http://informahealthcare.com/jmf ISSN: 1476-7058 (print), 1476-4954 (electronic) J Matern Fetal Neonatal Med, Early Online: 1–5 ! 2014 Informa UK Ltd. DOI: 10.3109/14767058.2014.926884
ORIGINAL ARTICLE
Chlorhexidine gluconate versus povidone iodine at cesarean delivery: a randomized controlled trial J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Washington on 08/29/14 For personal use only.
Cynelle M. Kunkle, Jennifer Marchan, Sara Safadi, Stephanie Whitman, and Ramen H. Chmait Department of Obstetrics and Gynecology, University of Southern California Medical Center, Los Angeles, CA, USA
Abstract
Keywords
Background/Aims: To compare the prevalence of positive bacterial cultures at the cesarean delivery (CD) incision site in patients with pre-operative application of chlorhexidine gluconate (CG) versus povidone iodine (PI). Methods: Women undergoing a scheduled CD at 36 gestational weeks were randomly assigned to receive CG or PI. A swab of the incision site was performed at 3 min after disinfectant application and at 18 post-operative hours, and the prevalence of cultures with any detected bacterial growth was compared for the two groups. Results: Of the 60 participants, 33 (55.0%) were in the PI group. There were no differences detected at 3 min, with 9.1% positive in the PI group versus 0% positive in the CG group (p ¼ 0.2499). However, at 18 h, women in the PI group were seven times more likely than women in the CG group to have a positive culture (16/33 [48.5%] versus 3/27 [11.1%], OR ¼ 7.53 [95% CI 1.67–38.83], p ¼ 0.0023). Multivariate logistic regression demonstrated similar results: OR ¼ 7.33 (95% CI 1.77–30.35), p ¼ 0.0060. Conclusion: The prevalence of positive bacterial cultures obtained at the site of the skin incision 18 h after CD was higher in the PI versus the CG group.
Cesarean delivery, chlorhexidine, iodine, skin disinfectant
Introduction Cesarean delivery (CD) is one of the most commonly performed surgical procedures in the United States. According to the National Vital Statistics report in 2011, the US national CD rate was 32.8; this rate increased by nearly 60% from 1996 to 2009 [1]. Compared to vaginal delivery, CD is associated with an increased incidence of post-operative infection [2]. This overall increased risk varies with the use of peri-operative antimicrobials and the underlying basis for the CD [2]. The rate of abdominal incisional infection following CD ranges from 3 to 15% with an average of 6% [2]. It is unclear if a relationship exists between type of disinfectant applied to the maternal abdomen and infection rates after CD. It is well documented that post-operative infections are associated with increased medical expenses and increased morbidity and mortality for patients. Furthermore, it is estimated that post-operative infections account for 17% of healthcare-associated infections with a projected annual cost of 3.5–10 billion dollars in the United States alone [3].
Address for correspondence: Dr. Ramen H. Chmait, Department of Obstetrics and Gynecology, University of Southern California Medical Center, 1300 North Vermont Avenue, Suite 710, Los Angeles, CA 90027, USA. Tel: 323-361-6074 (Office). E-mail: [email protected]
History Received 18 February 2014 Revised 28 April 2014 Accepted 19 May 2014 Published online 18 June 2014
Historically, povidone iodine 10% (PI) has been the most common pre-operative skin disinfectant used for CD. Recent data, although not conclusive, has suggested that 2% chlorhexidine gluconate with 70% isopropyl alcohol (CG) has improved antiseptic properties compared to PI [4]. To the best of our knowledge, there are no prospectively collected data on the skin disinfection efficacy of CG versus PI in the setting of CD. The purpose of this study was to compare rates of bacterial growth and infectious morbidity at the incisional site for CG versus PI in the setting of scheduled CD.
Materials and methods The study was approved by the Institutional Review Board for the Protection of Human Subjects at the Health Sciences Campus of the University of Southern California and registered at ClinicalTrials.gov, identifier: NCT01975805. We conducted a single-center, unblinded randomizedcontrolled trial that included women aged 18–45 years undergoing scheduled CD at 36 gestational weeks or greater at the University of Southern California Los Angeles County Medical Center (LAC + USC). Women were excluded from participating in the study for any of the following reasons: inability to give informed consent, presence of labor, current use of antimicrobials, known allergy to one or both of the disinfectants, current use of immunosuppressant drugs, presence of an active acute or chronic infection, current history of
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cancer, presence of an open wound, skin ulcer, sore, severe acne, a history of methicillin-resistant Staphylococcus aureus colonization or oxacillin-resistant Staphylococcus aureus colonization. Eligible women were recruited at the time of admission for their scheduled CD. Home disinfecting protocols and skin shaving was not routinely performed before scheduled CD, and PI (Scrub Care Preoperative Skin Prep Tray, Cardinal Health, Dublin, OH) was the disinfectant in use at the study site. Skin preparation was performed with either PI or CG (ChloraPrep, Cardinal Health, Dublin, OH). The choice of disinfectant was determined by simple randomization where each participant was independently assigned to either PI or CG without any regard for previous patient assignments. The operating surgeons could not be blinded because both agents possess distinctly different coloring when applied to the skin. After the placement of anesthesia, a member of the nursing staff cleaned the patient’s skin and applied the chosen agent using standard nursing protocol. All members of the nursing staff had participated in an in-service training prior to the start of the study. When the prepped area was dry at the 3-min time point, a sterile, cotton-tipped swab of the site of the planned incision was sent for culture. The cesarean technique was left to the discretion of the attending obstetrician and generally was performed using a Pfannenstiel or a midline vertical skin incision. All