Effectiveness of surgical skin preparation solutions in orthopaedic surgery: A systematic review of the current comparative literature

Abstract

BACKGROUND

Surgical site infection (SSI) is a major concern in orthopaedic surgery procedures as they can have devastating consequences for patients and their outcomes. Many infection prevention measures are routinely taken in order to prevent infection during surgery, the main one being surgical skin preparation prior to any incision.

AIM

To investigate the efficacy of different perioperative surgical skin preparation products commonly used in orthopaedic surgery.

METHODS

Seven databases were searched from inception to January 25, 2025, using a combination of keywords and medical subject headings terms, specifically for studies comparing any two surgical skin preparation products used at any point prior to skin incision for orthopaedic procedures. Titles and abstracts were screened and full texts reviewed based on inclusion criteria. Data was extracted on study design, interventions, and outcomes from studies that met inclusion criteria. Meta-analysis was not completed due to heterogeneity.

RESULTS

Thirty-two studies met the inclusion criteria in this systematic review. In extremity fracture surgery, evidence was mixed on whether iodine or chlorhexidine-based solutions are more effective at preventing SSI. No significant difference was found between iodine and chlorhexidine-based solutions in total joint arthroplasty, spine surgery, foot and ankle surgery, or upper extremity surgery. No tested preparation method was superior in reducing positive Cutibacterium acnes culture rates in upper extremity (shoulder) surgery. Adding adjuncts to iodine and chlorhexidine methods, such as isopropyl alcohol, hydrogen peroxide, or benzoyl peroxide showed no significant changes to SSI or bacterial cultures.

CONCLUSION

Current literature shows no significant difference between chlorhexidine-based and iodine-based skin preparation solutions in orthopaedic extremity or spine surgery regarding SSI prevention or culture results. Likewise, adding other antiseptic agents provided no clear benefit. While skin antisepsis is important, many different factors contribute to SSI risk outside of the skin preparation solution.

Key Words: Surgical skin prep; Orthopaedics; Iodine; Chlorhexidine; Infection

Core Tip: Perioperative surgical skin preparation techniques were found to be equivalent between iodine and chlorhexidine-based solutions in multiple orthopaedic surgery settings. Perioperative surgical skin preparation still remains critical for infection prevention in orthopaedic surgery. Surgeons may use their preference and surgical expertise for choosing the appropriate surgical skin preparation solution, as the current literature does not support a superior skin preparation solution.

INTRODUCTION

Surgical site infection (SSI) is one of the most significant complications in orthopaedic surgery[1,2]. SSIs can have devastating consequences for patients, including hardware failure[3], sepsis bacteremia[4], destruction of the bone and soft tissue structure[5], and even loss of limb[6]. SSIs are often difficult to diagnose and treat, and management often requires a multidisciplinary team to ensure appropriate infection eradication and reconstruction[7,8]. In addition, adverse patient outcomes, SSI in orthopaedic surgery has been shown to cost billions of dollars annually to the healthcare system in the United States[9-11]. Prevention of SSI remains a significant challenge for orthopaedic surgeons, despite surgeons routinely taking several preventative measures. Some of these measures include optimizing patient overall health status and nutrition, using perioperative antibiotics[12], using sterile techniques[13], and preparation of the surgical skin site[14].

Various techniques are utilized in performing a sterile surgical skin preparation during the preoperative period[14]. In some cases, surgeon or institutional protocol dictates a “pre-scrub” be performed of the surgical site in the preoperative holding area prior to entering the operating room, while others do not. Regardless, an antiseptic skin preparation is performed in the operating room immediately before draping the patient sterilely[15]. Various antiseptic products are used for skin preparation, including chlorhexidine gluconate in isopropyl alcohol, povidone-iodine solutions, or a combination of these items[16]. These products often times come in either the form of an alcohol based prep stick or aqueous solution paint application methods. These products are seen as critical in preventing SSI in orthopaedic surgery. A number of studies have evaluated these products and their role in preventing infection in orthopaedic surgery across several anatomic regions[16]. However, debate exists among orthopaedic surgeons regarding which skin preparation product is most effective for preventing SSIs.

Different anatomic regions of the body may have different bacterial strains present. One particularly challenging region is the shoulder, which harbors a high prevalence of Cutibacterium acnes (C. acnes)[17,18], the most common cause of shoulder prosthetic infections[19]. C. acnes are challenging to eradicate and slow to grow in culture (often taking up to two weeks to appear), making shoulder infections hard to identify and treat promptly[17-19]. Another challenging area is the foot, where numerous organisms reside around nails and interdigital spaces[20]. The toenails, sin crevices, pH, and distribution of sweat glands of the foot create a unique microbiome[20]. Feet are difficult to disinfect adequately, presenting a challenge for foot and ankle surgeons in preventing SSI. Understanding how to prepare these unique anatomic regions properly is critical to prevent SSIs of these regions. It remains unclear if any single perioperative skin preparation product is superior at preventing SSI in orthopaedic surgery. Therefore, this systematic review aims to evaluate the literature that compares various sterile surgical skin preparation products used prior to skin incision in orthopaedic surgery for preventing SSI. We hypothesized that no single preparation would be significantly more effective than others in this regard.

