Efficacy of skin preparation solutions in patients with total knee replacement: A randomized controlled trial

Abstract

Purpose

Surgical site infection following total knee replacement is considered as one of the most severe postoperative complications. The presence of bacteria at the surgical site is the most important risk factor and therefore it is essential to prevent infection through appropriate preoperative skin preparation. The purpose of this study was to examine the presence and type of native bacteria on the incision site and to assess which skin preparation is most effective to sterilize those native bacteria.

Methods

Scrub-and-paint 2 step method was used for standard preoperative skin preparation. 150 patients who underwent total knee replacement were grouped into 3 groups- Group 1 (povidone-iodine scrub-and-paint), Group 2 (chlorhexidine gluconate paint after povidone-iodine scrub), and Group 3 (povidone-iodine paint after chlorhexidine gluconate scrub). 150 specimens of post-preparation swabs were obtained and cultured. To analyze the native bacteria at the total knee replacement incision site, 88 additional swaps were performed before skin preparation and cultured.

Results

The positive rate of bacterial culture after skin preparation was 5.3% (8/150). Positive rates of the groups were 12% (6/50) in group 1, 2% (1/50) in group, 2 and 2% (1/50) in group 3 and positive rates of bacterial culture after skin preparation in group 2 and group 3 were lower than in group 1 (p = 0.037). Among the 55 patients who had positive bacterial culture prior to skin preparation, 26.7% (4/15) in group 1, 5.6% (1/18) in group 2, and 4.5% (1/22) in group 3 were positive. Group 1 showed 7.64 times higher positive bacterial culture rate after skin preparation than group 3 (p = 0.084)

Conclusion

During skin preparation prior to total knee replacement surgery, chlorhexidine gluconate paint after povidone-iodine scrub or povidone-iodine paint after chlorhexidine gluconate scrub had a superior effect on sterilizing native bacteria compared to povidone-iodine scrub-and-paint method.

Keywords

Osteoarthritis Total knee replacement Povidone-iodine Chlorhexidine gluconate Surgical drape

Introduction

Surgical site infection (SSI) is considered as one of the most severe postoperative complications, leading to the extension of hospital stay and increase in medical expenses, and even death.^1,2 Especially, SSI following total knee replacement (TKR) is a greater problem, and the incidence is increasing gradually.³ The Presence of bacteria at the surgical site is the most important risk factor and therefore it is essential to prevent direct inoculation of native bacteria through appropriate preoperative skin preparation.

Preoperative skin preparation requires appropriate antiseptic agent. Povidone-iodine (PVI) and chlorhexidine gluconate (CHG) are the most commonly used antiseptic agents.^4-6 Although several studies have assessed the efficacy of these agents, there is paucity of RCT on arthroplasty.

The purpose of this study was to examine the presence and type of native bacteria on the TKR incision site and to assess which skin preparation is most effective to sterilize those native bacteria. We evaluated and compared the efficacy of aqueous PVI and alcohol-based CHG as the most commonly used antiseptic agents in orthopedic surgery of extremities. We hypothesized that alcohol-based CHG is more effective than aqueous PVI. Scrub-and-paint 2 step method was used for standard preoperative skin preparation.^7-13

Methods

Patient population

This trial was approved by the institutional review board (approval number: CR-20-148) of our hospital and conducted in accordance with the declaration of Helsinki.

The study was a prospective randomized controlled trial of 150 osteoarthritis patients, treated primary TKR from 31 July 2020.

All subjects were informed and agreed voluntarily before the study. The exclusion criteria were: patients with open wound scar, repeated surgery at the same site, an ulcer or sore at the surgical site, acute or chronic systemic infection, and allergic to solution materials.

Patients were directed to take a shower the day before the surgery. Prior to preoperative skin preparation, the surgical site was shaved. A dry sponge and razor blade were used to remove all the foreign substances on the skin.

After routine antibiotic sensitivity screening, prophylactic intravenous antibiotics were injected 30 min before the skin incision. Patients having TKR were injected 2 g of cefazolin. Patients allergic to penicillin and/or cephalosporin were injected 1 g of vancomycin.

