Decompression Surgery With Antibiotic-impregnated Calcium Sulfate Can Achieve More Satisfactory Results Than Decompression Alone in Pediatric Hematogenous Osteomyelitis

The curative effect of antibiotic-impregnated Calcium Sulfate in pediatric ostemyelitis is unknown. The purpose of this study was to compare the outcomes of two treatment methods, decompression combined with antibiotic-impregnated calcium sulfate and decompression alone, for the treatment of pediatric Hemotogenous Osteomyelitis.


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Calcium Sulfate (CS) is a representative of bioabsorbable bone substitute, which was widely used in bone infection when loaded antibiotic. [1][2][3][4][5][6]. Existing clinical articles have focused on the e cacy of antibioticimpregnated CS in post-traumatic osteomyelitis, infection after internal xations and infected nonunion. [7][8][9][10] However, the e cacy of antibiotic-impregnated CS in pediatric Hematogenous Osteomyelitis(HO) is unclear. HO is different from non-HO both in pathogenesis and bacteriology. [11] The characteristics of HO include spread by hematogenous route [12], dominance of staphylococcus aureus. [13] A majority of pediatric HO can be cured by appropriate antibiotics administered sequentially via parenteral and oral routed. [12,14,15] Surgical is necessary when invalid intravenous antibiotic. However, pediatrics is different from adult due to the epiphyseal plate, the main purpose for surgery is decompression [13] in pediatrics compare with radical debridement [16] in adult. Local antibiotics delivery, with vancomycin or tobramycin impregnated CS, has been widely used in osteomyelitis due to its decent e cacy in adult, such as reducing infection recurrence and shortening treatment cycle. [7,8] A recent research article reported that tobramycin-impregnated CS pellets can reduce the risk of associated comorbidities, hospital stays, and healthcare costs in the treatment of HO in children and adolescents. [10] However, few comparative studies had been carried out to con rm those results. In this study, we want to nd the differences of infection recurrence rate, hospital stay, postopreative serum in ammatory markers, wound healing rate, pathological fracture and leakage of the incision when added this local antibiotic delivery.

Study Design and Setting
A retrospective study was performed analyzing pediatric HO patients treated in our hospital from January 2013 to December 2016. The main inclusion criteria were as follows: 1) pediatric patients aged below 18 years old. 2) patients with HO underwent surgical bone decompression. 3) patients persisted to the follow-up and had been followed for at least 24 months. The main exclusion criteria included: 1) patients suffered from direct spreading osteomyelitis, such as post-traumatic osteomyelitis, or infection after internal xation. 2) patients received a soft tissue surgery, 3) follow-up losted patients. The collectiong clinical data include name, sex, age, diagnosis, serum in ammatory indexs (White blood cell count, Erythrocyte Sedimentation Rate, C-reactive protein), bacteriology, imaging data, site of osteomyelitis, operation process, discharge date, surgery date, telephone number and duration of follow-up .

Description of Study Population
Forty-one patients met the criterion and were included in our study. (Figure 1) Twenty-one patients (13 boys, 8 girls), a mean age of 10.14 years old (range, 3-18 years old), received decompression surgery with antibiotic-impregnated CS were allocated to CS group. Twenty children (17 boys, 3 girls), a mean age of 11.85 years old (range, 2-18 years old), received decompression surgery alone were allocated to control group. (Table 1) All patients had no draining sinuses. All patients had no comorbidities such as sickle cell anemia, deep vein thrombosis, septic pulmonary embolism, pneumonia,empyema and endocarditis.

Description of surgery
The deep soft-tissue uid collections or abscesses and subperiosteal were removed. Decompression was performed by creating an appropriately placed cortical window in long bone osteomyelitis, followed by curettage of intraosseous abscess. Eggshell-like decompresion technology [17] was used in calcaneus osteomyelitis, followed by curettage of abscess.
Then difference between CS group and control group: The former one involves antibiotic-impregnated CS application to obliterate the dead space and release local antibiotic. 1g vancomycin (or 160mg gentamicin or both) and 10cc calcium sulfate were mixed thoroughly using the solvent provided by the manufacturer until a smooth paste is formed (approximately 30 s). Calcium sulfate (beads or blockshaped or both) is then placed or lled into the defect as well as supero-inferior medullary cavity. ( Figure  2) The paste is allowed to cure undisturbed for at least 15 min after mixing. The volume of calcium sulfate varied according to the size of the bone defect. No drainage tube was used. The later one without this antibiotic material, an irrigation tube was placed in the lower medullary cavity and a drainage tube was placed in the upper medullary cavity. (Figure 3) If the pus is small enough, we place a drainage tube only. In both CS group or control group, a cast or external xation were applied if bone is unstable after decompression.