MATERIALS AND METHODS

Study design

The study was exempt from institutional review board approval. This systematic review followed the preferred reporting items for systematic review and meta-analysis statement standards[21]. Meta-analysis was not conducted due to the numerous variations and variables among the studies that met the inclusion criteria.

Eligibility criteria

Studies were eligible for inclusion if they met the following criteria: (1) Studies were comparative studies evaluating skin preparation techniques in orthopaedic surgery; (2) Preoperative application of the preparation; and (3) Reported outcomes related to SSI rates or bacterial colonization/culture results. We excluded review articles, commentaries, letters, and studies of preoperative skin decontamination outside the immediate preoperative period, such as at-home washes or prolonged preoperative protocols.

Search strategy

PubMed/MEDLINE, Wiley, Cochrane Central, Google Scholar, Web of Science, Clinicaltrials.gov, and Embase databases were systematically searched for publications from inception until January 25, 2025. Search was limited to English-language studies. Comprehensive search strategies were developed using keywords, medical subject headings terms, and synonymous terms. The PubMed/MEDLINE search was adapted to the other databases. Supplementary Table 1 for the complete database search.

Study selection

One author (Puga TB) performed the search. Two authors (Haechten T and Qureshi I) excluded irrelevant articles and duplicates based on title and abstract. The remaining articles underwent an independent full-text review by two authors (Haechten T and Qureshi I) and were assessed for eligibility based on established criteria. Any conflicts were resolved by discussion among a third author (Puga TB).

Data extraction

Two authors (Haechten T and Qureshi I) independently extracted data from each included study using a standardized form. Extracted data included study characteristics (lead author, year, country), study design and level of evidence, sample size, details of the surgical skin preparations compared, and outcomes measured, as well as key findings. The two data sets were cross-checked for accuracy, and any discrepancies were resolved by the lead author (Puga TB).

Quality assessment

The Cochrane risk of bias 2 (ROB-2) for randomized control trials was used to evaluate clinical trial studies[22]. This risk of bias tool is composed of five domains which evaluates bias within randomized clinical trials. The bias is classified into three categories: High, some concern, and low. An overall bias assessment is produced upon the combination of the five domains. The methodological quality of the nonrandomized studies included in the review was evaluated using the methodological index for non-randomized studies (MINORS) criteria for comparative studies[23]. The MINORS criteria for non-comparative studies uses a validated 12-item checklist for comparative studies to ensure a critical appraisal of the study design through a standardized assessment. A maximum of 24 points is possible for comparative studies, and studies with scores less than 14 were considered poor quality.

Data synthesis

We did not perform a meta-analysis due to the substantial heterogeneity of interventions and outcomes across studies. Results are summarized narratively by anatomic region and surgery type. Where appropriate, we have summarized the range of effects observed but did not pool quantitative data.

RESULTS

Preferred reporting items for systematic review and meta-analysis flow diagram

A preliminary search of seven databases provided 3114 studies, and 1455 duplicates were removed. One thousand six hundred fifty-nine abstracts and titles were screened, and 1599 were removed for lack of relevance. Sixty reports were sought for retrieval. Thirty-two studies met the final inclusion criteria and were included in this study (Figure 1).

Figure 1 Preferred reporting items for systematic review and meta-analysis flowchart.

Studies evaluating multiple anatomical regions

Three studies evaluated more than one surgical anatomic region[24-26]. A level 3 retrospective cohort study published by Beber et al[24] that compared unspecified concentrations of chlorhexidine vs povidone-iodine in pediatric orthopaedics. This study found that there was no difference in SSI between the chlorhexidine and povidone-iodine groups for spine, hip, or lower extremity surgeries[24]. However, this study found a significant decrease in SSI when using povidone-iodine in “sports and upper extremities”[24]. A level 1 trial published by Sprague et al[25] that compared aqueous chlorhexidine vs aqueous iodine for open and closed fractures of the upper and lower extremities. This study found no difference in the number of SSI’s when using either aqueous chlorhexidine or iodine[25,26]. The study evaluated closed pelvis, acetabulum, and lower extremity fractures. In addition to the closed fractures, this study separately evaluated open upper and lower extremity fractures[25]. There was a significant decrease in SSI when using povidone-iodine for closed fractures, but no difference in open fractures (Table 1).

Table 1 Surgical skin preparation demographics and results of studies evaluating more than one anatomical area.