Skin preparation

This study used the most commonly used Ministry of Food and Drug Safety (MFDS) authorized antiseptic agents - PVP-I 10% in aqueous solution (Besetine Solution ®; Hyundai Pharm, Seoul, KOR) and CHG 2% and Ethanol 72% (Hexitanol ET 2% Solution ®; Firson, Cheonan, KOR).

A gauze soaked with first antiseptic agent was used to scrub the site for 5 min and wiped out with a blotting towel. After the skin was fully dried, the second agent was applied for 5 min and swabbed after it was fully dried.

Randomization and masking

The patients were grouped into 3 groups- Group 1 (PVI scrub-and-paint), Group 2 (CHG paint after PVI scrub), and Group 3 (PVI paint after CHG scrub), by block randomization. In our study, block randomization was used to allocate 50 people to each group. To maintain balance between groups, the block size was set to be 30. The blocked randomization list was generated by an independent observer not involved in this study. The randomization allocation was concealed in an envelope until arrival in the operation room. To assure allocation concealment, numbers were kept in sealed envelopes, which were opened by an independent observer to ensure masked blocking. After the independent observer completed all preparations including skin preparation, the investigator entered the operating room and performed surgery. Although skin preparation agents had different colors, iodine-impregnated drape was used after obtain a bacterial culture specimen to prevent investigators from distinguishing between 3 groups. The investigator and subjects were completely blinded to their randomization until completion of this study.

Analysis of culture

Bacterial culture specimen was obtained from the patella center, which is the incision site, with dry, sterile, cotton-tipped swabs. Every TKR operation used a midline skin incision and the medial parapatellar approach.

First, a bacterial culture specimen of 150 patients was obtained by swab from the patella center skin after using the preparation agents. In order to analyze the native bacteria at the TKR incision site, 88 additional swaps were performed before skin preparation. The swab was sealed and carried in a sterile transport container to a microbiology laboratory and incubated for 5 days.

To observe the positive rate of bacteria and classify each group, we used the following media: Sheep blood agar plate, for Gram positive, Gram negative, yeast, candida, etc. and MacConkey agar, for Pseudomonas, Acinetobacter, Salmonella, etc.

We also considered patient factors which can affect the positive rate of bacteria such as gender, age, body mass index (BMI), smoking, diabetes mellitus (DM), and corticosteroid use.

Statistical Analysis

Sample-size requirements were based on the findings of a prospective study evaluating positive cultures from the foot and ankle following surgical skin preparation.¹⁴ On the basis of the assumption that a 30% difference in positive culture rates would be clinically significant, the number of patients required to achieve 80% power at alpha = 0.05 was 45 patients per group. All the analyses were performed with IBM SPSS version 19.0 software (SPSS Inc., Chicago, IL) for Windows.

Descriptive statistics for all variables of interest were calculated. Continuous measures were summarized using means and standard deviations, whereas categorical measures were summarized using counts and percentages.

A Chi-square test was used on 3 groups to compare the positive rate of bacteria after skin preparation. Several patient factors and the presence of the bacteria were assessed by logistic regression analysis. A p value less than or equal to 0.05 was considered to be statistically significant.

Results

Analysis of bacterial culture before the skin preparation

There were no differences between patient characteristics (age, gender, BMI, smoking, DM, corticosteroid) between the Groups (Table 1). The positive rate of bacterial culture prior to skin preparation was 62.5% (55/88). Cultured bacteria were coagulase-negative Staphylococcus (38), Bacillus (11), and Micrococcus (6) (Figure 1).

Table 1.

Epidemiology of all patients.

Variable	Group1(N = 50)	Group2(N = 50)	Group3(N = 50)	Total (N = 150)	p Value
Age (years)	72.28±6.62	70.26±7.19	71.34±6.93	71.29±6.92	0.346
Gender (M/F)	(6/44)	(6/44)	(5/45)	(17/133)	0.937
Body Mass index (m/kg2)	25.76±3.33	25.32±4.47	25.82±3.77	25.64±3.87	0.785
Smoking (Yes/No)	(1/49)	(2/48)	(1/49)	(4/146)	0.777
DM (Yes/No)	(12/38)	(15/35)	(19/31)	(46/104)	0.318
Corticosteroid (Yes/No)	(5/45)	(10/40)	(5/45)	(20/130)	0.240

Abbreviations: N = number, M = male, F = female.

