Femoral head collapse after hip intra-articular corticosteroid injection: An institutional response to improve practice and increase patient safety.

INTRODUCTION: Femoral head collapse (FHC) is a rarely reported complication of hip intra-articular corticosteroid injection (IACSI). Upon observing a high rate of FHC after hip IACSI, we sought to (1) describe how we addressed the problem through a systematic evaluation of clinical data and institutional care practices followed by process improvement efforts; and (2) report our results.
METHODS: Patients receiving hip IACSI during a 27-month period underwent retrospective review to determine the rate of FHC and to identify associated patient factors or practice shortfalls. Findings led to institution-wide interventions: (1) to improve patient/provider awareness of this association; and (2) to develop/implement practice guidelines. Rates of FHC after hip IACSI and practice patterns among providers before and after intervention were compared.
RESULTS: Initial FHC rate after hip IACSI was 20.4%. Patient-related factors included body mass index (p = 0.025), history of cancer therapy (p = 0.012), Vitamin D level (p = 0.030), and multiple injections (p = 0.004). Volume/dose of injectate and post-injection surveillance methods varied widely. Quality improvement (QI) intervention resulted in fewer treatment referrals (from 851 to 436), fewer repeat injections (mean = 1.61 to 1.37; p = 0.0006), and a 5% lower FHC rate (p = 0.1292). Variation in practice patterns persisted, so a systems-based Clinical Pathway was established. DISCUSSION: When a high rate of FHC after hip IACSI was found to be associated with certain patient and practice factors, introduction of education materials and treatment guidelines decreased number of referrals, number of injections per patient, and FHC rate. In the absence of the systems-based Pathway, the type, dose, and volume of injectate and post-procedure follow-up remained variable.

Introduction

Intra-articular corticosteroid injection (IACSI) is considered a safe and effective treatment for hip osteoarthritis (OA) [1]. Femoral head collapse (FHC) is a complication of this treatment [2-7]. However, incidence of FHC after IACSI is unknown, and risk factors are not well-defined.

From 2015 to 2017, we observed several patients with hip OA treated with IACSI who developed FHC. Given limited information on risk factors for this adverse outcome and lack of best-practices for prevention, a quality improvement (QI) investigation was undertaken to address the problem. Initial correlation with patient-related factors led to an institution-wide campaign to educate patients and providers. Discovery of variation in procedural and peri-procedural practices led to the development and introduction of treatment guidelines for providers.

We conducted a retrospective study of patients undergoing hip IACSI in our medical center before and after QI intervention. Goals of this study were (1) to identify patient risk factors or practice shortfalls associated with FHC after IACSI; and (2) to assess the impact of a QI intervention on institutional care practices and patient outcomes.

Materials and methods

This was a single center, before/after quasi-experimental study designed to bring about immediate quality improvements in health delivery in our institution. The Institutional Review Board provided exemption for this investigation and there was no external funding.

Quality improvement inception

After witnessing multiple cases of FHC after hip IACSI, we reviewed and compared our experience and institutional care practices with evidence-based literature. Although evidence supported IACSI for treatment of hip OA, no strong evidence of association with FHC existed. FHC was not acknowledged as a potential complication by the American Academy of Orthopaedic Surgeons (AAOS) appropriate use criteria [1]. There was no consensus as to best/safest injectate, and limited/no consensus on post-injection follow-up practices. A QI investigation was undertaken to inform risk management and practice improvement.

Preliminary data collection and analysis

From October 1, 2015 through December 31, 2017, patients who underwent hip IACSI were identified using Radiology procedural records. Patients with artificial hips and patients injected prior to MRI-arthrography were excluded. The electronic medical record was reviewed for patient characteristics: age, sex, body mass index (BMI), hip pathology, alcohol abuse, tobacco use, chronic corticosteroid use, history of cancer therapy, diabetes mellitus, obstructive pulmonary disease, prior hip trauma, HIV/AIDS, hip IACSI prior to study period, and number of hip IACSIs during the study period. If obtained during the study period, hemoglobin A1c, albumin, and Vitamin D levels were tabulated.

Anterior-posterior pelvis and/or hip radiographs were reviewed using the Picture Archiving and Communication System (PACS) (Visage version 7.1, Richmond, Victoria, Australia). All patients studied had pre-injection radiographs. If a patient did not have a pelvis or hip radiograph available at least one-month post-injection, the patient was excluded from FHC analysis, but was included in analysis of post-injection radiographic follow-up. All radiographs were obtained using our institution’s standardized Radiology department protocol. No images were excluded for poor quality. Timing of pre- and post-injection radiographs was non-standardized. Each pre- and post-injection radiograph was compared side-by-side for interval changes. Post-injection FHC was defined radiographically as new loss of femoral head sphericity and was measured by comparing the contour of the weightbearing portion of the femoral head on each radiograph. For each hip image, a circle tool was used to outline the contour of the subchondral bone-edge in the weightbearing portion of the femoral head. Images were initially compared and interpreted by two orthopedic surgery residents and later independently verified by an attending orthopedic staff. In all cases, FHC was dramatic, easily detected, and the interim change in femoral head sphericity secondary to collapse was confirmed by official radiology reports (Fig 1).

Fig 1

FHC after hip IACSI.

72-year-old male with symptomatic right hip OA. Progression from moderate/severe radiographic hip OA to FHC after first-time hip IACSI. Patient subsequently had THA complicated by superior and posterior acetabulum bone loss necessitating use of an augmented acetabulum component and bone graft.

Quality improvement intervention

After the initial investigation, a workgroup was formed comprised of stakeholders from Orthopedics, Radiology, Physical Medicine/Rehabilitation, and Pharmacy. The work-group reviewed preliminary institutional data and evidence-based literature to develop treatment guidelines addressing: 1) indications/contraindications; 2) medications; 3) injection technique; and 4) post-injection surveillance (Fig 2). Education materials were also created (Fig 3). Next, a high-profile, well-coordinated, institution-wide, campaign to raise awareness of work-group findings and recommendations was undertaken to educate providers in Radiology, Orthopedics, Rheumatology, Physical Medicine/Rehabilitation, and Primary Care. Guidelines and patient-education materials were then distributed hospital-wide for their use in clinical practice. Work-group findings and practice recommendations were also highlighted at our institution’s annual research symposium. Over the next 27 months, the number of hip IACSI referrals, number of injections per hip, FHC rate, and post-injection radiograph rate were tabulated and compared to patients treated pre-intervention.

