Metal Ion Levels Not Sufficient as a Screening Measure for Adverse Reactions in Metal-on- Metal Hip Arthroplasties

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1 The Journal of Arthroplasty Vol. 28 No Metal Ion Levels Not Sufficient as a Screening Measure for Adverse Reactions in Metal-on- Metal Hip Arthroplasties Rory D. Macnair, MBBS, MRCS, MSc,* Henry Wynn-Jones, MBBS, FRCS (Tr&Orth),y James A. Wimhurst, MChir, MA, MB BChir, FRCS (TR&Orth),z Andoni Toms, BSc, MBBS, FRCS, FRCR,z and John Cahir, MBBS, FRCRz Abstract: This study aims to assess the accuracy of metal ion analysis in the diagnosis of adverse reaction to metal debris (ARMD) in patients with metal-on-metal hip arthroplasties by comparing the cobalt and chromium levels in 57 patients (62 hips) to findings on metal artifact reduction magnetic resonance imaging (MRI). An ARMD was detected using MRI in 18 (29%) of the hips. Forty patients had cobalt levels less than 7 μg/l, and 33 had chromium levels less than 7 μg/l, but 8 of these had an ARMD on MRI and only minimal symptoms (Oxford Hip Score 44/48). The incidence of ARMD was significantly higher when chromium concentration was above 7 μg/l (P =.02), but normal metal ion levels can be misleading and metal artifact reduction MRI imaging is advised in all patients. Keywords: metal ion levels, MAR MRI, metal-on-metal, hip, arthroplasty Elsevier Inc. All rights reserved. There are concerns over the new generations of metalon-metal (MoM) hip arthroplasty implants in both resurfacing devices and those coupling standard femoral stems with large-diameter head MoM bearings [1-5]. In response to reports of revisions due to soft tissue disease secondary to metal debris, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) released a Medical Device Alert in April 2010 [6]. Recommendations included regular follow-up and investigation of painful MoM hip arthroplasties with measurement of cobalt (Co) and chromium (Cr) levels in the blood and/or cross-sectional imaging, in particular if these levels are above 7 ppb (or μg/l). From the *Department of Orthopaedic Surgery, Royal Cornwall Hospital, Truro, Cornwall, UK; ythe Centre for Hip Surgery, Wrightington Hospital Wigan, Lancashire, UK; and znorfolk and Norwich University Hospital, Norwich, Norfolk, UK. Submitted October 24, 2011; accepted May 15, The Conflict of Interest statement associated with this article can be found at The authors are extremely grateful to the Gwen Fish Trust who provided funding for this study. Reprint requests: Rory D. Macnair, MBBS, MRCS, MSc, Department of Orthopaedic Surgery, Royal Cornwall Hospital, Truro, Cornwall, TR1 3LJ, UK Elsevier Inc. All rights reserved / $36.00/0 Specific imaging to detect abnormal soft tissue reaction includes magnetic resonance imaging (MRI) and ultrasound [7]. Magnetic resonance imaging with metal artifact reduction (MAR) sequences allows excellent visualization of periprosthetic tissues [8]. This study aims to assess the accuracy of metal ion analysis in the diagnosis of an adverse reaction to metal debris (ARMD) by comparing the Co and Cr levels in a cohort of patients with a MoM arthroplasty to their findings on MAR MRI. Materials and Methods This is a retrospective cohort study of patients who received Articular Surface Replacement (ASR; Depuy, Leeds, UK) components and had not undergone revision surgery. Between February 2005 and March 2008, 87 hip arthroplasties in 76 patients (11 bilateral) were performed by 5 surgeons. Thirteen patients have since had revision surgery. The early results of this series have recently been published [9]. Because the collection of CoCr blood levels had not previously been routine practice in our hospital, ethical approval was obtained to invite all patients for blood samples and also to obtain radiographs to allow Einzel- Bild-Roentgen-Analyse (EBRA) measurements to be performed. Four patients declined to join the study, and 2 were unable to attend for blood tests and radiographs. A total of 57 patients (62 hips) were therefore included. 78