Group 1: PVI scrub-and-paint

Group 2: CHG paint after PVI scrub.

Group 3: PVI paint after CHG scrub.

Positive rates were 53.6% (15/28) in group 1, 62.1% (18/29) in group 2, 71.0% (22/31) in group 3. Before skin preparation, there was no statistically significant difference in bacterial positive rate between the three groups (p = 0.386).

Analysis of bacterial culture after the skin preparation

The positive rate of bacterial culture after skin preparation was 5.3% (8/150). Positive rates of the groups were 12% (6/50) in goup1, 2% (1/50) in group, 2 and 2% (1/50) in group 3.

Positive rates of bacterial culture after skin preparation in group 2 and group 3 were lower than in group 1 (p = 0.037) (Table 2), but there was no significant difference between group 2 and group 3. It is also worth noting that all the positive bacterial cultures after skin preparation were Bacillus species.

Table 2.

A chi-square test to identify the difference in positive isolates after skin preparation.

	Group 1	Group 2	Group 3	Total	p Value
Positive	6 (12.0%)	1 (2.0%)	1 (2.0%)	8 (5.3%)	0.037
Negative	44 (88.0%)	49 (98.0%)	49 (98.0%)	142 (94.7%)	0.037
Total	50 (100.0%)	50 (100.0%)	50 (100.0%)	150 (100.0%)	—

Group 1: PVI scrub-and-paint.

Group 2: CHG paint after PVI scrub.

Group 3: PVI paint after CHG scrub.

Analysis of positive bacterial culture rate after skin preparation in patients with bacteria before skin preparation.

Among the 55 patients who had positive bacterial culture prior to skin preparation, 26.7% (4/15) in group 1, 5.6% (1/18) in group 2, and 4.5% (1/22) in group 3 were positive. Group 1 showed 7.64 times higher positive bacterial culture rate after skin preparation than group 3 (p = 0.084), and group 2 was 1.24 times higher than group 3, but the difference was not statistically significant. (p = 0.884) (Table 3)

Table 3.

Multiple variables logistic regression analysis of the difference in positive isolates after skin preparation.

Group	Crude			Adjusted^a
Group	OR	95% CI for OR	p Value	OR	95% CI for OR	p Value
G1 Vs G2	7.636	0.758/76.897	0.084	5.353	1.059/27.060	0.042
G2 Vs G3	1.235	0.072/21.241	0.884	2.293	0.438/12.016	0.326

Abbreviation: OR = odds ratio, CI = confidence interval, G1 = Group 1, G2 = Group 2, G3 = Group 3.

Group 1: PVI scrub-and-paint

Group 2: CHG paint after PVI scrub; Group 3: PVI paint after CHG scrub

^aAdjusted by gender, DM.

Multivariate logistic regression analysis of positive bacterial culture rate

No factor had a significant effect on positive bacterial culture rate in the multivariate analysis performed with age, sex, BMI, smoking, DM, and corticosteroid use as a covariate.

For logistic regression analysis performed by selecting sex and DM for Forward conditional method, group 1 showed a 5.35 times higher positive bacterial culture rate than group 3 (p = 0.042). Group 2 was 2.29 times higher than group 3, but there was no statistical significance (p = 0.326) (Table 3).

Notably, men had 7.23 times higher positive bacterial culture rate than women after skin preparation (p = 0.004). DM patients had a 3.16 times higher rate than those without DM, but there was no statistical significance (p = 0.080) (Table 4).

Table 4.

Analysis of multiple variables effects for positive isolates after skin preparation.

Variable	Adjusted OR (95% CI)	p Value
Gender	7.234 (1.895/27.620)	0.004^a
DM	3.162 (0.873/11.456)	0.080

Abbreviation: OR = odds ratio, CI = confidence interval.