Fig 2

Initial informal hip IACSI treatment guidelines derived by multidisciplinary work-group.

Fig 3

Procedure-specific education material available for all patients and providers at our institution.

Statistical analysis

Descriptive statistics were used to summarize patient characteristics (Table 1). To examine bivariate relationships between modifiable and non-modifiable patient-predictors and FHC, comparisons between patients with and without FHC were made. Pearson’s Chi-Square test was used for discrete variables, while two sample t-test was used for continuous variables. Statistical analysis was performed using SAS version 9.4 (Cary, North Carolina). P-values were considered statistically significant if < 0.05.

Table 1

Hip IACSI patient demographics and medical profiles.

Hip IACSI	851
Patients	458
Hips	531
Mean Hip IACSI During Study	1.61 ± 1.06
Hip IACSI Prior to Study Dates
Yes	74 (13.94%)
No	457 (86.06%)
Age (years)	67.77 ± 11.72
Sex
Male	502 (94.54%)
Female	29 (5.46%)
BMI (kg/m2)	31.42 ± 5.71
Hip Laterality
Right	294 (55.37%)
Left	237 (44.63%)
Diagnosis
Hip OA	496 (93.41%)
FAI	11 (2.07%)
AVN	8 (1.51%)
Labral Tear	8 (1.51%)
Hip Pain	4 (0.75%)
Hip Dysplasia	2 (0.38%)
Psoriatic Arthritis	2 (0.38%)
Alcohol Abuse
Yes	92 (17.33%)
No	439 (82.67%)
Tobacco Use
Yes	170 (32.02%)
No	361 (67.98%)
Chronic Steroid Use
Yes	24 (4.52%)
No	507 (95.48%)
History of Hip Trauma
Yes	14 (2.64%)
No	517 (97.36%)
History of Chemotherapy or Radiation Therapy
Yes	44 (8.29%)
No	487 (91.71%)
Obstructive Pulmonary Disease
Yes	80 (15.07%)
No	487 (84.93%)
Diabetes Mellitus
Yes	149 (28.06%)
No	382 (71.94%)
Serum Albumin (g/dL, reference range 3.5–5.2)	3.71 ± 0.45
Hemoglobin A1c (%, reference range 4.0–6.0)	6.08 ± 1.24
Serum Vitamin D (ng/mL, reference range 20–50)	26.21 ± 11.61

*Results are reported as the mean and standard deviation for continuous variables and the count and percentage for discrete variables.

**HIV/AIDS was not a significant variable in our analysis and was omitted from final data reporting in order to protect sensitive patient information.

Results

Initial quality improvement findings

Patient factors

From October 1, 2015 through December 31, 2017, 851 hip IACSIs were performed on 531 hips (458 patients). Mean number of IACSIs per hip = 1.61 ± 1.06. Seventy-four patients (13.9%) had an ipsilateral hip IACSI prior to this study period. The majority of patients were male [502 (94.5%) vs 29 (5.5%)]. There were 294 right hips (55.4%) and 237 left hips (44.6%). Mean age = 67.8 years ± 11.7 and mean BMI = 31.4 kg/m2 ± 5.7. Diagnoses included OA (93.4%), femoroacetabular impingement (FAI) (2.1%), avascular necrosis (AVN) (1.5%), labral tear (1.5%), unidentified hip pain (0.75%), dysplasia (0.38%), and psoriatic arthritis (0.38%) (Table 1).

Of 531 hips, 412 (77.6%) in 360 patients met inclusion criteria. Of 119 hips excluded, 75 hips (63.0%) lacked post-IACSI radiographs and 44 (37.0%) underwent THA prior to post-IACSI radiographs. To account for non-responder bias, patients excluded were compared to patients included in the analysis. Excluded patients were similar except for a higher mean hemoglobin A1c (6.41% vs. 5.99%, p = 0.012), lower number of injections per hip (1.44 vs. 1.67, p = 0.015), and a higher percentage of HIV/AIDS diagnoses (final numeric reporting was omitted to protect sensitive patient information).

Of 412 hips in the final analysis, 20.4% (84/412) developed FHC. Patients with FHC had a higher mean BMI (33.0 kg/m2 vs. 31.1 kg/m2, p = 0.025), higher percentage of cancer therapy (14.3% vs. 6.1%, p = 0.012), lower serum Vitamin D levels (23.1 ng/mL vs. 26.8 ng/mL, p = 0.030), and lower hemoglobin A1c levels (5.58% vs. 6.09%, p < 0.001). History of prior hip IACSI, age, sex, laterality, alcohol abuse, tobacco use, chronic steroid use, diabetes mellitus, hip trauma, HIV/AIDS, obstructive pulmonary disease, and serum albumin level were not significant. Hips with FHC underwent more IACSIs during the study period [2.05 (0.91/year) vs. 1.57 (0.70/year), p = 0.004]. There were 8 hips (1.51%) that had a diagnosis of avascular necrosis (AVN). One patient was excluded due to pre-existing FHC. Of the remaining 7 hips, 2 hips (2.38%) developed FHC, and 5 hips (1.52%) did not develop collapse after hip IACSI. (Table 2).

Table 2

Comparison of patient demographics and medical profiles: FHC vs. no FHC after hip IACSI.