Aftercare
All patients were routinely given intravenous antibiotics post operation. Cefmetazole, 100mg/kg/day, was chosen in most patients. Clindamycin, 30mg/kg/day, was chosen in a few patients who were allergic to cefmetazole. Vancomycin, 40 mg/kg/day, was chosen when the pathogenic bacterium showed resistance to cefmetazole. Postoperative antibiotic including cefmetazole (34 cases), clindamycin (7 cases), vancomycin (9 cases), some patients received combinations of medications. In CS group, intravenous antibiotics were administered for a mean of 10.9 days followed by oral antibiotics for a mean of 15.2 days. In control group, intravenous antibiotics were administered for a mean of 12.3 days followed by oral antibiotics for a mean of 16.4 days. In CS group, cleaning the wound regularly by anerdian skin disinfectant. In control group, normal saline solution was used to irrigate by continuous ow every day. No adjuvant dilute Betadine (povidone-iodine) wash or antibiotic powder in the wound was used. The irrigation tube was removed when the uid looks clear and the drainage tube was removed when the daily output is less than 5ml. The patients were released when their symptoms improved and the drain removed.

Outcome Measures
The patients are regually reviewed in the outpatient department. De ned outcome parameters included infection recurrence, hospital stay, wound healing duration, serum in ammatory markers, pathological fracture, leakage of the incision and follow-up time. Infection recurrence was de ned as a worsening clinical symptoms, an continuously increasing serum in ammatory markers, formation of sinus tract and(or) a continuing to be eroded bone tissue by X-ray. Hospital stay is calculated based on the number of days following surgery till discharge. Wound healing duration was de ned as the postoperation till incision healing with no exudation and suture removed. Pathological fracture was de ned fractures without apparent violence.

Statistical Analysis
Statistical analysis was performed using the SPSS (Version 13) software package (SPSS Inc, Chicago, IL). Descriptive statistics were conducted for all variables. Continuous variables were expressed as the mean standard deviation or the minimum and the maximum depending on data distribution. Student ttest was used for continuous variables. Nonparametric test was used for variance inhomogeneity. A chi square test was used for categorical variables between the two groups. Fisher exact test was used in cases in which one or more of the expected variables was less than ve. A value of p<0.05 was considered to be statistically signi cant.

Results
The locations of HO were 13 in tibial (5 in CS group), 9 in femur (6 in CS group), 6 in humerus (2 in CS group), 5 in calcaneus (3 in CS group), 4 in bula (3 in CS group), 2 in clavicle (1 in CS group), 1 in ulna in control gruop, 1 in radius in CS group. The outcomes of two groups were presented in table 2.