participants received weight-appropriate antibiotic dosing prior to incision. The fascia was closed with either polydioxanone (PDSII) (Ethicon, Somerville, NJ) or polyglactin 910 (Vicryl) (Ethicon, Somerville, NJ) suture and the subcutaneous layer closed with polyglactin 910 suture for all women with a subcutaneous layer greater than 2.0 cm of thickness. Skin closure was performed with either staples or absorbable sutures. A standard dressing was used to cover the incision. At 18 h after surgery the dressing was removed and study personnel sent a second swab of the incision site for culture. A standardized physical examination of the wound was performed by members of the study team and by the primary obstetrical caregivers. The wound was examined for evidence of erythema, induration, cellulitis, purulent drainage and wound seroma on post-operative days 1, 2 and 3. Staples were removed and thin adhesive strips were placed on postoperative day 3 or 4 prior to discharge for patients with a Pfannenstiel incision. Patients with a vertical skin incision returned at 10–14 post-operative days for staple removal. All other patients received a standard 2-week post-operative clinical appointment, and were examined again at that visit for the presence of erythema, induration, cellulitis, purulent drainage and wound seroma. Culture swabs were processed at the LAC + USC microbiology lab. For each swab received, the specimen was inoculated on blood agar plates using 0.01 mL. The plates were incubated at 35 C and read after 24 h of incubation. Plates were examined for colony forming units (CFU) of bacterial growth and categorized as any growth versus no growth. The primary microbiologist was blinded to the group from which the samples were obtained. The primary study outcome was the proportion of patients who had any bacterial growth at either 3 min after the application of the disinfectant or 18 post-operative hours. The 3-min time point was chosen, as this is the presumed
J Matern Fetal Neonatal Med, Early Online: 1–5
onset of action for both skin-prepping agents. In addition, if bacterial contamination is present at the time of skin incision, this is likely to increase the risk for post-operative wound infection. Given the paucity of data on the correlation between the timing of bacterial wound colonization and resulting wound infection, the decision was made to arbitrarily choose an 18-h intermediate endpoint. The secondary outcomes of interest were the rates of post-operative wound infection or wound seroma. Wound infection was defined as the presence of purulent drainage, cellulitis or the need for incision and drainage, or treatment with antibiotics for a clinical diagnosis of infection [5]. Wound seroma was defined as the presence of a fluid collection requiring drainage, packing or pressure dressing [5]. The following patient and surgical characteristics were evaluated: patient age, body mass index (BMI), history of pregestational or gestational diabetes mellitus, history of positive cultures for Group B Streptococcus (GBS), the residency year of the surgeon, whether the operation was a primary or repeat CD, the estimated blood loss (EBL), duration of surgery in minutes, type of skin incision, type of uterine incision, whether the uterus was exteriorized during the surgery, the use of staples versus suture for skin closure and duration of staple placement, and the presence of post-operative fever. The anticipated sample size was based on previously published data for orthopedic surgery, which had documented a 41% difference in positive bacterial cultures between PI and CG at 18 h after skin prepping [6]. We estimated that 30 participants per group were required to attain statistical significance for the primary outcomes taking into consideration an attrition rate of 20% for the 18-h time point (80% power, p ¼ 0.05). Patient and surgical characteristics were tested against each of the six potential outcomes (any growth at 3 min and at 18 h, and seroma or wound infection at 3 days and 2 weeks); these characteristics were also tested to determine if they were associated with the disinfectant treatment. Continuous variables were compared using Kruskal– Wallis testing and expressed as mean ± standard deviation (SD); categorical variables were compared using Chi-Square or Fisher’s exact tests as appropriate. Multivariable logistic regression models were constructed for the outcomes that were positively associated with the disinfectant groups (p50.10), and included patient characteristics also associated with the outcomes (p50.10). Effect sizes are expressed using odds ratios (OR) and 95% Confidence Intervals (CI). All calculations were performed using SAS statistical software v. 9.1 (SAS Institute Inc., Cary, NC).
Results Of 60 participating women, 33 (55.0%) were in the PI group. Data were complete for all patients with respect to the primary outcome (culture results at 3 min and at 18 postoperative hours). Because the secondary outcomes required outpatient follow-up at approximately 2 weeks, only 22/33 (67%) and 21/27 (77%) had complete study data for the PI and CG groups, respectively (p ¼ 0.5078) (Figure 1). Table 1 describes the entire study population, and each treatment group, by patient and surgical characteristics. Overall, the
Skin disinfection at cesarean delivery
DOI: 10.3109/14767058.2014.926884
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Assessed for eligibility (n= 75)
Excluded (n=15) Did not meet inclusion criteria (n= 10) Declined to parcipate (n= 5)
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Randomized (n=60)
Allocated to CG group (n= 27)
Allocated to PI group (n=33)
Received CG (n= 27)
Received PI (n= 33)
Follow up 2 weeks (n= 21) Lost to follow up (n=6)
Analysed for wound seroma (n=21)
Follow up 2 weeks (n= 22) Lost to follow up (n=11)
Follow up 3mins/18hrs (n= 27) Lost to follow up (n=0)
Analysed for wound infecon (n=21)
Analysed for primary outcome (n=27)
Analysed for wound seroma (n=21) Excluded from analysisa (n=1)
Follow up 3mins/18hrs (n= 33) Lost to follow up (n=0)
Analysed for wound infecon (n=22)
Analysed for primary outcome (n= 33)
PI, Povidone iodine; CG, Chlorhexidine gluconate. aExcluded from analysis secondary to missing data.