Collapse	YES	NO	P-Value
	N = 84	N = 328
	(20.4%)	(79.6%)
Hip IACSI	172	515	n/a
Patients	82	284	n/a
Hips	84	328	n/a
Mean Hip IACSI During Study	2.05 ± 1.40	1.57 ±1.01	0.0040 b
Hip IACSI Prior to Study Dates			0.7481a
Yes	14 (16.67%)	50 (15.24%)
No	70 (83.33%)	278 (84.76%)
Age (Years)	66.33 ±10.95	67.62 ±12.25	0.7481b
Sex			0.5634a
Male	78 (92.86%)	310 (94.51%)
Female	6 (7.14%)	18 (5.49%)
BMI	33.00 ±7.12	31.09 ±5.46	0.0245 b
Hip Laterality			0.2313a
Right	41 (48.81%)	184 (56.1%)
Left	43 (51.19%)	144 (43.9%)
Diagnosis			0.6083a
Hip OA	81 (96.43%)	301 (91.77%)
FAI	1 (1.19%)	8 (2.44%)
AVN	2 (2.38%)	5 (1.52%)
Labral Tear	0 (0%)	6 (1.83%)
Hip Pain	0 (0%)	4 (1.22%)
Hip Dysplasia	0 (0%)	2 (0.61%)
Psoriatic Arthritis	0 (0%)	2 (0.61%)
Alcohol Abuse			0.7781a
Yes	15 (17.86%)	63 (19.21%)
No	69 (82.14%)	265 (80.79%)
Tobacco Abuse			0.7346a
Yes	28 (33.33%)	103 (31.4%)
No	56 (66.67%)	225 (68.6%)
Chronic Steroid Use			0.6896a
Yes	5 (5.95%)	16 (4.88%)
No	79 (94.05%)	312 (95.12%)
History of Hip Trauma			0.6874a
Yes	3 (3.57%)	9 (2.74%)
No	81 (96.43%)	319 (97.26%)
History of Chemotherapy or Radiation Therapy			0.0124 a
Yes	12 (14.29%)	20 (6.1%)
No	72 (85.71%)	308 (93.9%)
Obstructive Pulmonary Disease			0.6690a
Yes	11 (13.1%)	49 (14.94%)
No	73 (86.9%)	279 (85.06%)
Diabetes Mellitus			0.0537a
Yes	16 (19.05%)	97 (29.57%)
No	68 (80.95%)	231 (70.43%)
Serum Albumin	3.67 (± 0.43)	3.74 (±0.45)	0.2169b
(g/dL, reference range 3.5–5.2)
Hemoglobin A1c	5.58 (± 0.60)	6.09 (± 1.22)	<0.0001 b
(%, reference range 4.0–6.0)
Serum Vitamin D (ng/mL, reference range 20–50)	23.14 (±11.25)	26.84 (11.28)	0.0301 b

aPearson’s Chi-Square Test.

bTwo Sample Test.

Significance was set at p < 0.05.

*Results are reported as the mean and standard deviation for continuous variables and the count and percentage for discrete variables.

**HIV/AIDS was not a significant variable in our analysis and was omitted from final data reporting in order to protect sensitive patient information.

While the rate of FHC after IACSI for patients excluded from our pre-intervention analysis is unknown, a best-case scenario would be that none developed collapse during the study period based on lack of need for radiographic follow-up. If this were the case, the initial FHC rate would be 15.8% (84/531).

Practice-related factors

Specialties that referred patients for hip IACSI included Orthopedics, Rheumatology, Physical Medicine/Rehabilitation, and Primary Care. Procedure-specific education materials did not exist. All hips were injected under fluoroscopy with 0.5% ropivacaine hydrochloride (range 3.0–6.0 mL), triamcinolone acetonide (range 1–2 mL; 40 mg/mL), and iopromide contrast (1 mL). Medication volume/dose were at discretion of the radiologist. No significant association was identified between FHC and local anesthetic or corticosteroid dosage, volume, or medication type. Post-procedure, patient follow-up with the referring provider varied. In most cases, decision for follow-up was left to the patient. Post-IACSI radiographs were ordered/obtained for only 77.6% of patients. Patients frequently underwent repeat injections without interval office visits or new radiographs.

Quality improvement intervention impact

In the 27 months after QI investigation and implementation of practice recommendations (Fig 2), reduction in number of procedures was 48.8% (851 to 436), reduction in number of hips injected was 39.6% (531 to 321), number of injections per hip reduced from 1.61 to 1.37 (p = 0.0006), reduction in post-IACSI FHC was 67.9% (84 to 27), and rate of FHC decreased from 20.4% to 15.1% (p = 0.1292) (Table 3). Variation in medication volume/dose persisted. Variation in radiographic follow-up requirement persisted as x-rays were obtained for only 55.8% of patients post-procedure.

Table 3

Hip IACSI QI impact.

	Pre-QI	Post-QI	P-Value
	10/1/2015-12/31/2017	1/1/2018-3/11/2020
Hip IACSI	851	436	n/a
Patients	458	280	n/a
Hips	531	321	n/a
Mean Hip IACSI	1.67 ± 1.12	1.37 ± 0.84	0.0006 b
Femoral Head Collapse Number	84	27	n/a
Femoral Head Collapse Percentage	20.4%	15.1%	0.1292 a

aPearson’s Chi-Square Test.

bTwo Sample Test.

Significance was set at p < 0.05.

*Results are reported as the mean and standard deviation for continuous variables and the count and percentage for discrete variables.

While the rate of FHC after IACSI for patients without post-injection radiographs is unknown, a best-case scenario would be that none developed collapse during the study period. If this were the case, the post-QI intervention FHC rate would be 8.4% (27/321).

Development of a clinical pathway for hip IACSI

During the investigation/intervention, the work-group was developing a systems-based Clinical Pathway for hip IACSI (Fig 4) to expand on the initial informal recommendations (Fig 2). Based on lessons-learned, the work-group created a flowchart to guide peri-procedural care. Through a series of meetings and reviews, this flowchart was revised to incorporate as many evidence-based care practices as possible. When evidence-based practices were not available, practices were adopted on the basis of community standards and/or consensus among work-group members. In addition to mapping out the sequence of patient care, the Pathway incorporated use of patient-education materials, standardized physician order-sets for medications and follow-up, and pharmacy involvement/oversight.

Fig 4

System-wide clinical pathway for hip IACSI.

Discussion

FHC after hip IACSI has been described in case reports and small case series. Suggested etiologies include toxicity from injectate, volume-related increased intracapsular pressure restricting femoral head blood supply, and occult subchondral fracture or AVN progressing to collapse with medication-related inhibition of joint pain [2-7]. While no cause-effect relationship is known, the association between such a common treatment and such a pathogenic process is concerning.