2 Metal Ion Levels Not Sufficient Screening Measure in Metal-on-Metal Hips Macnair et al 79 Table. Overview of Study Data (Mean, Range, SD) Total ASR ASR/Corail THR Demographics No Male-to-female ratio 45:17 12:4 33:13 Age (y) 53.9 (30-66) (30-62) (35-66) 6.8 Postoperative time (mo), range 45.4 (31-64) (31-55) (31-64) 6.1 Femoral head size (mm), range 49.4 (43-57) (45-57) (43-55) 3.2 Inclination angle (deg.), range 50.6 ( ) ( ) ( ) 7.8 Anteversion angle (deg.), range 10.5 ( ) ( ) ( ) 3.9 Outcome scores (range) OHS 38.8 (12-48) (21-48) (12-48) 10.8 UCLA activity score 6 (2-10) (4-10) (2-9) 1.9 Serum metal ion levels (range) Cr (μg/l) 10.8 ( ) ( ) ( ) 12.9 Co (μg/l) 14.5 ( ) ( ) ( ) 16.5 MRI grade* Not MoM C C C *MRI soft tissue reaction (C1, mild; C2, moderate; C3, severe). OHS, Oxford Hip Score; UCLA, University of California, Los Angeles. It has been routine practice at our institution for all patients with a MoM prosthesis to have MAR MRI. This relates to experiences with a previous MoM hip [10]. A research clinic was set up, and the patients attended for metal ion blood tests and radiographs on the same day and completed an Oxford Hip Score (OHS) [11] and University of California, Los Angeles activity score [12]. The mean age at the time of assessment in this clinic was 54 years (30-66 years). There were 45 men and 17 women. The mean time from primary procedure to assessment was 45 months (31-64 months). Patient demographics and implant details are outlined in Table. Implants Sixteen ASR resurfacing procedures were performed in 13 patients and 46 ASR Total Hip Replacements (THR) in 44 patients using an ASR acetabular component, a matched cobalt chrome ASR XL head, and a Corail titanium hydroxyapatite coated uncemented stem (Depuy). For comparative purposes, femoral head sizes of 51 mm or less were designated small, and 53 mm or more large. Metal Ion Analysis Venous blood was obtained using a 21-gauge stainless steel needle and vacutainer into a plain trace-element metal tube (Becton, Dickinson UK Ltd, Oxford, UK). All samples were refrigerated and sent for blinded trace-element analysis at the Biochemistry Department of Charing Cross Hospital, London, UK. The concentrations of Co and Cr in serum were measured using high-resolution, inductively coupled, plasma mass spectrometry. Radiologic Analysis Radiographs Digital standing anteroposterior pelvic radiographs obtained at the research clinic were assessed for acetabular component orientation using EBRA software (EBRA-Cup Release 2003; University of Innsbruck, Innsbruck, Austria) [13]. Metal Artifact Reduction MRI All magnetic resonance examinations were performed on a 1.5-T machine (Siemens Symphony; Siemens Healthcare, Erlangen, Germany) using sequences adapted for MAR and the images reviewed by 2 musculoskeletal radiologists (A.T. and J.C.). Findings were categorized as normal [14], abnormal and typical of an ARMD [4,7,8], or abnormal but typical of a disease other than a MoM reaction [14]. Those cases with characteristic findings of ARMD were graded as mild (C1), moderate (C2), or severe (C3) (Fig. 1) according to the classification of Anderson et al [15]. Statistical Analysis This was performed using SPSS version 18.0 (SPSS Inc, Chicago, Illinois). Nonparametric data were assessed with the Mann-Whitney U test. The relationship between ARMD on MAR MRI and all other variables was analyzed using logistic regression, and the χ 2 test was used to compare the incidence of ARMD between patients with CoCr levels above and below 7 μg/l. Statistical significance was defined as.05 or lower. Ethics Ethical approval for this study was granted by the Hertfordshire Ethics Committee (Research Ethics Committee reference 10/H0311/6).

