Effect IV Ibuprofen and Inflammatory Responses
Condition: Gallbladder Disease
MeSH terms: Gallbladder Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      This study is being done because the investigators wish to study ways to improve recovery
      after surgery. Injury, including surgical injury, causes inflammation. Inflammation is the
      body's attempt to protect itself and to start the healing process. Some surgical
      complications are related to the body's natural inflammatory response. Although mainly a
      healing response, inflammation can also have side effects which delay recovery. The
      investigators wish to determine the effect of a medication known as ibuprofen on recovery.
      You may know ibuprofen by the name Advil or Motrin. The medication will be given through the
      vein prior to the start of the surgery. Three blood samples will be taken, two while the
      patient is under anesthesia. The subject will be asked to complete several questionnaires.
    

Detailed description: 
      This is a randomized, double-blind, placebo-controlled, two-arm parallel, multi-center study.

      Thirty subjects (15 in each arm) will be enrolled. Subjects, over the age of 18, undergoing
      laparoscopic cholecystectomy under general anesthesia will be screened for eligibility to
      participate in the study. Subjects will be screened, recruited, and randomized during the
      preadmission visit or the day of surgery. Eligible subjects will be randomized to one of the
      two treatment group in a 1:1 ratio to receive either IV ibuprofen or matching placebo. Both
      men and women will be recruited, and there is no limitation as to racial and ethnic origin.

      Participation in the study will not alter the patient's anesthetic management. Routine
      anesthesia monitors used during general anesthesia will be used. Patients will receive either
      800mg IV ibuprofen or placebo pre-operatively. After pre-oxygenation, general anesthesia will
      be induced with lidocaine (1 mg/kg), propofol (1-2 mg/kg), and fentanyl (up to 5 mcg/kg).
      Tracheal intubation will be facilitated with rocuronium (0.6 mg/kg). Anesthesia will be
      maintained with air/oxygen (60%/40%), sevoflurane, and fentanyl. The anesthesiologist will be
      allowed to administer additional doses of fentanyl at his/her discretion. All patients will
      receive ondansetron 4 mg prior to the end of operation. Patients will be awakened and
      extubated in the OR and will be transferred to the Post Anesthesia Care Unit (PACU) after
      following simple commands. All patients will also be able to receive rescue doses of opioids
      as indicated by a Numeric Pain Rating Scale score >2 or upon request.

      ii. Sample Size Justification: The proposed study is a pilot trial designed to explore the
      relationship between inflammatory markers and the quality of recovery. To our knowledge this
      vital connection has never been investigated. Therefore, we cannot use commonly accepted
      methods of sample size calculations. Mahdy et al examined levels of IL-6, IL-10, and cortisol
      in patients undergoing urological surgery and treated with indomethacin versus placebo (12).
      A sample size of twenty three patients per group was sufficient to show a difference in
      cytokine levels. Tasdogan et al compared levels of interleukin (IL)-1, IL-6, and tumor
      necrosis factor (TNF)-alpha in patients requiring postoperative ventilation after abdominal
      surgery and treated with dexmedetomidine versus propofol (18). A sample size of twenty
      patients per group was sufficient to demonstrate the difference in cytokine concentrations.
      Kim et al studied changes in cytokine levels in patients undergoing total abdominal
      hysterectomy and pretreated with clonidine (19). These investigators studied ten patients per
      group. The sample size was sufficient to demonstrate changes in IL-6 related to surgical
      stress. Therefore, we believe, that a sample size of 30 patients per group is an adequate
      sample to demonstrate the changes in level of inflammatory markers and explore the quality of
      recovery.

      iii. IV ibuprofen administration The study drug will be given via intravenous infusion
      beginning after a placement of the IV line. The dose will be fixed at 800mg infused over 5
      minutes.

      iv. Inclusion criteria:

        1. Adults, 18 and over, who will undergo laparoscopic cholecystectomy.

        2. Subject is non-lactating and is either:

             1. Not of childbearing potential

             2. Of childbearing potential but is not pregnant at time of baseline as determined by
                pre-surgical pregnancy testing.

        3. Subject is American Society of Anesthesiologists physical status 1, 2, or 3. v.
           Exclusion criteria:

      1. Cognitively impaired (by history) 2. Subject requires chronic antipsychotic history 3.
      Subject is anticipated to require an additional surgery within 90 days after the intended
      surgery 4. Chronic use of steroids or opioids 5. Subject has received treatment with COX
      inhibitors within 3 days of study entry 6. Subject for whom opiates, benzodiazepines, and COX
      inhibitors are contraindicated vi. Endpoints: Concentration of the cytokines TNF-alpha,
      IL-1Beta, IL-2, IL-6, IL-10, and IFN-gamma as well as prostaglandin E2, cortisol and c
      reactive protein at different time points will be our primary outcome. Changes in mediator
      levels in the IV ibuprofen versus placebo groups will be compared. Plasma samples will be
      collected before administration of any drug (after placement of IV lines), before induction,
      at the end of the surgery in the operating room and 2-3 hours after the end of the surgery in
      the PACU.

      All plasma samples will be analyzed in the laboratory of Susan Gould-Fogerite. The secondary
      outcome parameters will be the quality of recovery score (QoR-40) to measure quality of
      recovery from surgery and a simple fatigue scale. Forty questions in five dimensions will be
      scored by patients on a five-point Likert scale. This assessment was developed and validated
      by Myles et al (20). Nine points fatigue scale is often used to assess progress of recovery
      in head trauma patients. Geriatric depression scale and digits backward and forward will be
      utilized. All metrics will be administered on the day of surgery, before the surgery, 2-3
      hours after the end of the surgery in the PACUand on postoperative days 1 and 3. Exploratory
      analysis will examine whether correlations exist between inflammatory mediator concentrations
      and the objective measures of recovery and fatigue.

      vii. Methods and Procedures

      1. Data monitoring plan Adverse events will include events reported by the subject and
      thought to be associated with the research. Unanticipated problems and adverse events will be
      gathered by study investigators. Adverse events will be evaluated at each study visit,
      including follow up telephone calls. Any serious adverse effects will be reported to the
      Institutional Review Board (IRB) according to regulatory requirements.
    

Intervention name(s): ibuprofen; sugar water/placebo
Intervention type(s): Drug; Other
Intervention description(s): single preoperative dose prior to surgery; single preoperative dose prior to surgery
Other intervention name(s): caldolor; 100mL. intravenous sugar water administered over 5 minutes
Intervention MeSH terms: Ibuprofen
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Treatment
Keywords: laparoscopic cholecystectomy