At the inception of this investigation, we had already managed several patients with FHC occurring shortly after hip IACSI. Cases were characterized by acute increase in hip pain and disability, radiographically-confirmed articular collapse, and adjustment in care plan to allow earliest possible total hip arthroplasty (THA). A small number of patients with FHC less than 3 months post-IACSI required delay in THA to decrease risk of prosthetic joint infection [8]. Consequently, their care was further complicated by an increase in sedentary behavior and presentation for surgery in a deconditioned state (Fig 5).

Fig 5

Rapid progression to FHC less than three months after hip IACSI in 66-year-old male with left hip OA.

After FHC, patient developed significant quad weakness and was unable to ambulate during January 2018 office visit. Left THA was delayed until three months after hip IACSI to reduce risk of PJI.

Initial QI analysis of FHC after IACSI suggested certain patient factors were associated (elevated BMI, history of cancer therapy, low Vitamin D level). Our analysis also revealed lack of consistency in volume/dose of injectate, time-interval between treatments, and post-injection follow-up. The practice inconsistencies permitted many patients to receive hip injections “on demand”, often without pre-injection clinical or radiographic evaluation. As our analysis also suggested that multiple IACSIs within a narrow time-frame (27 months) were associated with FHC, we recognized the need for improved organization/oversight.

To improve safety and consistency of hip IACSI, we created procedure-specific education materials. We also developed guidelines for procedural and peri-procedural practices and distributed to all referring and treating providers. Importantly, given the urgent need to improve patient safety, our initial intervention relied entirely on individual providers’ awareness and responsibility. The systems-based Clinical Pathway was in development (Fig 4), but not yet in place.

In the two years that followed the initial intervention, hip IACSIs decreased (approximately half as many) along with fewer repeat treatments. While it is not certain that these referral patterns resulted directly from providers following our recommendations, the rate of FHC after IACSI decreased by 5%. However, in the absence of the systems-based Clinical Pathway, volume/dose of injectate and post-injection follow-up remained variable.

Patient factors

Obesity

Patients who developed FHC after IACSI had higher mean BMIs (33.00 kg/m2 vs. 31.09 kg/m2, p = 0.025). Only one other study has analyzed BMI as a variable for FHC, and no association was noted [5]. Yet, obesity is associated with AVN and subchondral insufficiency fracture [9-11]. Such conditions may account for some cases of FHC in our analysis. Ultimately, as obese patients have increased risk for hip conditions characterized by unhealthy bone, treatments that decrease joint pain and may promote increased joint stress (e.g. IACSI) may also increase risk for FHC. For our obese patients, the decision for IACSI is always informed by complete clinical history and recent hip imaging.

History of treatment for malignancy

Patients developing FHC after IACSI had a higher percentage history of cancer therapy (14.3% vs. 6.1%, p = 0.012). Radiation and chemotherapy are linked to bone damage/loss and increased fracture risk [12, 13]. This association has important implications for palliative care of hip pain. For patients undergoing cancer therapy, THA may be contraindicated and hip IACSI preferred for symptomatic relief. We conclude that such patients should be selected carefully and followed closely if IACSI performed.

Low serum Vitamin D levels

Patients developing FHC after IACSI had lower serum Vitamin D levels. However, our finding must be interpreted with caution as these levels were not tested at standardized intervals around the time of each hip procedure. Furthermore, the role of Vitamin D levels in the evaluation and treatment of orthopaedic patients remains controversial, and supplementation therapy has not been found to prevent osteoporosis-related fractures [14, 15]. Ultimately, while the association is logical, no firm conclusion can be drawn from our analysis.

Avascular necrosis

The natural history of avascular necrosis of the femoral head is FHC. In our analysis there were only 8 hips (1.51%) that had a diagnosis of AVN (7 ultimately included in analysis). Of the patients with AVN there was a 28.57% FHC rate (2/7) after IACSI. While there is a possibility AVN was underdiagnosed in our patient population, we were limited by the retrospective nature of the review and the information contained in the medical record at the time of retrieval. Due to the slightly higher FHC rate seen with this diagnosis and the natural history of the disease, we consider AVN as a relative contraindication for hip IACSI.

Practice-factors

Volume/dose of medications injected

Initial investigation demonstrated variation in dose of triamcinolone acetonide (range, 40–80 mg/mL), volume of ropivacaine hydrochloride (range 3.0–6.0 mL), and total volume of injectate (range, 5–9 mL). We endeavored to research and recommend the best/safest medication mixture for our patients. This was challenging as there is no consensus as to what constitutes “best practice” for hip injectate.

Regarding medications, our literature review suggested all local anesthetics and corticosteroids have chondrotoxic effects, but that methylprednisolone acetate, dexamethasone, and ropivacaine hydrochloride were the least chondrotoxic [16-23]. With regard to total volume of injectate, literature review confirmed increased intra-capsular pressure may cause hip pathology (i.e. AVN) and provided insight into the relationship between volume of injection and intracapsular hip joint pressure [24]. To minimize risk related to increased intra-capsular pressure, we recommended injecting the lowest possible volume, ≤ 5mL [25] (Fig 6).

Fig 6

Hip IACSI medication recommendations based on best-available evidence literature review and local/community standards.

Final recommendations for medications were derived through collaboration with all clinical stakeholders. However, at the time of this study these recommendations were not yet part of the formal Clinical Pathway with standardized order-sets and pharmacy involvement/oversight. Despite efforts to encourage more consistent practice, without the system-based Pathway yet in place, the type, dose, and volume of medications injected remained highly variable.

Patients receiving multiple injections / lack of consistent follow-up after procedure

Patients treated with greater than one hip IACSI during the initial 27-month study period were more likely to develop FHC. While the number and frequency of hip IACSIs has never been reported as a risk factor for FHC, it is logical that repeated injections of medications with dose- and time-dependent toxicity in a narrow timeframe might increase risk of joint damage [16-23].