Figure 1. Randomization and follow-up of study participants. PI, Povidone iodine; CG, Chlorhexidine gluconate. aExcluded from analysis secondary to missing data.
Table 1. Univariate analysis of baseline patient characteristics by type of disinfectant.
Characteristics
Overall (N ¼ 60)
Povidone iodine (N ¼ 33)
Chlorhexidine gluconate (N ¼ 27)
Age (years)*
30.0 ± 5.7 29.0 (18–42) N ¼ 59 32.4 ± 6.0 32.0 (20–48) 697 ± 244 700 (100–1500) 79.2 ± 29.4 72.5 (40.0–162.0)
29.1 ± 6.5 29.0 (18–39) N ¼ 32 33.2 ± 5.9 33.2 (20.0–48.0) 639 ± 224 500 (100–1000) 74.9 ± 24.2 72.0 (40.0–144.0)
31.0 ± 4.4 30.0 (24–42) N ¼ 27 31.3 ± 6.1 29.7 (22.9–48.0) 767 ± 252 700 (250–1500) 84.4 ± 34.5 74.0 (40.0–162.0)
Body mass index (BMI)* Estimated blood loss (EBL)* Duration of surgery (minutes)* Skin incisiony Pfannenstiel Vertical Other Uterine Incisiony Low transverse Vertical Other Uterus exteriorizedy Closure of skin (staples)y Primary C-deliveryy Residency year Year 1y Year 2y Year 4y Diabetes mellitus (DM)y Post-operative fevery
p value 0.2728 0.2728 0.0910 0.0910 0.0505 0.0505 0.4710 0.3892
46 13 1 50 9 1
(76.7%) (21.7%) (1.7%) (83.3%) (15.0%) (1.7%)
56 (93.3%) 53 (88.3%) 14 (23.3%) 24 25 11 8 1
(40.0%) (41.7%) (18.3%) (13.3%) (1.7%)
*Mean ± standard deviation, yCategorical data are expressed as N (%).
27/46 6/13 0/1 29/50 4/9 0/1
(58.7%) (46.2%) (0%) (58.0%) (44.4%) (0%)
32 (97.0%) 28 (84.8%) 10 (30.3%) 13/24 15/25 5/11 8 1
(54.2%) (56.0%) (45.5%) (24.2%) (3.0%)
0.4047
24 (88.9%) 25 (92.6%) 4 (14.8%)
0.3179 0.4422 0.2231 0.7174
0 (0%) 0 (0%)
0.0063 1.0000
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J Matern Fetal Neonatal Med, Early Online: 1–5
only the incision type (Pfannenstiel yes or no) was included in the final logistic regression model (c-statistic 0.77): PI group OR 7.33 (95% CI 1.77–30.35), p ¼ 0.0060, and Pfannenstiel abdominal incision OR 8.00 (95% CI 0.90–71.40), P ¼ 0.0626. In an analysis excluding diabetic patients (N ¼ 8, all of whom were in the PI group), the results were similar (PI group OR ¼ 8.09 (95%CI 1.81–36.17), p ¼ 0.0062). There was no difference in our secondary outcomes, wound infection or wound seroma prevalence at 3 days or 2 weeks.
mean age (SD) was 30.0 (5.7) years, and the mean BMI (using pre-pregnancy weight) was 32.4 (6.0). Fourteen (23.3%) patients had a primary CD and the majority of abdominal incisions were Pfannenstiel (76.7%). Although the study groups were randomized, several patient characteristics differed between the two groups: (1) all eight diabetic patients were in the PI group; (2) all eight patients with a positive GBS culture were in the PI group; and (3) both BMI and EBL appeared somewhat lower in the PI group but this was not statistically significant (p40.05) (Table 1). Neither BMI, diabetes nor EBL were associated with bacterial growth at 3 min or 18 hours (Table 2). Table 3 describes the primary and secondary outcomes. At 3 min after application of the disinfectant there was no difference in bacterial growth between the two groups. At 18 post-operative hours there was a statistically significant difference in bacterial growth in the PI group compared to the CG group (16/33 [48.5%] versus 3/27 [11.1%], p ¼ 0.0023). Neither EBL or BMI, nor the presence of DM or GBS, were associated with the outcome, bacterial growth at 18 h. However, the following patient characteristics were associated (p50.10) with bacterial growth at 18 h: staples removed prior to five post-operative days (10/10 [100%] versus 30/41 [73.2%], p ¼ 0.0937), and Pfannenstiel abdominal incision (11/11 [100%] versus 35/49 [71.4%], p ¼ 0.0527). As the use of staples was highly associated with a Pfannenstiel abdominal incision (38/39 [97.4%] versus 2/12 [16.7%], p50.0001),
Discussion Our study demonstrated that CG was associated with less bacterial contamination at the CD incision site at 18 h compared to PI. These findings are in line with previous studies that have compared these two skin antiseptics at other surgical sites [6]. It has been postulated that the potential superiority of CG to PI in skin decontamination lies in the differences in the mechanism of action of the two antiseptics. CG is a cationic chlorinated biguanide that precipitates the bacterial cell membrane and cytoplasmic components [7]. Chlorhexidine resists neutralization by organic materials, it is active over a wide pH range, and has prolonged bactericidal activity. Isopropyl alcohol, in concentrations of 70–90%, disorganizes cell membrane lipids and also denatures cellular proteins by dehydration [7]. PI, in comparison, is an iodophor, which provides a slow release reservoir of free iodine. Free iodine combines irreversibly with proteins, oxidizing sulfhydryl groups, therefore, affecting protein structure and function
Table 2. Selected patient characteristics and bacterial growth at 3 min and 18 h.
