Clinical trial NCT02578745: Prophylactic Incisional Care in Obese Women at Cesarean
Official title: Prophylactic Negative Pressure Wound Therapy in Obese Women After Cesarean: a Pilot Randomized Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Wound Infections
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2015-10-19
Enrollment: 120
Sex: FEMALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Surgical site infections (SSIs) complicate 5 - 12% of cesareans. Negative pressure wound therapy (NPWT) - a closed, sealed system that applies negative pressure to the wound surface - has been used to treat open wounds since the late 1990s. Experimental evidence suggests NPWT promotes wound healing by removing exudate, approximating the wound edges, and reducing bacterial contamination. Although effectiveness of prophylactic NPWT is biologically plausible and non-randomized studies suggest benefit in reducing SSIs, good quality data is lacking. The objective of this pilot randomized controlled trial of 120 patients to test the hypothesis that prophylactic NPWT will reduce SSIs and other wound complications after cesarean in obese women. The investigators will randomly assign obese women undergoing cesarean delivery to Standard dressing or prophylactic NPWT with the PICO system after skin closure. The primary outcome will be a composite of superficial or deep SSIs per Centers for Disease Control and Prevention (CDC) criteria and other wound complications (separation, hematoma, seroma) after cesarean.

Secondary outcomes will include wound dehiscence (≥2 cm); hematoma; seroma; composite of wound complications; patient pain and satisfaction scores; physician office visit or emergency department (ED) visits for SSIs; and hospital readmission for wound complications.

Detailed description: Overview of the Proposed Trial

This will be a pilot randomized controlled trial. The investigators chose a randomized controlled trial, the 'gold standard' of clinical research design, with the goal of obtaining the highest quality evidence to inform clinical practice. Randomly allocating subjects to different interventions minimizes selection bias and results in groups that are comparable with regards to important confounding variables, both measured and unmeasured. Additionally, the broad inclusion criteria, simplicity of the interventions, and evaluation of effects of typical use of prophylactic NPWT make this a pragmatic trial. The investigators will follow the Consolidated Standards of Reporting Trials (CONSORT) guidelines in the conduct and reporting of this trial. We will use computer-generated block randomization stratified by study site and BMI category to assign participants to the two interventions. All subjects will receive standard infection prevention measures including skin antisepsis and weight-adjusted prophylactic antibiotics. Analysis will follow the intention-to-treat principle. The use of broad inclusion criteria and intention-to-treat analysis will allow a more conservative estimate of the effect of prophylactic NPWT and allow a better estimate of effectiveness and public health implications of practice change than would pure estimate of efficacy alone.

Conduct of the Trial Recruitment of study subjects: All women admitted to the labor and delivery units of the participating medical centers will be screened against inclusion and exclusion criteria. Eligible subjects will be approached by trained research staff for written consent to participate in the study. Subjects will be randomized only when the decision is made for cesarean delivery.

Randomization and allocation concealment: Enrolled subjects will be randomly assigned in a 1:1 ratio to NPWT or standard care using a computer-generated random sequence generated by the study statistician. A subject's group assignment will be revealed only after the decision is made to perform cesarean delivery.

Blinding: Although blinding of both subjects and physicians would be ideal, blinding is not possible in this trial. We will minimize systematic bias by applying the same standard infection prevention measures in all patients at each site. Further, the research personnel collecting outcomes data will be blinded to the group assignments of the subjects after the standard dressing or NPWT device have been removed. Importantly, diagnosis of the primary outcome will be objectively reviewed centrally by the PI in a blinded fashion using to CDC criteria.

Interventions: The interventions to be compared in this trial are standard care versus prophylactic NPWT after skin closure:

1. Standard care: Women assigned to standard care will receive routine postoperative wound dressing consisting of layers of gauze and adhesive tap. The dressing will be removed after 24 - 48 hours.
2. Prophylactic NPWT: Women assigned to prophylactic NPWT will have the PICO device applied and secured with fixation adhesion strips. The device will be monitored while the patient is in the hospital to confirm that it is functioning well. The device will be removed prior to discharge, typically on postoperative day 4.

Rationale for choosing PICO: There are no head-to-head trials of the two FDA-cleared prophylactic NPWT devices, and the preliminary data do not suggest one is superior to the other. However, there is a large price difference: $200 per PICO unit and $500 per Prevena unit. The investigators chose the less expensive device.

Data Collection: The investigators will collect detailed antepartum, intrapartum, and postpartum information from study participants. Relevant data will be collected initially to assess eligibility. Complete baseline information and outcome data will be collected by trained study nurses by direct interview and chart review.