Ref.	Level of evidence	Surgery type	Sample size (n)	Interventions	Comparisons	Key findings
Beber et al[24], 2022, United States	Retrospective cohort (level 3)	Pediatric sports/UE, pediatric trauma, pediatric hip and LE	1416	2% chlorhexidine gluconate in 70% isopropyl alcohol (U); povidone-iodine (U, concentration unspecified)	SSI between the two cohorts	No difference in SSI was noted for all procedures between the two cohorts; no difference in SSI was noted for spine or hip/LE procedures between the two cohorts; in sports/UE procedures, povidone-iodine had a significantly lower rate of SSI (P = 0.005)
Sprague et al[25], 2024, United States	Randomized crossover trial (level 1)	Open upper and lower extremity fractures	1638	Aqueous 4% chlorhexidine gluconate (P); aqueous 10% povidone-iodine (P)	Comparing SSI between the preparation cohorts	No statistical difference in SSI between the two preparation cohorts
Sprague et al[25], 2024, United States	Randomized control trial (level 1)	Closed pelvis/acetabulum and lower extremity fractures, open upper and lower extremity fractures	8485	2% chlorhexidine gluconate in 70% isopropyl alcohol (S); 0.7% iodine povacrylex in 74% isopropyl alcohol (S)	Comparing SSI between the preparation cohorts	Closed fractures using iodine povacrylex resulted in lower odds of an SSI when compared with the chlorhexidine group (P = 0.049); in open fractures, there was no difference in SSI between the two preparation cohorts

UE: Upper extremity; LE: Lower extremity; S: Stick application; P: Paint application; U: Unspecified application method; SSI: Surgical site infection.

Lower extremity (hip and knee)

Six studies focused on lower extremity surgeries, primarily hip and knee arthroplasty and fracture management (Table 2). Overall, none showed a clear advantage of one prep solution over another in lower extremity surgery. A level 1 randomized trial published by Cho et al[27] that compared isolated povidone-iodine vs povidone-iodine with chlorhexidine in total knee arthroplasty. This study found that isolated povidone-iodine had a significantly higher number of positive cultures than the povidone-iodine and chlorhexidine combination. A level 1 trial published by Droll et al[28] that compared chlorhexidine vs iodophor in total hip arthroplasty, and showed that iodophor skin preparation resulted in a significantly lower risk of having a positive culture. A prospective comparative study published by Rouquette et al[29] that compared iodine vs chlorhexidine along with drape types in volunteers, and found no difference in positive cultures. A level 1 randomized trial published by Morrison et al[30] that evaluated an additional application of iodine povacrylex after draping in total joint arthroplasty (TJA), and found that this additional application led to a decrease in SSI. A level 1 randomized trial published by Peel et al[31] that compared chlorhexidine vs iodine in total knee arthroplasty, and found that chlorhexidine led to a significantly higher risk of SSI. A level 1 trial published by Ritter et al[32] that compared chlorhexidine vs iodine in lower extremity fractures. This study found a significantly higher number of SSI’s and wound complications in the chlorhexidine group[32].

Table 2 Surgical skin preparation demographics and results of studies evaluating lower extremity surgery.

Ref.	Level of evidence	Surgery type	Sample size (n)	Interventions	Comparisons	Key findings
Cho et al[27], 2023, China	Randomized control trial (level 1)	Total knee arthroplasty	150 (50 per group)	10% povidone-iodine scrub-and-paint (P); 2% chlorhexidine gluconate in 72% ethanol paint after povidone-iodine scrub (P); 10% povidone-iodine paint after 2% chlorhexidine gluconate in 72% ethanol scrub (P)	Post preparation culture swabs between the groups	Povidone-iodine scrub-and-paint group had positive cultures in 12% of patients; chlorhexidine gluconate paint after povidone-iodine scrub had positive cultures in 2%; povidone-iodine paint after chlorhexidine gluconate had positive cultures in 2%; isolated povidone-iodine scrub-and-paint had a significantly higher number of positive cultures (P = 0.037)
Droll et al[28], 2022, Canada	Randomized control trial (level 1)	Total hip arthroplasty	105	2% chlorhexidine gluconate in 70% isopropyl alcohol (S); 0.7% iodophor in 74% isopropyl alcohol (S)	Comparison of cultures pre-preparation and post-preparation	The pre-preparation chlorhexidine group had positive cultures in 93% of patients, and the iodophor group had positive cultures in 94% of patients; after preparation, the iodophor had a lower relative risk of a positive culture than the chlorhexidine group (RR = 0.40, 95%CI: 0.18-0.85)
Rouquette et al[29], 2020, France	Prospective cohort study (level 2)	Thigh sampling of lower extremity volunteers	30	5% povidone-iodine in 95% ethanol with adhesive polyester draping (U); 5% povidone-iodine in 95% ethanol with adhesive iodine draping (U); 0.5% chlorhexidine in 90% ethanol with adhesive polyester draping (U); 0.5% chlorhexidine in 90% ethanol with adhesive iodine draping (U)	Culture growth at 30 minutes intervals up to 90 minutes after draping	No protocols demonstrated superiority in reducing bacterial load
Morrison et al[30], 2016, United States	Randomized control trial (level 1)	Total joint arthroplasty	600	7.5% povidone-iodine scrub, followed by 10% iodine paint, and 75% isopropyl alcohol (P); preparation of group one plus 0.7% iodine povacrylex in 74% isopropyl alcohol after draping (S)	Rate of SSI and blistering between the groups	The intervention group with the additional intervention after draping had significantly lower superficial SSI (P = 0.02); the intervention group had lower rates of blistering, but this was not statistically significant
Peel et al[31], 2019, Australia	Randomized control trial (level 1)	Total joint arthroplasty	780	0.5% chlorhexidine gluconate in 70% ethanol (S); 1% iodine in 70% ethanol (S)	Postoperative SSI and superficial wound complications	No difference in superficial wound complications between the chlorhexidine and iodine-based groups; significantly higher odds of SSI in the chlorhexidine group when compared with the iodine group (OR = 3.55; 95%CI: 1.20-10.44; P = 0.022)
Ritter et al[32], 2020, Germany	Randomized control trial (level 1)	Lower limb fractures	279	2% chlorhexidine in 70% isopropyl alcohol (S); 1% povidone-iodine in 50% 2-propanol (S)	Postoperative SSI and wound healing disorders	The povidone-iodine group had significantly higher rates of SSI and wound healing disorders than the chlorhexidine group (P = 0.022)