3 80 The Journal of Arthroplasty Vol. 28 No. 1 January 2013 Size of Femoral Component Significantly higher levels of Cr were seen with small compared with large heads (Mann-Whitney U test, P =.027) (Fig. 3). Gender Women had significantly higher Cr levels compared with men (Mann-Whitney U test, P =.01); however, they also had significantly smaller femoral components (Mann-Whitney U test, P = b.001). Fig. 1. Coronal proton density magnetic resonance demonstrating a large fluid-filled cavity with an irregular pseudocapsule (arrows) extending from the neck of an ASR THR laterally to lie deep to tensor fascia lata. Results Metal Ion Analysis There was a very high correlation between the concentrations of serum Co and Cr (correlation coefficient 0.923, P.001). In the analysis of metal ion levels and graphic presentation, unless stated, serum Cr has been used. Acetabular Orientation The acetabular implant positions are shown in Table. Hips placed with an inclination more than 50 had significantly higher Cr levels than those placed below 50 (Mann-Whitney U test, P =.002) (Fig. 2). However, no difference in Cr levels was seen when comparing hips placed inside and outside of a proposed safe range of anteversion for ASRs of between 10 and 20 [16] (Mann-Whitney U test, P =.965). Femoral Components The ASR THR was associated with higher metal ion levels than the resurfacing device, significantly so with Co (Mann-Whitney U test: Cr, P =.109; Co, P =.022) (Fig. 4). Bilateral Implants Eighteen hips (29%) were one of bilateral MoM hip arthroplasties in situ (n = 15; 8 for ASR THR, 6 for ASR, 1 for Birmingham Hip Resurfacing), or the contralateral MoM hip had been revised within the last year (n = 3, both ASR THR). The concentration of Cr ions was significantly higher in this group compared with unilateral hips (Mann-Whitney U test, P =.0018). Magnetic Resonance Imaging Numbers and grades of ARMD on MRI are outlined in Table. An ARMD was detected using MRI in 18 (29%) of the hips. There was a positive correlation between raised metal ion levels and ARMD on MRI (logistic regression: Cr, P =.031; Co, P =.024). The incidence of ARMD was significantly higher when Cr concentration was above 7 μg/l (χ 2 test, P =.02), but this was not the case for Co (χ 2 test, P =.317). The sensitivity of Cr concentration above 7 μg/l to ARMD on MRI was 56%, and specificity was 83%. The sensitivity and specificity of Co were 56% and 76%, respectively (Fig. 5). Using a cutoff figure of 4 μg/ L, the sensitivity and specificity of Cr were 61% and 66%, and those of Co were 72% and 66%, respectively. Fig. 2. Graph showing the effect of cup inclination angle on serum Cr levels (median values). Fig. 3. Box plot showing the ranges of serum Cr ions in small ( 51 mm) and large ( 53 mm) femoral head sizes.

