difficult to differentiate between septic and aseptic loosening. Aspiration of the joint and a positive culture may help to differentiate between the two. The presence of a sinus tract communicating with the prosthesis or internal fixation device is usually  confirmatory of a chronic infection.

Infected fixation devices which serve no purpose are routinely removed at the time of debridement. Treatment of infected joint replacements calls for removal of the implant and a 1-stage or 2-stage revision arthroplasty. Infections due to CNS are usually treated with a 1-stage approach, if the quality of the bone stock is good [45,46]. Antibiotic-containing cement is commonly used. Ure et al. [46] found no significant difference between the failure rates after a 1-stage and a 2-stage approach. Infections due to low-virulence microorganisms are likely to be treated with a 1-stage approach. Most orthopedic surgeons prefer a 2-stage approach for purulent infections due to virulent organisms, such as methicillin-resistant S. aureus. Such cases are usually treated by removal of the implant, through debridement, and 2–6 weeks of iv antimicrobial therapy before a new implant is reinserted. Antimicrobial therapy should be discontinued before implantation of the new device and intraoperative cultures taken. After the histopathologic specimens have been taken, antimicrobial therapy should be started before inserting the new implant.

Positive cultures denote failure to eradicate the infection. The presence of microbials will influence treatment with antimicrobial agents in the postoperative period. Negative culture indicates successful treatment. This will allow shortening of the duration of treatment with antimicrobial agents after reimplantation. 

Patients who are not fit for surgery can be treated with suppressive antimicrobial therapy. 

Conclusion 

The treatment of ODRIs relies on an accurate classification, proper diagnosis, isolation of the microbials causing the infection, and finding their susceptibility pattern. 

Infected bone fixation devices which serve no further purpose are always removed at the time of debridement. Early postoperative infections of joint arthroplasties can be successfully treated with debridement and long-term antimicrobial therapy provided that the implant is stable and quality of bone stock is good. Early and rapid treatment after onset of infection is mandatory. Antimicrobial agents effective against the isolated pathogen must be available and the patient must be compliant and able to tolerate long-term antimicrobial therapy. 

In other patients with joint arthroplasty infections with virulent organisms a two stage arthroplasty with long term antibiotic therapy may be required. The morbidity and mortality is higher with the 2-stage approach.

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