Initial investigation revealed repeat IACSIs were commonly ordered at the patient’s request, oftentimes without pre-procedure clinical or radiographic evaluation. A small number of patients were undergoing regularly scheduled hip IACSIs (i.e. every three or six months). While all patients who underwent first-time hip IACSI had pre-procedure hip radiographs, there was no consistent practice for post-IACSI imaging or imaging between procedures. Initial findings were that post-injection radiographs were obtained for 77.6% of patients. Without strong evidence to inform the ideal frequency of hip IACSIs and/or best follow-up practices, work-group consensus was to adopt a very conservative approach. Specifically, prior to referral for initial or repeat IACSI, guidelines recommended in-person evaluation with new radiographs to assess the hip and to review/discuss treatment alternatives.

After QI intervention, we observed a significant decrease in number of repeat injections per patient, mean = 1.61 vs. 1.37, (p = 0.0006). However, variation persisted in follow-up practices and the number of patients with post-injection radiographs decreased to 55.8% from 77.6%. Many patients continued to receive one or more injections between hip radiographs. Again, this persistent variation is attributed to lack of the systems-based Pathway during the study period and reliance on individual providers to follow work-group guidelines.

Strengths

To our knowledge, our experience with identifying and managing FHC after hip IACSI is the largest series ever reported. Our investigation was performed at a single institution in a single health system. The electronic medical record and integrated PACS facilitated complete and consistent data collection. Our study demonstrates how a QI investigation and intervention may improve patient safety. Our study also demonstrates the formidable challenges associated with implementing sustainable institution-wide change.

Limitations

The primary study limitation is its retrospective observational design comparing nonrandomized groups. A randomized controlled trial would better define the relationship between hip IACSI and FHC and/or establish any causality related to patient, provider, or environment. Although our initial QI investigation identified potential patient-related risk factors for FHC after IACSI and made recommendations for/against treatment based on these, the impact of our QI intervention on number of patients referred for hip IACSI with potential risk factors was not tracked or tabulated. Also, the unique population studied (predominantly older males) may limit the generalizability of findings and recommendations. It is also possible that all or some of the FHC observed in this study occurred as part of the natural progression of patients’ hip OA. However, to our knowledge, there is no natural history study that reports a similar or accepted rate of FHC in patients with hip OA.

Due to the retrospective nature of this work, the radiographic follow-up for pre- and post-intervention study groups was non-standardized. Additionally, the time to chart/radiographic review was shorter for the post-intervention group, thereby introducing the potential for a falsely decreased FHC rate in the post-intervention group. While the shorter length of radiographic follow up for the post-intervention group and the possibility of a falsely low FHC rate in this group is a weakness of our study, it strengthens our rationale for instituting the Clinical Pathway to standardize hip IACSI practices so to allow for further prospective study.

Finally, a large number of patients (22.4% pre-intervention and 44.2% post-intervention) were excluded from final analysis of occurrence of FHC due to lack of post-injection imaging. However, even if all patients initially excluded due to incomplete radiographic follow-up were included in the final analysis with the assumption of “no collapse”, FHC rates after IACSI remain high (i.e. pre-intervention = 15.8%; post-intervention = 8.4%). At our institution, even this “best case scenario” was sufficiently concerning to motivate further investigation and intervention.

Conclusion

When a QI investigation suggested FHC after hip IACSI was associated with certain patient and practice factors, we rapidly intervened with introduction of new education materials and treatment guidelines. This intervention decreased the number of hip injection referrals, number of repeat injections, and the rate of post-injection FHC. However, the intervention failed to improve the consistency of medications injected and post-procedure follow-up practices. The failure to change key practice patterns is attributed to the absence of the systems-based Clinical Pathway during the study period. Although the Pathway was in development during this time, progress was slow due to the need to involve multiple stakeholders in decision-making, time required to create standardized order-sets in the electronic medical record, and the lengthy process of gaining acceptance of a new workflow. As we were confronted with an immediate need to address a patient safety issue, our initial intervention that relied on patient/provider awareness and responsibility was all that was possible.

As a next step, to further improve quality, safety, and consistency of the practice of hip IACSI at our institution, we have introduced a formal systems-based Clinical Pathway for hip IACSI. At a minimum, standardization of this care practice should simplify future risk management. Future research will show if this Pathway improves clinical outcomes and/or further decreases rates of FHC.

8 Apr 2021

PONE-D-21-00877

Femoral Head Collapse After Hip Intra-Articular Corticosteroid Injection: An Institutional Response to Improve Practice and Increase Patient Safety

PLOS ONE

Dear Dr. Sechriest,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The authors are required to respond to all reviewers' comments and concerns especially the low rate of postinjection follow-up radiographs in the intervention group. Only 55.8% received a post-procedure x-ray of the hip. How did the authors exclude the development of FHC without follow-up radiographs? How did the authors accept this while the missing of a postinjection X-ray was an exclusion criteria.

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If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Osama Farouk

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: No

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Within this study the authors analyse the impact of a treatment algorism for intraarticular corticosteroid injection (IACSI) to reduce the number of femoral head collapse (FHC). Before the implementation of the algorithm the FHC rate after IACSI was 20.4% (84/412). The authors were able to calculate independent risk factors for the development of FHC (e.g. obesity or low serum Vitamin D levels) in the first group before the intervention.

The intervention consisted in a hospital guideline addressing: 1. indication; 2. medication; 3. injection-technique and 4. post-injection surveillance

As a result the authors show that there was a reduction in the number of injected patients down to 39.6%. The number of injections per hip was reduced at the same time from 1.6 to 1.3. and as significant result the rate of FHC decreased from 20.4% to 15.1%.

Critical comment

The authors are able to show that the amount of IACSI was significantly reduced after implementation of the treatment algorithm (851:436) in a comparable period. Unfortunately the reasons for the reduction of the number of interventions is not described. It is not shown if there was a reduction of number of patients with the mentioned comorbidities in the second group.

Another major concern is the low rate of postinjection follow-up radiographs in the intervention group. Only 55.8% received a post-procedure x-ray of the hip. How did the authors exclude the development of FHC without follow-up radiographs?

This is surprising, since the missing of a postinjection X-ray was an exclusion criteria in the first group.

FHC is not always easy to detect in plane radiographs in patients with osteoarthritis of the same hip. In order to have objective results a group of independent specialists (radiologists or orthopaedics) should have analysed the radiographs.