Hypothesis Testing Primary Aim: Determine the effectiveness of prophylactic NPWT in reducing the rate of SSIs and other wound complications after cesarean in obese women.

Hypothesis: Obese women will have lower rates of SSIs and other wound complications after cesarean with use of prophylactic NPWT than with standard care.

Primary outcome: The primary outcome for the trial is superficial or deep SSIs and other wound complications (separation, hematoma, seroma) after cesarean. This will be defined according to CDC criteria as infections at the surgical site occurring within 30 days of cesarean delivery, and classified as superficial, deep, or organ/space occupying. We will use active surveillance for SSIs including one patient phone call by the research coordinator within 30 days after surgery. The PI will blindly review de-identified inpatient and outpatient records of all subjects with suspected SSIs against CDC criteria to ensure standard diagnosis and classification.

Secondary outcomes: Wound dehiscence (≥2 cm); hematoma; seroma; composite of wound complications; patient pain and satisfaction scores (on a scale of 0 to 10) at discharge and postoperative day 14 (±2 days) and 28 (±2 days); physician office visit or ED visits for SSIs; and hospital readmission for SSIs.

Sample size calculation: The sample size for this pilot trial is 120; 60 in the prophylactic NPWT group and 60 in the standard treatment group. We estimated the sample size for the trial assuming a baseline SSI and wound complication rate of 24% based on a recent trial at our institution, and we a clinically significant 75% reduction effect size based on a recently published study.

CDC Criteria for defining and classifying surgical site infections (SSIs):

1. Superficial incisional (wound) infection infection occurs within 30 days after operative procedure; AND involves only skin and subcutaneous tissue of the incision; AND patient has at least one of the following:

   1. purulent drainage from the superficial incision,
   2. organisms isolated from an aseptically-obtained culture from the superficial incision or subcutaneous tissue,
   3. superficial incision that is deliberately opened by a surgeon, attending physician or other designee and is culture-positive or not cultured; and patient has at least one of the following signs or symptoms: pain or tenderness; localized swelling; erythema; or heat. A culture-negative finding does not meet this criterion,
   4. diagnosis of a superficial incisional SSI by the surgeon or attending physician or other designee.
2. Deep incisional (wound) infection

   Infection occurs within 30 days of operative procedure; AND involves deep soft tissues of the incision (e.g., fascial and muscle layers); AND patient has at least one of the following:
   1. purulent drainage from the deep incision,
   2. a deep incision that spontaneously dehisces, or is deliberately opened or aspirated by a surgeon, attending physician or other designee and is culture-positive or not cultured; and patient has at least one of the following signs or symptoms: fever (\>38°C), localized pain, or tenderness. A culture-negative finding does not meet this criterion,
   3. an abscess or other evidence of infection involving the deep incision that is detected on gross anatomical or histopathologic exam, or imaging test.
3. Organ/Space (endometritis, abscess)

Infection occurs within 30 days of operative procedure; AND infection involves any part of the body deeper than the fascial/muscle layers, that is opened or manipulated during the operative procedure; AND patient has at least one of the following:

1. purulent drainage from a drain that is placed into the organ/space (e.g., closed suction drainage system, open drain, T-tube drain, CT-guided drainage),
2. organisms isolated from an aseptically-obtained culture of fluid or tissue in the organ/space,
3. an abscess or other evidence of infection involving the organ/space that is detected on gross anatomical or histopathologic exam, or imaging test; AND meets at least one criterion for a specific organ/space infection site.

Secondary Aim 1: Assess the safety of prophylactic NPWT in obese women as measured by frequency of adverse events including skin blisters, erythema, wound bleeding and prolonged wound drainage.

Hypothesis: The rate of adverse events will not be significantly higher with use of prophylactic NPWT than with standard care.

Outcomes for secondary aim 1: Composite of adverse events potentially attributable to NPWT including skin blisters, erythema, wound bleeding, and prolonged (\>7 days) wound drainage.

Rationale: NPWT has been associated with adverse events including skin blisters, wound bleeding, and prolonged wound drainage. A high rate of skin blisters was reported when NPWT was used after orthopedic surgery. This was attributed to use of the adhesive dressing in the setting of marked swelling and edema. Although the adverse events noted with NPWT after cesarean have generally been minor and were comparable in frequency to use of standard dressing, it is essential to characterize the frequency of these events to permit risk-benefit counseling of patients.

Secondary Aim 2: Determine the effect of prophylactic NPWT on the frequency and identity of bacteria, including antibiotic-resistant organisms, isolated from SSIs after cesarean in obese women.

