Risk factors associated with surgical site infection in patients with musculoskeletal cancer

Fatores de risco associados à infecção de sítio cirúrgico em portadores de câncer musculoesquelético

Factores de riesgo asociados a la infección del sitio quirúrgico en pacientes con cáncer musculoesquelético

Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.

In recent years, the number of surgical interventions to treat cancer has increased throughout the world, reflecting a worldwide increase in the incidence of malignant neoplasias¹. It is estimated that there will be 625,000 new cases of cancer in the three-year period between 2020 and 2022 in Brazil². Despite the development of less invasive treatment involving medication, surgery remains a fundamental tool in treatment of musculoskeletal cancer³.

Surgery is a treatment method of great importance for patients, as it plays a fundamental role in loco-regional control of the disease and in establishing the parameters of the recommended cancer treatment. Surgical site infections (SSI) have been shown to be the most common complication during treatment⁴ .

Despite the significant preventive potential of surgery, it is important that SSI are avoided, given that such infections continue to be a major concern in orthopedic oncology and represent a challenge as great as cancer recurrence, with an incidence between 3, 2 and 35.55%. ^1,5,6

The risk of infection may lead to devastating musculoskeletal complications, requiring bone resection and prosthetic use⁴ . This complication may also result in physical, social and/or psychological damage to patients, along with longer stays in hospital, increased risk of re-hospitalization, the need for further surgery, the persistence of painful symptoms, the need for antibiotics, possible loss of implants, limb amputation, infections and death,⁷ thus substantially increase the cost of treatment⁸.

Numerous factors have been associated with the development of SSI. These risk factors are commonly divided into modifiable and non-modifiable factors. Potentially modifiable factors include a pre-operative antiseptic bath in the case of major surgery and/or implant insertion, routine hair removal discontinuation, hospitalization length of less than 24 hours, blood sugar level control immediately prior to and following surgery, smoking, recent history of immunosuppression, obesity and effective infusion of prophylactic antibiotics for up to 60 minutes prior to surgical incision. Non-modifiable factors include advanced age, history of prior infections, and advanced-stage cancer. SSI also tend to be associated with emergency surgery, lengthy surgery, surgery involving large teams, blood transfusion, an skin antisepsis quality in patients and hand hygiene among the care team. ^9-10

Numerous inflammatory markers have been proposed for infection identification, including high-sensitivity and -specificity cytokines, which are considered to be important mediators in the host’s response to infection and C-reactive protein levels and are thus used for early identification of infection, along with clinical evaluation and other laboratory examinations. ¹¹

Considering the greater complexity of the disease, SSI in patients with bone cancer deserve more extensive studies in the scientific community. In addition to the underlying disease-related disorders, the aggressive nature of cancer treatment causes significant immune imbalance, increasing the risk of infection during surgery. Moreover, treating the infection can, in turn, delay or even prevent cancer treatment. ^1,7

The objective was to assess the frequency of infections in oncological orthopedic surgeries and the associated risk factors and inflammatory markers in a reference hospital in the state of Pernambuco.

An observational, analytical, cross-sectional study was carried out with 110 individuals of both sexes, of any age, diagnosed with primary or secondary bone cancer and confirmed by histopathological examination and undergoing orthopedic surgery, between July 2019 and July 2020, at the Hospital de Câncer de Pernambuco, in Recife, Brazil. Individuals who, upon hospital admission, had skin/soft tissue infection in the topography of the limb to be surgically treated and individuals with benign tumors were excluded. Written consent was obtained from participants through the Informed Consent Form, for cases over 18 years of age, and the Clarified Assent Form, for those under 18 years of age. The study was approved by the Research Ethics Committee of the Hospital de Cancer de Pernambuco, CAAE (13514019.2.0000.5205) ethics opinion (3.399.327) in accordance with Resolution 466/12 of the Brazilian National Health Council (CNS).