Reviewer #2: This is the largest study of this kind, looking at the incidence of Femoral Head Collapse after Intraarticular Steroid Injection. Although retrospective in nature, this provides a basis for future study in this particular population. The data does support the conclusions. The statistical analysis was appropriate and rigorous. The data was available for review. The manner in which this manuscript is written flows well and is easily understandable.

Reviewer #3: Thank you for your paper, it represent a hard and continuous effort to improve practice, though I think it may not represent a clear research topic rather than documenting your internal audit of your practice

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

12 Jun 2021

Response to Reviewer Comments

PONE-D-21-00877

Editor:

1) Only 55.8% received a post-procedure x-ray of the hip. How did the authors exclude the development of FHC without follow-up radiographs? How did the authors accept this while the missing of a post injection X-ray was an exclusion criteria?

Author Response (part a): A goal of this study was to identify variation in practice of obtaining post-procedure X-rays of the injected hip before and after quality improvement (QI) intervention. For patients without post-procedure X-rays, we were unable to conclude if they experienced FHC, so they were excluded from the FHC analysis only. However, we included these patients in our analysis of radiographic follow-up and have reported rates of radiographic follow-up to illustrate variation in post-injection X-ray practices. We have clarified our exclusion criteria as below:

• “If a patient did not have a hip radiograph available at least one-month post-injection, the patient was excluded from FHC analysis, but was included in analysis of post-injection radiographic follow-up.” (Materials and Methods, lines 112-114)

Author Response (part b): While we cannot determine if patients without post-injection radiographs developed FHC during the study period, we can illustrate variation in practice of radiographic follow-up post-procedure. This point has been further clarified in the manuscript as below:

• Variation in radiographic follow-up requirement persisted as x-rays were obtained for only 55.8% of patients post-procedure.” (Results, lines 191 – 192).

• “After QI intervention, we observed a significant decrease in number of repeat injections per patient, mean = 1.61 vs. 1.37, (p = 0.0006). However, variation persisted in follow-up practices and the number of patients with post-injection radiographs decreased to 55.8% from 77.6%.” (Discussion, lines 305 – 308).

• “Finally, a large number of patients (22.4% pre-intervention and 44.2% post-intervention) were excluded from final analysis of occurrence of FHC due to lack of post-injection imaging.” (Discussion, lines 332 – 334).

Reviewer 1

1) The authors are able to show that the amount of IACSI was significantly reduced after implementation of the treatment algorithm (851:436) in a comparable period. Unfortunately, the reasons for the reduction of the number of interventions is not described.

Author Response: We suggest that our QI investigation and recommendations (Figure 2) followed by the high-profile, institution-wide awareness campaign were responsible for the dramatic reduction in provider referrals for hip injections at our institution. We have added an explanation and clarification of this important point as follows:

• “…a high-profile, well-coordinated, institution-wide, campaign to raise awareness of work-group findings and recommendations was undertaken to educate providers in Radiology, Orthopedics, Rheumatology, Physical Medicine / Rehabilitation, and Primary Care. Guidelines and patient-education materials were then distributed hospital-wide for their use in clinical practice. Work-group findings and practice recommendations were also highlighted at our institution’s annual research symposium.” (Materials and Methods, lines 127 – 132).

• “In the 27 months after QI investigation and implementation of practice recommendations (Figure 2), reduction in number of procedures was 48.8% (851 to 436), reduction in number of hips injected was 39.6% (531 to 321), number of injections per hip reduced from 1.61 to 1.37 (p = 0.0006), reduction in post-IACSI FHC was 67.9% (84 to 27), and rate of FHC decreased from 20.4% to 15.1% (p = 0.1292) (Table 3).” (Results, lines 186 – 190).

2) It is not shown if there was a reduction of number of patients with the mentioned comorbidities in the second group.

Author Response: The reviewer makes a good point. The impact of our QI intervention on number of patients referred for hip IACSI with potential risk factors associated with FHC was not tracked or tabulated. This is a weakness of our study and has been acknowledged as below:

• “Although our initial QI investigation identified potential patient-related risk factors for FHC after IACSI and made recommendations for/against treatment based on these, the impact of our QI intervention on number of patients referred for hip IACSI with potential risk factors was not tracked or tabulated.” (Discussion, lines 324 – 327.)

3) Another major concern is the low rate of post-injection follow-up radiographs in the intervention group. Only 55.8% received a post-procedure x-ray of the hip. How did the authors exclude the development of FHC without follow-up radiographs? This is surprising, since the missing of a post-injection X-ray was an exclusion-criteria in the first group.

Author Response (part a): A goal of this study was to identify variation in practice of obtaining post-procedure X-rays of the injected hip before and after quality improvement (QI) intervention. For patients without post-procedure X-rays, we were unable to conclude if they experienced FHC, so they were excluded from the FHC analysis only. However, we included these patients in our analysis of radiographic follow-up and have reported rates of radiographic follow-up to illustrate variation in post-injection X-ray practices. We have clarified our exclusion criteria as below:

• “If a patient did not have a hip radiograph available at least one-month post-injection, the patient was excluded from FHC analysis, but was included in analysis of post-injection radiographic follow-up.” (Materials and Methods, lines 112-114)

Author Response (part b): While we cannot determine if patients without post-injection radiographs developed FHC during the study period, we can illustrate variation in practice of radiographic follow-up post-procedure. This point has been further clarified in the manuscript as below:

• “Variation in radiographic follow-up requirement persisted as x-rays were obtained for only 55.8% of patients post-procedure.” (Results, lines 191 – 192).

• “After QI intervention, we observed a significant decrease in number of repeat injections per patient, mean = 1.61 vs. 1.37, (p = 0.0006). However, variation persisted in follow-up practices and the number of patients with post-injection radiographs decreased to 55.8% from 77.6%.” (Discussion, lines 305 – 308).

• “Finally, a large number of patients (22.4% pre-intervention and 44.2% post-intervention) were excluded from final analysis of occurrence of FHC due to lack of post-injection imaging.” (Discussion, lines 332 – 334).