Characteristics Body mass index (BMI)* Diabetes mellitus (DM)y Estimated blood loss (EBL)* Characteristics Body mass index (BMI)*
Diabetes mellitus (DM)y Estimated blood loss (EBL)*
3 Minutes Any growth (N ¼ 3)
3 Minutes No growth (N ¼ 57)
N¼3 36.0 ± 3.3 35.0 (33.3–39.7) 1 (33.3%) 900 + 100 900 (800–1000) 18 Hours Any growth (N ¼ 19) N ¼ 19
N ¼ 56 32.2 ± 6.1 32.0 (20–48) 7 (12.3%) 686 + 245 700 (100–1500) 18 Hours No growth (N ¼ 41) N ¼ 40
0.1287 0.1287 0.1287 0.3542 0.0554 0.0554 p value
31.9 ± 5.4 32.0 (24.5–47.0) 4 (21.1%) 645 + 196 600 (350–1000)
32.6 ± 6.3 32.0 (20.0–48.0) 4 (9.8%) 721 + 261 700 (100–1500)
0.6730 0.6730 0.2487 0.2388
p value
0.6730
*Mean ± standard deviation, yCategorical data are expressed as N (%). Table 3. Univariate analysis of primary and secondary outcomes by disinfectant type.
Outcome Bacterial growth 3 minutes* Bacterial growth 18 hours* Wound seroma (3 days)* Wound seroma (2 Weeks)* Wound infection (3 days)* Wound infection (2 Weeks)* NA, not applicable. *Categorical data expressed as N (%).
Overall (N ¼ 60) 3 19 0/60 7/42 0 3/43
(5.0%) (31.7%) (0%) (16.7%) (0%) (7.0%)
Povidone iodine (N ¼ 33) 3 16 0 3/21 0 1/22
(9.1%) (48.5%) (0%) (14.3%) (0%) (4.5%)
Chlorhexidine gluconate (N ¼ 27) 0 3 0 4/21 0 2/21
(0%) (11.1%) (0%) (19.0%) (0%) (9.5%)
p value 0.2449 0.0023 NA 1.0000 NA 0.6069
Skin disinfection at cesarean delivery
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DOI: 10.3109/14767058.2014.926884
while limiting bacterial activity [7]. These chemical differences have translated to improved clinical outcomes. In a prospective randomized controlled study, chlorhexidine scrub provided superior skin decontamination in foot and ankle surgery when compared to iodine-based scrub [7]. Furthermore, in a study evaluating post-cleansing colony counts for amniocentesis, a statistically significant difference was discovered favoring CG as a more efficacious abdominal cleanser compared to PI [8]. Strengths of our study include its prospective randomizedcontrolled design and the use of an objective primary outcome. Furthermore, data for the primary outcome were obtained during hospitalization, which limited attrition. Although the surgeons were not blinded to the assignment of the intervention, the primary outcome was determined using quantitative measurements by microbiologists that were blinded. A principal limitation of this study is that no matching or stratified randomization was able to be performed to control for covariates that are conceptually associated with incisional infection, such as diabetes or GBS colonization. However, we analyzed the data including and excluding diabetics and found the same results. We could not reliably control for GBS colonization because this information was unavailable for all patients. Additionally, the study was not powered sufficiently to test our secondary aim of determining differences in postoperative wound infection or wound seroma rates. Furthermore, the study results pertain only to patients undergoing a scheduled CD, as laboring patients were excluded. The decision to exclude laboring patients was made primarily to limit potential confounding factors for postpartum infection, such as duration of labor and prolonged membrane rupture.
5
In conclusion, the evidence discovered in this study suggests that, at 18 post-operative hours after CD, CG provided superior skin decontamination to PI. This finding represents an intermediate outcome, and performance of larger randomized controlled trial is required to assess whether these results lead to a decreased risk of post-operative infection.
Declaration of interest The authors report no conflict of interest. No financial support was provided to conduct this study.