^ap value less than or equal to 0.05 was considered to indicate statistical significance.

Discussion

Infection after TKR is one of the most serious complications,¹⁵ which leads to increased treatment costs and mortality. Therefore, it is important to prevent infections. Since 2/3 of SSI is localized at the incision site¹⁶ surgical site skin preparation with antiseptic solution before surgical incision is an important infection prevention measure. However, it is not clear which antiseptic skin preparation is the most effective in preventing infection, and therefore further research is required.

Currently, PVI and chlorhexidine gluconate (CHG) are the most commonly used preoperative skin antiseptics,^4-6,17 and povidone-iodine is the most commonly used surgical skin preparation agent in orthopedic surgery.

PVI works as an antibiotic that has an affinity to bacterial cell membranes, rapidly penetrates into micro-organisms, and induces cell death by inhibiting microbial protein synthesis required for survival.¹⁸

CHG changes osmotic equilibrium by binding to bacterial cell wall surface which is negatively charged. It changes the permeability of the cell wall thereby inducing leakage of the cytoplasmic component which makes bacterial apoptosis.¹⁹ Alcohol-based CHG is more commonly used in skin preparation since it dries quickly and has a better disinfection effect.⁸

Although studies have shown that the paint-only one-step method is equally effective against bacteria compared to the traditional two-step and pre-operative skin preparation methods,^20,21 it is still controversial, and currently, most hospitals use the traditional two-step scrub-and-paint method.^7,8

While several studies have shown that Alcohol-based PVI is less effective does not lower SSI risk compared to aqueous PVI^22,23 other studies have shown that alcohol-based CHG is superior to aqueous PVI in skin disinfection at the surgical site,^7-10 but many studies have shown that there is no significant difference.^11-13

Bibbo et al.⁷ have found that chlorhexidine-alcohol is superior to povidone-iodine in reducing bacterial carriage in foot and ankle surgeries. In the povidone-iodine preparation group of this study, 53 (79%) of 67 patients had positive cultures after skin preparation. In the chlorhexidine-alcohol preparation group, only 23 (38%) of 60 patients had positive culture after skin preparation. Overall, the povidone-iodine preparation group had more positive culture than the chlorhexidine-alcohol preparation group.

On the other hand, Rodrigues et al.¹¹ have found similar incidence of SSI in operations classified as clean or potentially contaminated for which skin preparation was done with povidone-iodine and chlorhexidine-alcohol. Seven of 102 patients in the povidone-iodine group and 11 of 103 patients in the chlorhexidine-alcohol group undergoing clean and potentially contaminated operation turned out to have SSI. Thus, there was no superiority of one antiseptic solution over the other.

Therefore, the author divided the patients who underwent TKR by one surgeon into three groups (PVI scrub and paint, CHG paint after PVI scrub, and PVI paint after CHG scrub groups) to access which agent was the most effective in sterilizing native bacteria on TKR incision site. Patients in each group were sterilized by verified preoperative skin preparation antiseptic agents, aqueous PVI, and Alcohol-based CHG. The use of PVI and CHG interchangeably was more effective than PVI alone in reducing bacteria after skin preparation.

There was bacterial culture prior to skin preparation, 62.5% (55/88) were cultured. The cultured bacteria were coagulase-negative Staphylococcus (38), Bacillus (11), and Micrococcus (6) in the order. There was also bacterial culture after skin preparation, 5.3% (8/150) were cultured, which were all bacillus species.

Bacillus species are a type of bacteria that exists in any environment. In the past, it was considered pollutants or non-pathogenic organisms.²⁴ However, cases were reported that Bacillus species cause infection in orthopedic surgery,²⁵ and cases of infection after knee surgery have also been reported. So this bacteria cannot be taken lightly.²⁶

In the bacterial culture performed after skin preparation, there was a statistically significant difference in the positive rate between group 1 (6/50) and groups 2 (1/50), and 3 (1/50).