Author Response (part c): Even though the lack of radiographic follow-up precluded a complete analysis of the incidence of FHC after IACSI at out institution, the data collected was sufficiently concerning to warrant QI investigation and intervention to promote patient safety. This point is highlighted in the manuscript as follows:

• “However, even if all patients initially excluded due to incomplete radiographic follow-up were included in the final analysis with the assumption of “no collapse”, FHC rates after IACSI remain high (i.e. pre-intervention = 15.8%; post-intervention = 8.4%). At our institution, even this “best case scenario” was sufficiently concerning to motivate further investigation and intervention.” (Discussion, lines 334– 338).

4. FHC is not always easy to detect in plane radiographs in patients with osteoarthritis of the same hip. In order to have objective results a group of independent specialists (radiologists or orthopedics) should have analyzed the radiographs.

Author Response: Pre- and post-injection radiographs were compared side-by-side with the criteria of obvious loss of sphericity of the femoral head as the definition of collapse. Each radiograph was reviewed by an orthopedic surgery resident and later reviewed by the senior author, an orthopedic surgery attending. In every case, FHC was dramatic, easily detected, and further verified by our institution’s official radiology reports. We have added an explanation and clarification of this important point as follows:

• “Each pre- and post-injection radiograph was compared side-by-side for interval changes. Post-injection FHC was defined radiographically as new loss of femoral head sphericity (Figure 1). Images were initially compared and interpreted by two orthopedic surgery residents and later independently verified by an attending orthopedic staff. In all cases, official radiology reports confirmed an interim change in femoral head sphericity as well.” (Materials and Methods, lines 115 – 119).

Reviewer #2:

This is the largest study of this kind, looking at the incidence of Femoral Head Collapse after Intraarticular Steroid Injection. Although retrospective in nature, this provides a basis for future study in this particular population. The data does support the conclusions. The statistical analysis was appropriate and rigorous. The data was available for review. The manner in which this manuscript is written flows well and is easily understandable.

Author Response: We appreciate the positive comments regarding our manuscript and thank the reviewer.

Reviewer #3:

Thank you for your paper, it represents a hard and continuous effort to improve practice, though I think it may not represent a clear research topic rather than documenting your internal audit of your practice

Author Response: We appreciate the reviewer’s comments regarding our manuscript. This was a single center, before/after quasi-experimental study of our experience with hip injections. We have presented our results in the form of data and eye-witness experiences. We have added an explanation and clarification of this important point as follows:

• “This was a single center, before/after quasi-experimental study designed to bring about immediate quality improvements in health delivery in our institution. The Institutional Review Board provided exemption for this investigation and there was no external funding.” (Materials and Methods, lines 88 – 90).

16 Aug 2021

PONE-D-21-00877R1

Femoral Head Collapse After Hip Intra-Articular Corticosteroid Injection: An Institutional Response to Improve Practice and Increase Patient Safety

PLOS ONE

Dear Dr. Sechriest,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 30 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

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An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Osama Farouk

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #4: Yes

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #4: Yes

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #4: Yes

Reviewer #5: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #4: Yes

Reviewer #5: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #4: Dear authors, I had the opportunity to review your work, and I hope that my comments will help improve the quality and strengthen your manuscript.

I encourage the authors to strictly follow the journal instructions; for example, it is not advised by the journal to insert the table or figure legends inside the manuscript.

Dear authors, I had the opportunity to review your work, and I hope that my comments will help improve the quality and strengthen your manuscript.

-The authors had responded rigorously to the comments raised after the initial submission; however, I have some minor comments

-line 93, the authors reported: “witnessing a high rate” how much are they considered high? Is there a certain percentage they calculated, or data were reported from a previous survey or study in their institution?

-line 116, the authors reported comparing the x-rays side by side; what was the exact tool used to judge the sphericity of the femoral head, how did they judge the proper rotation of the included radiographs? Did they exclude any cases due to bad-quality radiographs? Did the two residents performed checking of the whole x rays or these were split between them?

-line 189: “reduction in post-IACSI FHC was 67.9% (84 to 27)” was this reduction possibly due to the reduced number of patients who had an injection? Or due to a relatively shorter time of follow up after implementing the quality improvement protocol?

-I would like the authors to add a statement in the acknowledgment thanking the residents for their effort if they were not listed as authors.

Reviewer #5: Thank you so much for this interesting research topic.

-I wonder whether the inclusion of AVN cases ( 8 cases) and given the possibility that the natural progression of the disease rather than the IACSI was the cause of collapse rather than the IACSI??? I think this is worse elaborating upon specifically referring to the AVN cases please.

- Could you please elaborate more about the effect of the injection dose /material on the rate of collapse among those who have developed collapse and those who haven't please.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #4: Yes: Ahmed A. Khalifa, M.D., FRCS, MSc.

Reviewer #5: Yes: Mahmoud Abdel Karim

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

31 Aug 2021

Response to Reviewer Comments

PONE-D-21-00877R1

Reviewer 4:

1) Line 93, the authors reported: “witnessing a high rate” how much are they considered high? Is there a certain percentage they calculated, or data were reported from a previous survey or study in their institution?

Author Response:

At the end of 2017, we had observed and treated multiple patients who returned to clinic after hip intra-articular corticosteroid injection (IACSI) with debilitating symptoms secondary to femoral head collapse (FHC). Prior to our investigation, there was no known or previously reported rate of FHC at our institution. Additionally, there is a paucity of cases documented in the literature, and available case reports and series do not define any true incidence. However, FHC is considered a rare complication after IACSI. We have revised our manuscript as follows:

• “After witnessing multiple cases of FHC after hip IACSI, we reviewed and compared our experience and institutional care practices with the evidence-based literature.” (Materials & Methods, lines 93 - 94)

Reviewer 4:

2) Line 116, the authors reported comparing the x-rays side by side; what was the exact tool used to judge the sphericity of the femoral head, how did they judge the proper rotation of the included radiographs? Did they exclude any cases due to bad-quality radiographs? Did the two residents performed check of the whole x-rays or these were split between them?