References 1. Martin JA, Hamilton BE, Ventura SJ, et al. Births: final data for 2011. Natl Vital Stat Rep 2013;62:1–90. 2. Chaim W, Bashiri A, Bar-David J, et al. Prevalence and clinical significance of postpartum endometritis and wound infection. Infect Dis Obstet Gynecol 2000;8:77–82. 3. Thompson KM, Oldenburg WA, Deschamps C, et al. Chasing zero: the drive to eliminate surgical site infections. Ann Surg 2011;254: 430–6. 4. Dumville JC, McFarlane E, Edwards P, et al. Preoperative skin antiseptics for preventing surgical wound infections after clean surgery. Cochrane Database Syst Rev 2013:28;3. 5. Darouiche RO, Wall Jr MJ, Itani KM, et al. Chlorhexidine-alcohol versus povidone-iodine for surgical-site antisepsis. N Engl J Med 2010;362:18–26. 6. Bibbo C, Patel DV, Gehrmann RM, Lin SS. Chlorhexidine provides superior skin decontamination in foot and ankle surgery. Clin Orthop Relat Res 2005;438:204–8. 7. Adler MT, Brigger KR, Bishop KD, Mastrobattista JM. Comparison of bactericidal properties of alcohol-based chlorhexidine versus povidone-iodine prior to amniocentesis. Am J Perinatol 2012;29:455–8. 8. Whitehouse JD. The impact of surgical-site infections following orthopedic surgery at a community hospital and a university hospital: adverse quality of life, excess length of stay, and extra cost. Infect Control Hosp Epidemiol 2002;23:183–9.
ORIGINAL ARTICLE
Chlorhexidine gluconate versus povidone iodine at cesarean delivery: a randomized controlled trial J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Washington on 08/29/14 For personal use only.
Cynelle M. Kunkle, Jennifer Marchan, Sara Safadi, Stephanie Whitman, and Ramen H. Chmait Department of Obstetrics and Gynecology, University of Southern California Medical Center, Los Angeles, CA, USA
Abstract
Keywords
Background/Aims: To compare the prevalence of positive bacterial cultures at the cesarean delivery (CD) incision site in patients with pre-operative application of chlorhexidine gluconate (CG) versus povidone iodine (PI). Methods: Women undergoing a scheduled CD at 36 gestational weeks were randomly assigned to receive CG or PI. A swab of the incision site was performed at 3 min after disinfectant application and at 18 post-operative hours, and the prevalence of cultures with any detected bacterial growth was compared for the two groups. Results: Of the 60 participants, 33 (55.0%) were in the PI group. There were no differences detected at 3 min, with 9.1% positive in the PI group versus 0% positive in the CG group (p ¼ 0.2499). However, at 18 h, women in the PI group were seven times more likely than women in the CG group to have a positive culture (16/33 [48.5%] versus 3/27 [11.1%], OR ¼ 7.53 [95% CI 1.67–38.83], p ¼ 0.0023). Multivariate logistic regression demonstrated similar results: OR ¼ 7.33 (95% CI 1.77–30.35), p ¼ 0.0060. Conclusion: The prevalence of positive bacterial cultures obtained at the site of the skin incision 18 h after CD was higher in the PI versus the CG group.
Cesarean delivery, chlorhexidine, iodine, skin disinfectant
Introduction Cesarean delivery (CD) is one of the most commonly performed surgical procedures in the United States. According to the National Vital Statistics report in 2011, the US national CD rate was 32.8; this rate increased by nearly 60% from 1996 to 2009 [1]. Compared to vaginal delivery, CD is associated with an increased incidence of post-operative infection [2]. This overall increased risk varies with the use of peri-operative antimicrobials and the underlying basis for the CD [2]. The rate of abdominal incisional infection following CD ranges from 3 to 15% with an average of 6% [2]. It is unclear if a relationship exists between type of disinfectant applied to the maternal abdomen and infection rates after CD. It is well documented that post-operative infections are associated with increased medical expenses and increased morbidity and mortality for patients. Furthermore, it is estimated that post-operative infections account for 17% of healthcare-associated infections with a projected annual cost of 3.5–10 billion dollars in the United States alone [3].
Address for correspondence: Dr. Ramen H. Chmait, Department of Obstetrics and Gynecology, University of Southern California Medical Center, 1300 North Vermont Avenue, Suite 710, Los Angeles, CA 90027, USA. Tel: 323-361-6074 (Office). E-mail: [email protected]
History Received 18 February 2014 Revised 28 April 2014 Accepted 19 May 2014 Published online 18 June 2014
Historically, povidone iodine 10% (PI) has been the most common pre-operative skin disinfectant used for CD. Recent data, although not conclusive, has suggested that 2% chlorhexidine gluconate with 70% isopropyl alcohol (CG) has improved antiseptic properties compared to PI [4]. To the best of our knowledge, there are no prospectively collected data on the skin disinfection efficacy of CG versus PI in the setting of CD. The purpose of this study was to compare rates of bacterial growth and infectious morbidity at the incisional site for CG versus PI in the setting of scheduled CD.
Materials and methods The study was approved by the Institutional Review Board for the Protection of Human Subjects at the Health Sciences Campus of the University of Southern California and registered at ClinicalTrials.gov, identifier: NCT01975805. We conducted a single-center, unblinded randomizedcontrolled trial that included women aged 18–45 years undergoing scheduled CD at 36 gestational weeks or greater at the University of Southern California Los Angeles County Medical Center (LAC + USC). Women were excluded from participating in the study for any of the following reasons: inability to give informed consent, presence of labor, current use of antimicrobials, known allergy to one or both of the disinfectants, current use of immunosuppressant drugs, presence of an active acute or chronic infection, current history of
J Matern Fetal Neonatal Med Downloaded from informahealthcare.com by University of Washington on 08/29/14 For personal use only.
