Analysis of the Etiopathogenesis of Postoperative Complications in Orthopedic Patients Using Knee and Hip Arthroplasty as an Example

1. Relevance and Rationale A significant number of conditions encountered by orthopedic traumatologists have a progressive course, and the question of reconstructive surgery using various types of implants invariably arises in the terminal stages. The scientific novelty of this study lies in the large-scale prospective study of patients before and after endoprosthetic replacement with endosseous implants. This study will include an assessment of mineral homeostasis, somatic status, and immune status. It will also provide a morphological characterization of bone tissue in the implantation area and, in patients with periimplantitis, an assessment of the microbiota around the implants. The clinical problem addressed by this project-assessing the prevalence of complications after large joint replacement in the Russian Federation-has several limitations, primarily related to the collection and analysis of statistical data. However, according to a 2019 epidemiological study, In 2018, 6,606 cases of implant-associated infection after knee or hip arthroplasty were registered in the country, accounting for 2.91% of primary surgeries [Sereda A.P. et al. Epidemiology of hip and knee arthroplasty and periprosthetic infection in the Russian Federation // Traumatology and Orthopedics of Russia. Vreden Russian Research Institute of Traumatology and Orthopedics, 2021. Vol. 27, No. 3. P. 84-93.]. Description of the problem being solved

1. An increase in the number of patients with peri-implant infection, aseptic instability, periprosthetic fractures, the need for re-hospitalization and surgeries, an unpredictable outcome of retreatment, excess mortality, and a high economic burden. 2. The problem affects a wide range of age groups of patients who have undergone knee and hip arthroplasty, as well as traumatologists and orthopedists working in the trauma and orthopedic centers of the Moscow Health Department. 3. A progressive increase in the incidence of peri-implant infection, aseptic instability, periprosthetic fractures, an increased financial burden on Moscow healthcare, an increase in mortality associated with this disease, and an increase in disability.

   Due to the widespread development of high-tech medical care in traumatology and orthopedics, provided to patients with severe forms of osteoarthritis of the hip and knee joints and aseptic necrosis, and the increase in the number of knee and hip arthroplasties, there is a proportional increase in serious complications after arthroplasty, and the most formidable of these

   and economically costly is the development of Peri-implant infection. Currently, the incidence of peri-implant infection is approaching epidemic proportions. It is worth noting that peri-implant infection is not always associated with poor surgical technique or poor quality prostheses.

   Often, the causes of this life-threatening complication are not fully understood. Currently, no large-scale prospective or retrospective study of the causes of peri-implant infection has been conducted in Russia or in Moscow. The pathogenesis has not been fully elucidated, and methodological approaches to prevention and treatment for this group of patients have not been developed, making this topic relevant and promising. The project's results will establish the key pathogenesis of peri-implant infection, determine the risk spectrum for this complication, identify individual patient characteristics that increase the risk of developing this complication, determine the underlying mechanisms of this complication, and identify alternative management options for these patients. Based on the data obtained, diagnostic algorithms and recommendations for treatment strategies and preoperative preparation for patients with severe forms of hip and knee osteoarthritis, femoral head fractures, and aseptic necrosis will be developed. Guidelines for the antemortem and postmortem diagnosis of peri-implant infection will also be developed. These guidelines will be used by general practitioners, rheumatologists, orthopedic traumatologists, pathologists, rehabilitation physicians, general practitioners, and endocrinologists. The program's implementation and implementation of its results are aimed at reducing the contribution of peri-implant infection to morbidity and mortality. 2. Objectives and Tasks The Project's Objective is to establish the etiopathogenesis and morphological changes in tissues following complications of large joint replacement (PJI, aseptic instability, etc.) in patients of different age groups, assessing somatic and immune status, calcium mineral balance, and its metabolism, and to develop guidelines for preoperative examination.