Author Response (part a):

Each radiograph was reviewed using the picture archiving and communication system (PACS). Pre- and post-injection radiographs were compared side by side for loss of contour secondary to collapse. For each hip image, a circle tool was used to outline the contour of the subchondral bone-edge in the weightbearing portion of the femoral head. We have added an explanation and clarification of methodology as follows:

• “Post-injection FHC was defined radiographically as new loss of femoral head sphericity and was measured by comparing the contour of the weightbearing portion of the femoral head on each radiograph. For each hip image, a circle tool was used to outline the contour of the subchondral bone-edge in the weightbearing portion of the femoral head.” (Materials & Methods, lines 117 -121)

Author Response (part b):

The authors examined pre- and post-hip IACSI anterior-posterior (AP) pelvis or hip radiographs. Standard AP pelvis and/or hip radiographs were obtained. Per radiology department protocol, radiographs were reviewed by a radiology technician in real-time to ensure correct position and rotation is obtained. If a radiograph was inadequate a new radiograph was obtained prior to releasing the radiograph to PACS. There were no radiographs excluded due to malrotation. This point is highlighted in the manuscript as follows:

• “All radiographs were obtained using our institution’s standardized Radiology department protocol. No images were excluded for poor quality.” (Materials & Methods, lines 114-116)

Author Response (part c):

Each patient was reviewed independently by one of two orthopedic surgery residents. All patient radiographs then underwent confirmatory review by the senior author. This point is clarified in the manuscript as follows:

• “Images were initially compared and interpreted by two orthopedic surgery residents and later independently verified by an attending orthopedic staff. In all cases, FHC was dramatic, easily detected, and the interim change in femoral head sphericity secondary to collapse was confirmed by official radiology reports.” (Materials & Methods, lines 121-124)

Reviewer 4:

3) Line 189. “Reduction in post-IACSI FHC was 67.9% (84 to 27)” was this reduction possibly due to reduced number of patients who had an injection? Or due to a relatively shorter time of follow up after implementing the quality improvement protocol?

Author Response:

The reviewer raises a very important point. We agree that, due to the shorter length of radiographic follow up for the post-intervention group, there is a possibility of bias impacting the results, falsely lowering the rate of FHC. While this is a weakness of our study, the possibility of a falsely low FHC rate in the post-intervention group strengthens our rationale for instituting the Clinical Pathway to standardize and study hip IACSI best practices. This weakness is acknowledged and addressed in the manuscript as follows:

• “Due to the retrospective nature of this work, the radiographic follow-up for pre- and post-intervention study groups was non-standardized. Additionally, the time to chart/radiographic review was shorter for the post-intervention group, thereby introducing the potential for a falsely decreased FHC rate in the post-intervention group. While the shorter length of radiographic follow up for the post-intervention group and the possibility of a falsely low FHC rate in this group is a weakness of our study, it strengthens our rationale for instituting the Clinical Pathway to standardize hip IACSI practices so to allow for further prospective study.” (Discussion, lines 351-357)

Reviewer 4:

4) I would like the authors to add a statement in the acknowledgement thanking the residents for their effort if they were not listed as authors.

Author Response:

The residents responsible for the chart review are included as first and second authors.

Reviewer 5

1) I wonder whether the inclusion of AVN cases (8 cases) and given the possibility that the natural progression of the disease rather than the IACSI was the cause of the collapse rather than the IACSI??? I think this is worth elaborating upon specifically referring to the AVN cases please.

Author Response:

Avascular necrosis (AVN) or similar pathologies contributed to some of the FHCs observed at our institution. As this review was limited by its retrospective nature, we studied all patients referred for hip IACSI, including the 8 hips with a diagnosis of AVN. We have reported the diagnoses documented for all patients referred for hip IACSI as we felt it important to include all patients to best determine associated risk factors for FHC. Per the reviewer’s suggestions, we have added to the manuscript with additional information on the AVN cases as follows:

• “There were 8 hips (1.51%) that had a diagnosis of avascular necrosis (AVN). One patient was excluded due to pre-existing FHC. Of the remaining 7 hips, 2 hips (2.38%) developed FHC, and 5 hips (1.52%) did not develop collapse after hip IACSI.” (Results, lines 174 - 176)

• “The natural history of avascular necrosis of the femoral head is FHC. In our analysis there were only 8 hips (1.51%) that had a diagnosis of AVN (7 ultimately included in analysis). Of the patients with AVN there was a 28.57% FHC rate (2/7) after IACSI. While there is a possibility AVN was underdiagnosed in our patient population, we were limited by the retrospective nature of the review and the information contained in the medical record at the time of retrieval. Due to the slightly higher FHC rate seen with this diagnosis and the natural history of the disease, we consider AVN as a relative contraindication for hip IACSI.” (Discussion, lines 279 - 285)

Reviewer 5

2) Could you please elaborate more about the effect of the injection dose/material on the rate of collapse among those who have developed collapse and those who haven’t please?

Author Response:

The reviewer raises an excellent point. There is basic science evidence showing dose and volume-dependent chondrotoxicity with local anesthetics and corticosteroids. However, in our study, the variation in dosage and volume of hip injectate between providers was very substantial such that no association could be readily identified between FHC and the injectate. Ultimately, in response to this provider-to-provider variation and using the best available evidence to inform the safest medications and dosages for joint injections, the recommendation for the least toxic medications in the lowest effective dosage and volume were made. This point has been further clarified in the manuscript as below:

• “No significant association was identified between FHC and local anesthetic or corticosteroid dosage, volume, or medication type.” (Results, lines 188 - 190)

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

18 Oct 2021

Femoral Head Collapse After Hip Intra-Articular Corticosteroid Injection: An Institutional Response to Improve Practice and Increase Patient Safety

PONE-D-21-00877R2

Dear Dr. Sechriest,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Osama Farouk

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #4: All comments have been addressed

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Reviewer #4: Yes

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Reviewer #4: Yes

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Reviewer #4: Yes

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Reviewer #4: Yes

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Reviewer #4: Dear authors, i was glad to review the revised version of your manuscript. Thanks for addressing all the raised issues, hope you all the best.

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Reviewer #4: Yes: Ahmed A. Khalifa, M.D., FRCS, MSc

21 Oct 2021

PONE-D-21-00877R2

Femoral Head Collapse After Hip Intra-Articular Corticosteroid Injection: An Institutional Response to Improve Practice and Increase Patient Safety

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