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C. M. Kunkle et al.
cancer, presence of an open wound, skin ulcer, sore, severe acne, a history of methicillin-resistant Staphylococcus aureus colonization or oxacillin-resistant Staphylococcus aureus colonization. Eligible women were recruited at the time of admission for their scheduled CD. Home disinfecting protocols and skin shaving was not routinely performed before scheduled CD, and PI (Scrub Care Preoperative Skin Prep Tray, Cardinal Health, Dublin, OH) was the disinfectant in use at the study site. Skin preparation was performed with either PI or CG (ChloraPrep, Cardinal Health, Dublin, OH). The choice of disinfectant was determined by simple randomization where each participant was independently assigned to either PI or CG without any regard for previous patient assignments. The operating surgeons could not be blinded because both agents possess distinctly different coloring when applied to the skin. After the placement of anesthesia, a member of the nursing staff cleaned the patient’s skin and applied the chosen agent using standard nursing protocol. All members of the nursing staff had participated in an in-service training prior to the start of the study. When the prepped area was dry at the 3-min time point, a sterile, cotton-tipped swab of the site of the planned incision was sent for culture. The cesarean technique was left to the discretion of the attending obstetrician and generally was performed using a Pfannenstiel or a midline vertical skin incision. All participants received weight-appropriate antibiotic dosing prior to incision. The fascia was closed with either polydioxanone (PDSII) (Ethicon, Somerville, NJ) or polyglactin 910 (Vicryl) (Ethicon, Somerville, NJ) suture and the subcutaneous layer closed with polyglactin 910 suture for all women with a subcutaneous layer greater than 2.0 cm of thickness. Skin closure was performed with either staples or absorbable sutures. A standard dressing was used to cover the incision. At 18 h after surgery the dressing was removed and study personnel sent a second swab of the incision site for culture. A standardized physical examination of the wound was performed by members of the study team and by the primary obstetrical caregivers. The wound was examined for evidence of erythema, induration, cellulitis, purulent drainage and wound seroma on post-operative days 1, 2 and 3. Staples were removed and thin adhesive strips were placed on postoperative day 3 or 4 prior to discharge for patients with a Pfannenstiel incision. Patients with a vertical skin incision returned at 10–14 post-operative days for staple removal. All other patients received a standard 2-week post-operative clinical appointment, and were examined again at that visit for the presence of erythema, induration, cellulitis, purulent drainage and wound seroma. Culture swabs were processed at the LAC + USC microbiology lab. For each swab received, the specimen was inoculated on blood agar plates using 0.01 mL. The plates were incubated at 35 C and read after 24 h of incubation. Plates were examined for colony forming units (CFU) of bacterial growth and categorized as any growth versus no growth. The primary microbiologist was blinded to the group from which the samples were obtained. The primary study outcome was the proportion of patients who had any bacterial growth at either 3 min after the application of the disinfectant or 18 post-operative hours. The 3-min time point was chosen, as this is the presumed
J Matern Fetal Neonatal Med, Early Online: 1–5
onset of action for both skin-prepping agents. In addition, if bacterial contamination is present at the time of skin incision, this is likely to increase the risk for post-operative wound infection. Given the paucity of data on the correlation between the timing of bacterial wound colonization and resulting wound infection, the decision was made to arbitrarily choose an 18-h intermediate endpoint. The secondary outcomes of interest were the rates of post-operative wound infection or wound seroma. Wound infection was defined as the presence of purulent drainage, cellulitis or the need for incision and drainage, or treatment with antibiotics for a clinical diagnosis of infection [5]. Wound seroma was defined as the presence of a fluid collection requiring drainage, packing or pressure dressing [5]. The following patient and surgical characteristics were evaluated: patient age, body mass index (BMI), history of pregestational or gestational diabetes mellitus, history of positive cultures for Group B Streptococcus (GBS), the residency year of the surgeon, whether the operation was a primary or repeat CD, the estimated blood loss (EBL), duration of surgery in minutes, type of skin incision, type of uterine incision, whether the uterus was exteriorized during the surgery, the use of staples versus suture for skin closure and duration of staple placement, and the presence of post-operative fever. The anticipated sample size was based on previously published data for orthopedic surgery, which had documented a 41% difference in positive bacterial cultures between PI and CG at 18 h after skin prepping [6]. We estimated that 30 participants per group were required to attain statistical significance for the primary outcomes taking into consideration an attrition rate of 20% for the 18-h time point (80% power, p ¼ 0.05). Patient and surgical characteristics were tested against each of the six potential outcomes (any growth at 3 min and at 18 h, and seroma or wound infection at 3 days and 2 weeks); these characteristics were also tested to determine if they were associated with the disinfectant treatment. Continuous variables were compared using Kruskal– Wallis testing and expressed as mean ± standard deviation (SD); categorical variables were compared using Chi-Square or Fisher’s exact tests as appropriate. Multivariable logistic regression models were constructed for the outcomes that were positively associated with the disinfectant groups (p50.10), and included patient characteristics also associated with the outcomes (p50.10). Effect sizes are expressed using odds ratios (OR) and 95% Confidence Intervals (CI). All calculations were performed using SAS statistical software v. 9.1 (SAS Institute Inc., Cary, NC).