S: Stick application; P: Paint application; U: Unspecified application method; SSI: Surgical site infection; RR: Risk ratio; CI: Confidence interval; OR: Odds ratio.

Foot and ankle

Nine studies were included that evaluated foot and ankle surgery. Three studies found that addition of isopropyl alcohol reduced the incidence of positive skin bacterial cultures in foot and ankle surgery, but there was no difference in the rate of SSI[33-37]. Keblish et al[36] combined the use of bristled brushes in addition to the isopropyl alcohol. However, a level 1 clinical trial published by Mehraban et al[37] found that the addition of isopropyl alcohol had no difference in positive culture rates in foot and ankle surgery.

Chlorhexidine vs iodine in foot and ankle surgery

Two level 1 randomized clinical trials found that the use of chlorhexidine when compared with iodine had a lower number of positive cultures in foot and ankle surgery[38-41]. One of those studies, Ostrander et al[38] found that this decrease in positive cultures was found at both the hallux and between the fourth and fifth toes. However, contrary to the findings of these two level 1 studies, three other level 1 studies found that chlorhexidine when compared with iodine had no statistically significant difference in the rate of positive cultures in foot and ankle surgery[39] (Table 3).

Table 3 Surgical skin preparation demographics and results of studies in foot and ankle surgery.

Ref.	Level of evidence	Surgery type	Sample size (n)	Interventions	Comparisons	Key findings
Becerro de Bengoa Vallejo et al[33], 2009, Spain	Prospective randomized comparative study (level 2)	Foot	28	4% chlorhexidine gluconate scrub for 5 minutes + 70% isopropyl alcohol paint (P); 7.5% povidone-iodine scrub for 5 minutes + 10% povidone-iodine paint (P); prewash with 70% isopropyl alcohol for 3 minutes + 7.5% povidone-iodine scrub for 5 minutes + 10% povidone-iodine paint (P); 4% chlorhexidine gluconate immersion + prewash with 70% isopropyl alcohol for 3 minutes + 7.5% povidone-iodine scrub for 5 minutes + 10% povidone-iodine paint (P)	Culture growth of nail fold and first web space	The nailfold remained contaminated regardless of preparation type; the addition of alcohol may reduce the bacterial load in foot surgery, however, study results are limited due to lack of measurement of clinical infections
Cheng et al[34], 2009, United Kingdom	Randomized control trial (level 1)	Forefoot surgery	50	0.5% chlorhexidine gluconate in 70% isopropyl alcohol (S); 1% povidone-iodine in 23% isopropyl alcohol (S)	Culture growth before and after skin preparation	No significant difference in colony growth between skin preparation methods
Hunter et al[35], 2016, United States	Randomized control trial (level 1)	Foot and ankle surgeries	95	4% chlorhexidine application followed by 70% isopropyl alcohol rinse (P); 70% isopropyl alcohol followed by 4% chlorhexidine (P)	Cultures and postoperative SSI between the cohorts	The alcohol followed by chlorhexidine group showed a significant difference in positive cultures after draping (P = 0.02) and postoperatively (P = 0.05); there was no difference in SSI between the two cohorts
Keblish et al[36], 2005, United States	Randomized control trial (level 1)	Foot and ankle of volunteers	50	10% povidone-iodine alone (P); 10% povidone-iodine alone and 70% isopropyl alcohol pre-wash (P); 10% povidone-iodine and scrubbing with bristled brush (P); 70% isopropyl alcohol and scrubbing with bristled brush (N/A)	Cultures of hallux nailfold, interdigital web spaces, and anterior ankle	1.70% isopropyl alcohol and scrubbing with bristled brush showed a significant reduction in positive cultures from the nail-fold when compared with other preparation methods (P < 0.001); quantitative analysis found that bristled brushes had a significant decrease in heavy growth when compared to no bristles (P < 0.01)
Mehraban et al[37], 2021, United States	Randomized control trial (level 1)	Foot and ankle surgery	242	70% isopropyl alcohol followed by 2% chlorhexidine in 70% isopropyl alcohol (S); 7.5% povidone-iodine followed by 70% isopropyl alcohol followed by 2% chlorhexidine in 70% isopropyl alcohol (P + S)	Culture taken from the hallux nailfold	There was no significant difference in culture rate between cohorts
Ostrander et al[38], 2005, United States	Randomized control trial (level 1)	Foot and ankle surgery	125	2% chlorhexidine gluconate in 70% isopropyl alcohol (S); 0.7% iodine in 74% isopropyl alcohol (S); 3% chloroxylenol (S)	Culture at the toe and hallux sites	The chlorhexidine culture was significantly lower at both hallux (P = 0.01) and small toe site (P = 0.05) than the iodine group, and the iodine group was significantly lower than chloroxylenol (P = 0.001)
Rugpolmuang et al[39], 2012, Thailand	Randomized control trial (level 1)	Foot of volunteers	20	4% chlorhexidine gluconate scrub then painted with 2% chlorhexidine in 70% alcohol (P + S); 7.5% povidone-iodine scrub then painted with 10% povidone-iodine (P)	Cultures taken from toes, nail fold, interdigital spaces	There was no significant difference in culture rate between cohorts
Shadid et al[40], 2019, Netherlands	Randomized control trial (level 1)	Foot surgery	49	0.5% chlorhexidine with 70% isopropyl alcohol (S); 1% iodine with 70% isopropyl alcohol (S)	Cultures, complications and postoperative SSI between cohorts	There was no significant difference in SSI, complications or cultures between cohorts
Talhaoğlu and Çürük[41], 2023, Türkiye	Randomized trial (level 1)	Diabetic foot debridement	60	0.05% chlorhexidine gluconate before and after debridement, 10% povidone iodine (P + S); 10% povidone iodine (P)	Cultures taken after debridement	Microbial growth was 46.7% in the chlorhexidine group after debridement and 83.3% in the iodine alone group (P = 0.05); the mean number of species per foot was reduced in the chlorhexidine group (P = 0.05)