2. Recruitment of a cohort of patients within the study of at least 600 people for a comprehensive assessment of the patient's baseline status: assessment of mineral metabolism (total calcium, serum magnesium, inorganic phosphorus, 25OH vitamin D, osteocalcin, BetaCross laps, P1NP bone matrix formation marker, parathyroid hormone); assessment of the immune status (Interleukin 10 (IL-10, Interleukin 10, IL-10), Interleukin 1 beta (IL-1beta, IL-1b, Interleukin 1 beta, IL-1b), Interleukin 6 (IL-6, Interleukin 6, IL-6), Interleukin 8 (IL-8, Interleukin 8, IL-8), C4 Component of the complement system (Complement Component C4), TNF (Tumor necrosis factor, Tumor necrosis factor alpha, TNFalpha, sachectin), Lymphocyte phenotyping (main subsets panel): CD3, CD4, CD8, CD19, CD16, 56); microbiological research and PCR research, as well as somatic status (therapist, rheumatologist) and analysis of the results of the instrumental research methods (MRI, CT, densitometry, radiography).; 3. The study includes a single, less often double study in each patient from the group of the above-mentioned indicators at the preoperative stage.; 4. Conducting a study in each patient with complications of osseointegration of the endoprosthesis from the group of the above-mentioned indicators at the postoperative stage.; 5. Endoprosthetics/revision endoprosthetics of the knee and hip joint.; 6. Collection of tissue samples and metal structures (their fragments) from peri-implant areas for an intravital pathological examination of the patient, scanning electron microscopy, sonication with subsequent microbiological examination (at least 5 samples) to form a characteristic of the microbiota in patients with developed complications.; 7. Evaluation of the obtained results of the correlation dependence of the patient's somatic, immune, and homeostatic (mineral) status on the development of postoperative complications, statistical data analysis, and database creation. 8. Implementation of the results of the work into clinical practice at least at the State Budgetary Healthcare Institution "City Clinical Hospital No. 31 named after Academician G.M. Savelyeva of the Moscow Health Department." 9. Characterize pathomorphological and immunohistochemical changes, including an assessment of local immunity (CD3, CD4, CD8, CD20, CD56, CD68) in the peri-implant area.

Study Design Materials and Methods Sample size of patients participating in the study: 750 patients Rationale for sample size calculation Power calculations were performed for a minimum number of patients of 400-450

1. Power Formula For a t-test for the difference between two independent means: Power = 1 - β = P(T>t_{crit} \| H_{1} ) where T is a non-central t-distribution with degrees of freedom: df = n₁ + n₂ - 2 non-centrality parameter: δ = d ⋅ √(n₁ n₂ / (n₁ + n₂)) t_{crit} = t_{1-α/2, df} (two-tailed critical t) Total: Power = 1 -F_{nc}(t_{crit}; df, δ) F_{nc} is the distribution function of non-central t.

2. Substitute the numbers n₁ = n₂ = 200, df = 398α = 0.05 → t_{crit} ≈ 1.968 Cohen's d = 0.3 δ = 0.3 × √(200 200 / 400) = 0.3 × √100 = 3.0

   Calculate the probability:

   Power = 1 -F_{nc}(1.968; 398, 3.0) ≈ 0.70 Answer: power ≈ 70%.

3. Cohen's d d = (μ₁ - μ₂) / σ μ₁, μ₂ - means of two groups σ - "overall" standard deviation (pooled SD) Interpretation (Cohen, 1988): 0.2 - small effect 0.5 - medium effect 0.8 - large effect Description of cohorts/groups of patients Cohort #1: Patients with hip pathology who are indicated for hip arthroplasty Size of group/cohort #1, people: 300

Inclusion criteria for group/cohort #1:

Patients 45 years and older Idiopathic coxarthrosis Stage 3 Secondary coxarthrosis stage 3 (ANFH, post-traumatic coxarthrosis, rheumatoid arthritis, etc.)

Exclusion criteria for Group/Cohort No. 1:

Patients with infection of the hip joint; Patient's refusal to participate in the study; Inability to follow up the patient for 3 years; History of psychiatric illness; Somatic illnesses in the decompensation stage Group/Cohort #2 Size, Persons: 300

The indicators that will be assessed in the study of cohort/group No. 1 before the primary operation and before surgery in case of revision intervention are:

Beta-Cross Laps

Chemical Blood Count

Bone Matrix Formation Marker P1NP

Parathyroid Hormone Wound Microbiota Culture

Total Calcium

25OH Vitamin D

Serum Magnesium

Interleukin 10

Interleukin 1 Beta Interleukin 6 Interleukin 8

Tumor necrosis factor Phagocytic activity of leukocytes

Detection of herpes viruses by PCR Immunohistochemistry of six (6) types of antibodies (CD3, CD4, CD8, CD20, CD56, CD68) Lymphocyte phenotyping (major subsets) - CD3, CD4, CD8, CD19, CD16, CD56