Results Of 60 participating women, 33 (55.0%) were in the PI group. Data were complete for all patients with respect to the primary outcome (culture results at 3 min and at 18 postoperative hours). Because the secondary outcomes required outpatient follow-up at approximately 2 weeks, only 22/33 (67%) and 21/27 (77%) had complete study data for the PI and CG groups, respectively (p ¼ 0.5078) (Figure 1). Table 1 describes the entire study population, and each treatment group, by patient and surgical characteristics. Overall, the
Skin disinfection at cesarean delivery
DOI: 10.3109/14767058.2014.926884
3
Assessed for eligibility (n= 75)
Excluded (n=15) Did not meet inclusion criteria (n= 10) Declined to parcipate (n= 5)
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Randomized (n=60)
Allocated to CG group (n= 27)
Allocated to PI group (n=33)
Received CG (n= 27)
Received PI (n= 33)
Follow up 2 weeks (n= 21) Lost to follow up (n=6)
Analysed for wound seroma (n=21)
Follow up 2 weeks (n= 22) Lost to follow up (n=11)
Follow up 3mins/18hrs (n= 27) Lost to follow up (n=0)
Analysed for wound infecon (n=21)
Analysed for primary outcome (n=27)
Analysed for wound seroma (n=21) Excluded from analysisa (n=1)
Follow up 3mins/18hrs (n= 33) Lost to follow up (n=0)
Analysed for wound infecon (n=22)
Analysed for primary outcome (n= 33)
PI, Povidone iodine; CG, Chlorhexidine gluconate. aExcluded from analysis secondary to missing data.
Figure 1. Randomization and follow-up of study participants. PI, Povidone iodine; CG, Chlorhexidine gluconate. aExcluded from analysis secondary to missing data.
Table 1. Univariate analysis of baseline patient characteristics by type of disinfectant.
Characteristics
Overall (N ¼ 60)
Povidone iodine (N ¼ 33)
Chlorhexidine gluconate (N ¼ 27)
Age (years)*
30.0 ± 5.7 29.0 (18–42) N ¼ 59 32.4 ± 6.0 32.0 (20–48) 697 ± 244 700 (100–1500) 79.2 ± 29.4 72.5 (40.0–162.0)
29.1 ± 6.5 29.0 (18–39) N ¼ 32 33.2 ± 5.9 33.2 (20.0–48.0) 639 ± 224 500 (100–1000) 74.9 ± 24.2 72.0 (40.0–144.0)
31.0 ± 4.4 30.0 (24–42) N ¼ 27 31.3 ± 6.1 29.7 (22.9–48.0) 767 ± 252 700 (250–1500) 84.4 ± 34.5 74.0 (40.0–162.0)
Body mass index (BMI)* Estimated blood loss (EBL)* Duration of surgery (minutes)* Skin incisiony Pfannenstiel Vertical Other Uterine Incisiony Low transverse Vertical Other Uterus exteriorizedy Closure of skin (staples)y Primary C-deliveryy Residency year Year 1y Year 2y Year 4y Diabetes mellitus (DM)y Post-operative fevery
p value 0.2728 0.2728 0.0910 0.0910 0.0505 0.0505 0.4710 0.3892
46 13 1 50 9 1
(76.7%) (21.7%) (1.7%) (83.3%) (15.0%) (1.7%)
56 (93.3%) 53 (88.3%) 14 (23.3%) 24 25 11 8 1
(40.0%) (41.7%) (18.3%) (13.3%) (1.7%)
*Mean ± standard deviation, yCategorical data are expressed as N (%).
27/46 6/13 0/1 29/50 4/9 0/1
(58.7%) (46.2%) (0%) (58.0%) (44.4%) (0%)
32 (97.0%) 28 (84.8%) 10 (30.3%) 13/24 15/25 5/11 8 1
(54.2%) (56.0%) (45.5%) (24.2%) (3.0%)
0.4047
24 (88.9%) 25 (92.6%) 4 (14.8%)
0.3179 0.4422 0.2231 0.7174
0 (0%) 0 (0%)
0.0063 1.0000
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C. M. Kunkle et al.
J Matern Fetal Neonatal Med, Early Online: 1–5
only the incision type (Pfannenstiel yes or no) was included in the final logistic regression model (c-statistic 0.77): PI group OR 7.33 (95% CI 1.77–30.35), p ¼ 0.0060, and Pfannenstiel abdominal incision OR 8.00 (95% CI 0.90–71.40), P ¼ 0.0626. In an analysis excluding diabetic patients (N ¼ 8, all of whom were in the PI group), the results were similar (PI group OR ¼ 8.09 (95%CI 1.81–36.17), p ¼ 0.0062). There was no difference in our secondary outcomes, wound infection or wound seroma prevalence at 3 days or 2 weeks.