4 Metal Ion Levels Not Sufficient Screening Measure in Metal-on-Metal Hips Macnair et al 81 Fig. 4. Box plot showing the ranges of serum Cr ions for the ASR and ASR THR. The inferior, middle, and superior horizontal lines represent the first quartile, median, and third quartiles. The whiskers protruding from the box correspond to the limits of the data, beyond which values are considered outliers ( ) and extreme outliers (*). Clinical Outcome Scores Details are included in Table. Forty patients had Co levels less than 7 μg/l, and 33 had Cr levels less than 7 μg/l, but 8 of these had an ARMD on MRI. All 8 patients had minimal symptoms (OHS 44/48). Discussion Factors associated with complications in MoM arthroplasty include small component size, female gender, and high acetabular component inclination [17-20]. In this study, metal ions were significantly raised with femoral head sizes of 51 mm or less, in women and in acetabular components placed with an inclination angle of more than 50. Of the modern MoM arthroplasties, the ASR has been shown to perform very poorly in outcome reports compared with other prostheses. The ASR THR failure rate exceeds that of the resurfacing arthroplasty [9,21]. This study has also shown raised blood levels of Co in preference to Cr in the ASR THR group, as was the case reported by Langton et al [21], when abnormal wear Fig. 5. Metal ion levels compared with ARMD on MRI. was found at the head-neck junction. Cobalt levels above 7 μg/l, unlike Cr, were not significantly associated with an ARMD on MRI. This is likely to be caused by higher Co levels in the THR group. Despite the ASR components being associated with very poor clinical results, the full data set, including MRI, metal ion levels and outcome scores in this cohort study, allows comparison and analysis of these methods of ARMD monitoring and diagnosis. No patients in this study had undergone revision surgery at the time of assessment in the research clinic, but a spectrum of symptoms was seen. The majority of published material has looked at symptomatic MoM hip arthroplasties, but investigation of asymptomatic hips has been advised [22]. Currently, there is no accepted cutoff level for blood metal ion levels. De Smet et al [23] found that Cr concentrations higher than 17 μg/l or Co concentrations higher than 19 μg/l were likely to be associated with metallosis at revision surgery. Hart et al [24] defined a threshold level of 7 μg/l for either Cr or Co, and these levels were adopted by the UK MHRA for their safety alert published in April 2010 [6]. In this study, of 62 cases, 22 (35.5%) had Cr levels higher than 7 μg/l and 29 (46.8%) had Co levels above this threshold. Another study proposed an optimal cutoff level for Co or Cr to be 4.97 μg/l [25]. The MHRA advises cross-sectional imaging when CoCr levels are higher than 7 μg/l. Metal artifact reduction MRI demonstrates soft tissue abnormalities when plain radiographs are normal [8,10] and metal debris can also be seen [26]. Ultrasound has also been used to identify solid or cystic masses [7]. Both ultrasound and MRI, and combinations of the 2, have been used for screening for ARMD in the United Kingdom. The decision to use ultrasound or MRI has depended on both cost and local capacity in the different modalities, but there is no known difference in sensitivity for ARMD, although grading systems have been described for MRI and not ultrasound [15,27], making comparison of results possible for MRI. Computed tomography is typically reserved for those patients with contraindications to MRI and where ultrasound is unavailable. In the clinical review of ASR components by Wynn- Jones et al [9], all 6 patients with an MRI diagnosis of ARMD who underwent revision surgery had histologic findings of aseptic lymphocyte-dominated vasculitisassociated lesion (ALVAL). This strengthens the case for MAR MRI to be considered as the criterion standard for ARMD diagnosis. The sensitivity and specificity of blood metal ion levels to predict ARMD on MRI are relatively low, being only 56% and 83% for Cr and 56% and 76% for Co, respectively. Reducing the threshold figure to 4μg/L marginally improved the sensitivity for Cr and Co, but the specificity was reduced. A review of MoM hips in