The collection of clinical and epidemiological, sociodemographic data, such as lifestyle, tobacco use, Body Mass Index (BMI), immunosuppressant use in the last six months, bacterial infection in the last 30 days, presence of SSI, cancer type and cancer site, preoperative hospital stay, surgery duration, antibiotic prophylaxis, preoperative bath, glycemic control, preoperative shaving, degree of contamination, implant insertion, number of surgery participants ≥5, blood transfusion, was extracted from patients’ records. Blood samples were collected to assess inflammatory markers. We found the frequency of SSI, identification of microorganisms isolated in blood samples in SSI, risk factors and profile of Th1 and Th2 inflammatory markers (IL-2, IL-4, IL-6, IL-10, TNF and IFN-Ƴ) using the flow cytometry technique up to 48 hours after the diagnosis of SSI using the SPSS (Statistical Package for the Social Sciences), version 21.0 (IBM, Armonk, NY). After diagnosis of SSI in accordance with the criteria of the Brazilian National Healthcare Safety Network, the Centers for Disease Control and Prevention and the Brazilian Health Regulatory Agency (ANVISA - Agência Nacional de Vigilância Sanitária), blood samples were collected, centrifuged and stored at -20°C, and then sent to the Marcelo Magalhães Laboratory, for measuring ultrasensitive C-reactive protein levels using the immunoturbidimetric method, and to the Department of Immunology at the Instituto Aggeu Magalhãe/FIOCRUZ, to ascertain the IL-2, INFγ and TNF (Th1) and IL-4, IL-6, IL-10 (Th2) cytokine profile by way of flow cytometry using the Cytometric Bead Array (CBA) method.

Clinical data on patients’ lifestyle and previous and current medical history included smoking, BMI, immunosuppressant use in the past six months, bacterial infection in the last 30 days, and type and location of cancer. The variables relating to the healthcare process were length of hospital stay prior to surgery, surgery duration, antibiotic prophylaxis, preoperative bath, blood sugar control, hair removal prior to surgery, contamination level, implant insertion, number of team members participating in surgery ≥5, and blood transfusion. Preoperative, transoperative and postoperative variables for patients with a diagnosis of bone cancer following histopathological examination were taken from medical records in the first 24 hours after surgery.

During the study period, 110 patients undergoing orthopedic surgical procedures diagnosed with bone cancer were recruited. Of this total, 10/110 (9.1%) had SSI. Most patients were female, five with SSI and 54 without SSI (59%), and the mean age was 31 years of age for patients with SSI and 26 years of age for patients without SSI (Table 1).

Table 1
Distribution of orthopedic oncology surgery patients by age and sex

Caption: SD = standard deviation; t = Student’s t test

With regard to the previous and current medical history of patients developing SSI, the most frequent type of musculoskeletal cancer was sarcoma (7/10; 70%) in SSI, and 53/100 (53%) individuals did not have SSI, which is considered to be the most prevalent type of tumor in the population under study. The tumor was mostly located in the pelvis or upper limbs (10/10; 100%) in SSI, and 70/100 (70%) individuals did not have SSI, which also reflected the prevalence in the sample as a whole (Table 2).

With regard to lifestyle, (10/100) 10% of individuals included in the sample were current smokers, although none of these developed an SSI. The mean BMI exceeded 25 in 60% of the group of patients who developed SSI. The mean BMI was similar between the SSI and non-SSI groups. Immunosuppressant use <6 months was more frequent in individuals with SSI (1/10; 10%), and the presence of bacterial infection <4 months was 1/10 (10%) in patients with SSI and 97/100 (97%) in patients without SSI. None of these variables were statistically significant (Table 2).

Table 2
Lifestyle and past and current medical history of orthopedic oncology surgery patients

Caption: SD = standard deviation; P25 = 25th percentile; P75 = 75th percentile 75; MW = Mann-Whitney test; t= Student’s t test.

Caption: SD = standard deviation; P₂₅ = 25^th percentile; P₇₅ = 75^th percentile 75; MW = Mann-Whitney test; t= Student’s t test.