We thought it was important to compare the positive bacteria culture rate after skin preparation in patients with bacteria before skin preparation to see the antiseptic effect of skin preparation. Our results showed that group 1 had 7.64 times higher positive bacterial culture rate after skin preparation than group 3 (p = 0.084), and group 2 was 1.24 times higher than group 3. However, the difference was not statistically significant (p = 0.884) (Table3)

Gender is an important factor in determining the microorganisms colonizing human skin.²⁷ Several studies have shown that there is a sex difference in the flora of organisms living in the skin due to the difference in sebum excretion, a sexual hormone, and skin surface pH.^28,29 In fact, there are more bacteria present in males’ skin than in females’ skin.²⁷ Also, several studies have shown that diabetes is a risk factor for surgical site infection.³⁰

Since no factor had a significant effect on positive bacterial culture rate in the multivariate analysis performed with age, sex, BMI, smoking, DM, and corticosteroid use as a covariate, logistic regression analysis was performed by selecting sex and DM for forward conditional method.

Our study showed that men had 7.23 times more positive bacterial culture rate after skin preparation than women. Diabetic patients had a 3.16 times higher positive rate than non-diabetic patients. But the difference was not statistically significant (p = 0.080)

The present study has several limitations. First, culture specimens obtained before applying skin preparation agent were from only 88 patients, which could affect the actual bacterial positive culture rate. Second, in our study, there was no control over the false positive or false negative. Third, we used qualitative culture data to access the effect of skin preparation. In the future, studies including quantitative cultures should be conducted. Forth, there are many factors involved in the occurrence of clinical infection but were not considered in this study. However, a positive bacteria culture at the surgical incision site will certainly have a negative impact on infection, unlike a negative culture.

Despite these limitations, the strong point of this study is, to the best of our knowledge, the first study to reveal the native bacteria present in the knee region and show an effective skin preparation method.

Conclusion

During skin preparation prior to TKR surgery, CHG paint after PVI scrub or PVI paint after CHG scrub had a superior effect on sterilizing native bacteria compared to PVI scrub-and-paint method. Also, more attention is needed for male patients since men had a higher bacterial positive culture rate than women after skin preparation.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Catholic University of Daegu (The grant of Research Institute of Medical Science).

ORCID iDs

Won-Kee Choi

Suk-Kyoon Song

References

De Lissovoy

Fraeman

Hutchins

, et al. Surgical site infection: incidence and impact on hospital utilization and treatment costs. Am J Infect Control 2009; 37: 387–397.

Astagneau

Rioux

Golliot

INCISO Network Study Group , et al. Morbidity and mortality associated withsurgical site infections: results from the 1997–1999 INCISO surveillance. J Hosp Infect 2001; 48: 267–274.

Kunutsor

Whitehouse

Blom

INFORM Team , et al. Patient-related risk factors for periprosthetic joint infection after total joint arthroplasty: a systematic review and meta-analysis. PloS One 2016; 11: e0150866.

Digison

. A review of anti-septic agents for pre-operative skin preparation. Plast Surg Nurs 2007; 27: 185–189.

Edmiston

Jr Okoli

Graham

, et al. Evidence for using chlorhexidine gluconate preoperative cleansing to reduce the risk of surgical site infection. AORN Journal 2010; 92: 509–518.

Chen

Guo

, et al. Preoperative antisepsis with chlorhexidine versus povidone-iodine for the prevention of surgical site infection: a systematic review and meta-analysis. World J Surg 2020; 44: 1412–1424.

Bibbo

Patel

Gehrmann

, et al. Chlorhexidine provides superior skin decontamination in foot and ankle surgery: a prospective randomized study. Clin Orthop Relat Res 2005; 438: 204–208.

Darouiche

Wall

Jr Itani

KMF

, et al. Chlorhexidine–alcohol versus povidone–iodine for surgical-site antisepsis. N Engl J Med 2010; 362: 18–26.

Johnson

Daley

Zywiel

, et al. Preoperative chlorhexidine preparation and the incidence of surgical site infections after hip arthroplasty. J Arthroplasty 2010; 25: 98–102.

10.