Densitometry

MRI of the hip joint

CT scan of the hip joint

Pelvic X-ray Pathological examination of a femoral head bone section Pathological examination of intra-articular tissues

X-ray of the hip joint Sonication of removed implants and subsequent microbiological examination Physician's report Sampling of throat and nasal discharge PCR testing for infectious agents (virals, bacteria, fungi) with assessment of the microbiota in the peri-implant area EGD

Inorganic phosphorus

Total protein

Albumin ALT AST

Creatinine

Urea

Uric acid

Glucose

Glycated hemoglobin

Total bilirubin

Direct bilirubin

Gamma-GT

Blood Fe

Cholesterol

Triglycerides

Potassium

Sodium

Chloride

C-reactive protein

ESR

Rheumatoid factor

APTT

INR

Inclusion Criteria for Group/Cohort #2:

Patients 45 years and older Stage 3 idiopathic gonarthrosis Stage 3 secondary gonarthrosis (aseptic necrosis, post-traumatic gonarthrosis, rheumatoid arthritis, etc.)

Exclusion Criteria for Group/Cohort #2:

Patients with knee joint infection Patient refusal to participate in the study Inability to follow up for 3 years History of psychiatric illness Somatic illness in the stage of decompensation Justification for the absence of a control group

The indicators that will be assessed in the study of cohort/group No. 2 before the primary operation and before surgery in case of revision intervention are:

Beta-Cross Laps

Chemical Blood Count

Bone Matrix Formation Marker P1NP

Parathyroid Hormone Wound Microbiota Culture

Total Calcium

25OH Vitamin D

Serum Magnesium

Interleukin 10

Interleukin 1 Beta Interleukin 6 Interleukin 8

Tumor necrosis factor Phagocytic activity of leukocytes

Detection of herpes viruses by PCR Immunohistochemistry of six (6) types of antibodies (CD3, CD4, CD8, CD20, CD56, CD68) Lymphocyte phenotyping (major subsets) - CD3, CD4, CD8, CD19, CD16, CD56

Densitometry

MRI of the hip joint

CT scan of the hip joint

Pelvic X-ray Pathological examination of a femoral head bone section Pathological examination of intra-articular tissues

X-ray of the hip joint Sonication of removed implants and subsequent microbiological examination Physician's report Sampling of throat and nasal discharge PCR testing for infectious agents (virals, bacteria, fungi) with assessment of the microbiota in the peri-implant area EGD

Inorganic phosphorus

Total protein

Albumin ALT AST

Creatinine

Urea

Uric acid

Glucose

Glycated hemoglobin

Total bilirubin

Direct bilirubin

Gamma-GT

Blood Fe

Cholesterol

Triglycerides

Potassium

Sodium

Chloride

C-reactive protein

ESR

Rheumatoid factor

APTT

INR

This scientific work is a cohort study, which does not imply a control group. Whether patients participating in the study will sign written informed consent: Yes Whether approval from the ethics committee for conducting research with patients will be obtained: Yes Name of the ethics committee: Ethics Committee of the State Budgetary Healthcare Institution City Clinical Hospital No. 31 named after Academician G.M. Savelyeva, Department of Health of the City of Moscow Conclusion Reduction in the development of postoperative complications, with a special emphasis on preventing periprosthetic infection. This serious complication not only causes significant suffering to the patient but also requires long-term, multi-stage, and expensive treatment, including revision surgery. To Improving the quality and standardization of medical care in primary arthroplasty by implementing proven clinical protocols for preoperative diagnosis and patient selection. A key component is an individualized approach that takes into account the patient's comorbidities, minimizing the risk of perioperative negative consequences. A logical continuation of this work is reducing the number of readmissions due to complications such as instability of endoprosthesis components and wound infection.

Achieving this goal directly depends on the effectiveness of the measures taken at the previous stages, as well as on establishing a high-quality preoperative diagnostic system. An integral and extremely significant result of implementing all of the above measures is a significant reduction in the economic burden associated with the treatment of these postoperative complications. Each complication entails direct costs for repeat surgeries, expensive antibiotics, prolonged hospital stays and subsequent rehabilitation, as well as indirect losses due to prolonged patient disability. Thus, investments in prevention, quality improvement, and standardization of medical care not only improve clinical outcomes and patient satisfaction, but also demonstrate high cost-effectiveness, reducing the burden on the healthcare system and optimizing resource allocation.