S: Stick application; P: Paint application; P + S: Paint and stick; N/A: Not applicable; SSI: Surgical site infection.

Upper extremity (shoulder and hand)

Nine studies evaluating surgical skin preparation in the upper extremity were included in this review[42-50]. A prospective level 2 study published by Blonna et al[42] found that the addition of chlorhexidine to povidone-iodine led to a significant decrease in positive coagulase negative Staphylococci cultures. Two studies compared chlorhexidine vs iodine in upper extremity surgery and found both products led to a decrease in positive cultures for aerobic and anaerobic types of bacteria[44,47]. However, none of these studies found any difference in the positive culture rate for C. acnes. Wade et al[51] was a prospective cohort study that compared aqueous chlorhexidine vs aqueous iodine in emergent and elective upper extremity surgery. This study found that there was a significant decrease in SSI with the use of aqueous chlorhexidine for elective upper extremity surgery. It also found that aqueous iodine had a significant decrease in SSI in emergency upper extremity surgery. Three studies evaluated the addition of hydrogen peroxide in shoulder surgery, and found no difference in positive culture rates of C. acnes or SSI[43,46,50]. Hancock et al[45] evaluated the addition of benzoyl peroxide and also found no difference in the positive culture rates of C. acnes. A level 1 randomized control trial published by Xu et al[49] compared chlorhexidine vs iodine in hand surgery and found that iodine had a significantly lower rate of positive cultures when compared with chlorhexidine (Table 4).

Table 4 Surgical skin preparation demographics and results of studies evaluating upper extremity surgery.