Bebko

Green

Awad

. Effect of a preoperative decontamination protocol on surgical site infections in patients undergoing elective orthopedic surgery with hardware implantation. JAMA Surg 2015; 150: 390–395.

11.

Rodrigues

Simoes

MdLPB

. Incidence of surgical site infection with pre-operative skin preparation using 10% polyvidone-iodine and 0.5% chlorhexidine-alcohol. Rev Col Bras Cir 2013; 40: 443–448.

12.

Srinivas

Kaman

Raj

, et al. Comparison of the efficacy of chlorhexidine gluconate versus povidone iodine as preoperative skin preparation for the prevention of surgical site infections in clean-contaminated upper abdominal surgeries. Surg Today 2015; 45: 1378–1384.

13.

Paocharoen

Mingmalairak

Apisarnthanarak

. Comparison of surgical wound infection after preoperative skin preparation with 4% chlorhexidine [correction of chlohexidine] and povidone iodine: a prospective randomized trial. Medical Journal of the Medical Association of Thailand 2009; 92: 898–902.

14.

Ostrander

Botte

Brage

. Efficacy of surgical preparation solutions in foot and ankle surgery. J Bone Joint Surg Am 2005; 87: 980–985.

15.

Kurtz

Lau

Watson

, et al. Economic burden of periprosthetic joint infection in the United States. J Arthroplasty 2012; 27: 61–65.

16.

Mangram

Horan

Pearson

, et al. Guideline for prevention of surgical site infection, 1999. Infect Control Hosp Epidemiol 1999; 20: 247–280.

17.

Mulberrry

Snyder

Heilman

, et al. Evaluation of a waterless, scrubless chlorhexidine gluconate/ethanol surgical scrub for antimicrobial efficacy. Am J Infect Control 2001; 29: 377–382.

18.

Fleischer

Reimer

. Povidone-iodine in antisepsis–state of the art. Dermatology 1997; 195 Suppl 2: 3–9.

19.

Perl

Milstone

Passaretti

Chlorhexidine: expanding the armamentarium for infection control and prevention. Clin Infect Dis 2008; 46: 274–281.

20.

Ellenhorn

JDI

Smith

Schwarz

, et al. Paint-only is equivalent to scrub-and-paint in preoperative preparation of abdominal surgery sites. J Am Coll Surg 2005; 201: 737–741.

21.

Gilliam

Nelson

. Comparison of a one-step iodophor skin preparation versus traditional preparation in total joint surgery. Clin Orthop Relat Res 1990: 250, 258–260.

22.

Saltzman

Nuber

Gryzlo

, et al. Efficacy of surgical preparation solutions in shoulder surgery. J Bone Joint Surg Am 2009; 91: 1949–1953.

23.

Hort

DeOrio

. Residual bacterial contamination after surgical preparation of the foot or ankle with or without alcohol. Foot Ankle Int 2002; 23: 946–948.

24.

Ashkenazi-Hoffnung

Kaufman

Bromberg

, et al. Seasonality of Bacillus species isolated from blood cultures and its potential implications. Am J Infect Control 2009; 37: 495–499.

25.

Ryan

Kavanagh

Wall

, et al. Bacterial joint infections in England and Wales: analysis of bacterial isolates over a four year period. Br J Rheumatol 1997; 36: 370–373.

26.

Wiedermann

Stockner

Plattner

. Bacillus species infective arthritis after knee arthroscopy. Surg Infect 2010; 11: 555–558.

27.

Marples

. Sex, constancy, and skin bacteria. Arch Dermatol Res 1982; 272: 317–320.

28.

Kim

M-K

Patel

Shinn

, et al. Evaluation of gender difference in skin type and pH. J Dermatol Sci 2006; 41: 153–156.

29.

Zouboulis

Chen

W-C

Thornton

, et al. Sexual hormones in human skin. Hormone and Metabolic Research 2007; 39: 85–95.

30.

Martin

Kaye

Knott

, et al. Diabetes and risk of surgical site infection: a systematic review and meta-analysis. Infect Control Hosp Epidemiol 2016; 37: 88–99.