With regard to healthcare-related variables, all surgical procedures were elective, and most were classified as clean (10/10; 100%) in patients with SSI, and 97/100 (97%) patients did not have SSI, with hospital stay before surgery longer than 24 hours in 60% of patients who developed SSI and mean surgery duration from 61 to 120 minutes, with surgery performed by a care team of five or more participants in 80% of cases that developed ISC. Blood glucose was controlled in 3/100 (2.72%) patients without SSI. None of the surgical procedures were preceded by an antiseptic bath and all involved administration of the recommended prophylactic antibiotic, with no available record of duration of administration. Forty percent 4/10 of patients who received an orthopedic implant during surgery developed SSI (Table 3).

Bivariate analysis showed that a number of team members actively participating in the surgery equal to or greater than five (Odds Ratio [OR] 5.524; Confidence Interval [95%CI] 1.116 – 27.348; p = 0.041) and the need for intraoperative transfusion (OR 7.667; 95%CI 1.786 – 32.910; p = 0.012) suggested an association with SSI. The other independent variables had no significant effect on the risk of developing SSI (Table 3).

Table 3
Healthcare process indicators of orthopedic oncology surgery patients

Caption: P25 = 25th Percentile; P75 = 75th Percentile; MW = Mann-Whitney test.

Factors with p-value <0.20 in univariate analysis included in multiple logistic regression were age, length of hospital stay, hair removal, pelvic surgery, number of team members who participated in the surgery ≥5 and intraoperative blood transfusion. The variables were selected using the forward stepwise method, with a significance level of 0.05 for inclusion of variables and of 0.10 for removal. Multivariate analysis revealed that the need for intra-operative transfusion (OR 8.22; 95%CI 1.81-27.37; p = 0.006) was the only risk factor for developing SSI.

Outcomes for patients with surgical site infection

According to the classification of infections, all were classified as deep. Patients who developed SSI needed to be admitted to hospital again and underwent further surgery, most of them one or two further procedures, three of these involving amputation of the infected limb. The micro-organism most commonly found in cases with a positive culture was Staphylococcus aureus, identified in 50%. In two of these ten patients, the surgeon identified signs and symptoms of purulent secretion, indicating infection at the site of surgery despite a negative culture in accordance with the criteria of the National Health Security Network of the Centers for Disease Control and Prevention. The mean length of hospital stay after diagnosis of infection was 11 to 20 days, and 50% of patients required intensive care. No SSI-related deaths were recorded among these patients. Three patients with SSI underwent amputation. During the study, none of these patients with SSI died (Table 4).

Table 4
Characterization of SSI orthopedic oncology surgery patients

Inflammatory markers

Ultrasensitive CRP levels, used to assess the immune response after SSI, were >5 mg/dl in 100% of the samples analyzed. Four patients had CRP between 5-25 mg/L (44.44%); two patients had CRP between 26-100mg/L (22.22%); two had CRP between 100-200mg/L (22.22%); and one patient had CRP above 200 mg/L (11.11%).

With regard to cytokines, interleukin 6 (IL-6) presented the highest levels, between 6.68 and 58.76pg/mL. The others did not show any significant variations (Figure 1).

Figure 1
Distribution of cytokine levels measured in pg/ml using the Cytometric Bead Array method

The results of this study indicate an incidence of infection of 9.09%, a similar value reported in a study of risk factors for SSI in orthopedic oncology that found that 10.9% of patients developed SSI ⁵. On the other hand, the incidence of postoperative infection of deep bone tumors ranged from 3.2% to 10.9%. ^1,6 All the procedures included in the study were classified as clean and the incidence of SSI for this category of procedure was higher than the rate considered acceptable (1 to 5%)⁹.