Ref.	Level of evidence	Surgery type	Sample size (n)	Interventions	Comparisons	Key findings
Blonna et al[42], 2018, Italy	Prospective comparative study (level 2)	Proximal humerus fracture	40	1% povidone iodine in 50% isopropyl alcohol (P); 4% chlorhexidine followed by 1% povidone iodine in 50% isopropyl alcohol (P)	Comparison of positive culture rates	The 4% chlorhexidine followed by 1% povidone iodine in 50% isopropyl alcohol produced a significant decrease in positive coagulase-negative Staphylococci cultures when compared to the single preparation (P < 0.001)
Crutcher et al[43], 2024, United States	Randomized control trial (level 1)	Shoulders of volunteers	72	2% chlorhexidine in 70% isopropyl alcohol alone (S); 3% hydrogen peroxide followed by 2% chlorhexidine in 70% isopropyl alcohol (S)	Comparison of culture growth for C. acnes	No statistically significant difference in culture rate between the two interventions
Dörfel et al[44], 2021, Germany	Prospective crossover (level 2)	Shoulders of volunteers	16	2% chlorhexidine in 70% isopropyl alcohol (S); 3.24% povidone-iodine in 38.9% isopropyl alcohol and 37.3% ethanol (P)	Comparison of culture growth for aerobic and anaerobic bacteria	Aerobic skin flora was significantly reduced by povidone-iodine at 2.5 minutes of application than chlorhexidine (P = 0.04), but not at thirty minutes or three hours; anaerobic skin flora was significantly reduced by povidone-iodine at 2.5 minutes (P < 0.01) and 30 minutes (P < 0.01) of application than chlorhexidine, but not at three hours
Hancock et al[45], 2018, New Zealand	Randomized control trial (level 1)	Shoulder of volunteers	22	Two applications of 2% chlorhexidine in alcohol (S); 5% benzoyl peroxidase wash + 2% chlorhexidine in alcohol (S)	Comparison of culture growth for C. acnes of the anterior deltoid and axilla	No statistically significant difference in culture growth between the two groups
Mizels et al[46], 2024, United States	Prospective comparative study (level 3)	Total shoulder arthroplasty	61	70% ethyl alcohol followed by two applications of 2% chlorhexidine in 70% isopropyl alcohol (S); 70% ethyl alcohol followed by hydrogen peroxide followed by two applications of 2% chlorhexidine in 70% isopropyl alcohol (S)	Comparison of patient reported outcomes, infection rate, and revision surgeries	No statistical difference was found in patient reported outcomes between groups; no statistical difference was found in revision or infection rate between groups
Saltzman et al[47], 2009, United States	Randomized control trial (level 1)	All shoulder surgeries	150	2% chlorhexidine gluconate in 70% isopropyl alcohol (S); 0.7% iodophor 74% isopropyl alcohol (S); 0.75% iodine scrub and 1.0% iodine paint (P)	Comparing positive culture rate of the different preparation methods	The positive culture rate was significantly lower in the chlorhexidine group than the iodophor (P = 0.01) or iodine paint (P < 0.001) groups; chlorhexidine and iodophor significantly reduced positive coagulase-negative Staphylococcus cultures (P < 0.001 for both groups); no significant difference noted for positive C. acnes cultures between the groups
Wade et al[51], 2021, United Kingdom	Prospective cohort (level 2)	Upper limb surgeries	2454	Aqueous or alcoholic chlorhexidine (P) (concentration unspecified); aqueous or alcoholic povidone-iodine (P) (concentration unspecified)	Comparison of 90 days SSI between the two groups	Alcoholic povidone iodine produced a decreased risk of SSI in emergency upper extremity surgery (HR = 0.15; 95%CI: 0.02-0.94); alcoholic chlorhexidine produced a decreased risk of SSI in elective upper extremity surgery (HR = 0.30; 95%CI: 0.11-0.83)
Xu et al[49], 2017, United States	Randomized control trial (level 1)	Hand surgery	240	10% povidone-iodine (P); 2% chlorhexidine gluconate in 70% isopropyl alcohol (S); 0.7% iodine in 74% isopropyl alcohol (S)	Comparison of positive cultures	1.2% chlorhexidine gluconate and 70% isopropyl alcohol had higher rates of positive cultures than the 10% povidone-iodine and 0.7% iodine and 74% isopropyl alcohol groups (P < 0.001)
Yamakado[50], 2021, Japan	Randomized control trial (level 1)	Arthroscopic rotator cuff repair	151	1% chlorhexidine gluconate in 70% isopropyl alcohol (S); chlorhexidine alcohol with 3% hydrogen peroxide (S)	Comparison of the cultures of cut arthroscopic sutures and SSI	There was no statistically significant difference in the positive culture rate for C. acnes or number of SSI between the two groups

S: Stick application; P: Paint application; SSI: Surgical site infection; C. acnes: Cutibacterium acnes; HR: Hazard ratio; CI: Confidence interval.

Spine

Five studies evaluating surgical skin preparation in spine surgery met inclusion criteria[52-56]. None of these studies found a significant difference in SSI rates between chlorhexidine-based and iodine-based preparations. A level 1 randomized clinical trial published by Dromzee et al[52] evaluated the use of cyanoacrylate liquid vs no cyanoacrylate liquid in pediatric scoliosis for SSI. This study found no significant difference in SSI with the use of cyanoacrylate liquid. A level 2 prospective cohort published by Ghobrial et al[53] compared chlorhexidine to povidone-iodine for rates of positive cultures and SSIs in spine surgery. This study found no statistically significant difference in the rate of SSI or positive cultures between the two skin preparation groups. A level 2 retrospective comparative study published by Madariaga et al[54] compared povidone-iodine vs povidone-iodine and hydrogen peroxide that evaluated C. acnes culture rates and SSI in cervical spine surgery. This study found no difference in the positive culture rates of C. acnes and SSI between the skin preparation methods. A level 1 controlled trial published by Savage et al[55] evaluated chlorhexidine vs iodine in lumbar spine surgery for positive culture rates and SSI. This study found no significant difference between preparation methods for positive culture rates and SSI. A level 2 prospective study published by Yoshii et al[56] that compared chlorhexidine vs iodine in posterior spine surgery for positive culture rates and SSI. The study found no statistical difference in SSI, but found lower rates of positive cultures in the chlorhexidine group when compared with the iodine preparation methods (Table 5).

Table 5 Surgical skin preparation demographics and results of studies evaluating spine surgery.