5 82 The Journal of Arthroplasty Vol. 28 No. 1 January 2013 Cardiff showed a sensitivity of 50% and a specificity of 74% when using the MHRA guidance of 7 μg/l to predict ARMD on MRI [28]. These findings highlight the problem of using metal ion levels alone in MoM arthroplasty surveillance. In this study, a serum Cr level of 2.9 μg/l and a Co level of 2.3 μg/l were seen in 1 patient with severe MoM soft tissue disease, and the lowest levels in an ARMD case were 0.5 and 0.7 μg/l, respectively. High Co and Cr levels, as well as assisting in the diagnosis of ARMD, can have systemic effects including changes in lymphocyte count [24]. The long-term effects of raised levels are still a concern. Kwon et al [29] reported a 4% incidence of asymptomatic pseudotumors; however, these patients were not truly asymptomatic because they had low functional scores. In a series of 75 MoM hips, Wynn-Jones et al [21] found that a quarter of the patients with a best possible OHS had MRI-based evidence of ARMD. In this study, 8 of the 18 cases of ARMD on MRI had low (b7 μg/l) metal ion levels. All 8 of these had minimal symptoms, half of them with a perfect OHS of 48 and the other 4 scoring at least 44 of 48. This presence of ARMD on MRI in patients who are completely asymptomatic with low metal ion levels below advised cutoff levels is of particular concern. Limitations There are a number of limitations with this study. First, nearly a third of the hips included are one of bilateral hip arthroplasties, either in situ or recently revised, which are known to have higher metal ion levels [20]. Onethird of these had ARMD on MRI. There are more THRs than resurfacings in this cohort, by a factor of 3 to 1, and they also had higher metal ion levels. Serum levels of Cr and Co were measured in our study. It is known that whole blood metal ion concentrations are more accurate [30], although serum Co and Cr levels have correlated well in other studies [18]. Conclusions Metal-on-metal implants at risk for failure are associated with raised Co and Cr levels. However, metal ion analysis alone is not sufficient to exclude all cases of ARMD and be used reliably as an isolated screening tool. The use of soft tissue imaging, ideally with MAR MRI, is the safest method of ARMD diagnosis in MoM implants. References 1. Langton DJ, Jameson SS, Joyce TJ, et al. Early failure of metal-on-metal bearings in hip resurfacing and largediameter total hip replacement: a consequence of excess wear. J Bone Joint Surg Br 2010;92-B: Bolland BJRF, Culliford DJ, Langton DJ, et al. High failure rates with a large-diameter hybrid metal-on-metal total hip replacement: clinical, radiological and retrieval analysis. J Bone Joint Surg Br 2011;93-B: Eswaramoorthy V, Moonot P, Kalairajah Y, et al. The Metasul metal-on-metal articulation in primary total hip replacement: clinical and radiological results at ten years. J Bone Joint Surg Br 2008;90-B: Pandit H, Glyn-Jones S, McLardy-Smith P, et al. Pseudotumours associated with metal-on-metal hip resurfacings. J Bone Joint Surg Br 2008;90-B: Ollivere B, Darah C, Barker T, et al. Early clinical failure of the Birmingham metal-on-metal hip resurfacing is associated with metallosis and soft tissue necrosis. J Bone Joint Surg 2009;91-B: No authors listed. Medical Device Alert: all metal-onmetal (MoM) hip replacements (MDA/2010/033). medicaldevicealerts/con79157 (date last accessed ). 