The present study found that most cases of SSI involved patients aged over 55 years ¹⁰, who considered belonging to this age group a significant risk factor for SSI, along with overweight and obesity. It also reported obesity to be an independent risk factor for SSI (OR: 1.43; 95%CI: 1.13-2.00) in a study of patients undergoing internal fixation of calcaneal fractures. ¹²

The present study also identified that patients receiving a blood transfusion for volume loss were around eight times more likely to have an SSI (OR 8.22; 95%CI 1.81-27.37; p = 0.006) compared to patients with no volume loss. Patients who receive perioperative blood transfusion are at increased risk of developing SSI. ¹³ In a cohort study with 222 patients undergoing orthopedic surgery with implants, in which those who received perioperative blood transfusion had a three times greater risk of developing SSI compared to the group not submitted to blood transfusion (HR: 3.08; 95%CI: 1.31-7.26,)⁸ . These findings are supported by a study that found that blood transfusion is a risk factor for developing SSI, being 2.6 times more likely to develop an infection compared to those who did not receive a blood transfusion, in addition to having a longer hospital stay. ¹⁴

The number of colony forming units (CFU) collected in sterile containers in the operating room through microbiological analysis was not significantly associated with the number of individuals in the room. ¹⁵However, the presence of five or more members of the care team at surgery has been an independent risk factor for SSI. ¹⁶

Studies show that implant use in orthopedic oncologic surgery has increased the likelihood of deep infection¹ . General procedures associated with orthopedic diagnosis and treatment, implantation or removal of a musculoskeletal device had the highest prevalence of infections related to implantable orthopedic devices. ¹⁷ The study found that 40% of surgeries that led to infection involved the insertion of an implant.

Smokers are about 6.4 times more likely to develop SSI than non-smokers, ¹⁸ despite the fact that in this study none of the patients with SSI reported being a smoker. No patient who developed SSI had a previous or concomitant infection.

Studies show that patients undergoing bone tumor resection at any site followed by reconstruction are risk factors for SSI⁶ . Our findings indicate that all infections occurred after surgical interventions involving tumors in the lower limbs and pelvis.

In the present study, length of hospital stay before surgery was greater than 24 hours in 60% of SSI cases, although this number was not statistically significant. Musculoskeletal tumor patients undergoing surgery were at higher risk for SSI. ¹⁹

Surgery duration has been considered an independent risk factor for deep wound infection. ²⁰ The present study found that the mean surgery duration ranged from 85 to 90 minutes, although it was not a risk factor for infections in cancer patients.

Hyperglycemia was associated with a higher incidence of SSI. ²¹ This study showed the absence of glycemic control in 97.27% of the total sample and 100% of the SSI group.

SSI prevention through an antiseptic bath before major surgeries or implants was not performed in any of the patients, and this can be explained by the lack of an effective protocol at the institution. It was therefore not possible to investigate the effectiveness of this measure.

With regard to prophylactic antibiotics, it is stated in the literature that antibiotic infusion should occur up to 60 minutes prior to surgical incision, in order to ensure serum concentrations sufficient to prevent SSI ¹, although no reports of this time being abided by were found in the research.

The microorganism most commonly involved in orthopedic SSI is Staphylococcus aureus. The same conclusion was made about infections in orthopedic surgery published between 2015 and 2020. ²² This is corroborated by the findings of the present study.

We found that all patients with SSI were reoperated on and re-hospitalized, requiring intensive care in the most severe cases.

The CRP level, when used with other clinical interventions, has been highly effective in diagnosing SSI and can be used as a criterion to select patients who may need an invasive intervention due to infectious complications, ²³ showing a sustained increase in protein levels in cases of postoperative infection. In our study, postoperative levels exceeded the reference level (>5 mg/dl) in all samples.

For cytokines, the study showed that interleukin 6 occurred at high levels in 87.5% of the measured samples. Inflammatory markers such as CRP and IL-6 in lesion fluid hold promise for predicting SSI in the clinic. ²⁴ Serial estimation of postoperative CRP and IL 6 can predict infections and can be used routinely in general surgical practice. ²⁵

It is not possible to generalize the study findings to other individuals due to the underlying disease character of the population studied. The larger sample size could contribute to a better understanding of the associations studied.

The study found that surgical team with five or more members and blood transfusion were risk factors associated with the development of SSI in orthopedic surgery in patients with bone cancer. Among the inflammatory markers, interleukin 6 (IL-6) showed the highest correlation with the outcome. More studies are needed to determine the degree of modulation of inflammatory responses in this population. Patients who develop SSI require longer hospital stays for adjuvant therapy involving antibiotics and reoperation for infection control and, in some cases, involving amputation.