Ref.	Level of evidence	Surgery type	Sample size (n)	Interventions	Comparisons	Key findings
Dromzee et al[52], 2012, France	Randomized clinical trial (level 1)	Pediatric scoliosis	56	Cyanoacrylate liquid (N/A); no cyanoacrylate liquid	Comparison of surgical site infection	No statistically significant difference in surgical site infection
Ghobrial et al[53], 2018, United States	Prospective cohort (level 2)	All spine cases	6959	2% chlorhexidine gluconate and 70% isopropyl alcohol (S); 7.5% povidone iodine solution (P)	Comparing culture rates and surgical site infections	There was no statistically significant difference between cohorts for culture growth or surgical site infections
Madariaga et al[54], 2024, United States	Retrospective comparative study (level 2)	Cervical spine	86	0.7% iodine povacrylex in 74% isopropyl alcohol (S); 0.77% iodine povacrylex in 74% isopropyl alcohol and 3% hydrogen peroxide (S)	Comparing post prep C. acnes culture and surgical site infection	There was no statistically significant difference in culture rate between cohorts
Savage et al[55], 2012, United States	Randomized control trial (level 1)	Lumbar spine surgery	100	2% chlorhexidine gluconate in 70% isopropyl alcohol (S); 0.7% available iodine in 74% isopropyl alcohol (S)	Comparing post prep culture rates and surgical site infection	There was no statistically significant difference in positive culture rate between cohorts
Yoshii et al[56], 2018, Japan	Prospective comparative study (level 2)	Posterior spine surgery	190	0.5% chlorhexidine in 79% ethanol (S); 10% povidone iodine (P)	Comparing culture rate and surgical site infection	There was no significant difference in culture rates immediately after skin preparation (P = 0.49); the positive culture rate after wound closure was significantly lower in the chlorhexidine group than the iodine group (P = 0.046)

N/A: Not applicable; S: Stick application; P: Paint application; C. acnes: Cutibacterium acnes.

Quality assessment

The MINORS criteria quality assessment for comparative studies found that all of the studies included in this systematic review were considered fair or high quality (Table 6). Randomized clinical trials were evaluated for bias using the Cochrane ROB-2 assessment tool. The Cochrane ROB-2 trials found that the clinical trials by Keblish et al[36] and Rugpolmuang et al[39] both had high risk of bias. The remainder of the randomized clinical trials had either some concerns for bias or low risk of bias per the Cochrane ROB-2 assessment tool (Figure 2).

Figure 2 Cochrane risk of bias 2 assessment.

Table 6 Methodological index for non-randomized studies criteria of comparative studies.

MINORS criteria quality assessment
Ref.	Beber et al[24], 2022	Becerro de Bengoa Vallejo et al[33], 2009	Blonna et al[42], 2018	Dörfel et al[44], 2021	Ghobrial et al[53], 2018	Madariaga et al[54], 2024	Mizels et al[46], 2024	Rouquette et al[29], 2020	Wade et al[51], 2021	Yoshii et al[56], 2018
Clearly stated aim	2	2	2	2	2	2	2	2	2	2
Inclusion of consecutive patients	2	2	2	2	2	2	2	2	2	2
Prospective collection of data	2	2	2	2	2	2	2	2	2	2
Appropriate endpoints	2	1	2	2	2	2	2	2	2	2
Unbiased assessment endpoints	1	1	1	1	2	2	2	1	2	2
Appropriate follow-up	2	2	2	2	2	2	2	2	2	2
Loss to follow-up	2	2	2	2	2	2	2	2	1	2
Prospective calculation of study size	2	0	2	2	2	2	0	0	0	0
Adequate control group	2	1	2	1	2	2	2	2	1	2
Contemporary groups	2	1	1	1	2	2	2	2	1	2
Baseline equivalence of groups	2	1	1	1	2	2	2	2	1	2
Adequate statistical analysis	2	2	2	2	2	2	2	2	2	2
Cumulative MINORS score	23	17	21	20	24	24	22	21	18	22

MINORS: Methodological index for non-randomized studies; 0: Not reported; 1: Reported but inadequate; 2: Reported and adequate.

DISCUSSION

This systematic review demonstrated conflicting results regarding SSI with different surgical skin preparations. Mixed results regarding the rate of SSIs were found in extremity fractures with both iodine skin preparations compared to chlorhexidine preparations[25,26,32,49]. Iodine based preparation solutions were found to have lower rates of SSI in pediatric upper extremity and sports surgeries. One study evaluating preparation in hand surgery found that chlorhexidine-based solutions had higher rates of SSI when compared with iodine-based solutions in emergency surgery[49]. This study also found that chlorhexidine had lower rates of SSI in elective upper extremity surgery. No studies in this review found any difference between preparation techniques and the incidence of C. acnes positive culture rates in upper extremity surgery. Studies in TJA showed equivalence between iodine-based preparations and chlorhexidine-based preparations[27,28,30,31]. In spine surgery, chlorhexidine had lower rates of positive cultures, but no effect on SSI. The literature in foot and ankle surgery remains contradictory, with preparation solutions having mixed effects across studies. These results suggest there are no significant differences between chlorhexidine and iodine-based preparation solutions in extremity and spine surgery.

Studies evaluating skin preparations in extremity fracture surgery support the use of iodine-based preparation solutions over chlorhexidine, while others do not[25,26,32]. In the orthopaedic trauma setting, surgical skin preparation is likely only one small component in the development of SSIs. Open fractures have an increased risk of infection due to the introduction of bacteria through a compromised skin barrier, and one of the most important factors in preventing infection in open fractures is time to antibiotic administration[57]. Trauma patients may also be predisposed to potential wound complications due to the high energy mechanisms, concomitant systemic injury/comorbidity, potential lack of soft tissue coverage in certain anatomic areas, and degree of wound contamination[58]. When compared with patients being treated in an elective setting, patients being treated acutely for fractures are also less likely to be surgically optimized with factors such as poor glycemic control contributing to infection risk[59]. These additional factors in the trauma setting likely minimize the effects of surgical skin preparation, and may be a reason why the literature is mixed regarding the iodine and chlorhexidine-based solutions.