7. Fang CS, Harvie P, Gibbons CL, et al. The imaging spectrum of peri-articular inflammatory masses following metal-on-metal hip resurfacing. Skeletal Radiol 2008;37: Toms AP, Marshall TJ, Cahir J, et al. MRI of early symptomatic metal-on-metal total hip arthroplasty: a retrospective review of radiological findings in 20 hips. Clin Radiol 2008;63: Wynn-Jones H, Macnair R, Wimhurst J, et al. Silent soft tissue pathology is common with a modern metal-onmetal hip arthroplasty: early detection with routine metal artifact-reduction MRI scanning. Acta Orthop 2011;82: Donell ST, Darrah C, Nolan JF, et al. Early failure of the Ultima metal-on-metal total hip replacements in the presence of normal plain radiographs. J Bone Joint Surg Br 2010;92-B: Murray DW, Fitzpatrick R, Rogers K, et al. The use of Oxford hip and knee scores. J Bone Joint Surg Br 2007;89: Amstutz HZ, Thomas BJ, Jinnah R, et al. A comparison of total joint and surface replacement arthroplasty. J Bone Joint Surg Am 1984;66-A: Langton DJ, Sprowson AP, Mahadeva D, et al. Cup anteversion in hip resurfacing: validation of EBRA and the presentation of a simple clinical grading system. J Arthroplasty 2010;25: Cahir JG, Toms AP, Marshall TJ, et al. CT and MRI of hip arthroplasty. Clin Radiol 2007;62: Anderson H, Toms AP, Cahir JG, et al. Grading the severity of soft tissue changes associated with metal-on-metal hip replacements: reliability of an MR grading system. Skeletal Radiol 2011;40: Langton DJ, Sprowson AP, Joyce TJ, et al. Blood metal ion concentrations after hip resurfacing arthroplasty: a comparative study of Articular Surface Replacement and Birmingham Hip Resurfacing arthroplasties. J Bone Joint Surg Br 2009;91-B: Glyn-Jones S, Pandit H, Kwon Y-M, et al. Risk factors for inflammatory pseudotumour formation following hip resurfacing. J Bone Joint Surg Br 2009;91-B: Langton DJ, Jameson SS, Joyce TJ, et al. The effect of component size and orientation on the concentration of metal ions after resurfacing arthroplasty of the hip. J Bone Joint Surg Br 2008;90-B:1143.

6 Metal Ion Levels Not Sufficient Screening Measure in Metal-on-Metal Hips Macnair et al De Haan R, Pattyn C, Gill HS, et al. Correlation between inclination of the acetabular component and metal ion levels in metal-on-metal hip resurfacing replacement. J Bone Joint Surg Br 2008;90-B: Hart AJ, Buddhdev P, Winship P, et al. Cup inclination angle greater than 50 degrees increases whole blood concentrations of cobalt and chromium ions after metalon-metal hip resurfacing. Hip Int 2008;18: Langton DJ, Jameson SS, Joyce TJ, et al. Accelerating failure rate of the ASR total hip replacement secondary to taper junction failure. J Bone Joint Surg Br 2011; 93-B: Sabah SA, Mitchell AW, Henckel J, et al. Magnetic resonance imaging in painful metal-on-metal hips: a prospective study. J Arthroplasty 2011;26: De Smet K, De Haan R, Calistri A, et al. Metal ion measurement as a diagnostic tool to identify problems with metal-on-metal hip resurfacing. J Bone Joint Surg Am 2008;90-A(Suppl 4): Hart AJ, Skinner JA, Winship P, et al. Circulating levels of cobalt and chromium from metal-on-metal hip replacement are associated with CD8 + T-cell lymphopenia. J Bone Joint Surg Br 2009;91-B: Hart AJ, Sabah SA, Bandi AS, et al. Sensitivity and specificity of blood cobalt and chromium metal ions for predicting failure of metal-on-metal hip replacement. J Bone Joint Surg Br 2011;93-B: Toms AP, Nolan J, Barker T, et al. Early failure of a Birmingham resurfacing hip replacement with lymphoreticular spread of metal debris: pre-operative diagnosis with MR. Br J Radiol 2009;82: Hauptlfeisch J, Pandit H, Grammatopoulos G, et al. A MRI classification of periprosthetic soft tissue masses (pseudotumours) associated with metal-on-metal resurfacing hip arthroplasty. Skeletal Radiol 2012;41: Malek I, King A, Sharma H. Investigation of painful MoM hips: sensitivity, specificity and predictor value of serum metal ions for ARMD based on MHRA guidance. British Hip Society Annual Meeting, Torbay, March; Kwon YM, Ostlere SJ, McLardy-Smith P, et al. Asymptomatic pseudotumours after metal-on-metal hip resurfacing arthroplasty prevalence and metal ion study. J Arthroplasty 2011;26: Daniel J, Ziaee H, Pynsent PB, et al. The validity of serum levels as a surrogate measure of systemic exposure to metal ions in hip replacement. J Bone Joint Surg Br 2007;89:736.