mean age (SD) was 30.0 (5.7) years, and the mean BMI (using pre-pregnancy weight) was 32.4 (6.0). Fourteen (23.3%) patients had a primary CD and the majority of abdominal incisions were Pfannenstiel (76.7%). Although the study groups were randomized, several patient characteristics differed between the two groups: (1) all eight diabetic patients were in the PI group; (2) all eight patients with a positive GBS culture were in the PI group; and (3) both BMI and EBL appeared somewhat lower in the PI group but this was not statistically significant (p40.05) (Table 1). Neither BMI, diabetes nor EBL were associated with bacterial growth at 3 min or 18 hours (Table 2). Table 3 describes the primary and secondary outcomes. At 3 min after application of the disinfectant there was no difference in bacterial growth between the two groups. At 18 post-operative hours there was a statistically significant difference in bacterial growth in the PI group compared to the CG group (16/33 [48.5%] versus 3/27 [11.1%], p ¼ 0.0023). Neither EBL or BMI, nor the presence of DM or GBS, were associated with the outcome, bacterial growth at 18 h. However, the following patient characteristics were associated (p50.10) with bacterial growth at 18 h: staples removed prior to five post-operative days (10/10 [100%] versus 30/41 [73.2%], p ¼ 0.0937), and Pfannenstiel abdominal incision (11/11 [100%] versus 35/49 [71.4%], p ¼ 0.0527). As the use of staples was highly associated with a Pfannenstiel abdominal incision (38/39 [97.4%] versus 2/12 [16.7%], p50.0001),
Discussion Our study demonstrated that CG was associated with less bacterial contamination at the CD incision site at 18 h compared to PI. These findings are in line with previous studies that have compared these two skin antiseptics at other surgical sites [6]. It has been postulated that the potential superiority of CG to PI in skin decontamination lies in the differences in the mechanism of action of the two antiseptics. CG is a cationic chlorinated biguanide that precipitates the bacterial cell membrane and cytoplasmic components [7]. Chlorhexidine resists neutralization by organic materials, it is active over a wide pH range, and has prolonged bactericidal activity. Isopropyl alcohol, in concentrations of 70–90%, disorganizes cell membrane lipids and also denatures cellular proteins by dehydration [7]. PI, in comparison, is an iodophor, which provides a slow release reservoir of free iodine. Free iodine combines irreversibly with proteins, oxidizing sulfhydryl groups, therefore, affecting protein structure and function
Table 2. Selected patient characteristics and bacterial growth at 3 min and 18 h.
Characteristics Body mass index (BMI)* Diabetes mellitus (DM)y Estimated blood loss (EBL)* Characteristics Body mass index (BMI)*
Diabetes mellitus (DM)y Estimated blood loss (EBL)*
3 Minutes Any growth (N ¼ 3)
3 Minutes No growth (N ¼ 57)
N¼3 36.0 ± 3.3 35.0 (33.3–39.7) 1 (33.3%) 900 + 100 900 (800–1000) 18 Hours Any growth (N ¼ 19) N ¼ 19
N ¼ 56 32.2 ± 6.1 32.0 (20–48) 7 (12.3%) 686 + 245 700 (100–1500) 18 Hours No growth (N ¼ 41) N ¼ 40
0.1287 0.1287 0.1287 0.3542 0.0554 0.0554 p value
31.9 ± 5.4 32.0 (24.5–47.0) 4 (21.1%) 645 + 196 600 (350–1000)
32.6 ± 6.3 32.0 (20.0–48.0) 4 (9.8%) 721 + 261 700 (100–1500)
0.6730 0.6730 0.2487 0.2388
p value
0.6730
*Mean ± standard deviation, yCategorical data are expressed as N (%). Table 3. Univariate analysis of primary and secondary outcomes by disinfectant type.
Outcome Bacterial growth 3 minutes* Bacterial growth 18 hours* Wound seroma (3 days)* Wound seroma (2 Weeks)* Wound infection (3 days)* Wound infection (2 Weeks)* NA, not applicable. *Categorical data expressed as N (%).
Overall (N ¼ 60) 3 19 0/60 7/42 0 3/43
(5.0%) (31.7%) (0%) (16.7%) (0%) (7.0%)
Povidone iodine (N ¼ 33) 3 16 0 3/21 0 1/22
(9.1%) (48.5%) (0%) (14.3%) (0%) (4.5%)
Chlorhexidine gluconate (N ¼ 27) 0 3 0 4/21 0 2/21
(0%) (11.1%) (0%) (19.0%) (0%) (9.5%)
p value 0.2449 0.0023 NA 1.0000 NA 0.6069
Skin disinfection at cesarean delivery
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DOI: 10.3109/14767058.2014.926884
while limiting bacterial activity [7]. These chemical differences have translated to improved clinical outcomes. In a prospective randomized controlled study, chlorhexidine scrub provided superior skin decontamination in foot and ankle surgery when compared to iodine-based scrub [7]. Furthermore, in a study evaluating post-cleansing colony counts for amniocentesis, a statistically significant difference was discovered favoring CG as a more efficacious abdominal cleanser compared to PI [8]. Strengths of our study include its prospective randomizedcontrolled design and the use of an objective primary outcome. Furthermore, data for the primary outcome were obtained during hospitalization, which limited attrition. Although the surgeons were not blinded to the assignment of the intervention, the primary outcome was determined using quantitative measurements by microbiologists that were blinded. A principal limitation of this study is that no matching or stratified randomization was able to be performed to control for covariates that are conceptually associated with incisional infection, such as diabetes or GBS colonization. However, we analyzed the data including and excluding diabetics and found the same results. We could not reliably control for GBS colonization because this information was unavailable for all patients. Additionally, the study was not powered sufficiently to test our secondary aim of determining differences in postoperative wound infection or wound seroma rates. Furthermore, the study results pertain only to patients undergoing a scheduled CD, as laboring patients were excluded. The decision to exclude laboring patients was made primarily to limit potential confounding factors for postpartum infection, such as duration of labor and prolonged membrane rupture.
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In conclusion, the evidence discovered in this study suggests that, at 18 post-operative hours after CD, CG provided superior skin decontamination to PI. This finding represents an intermediate outcome, and performance of larger randomized controlled trial is required to assess whether these results lead to a decreased risk of post-operative infection.
Declaration of interest The authors report no conflict of interest. No financial support was provided to conduct this study.
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