Hypothesis: Prophylactic NPWT will be associated with a reduction in the rate of positive wound cultures and antibiotic-resistant bacteria isolated from SSIs after cesarean.

Outcomes for secondary aim 2: Rate of positive wound cultures and proportion of specific organisms, especially drug-resistant bacteria (e.g. MRSA) isolated from SSIs after cesarean.

Wound cultures and antimicrobial sensitivity testing: Physicians will follow clinical protocols that warrant collection of swabs from all accessible SSIs for routine aerobic and anaerobic cultures.

Data Analysis Plan Overview: Data analyses will adhere closely to the CONSORT guidelines. Analyses will follow the intention-to-treat principle in which subjects will be analyzed in the group to which they were randomized, regardless of whether or not they received the assigned intervention.

Primary Analysis: Descriptive statistics will characterize the group of individuals recruited and investigate comparability of the two groups at baseline. Formal statistical testing will be limited to selected baseline characteristics considered to be prognostic factors for the primary outcome such as emergent cesarean, type of skin incision, and prolonged rupture of membranes. The categorical prognostic factors will be compared between trial groups by using the Fisher's exact test. Continuous prognostic factors will be compared using the Mann-Whitney U test.

The primary outcome and other categorical secondary outcomes will be compared between intervention groups by using the Cochran-Mantel-Haenszel test.The investigators will calculate common relative risks and 95% confidence intervals associated with the primary and secondary outcomes. The investigators will also conduct time-to-event analyses by using Kaplan Meier and Cox regression models to examine the pattern of SSIs in the two groups.

Secondary Analyses: The investigators will perform other analyses aimed at obtaining adjusted estimates of treatment effectiveness, adjusting for baseline subject characteristics (covariates). The objectives of these analyses are to estimate the influence of covariates on the outcome and to use covariates to improve the estimated difference between treatment groups. Stepwise logistic regression models will be used to identify and estimate the effect of multiple prognostic factors on the probability of SSI and other categorical outcomes. Interaction tests will be used to determine whether the effectiveness of prophylactic NPWT differs across these subgroups such as BMI category and type of skin incision. These secondary analyses will be considered exploratory.

Safety monitoring

The interventions compared in this trial are both currently used in clinical obstetric practice. Further, the adverse events reported with use of prophylactic NPWT at cesarean were minor and their frequency was comparable to rates with standard dressing. Therefore, no serious or life-threatening adverse events are expected. Nonetheless, the following measures will be taken to monitor and investigate adverse events:

1. Adverse events reporting: Detailed information concerning adverse events will be collected and evaluated throughout the trial. If a participant develops an adverse event, the participant's physician and PI will ascertain the safety of continuing the intervention.
2. Interim analyses: The investigators anticipate one interim analyses after 60 patients have recruited. Although early stopping decisions cannot be based purely on a mathematical stopping rule, we will use the Haybittle-Peto stopping rule as a guide. Under this rule, the interim analyses of the primary outcome would have to demonstrate an extreme difference between groups (P \<0.001) to justify premature disclosure. This rule has the advantages that the exact number of interim analyses need not be specified in advance and the overall type I error is preserved at 0.05; therefore, samples size adjustment is not needed.

Eligibility criteria: Inclusion Criteria:

* Gestational age ≥23weeks
* BMI≥30 at the time of delivery
* Planned or unplanned cesarean delivery (procedure in which NPWT is being tested)

Exclusion Criteria:

* Non-availability for postoperative follow-up (follow-up is needed to ascertain study outcomes)
* Contraindication to NPWT applicable to women undergoing cesarean (device will not be used in patients with contraindications): Pre-existing infection around incision site, Bleeding disorder, Therapeutic anticoagulation, Allergy to any component of the dressing (e.g. silicone, adhesive tape)

Primary outcomes:
measure: Number of Participants With Composite Surgical Site Infection (SSI) or Other Wound Complication.
timeFrame: 30 days
Secondary outcomes:
measure: Number of Participants With Any COMPONENT of SSI or Composite Wound Complication
timeFrame: 30 days
measure: Pain Score on a 0 to 10 on Likert Scale
timeFrame: Postoperative days 2
measure: Number of Participants With Positive Wound Culture
timeFrame: 30 days
measure: Number of Participants With Methicillin-resistant Staphylococcus Aureus.
timeFrame: 30 days
measure: Number of Participants With Any Prophylactic Negative Pressure-related Adverse Events.
timeFrame: 30 days
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Methodius G Tuuli, MD, MPH
role: PRINCIPAL_INVESTIGATOR
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