Discussion
Hematogenous osteomyelitis(HO) can be cured by intravenous antibiotic in most of teenagers and children. [18] Therefore, most researchers concentrated on early diagnosis, antibiotic therapy and interdisciplinary cooperation instead of the right timing and method of surgery. [12,18] No consensus has been reached on the timing and method of surgery so far. Copley presented a Severity of Illness Score [19] for pediatric acute HO in 2016. He put CRP in a prominent position and indicated that patients may require multiple surgical procedures when severe scores was 8~10. [12] However, in our experience, surgery were considered candidates when exist with abscesses or fail to respond to antibiotic therapy after 48 hours to 72 hours. Otherwise, the positive rate and accuracy rate were highest in intraoperative specimen culture than interventional radiology culture and blood culture. [18] A positive and accuracy culture is crucial for diagnosing osteomyelitis. Hence,to some extent, surgery is both diagnosis and treatment. In terms of methods of surgery, Copley put forward "decompression and drainage" in 2009. [20] The Although any water-soluble antibiotic can be incorporated into the calcium sulfate,the ideal choice of antibiotic remains controversial. The choice of local antibiotic was empirical depending on local epidemiological data in patients who had no accurate bacterial data. We chose vancomycin in gram staining positive cases or in highly suspected staphylococcus aureus cases and gentamicin in gram staining negative cases. We chose vancomycin and gentamicin together in hard-to-identify bacterial cases. Compared with long-term intravenous antibiotics, local antibiotic had its unique advantages. One is effective and higher antibiotic concentrations are obtained in the local area of infected bone through the systems for a prolonged period of time. The other is to prevent the adverse events related to systemic chemotherapy and reduce the risk of systemic toxicity. [21] Zhang et al [22] measured the blood vancomycin levels in 24 osteomyelitis patients locally applied with vancomycin-impregnated calcium sulfate beads (range from 1.5 ml to 5 ml with a ratio of 1 g vancomycin:5 ml calcium sulfate). The results showed that the mean blood vancomycin level was still within a safe range for application. P. Wahl et al [23] found that even 6 g vancomycin was applied locally, the systemic concentration remained within a safe range and local concentration was still below the reported cell toxicity thresholds. In our study, patients in two groups received intravenous and oral routed antibiotic. Adverse events related to systemic chemotherapy and systemic toxicity do not happened in two groups.
Davis WT et al [24] reported multiple surgeries were underwent in Methicillin-resistant Staphylococcus aureus(MRSA) patients. In their's research, they emphasize that improving treatment for MRSA osteomyelitis should involve reevaluation of surgical techniques, such as utilizing local antibiotics. In our study, no patient recured in CS group including 5 cases of MRSA. Four patients recured in control group including 3 cases of MRSA and 1 case of negative culture. (Figure 4) Local antibiotics has exhibited excellent curative effect especially in MRSA infection. It is known to us, successful surgical eradication of osteomyelitis requires the use of antibiotics. Systemic antibiotic treatment cannot achieve su cient release of antibiotic in the area of infected bone due to poor blood supply resulting from soft tissue scarring and bone sclerosis. [8,25] A residual focus of infection may result in a new infection in the area of a low local bactericidal concentration of antibiotics. Moreover, long-term usage of antibiotics can promote the growth of bacterial drug resistance. [26] Prior research shows that the infections evolved to have greater invasive properties and were associated with substantial abscess formation in the era of MRSA. [24] Hence, this may lead to more surgical drainage procedures. Inserting antibiotic at the site of infection has a lot of potential merit,such as higher antibiotic concentrations in the local area of infected bone through the systems for a prolonged period of time. Although difference in post operative management may explain the difference in hospital stay. But exactly the lling of the antibiotic cement result in different post operative management. It is also a potential merit of inserting antibiotic at the site of infection. Andreacchio et all [10] reported that tobramycin-impregnated CS can reduce the hospital stays in pediatric HO. In our study, we also found the use of antibiotic-impregnated CS can obviously reduce the hospital stays in pediatric HO compare with nothing.
CS simillary has its disadvantage, such as wound complication. [27][28][29] Wound complication may resulting in a delayed healing incision. A commonly reported observation associated with the use of calcium sulfate when used surgically is a uid discharge from the wound/surgical site, occurring in 4% to 51% of cases. [7,30,31] The reported duration of uid discharge is variable, ranging from 2 to 24 weeks duration. [31] In our study, one patient in CS group had a aseptic exudation. This lead to a delayed stitches removing in 29 days post operation. However, in our study, the application of CS did not prolong wound healing duration compare with nothing.(p=0.65) How to prevent aseptic exudation of antibioticimpregnated CS is an urgent problem to be solved. In view of this, we present our own experience: 1. Keep the CS from getting too wet; 2. Place the CS in the area rich in soft tissue.
Masquelet [32] proposed two steps operation technique for the treatment of chronic osteomyelitis. First step is a sharp debridement of necrotic tissue, abundant lavage, sequestrectomy, and removal of any hardware and/or foreign bodies, followed by insertion of antibiotic-impregnated Polymethylmethacrylate(PMMA). Second step is an additional surgical procedure required for removal of the beads and subsequent bone grafting. This technique can be used in case of initial infection and to control established infection before nal bone reconstruction. Canavese et al. [33] reported successful treatment of 5 cases chronic pediatric osteomyelitis with debridement, antibiotic-laden PMMA and bone graft substitute. Four cases were infected after internal xation and one case was not mentioned initiating event. Bar-On et al. [34] reported successful treatment of 4 cases chronic pediatric osteomyelitis by intramedullary reaming and antibiotic-impregnated PMMA. Two cases were infected after internal xation and just two cases were infected hematogenous. Masquelet technique may not suitable in HO because of its big surgical trauma and additional additional surgical procedure. In our study,the insertion of CS did not result in a big surgical trauma and additional additional surgical procedure. However, unfortunately, we don't have any cases to compare the e ency in pediatric HO between the two methods.

Limitations
Our study was not a a prospective, randomized clinical trial. Thus a large-sample randomized controlled clinical trial should be necessary to evaluate the effect of the antibiotic-impregnated CS in the treatment for pediatric HO.

Conclusion
Antibiotic-impregnated CS can reduce infection recurrence and shorten the mean hospital stay in pediatric HO. The curative effect of antibiotic-impregnated Calcium Sulfate in pediatric ostemyelitis is satisfactory. We therefore recommend treating these patients with antibiotic-impregnated CS.

Declarations
Ethics approval and consent to participate Medical Ethics Committee of Nanfang Hospital of Southern Medical University has approved the research. The patients' parents agreed to participate in this study and a signed consent form was obtained from the patient's parents prior to the study. All procedures were conducted according to the Declaration of Helsinki.

Consent for publication
Written informed consent has been obtained from the parent for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Availability of data and materials
The data supporting our ndings comes from Southern Medical University Nanfang hospital. The images and data sets used in the current study are available from the corresponding author if necessary.

Competing interests
The authors declare that they have no competing interests.

Funding
This study was not externally founded.