This review found no studies that demonstrated a reduction in the incidence of positive C. acnes cultures in upper extremity surgery with either iodine or chlorhexidine solutions. While both chlorhexidine and iodine-based solutions help decrease the rates of overall positive cultures in upper extremity surgery[44,47], their effect does not persist with C. acnes. The addition of hydrogen or benzoyl peroxide also did not show any effect upon C. acnes[43,45,46,50]. Diagnosis and eradication of C. acnes remains a major challenge in SSIs[17,19].

In lower extremity surgeries, there was no difference between chlorhexidine and iodine-based solutions for TJA. Many total joint procedures have additional preparation methods that start with wipes or showers of these solutions spanning a week prior to surgery[60,61]. In isolation, it is clear that there is no difference between perioperative solutions, and that the time leading up to surgery may be most important with surgical optimization and multiple days of skin preparation. In the foot and ankle region, literature is mixed regarding what skin preparation methods are effective. The foot oftentimes can be a harbor for bacteria with the nails and interdigital spaces[20]. One study showed bristle brushing may have an impact on decreasing bacteria, however, his study was found to be at high risk of bias[36]. Future studies can evaluate if brushing does help reduce bacteria in the foot. However, at this time there is no clear surgical preparation methods that show superiority in foot and ankle surgery.

Spine surgeries found no clearly superior surgical preparation method when comparing iodine and chlorhexidine-based solutions. These findings were consistent, even in posterior spinal surgeries which are known to have higher rates of infection[56]. Similarly to trauma surgery, there are likely a number of factors that influence spine surgery SSI, and minimize the effect of surgical skin preparation. Some of these factors include traumatic spine injuries, host comorbidities, operative time, comorbidities, and intrawound antibiotic use[62,63]. While surgical skin preparation is a critical step in reducing bacteria, it is clear that both iodine and chlorhexidine-based solutions are effective, but do likely have a small influence in SSIs relative to other prophylactic measures in use today.

Currently in orthopaedic surgery there is no superior skin preparation method when comparing iodine and chlorhexidine. Additional methods such as the use of hydrogen peroxide, benzoyl peroxide, or combinations of all these preparation solutions also showed no superiority. There are likely many factors that ultimately influence SSIs, and surgical skin preparation is one important but small factor in the overall picture. Factors such as patient comorbidities, patient optimization, operative time, and perioperative antibiotics likely play a bigger role than the specific skin preparation products in SSI prevention. Future studies can further evaluate if any surgical skin preparation products significantly improve the rates of SSIs. However, at this time with the current available literature, there is no clear recommendation for any single skin preparation method.

Limitations

The results of this study should be evaluated within the context of the studies limitations. The first limitation is the potential for missed literature. Our search was comprehensive and evaluated seven major databases. However, we may have missed relevant studies not indexed in the searched databases or published in other languages. The second limitation is that this study only evaluated interventions in the perioperative period, and did not include home washes or wipes, which may play a role in SSI[60,61]. This study was completed to evaluate if any difference truly exists in the methods used for the preoperative skin prep without consideration of additional preparation beyond the immediate preoperative period. The home preparation and similar products were excluded to create a consistent comparison directly prior to surgical intervention. This is a big limitation of this study, as this is common place for many arthroplasty surgeries. Another limitation is the heterogeneity of the included studies’ interventions and outcomes, which prevented us from conducting a meta-analysis. This may represent the large variability in available high-quality data, which does limit the conclusions and results of this study. As a result, our conclusions are based on qualitative synthesis and could miss detecting a small but clinically important difference if one exists. Additionally, there are many factors that may play into infection in orthopaedic surgery, and preoperative surgical skin preparation is just one consideration. Additional factors influence SSI, such as comorbidities and health of the patient, open wound contamination, extent of injury, post-surgical care, perioperative antibiotics, operative time, and surgical techniques[57,59,62,63]. Because of these numerous confounding factors, even a large sample might find it difficult to attribute SSI differences to skin prep alone. However, it is important to evaluate all of the many factors that may contribute to infection and is why these results are important considerations for orthopaedic surgeons.

CONCLUSION

The current literature suggests there are no significant differences between chlorhexidine and iodine-based preparation solutions in orthopaedic surgery for extremity and spine surgeries for reducing SSI or positive cultures. Addition of adjunct products to these methods also showed no significant differences. While perioperative surgical skin preparation is an essential part of sterile surgical preparation, there are likely many additional factors that influence SSIs. Further research may identify specific contexts or new agents that confer an advantage, but based on current evidence, either chlorhexidine or iodine preparations are appropriate choices.

ACKNOWLEDGEMENTS

The authors would like to acknowledge Dr. Michele McCarroll, PhD and Devika Pavuluri, MPH, for their assistance with project organization and data collection.