Clinical trial NCT01938040: Effect IV Ibuprofen and Inflammatory Responses
Official title: Randomized, Double Blind, Pilot Study on the Effect of Intravenous Ibuprofen on Inflammatory Responses in Patients Undergoing Surgery With General Anesthesia: Correlation With Clinical Outcomes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Gallbladder Disease
Keywords: laparoscopic cholecystectomy
Lead sponsor: Rutgers, The State University of New Jersey
Sponsor class: OTHER
First posted: 2013-09-10
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* undergoing laparoscopic cholecystectomy under general anesthesia
* American Society of Anesthesiologists status of 1, 2 or 3 (as determined by the anesthesiologists)
* not pregnant of breast feeding

Exclusion Criteria:

* cognitively impaired
* using antipsychotic drugs
* chronic use of steroids or opioids
* subject has received COX inhibitors within 3 days if surgery
* subjects for whom opiates, benzodiazepines and COX inhibitors are contraindicated
* subjects with a history of bleeding disorders or peptic ulcer disease

Primary outcomes:
measure: Stress Response Inflammation Markers :Cortisol and C Reactive Protein (CRP)
timeFrame: 2 hours following end of surgery
Secondary outcomes:
measure: Immune Response IL-6
timeFrame: 2 hours postoperatively in PACU
measure: Quality of Recovery-40
timeFrame: preoperatively and -postoperative days 1 and 3
measure: Modified Fatigue Severity Scale
timeFrame: preoperative-postoperative day 1 and day 3
measure: Immune Response:Serum Concentration of IL-10,
timeFrame: 2 hours post arrival in PACU
measure: Cognitive Recovery.
timeFrame: preoperatively- 2 hours in PACU, Post op day #1, post op day#3
measure: Geriatric Depression Scale
timeFrame: Preoperatively, post operative day 1 and post op day3
Other outcomes:
measure: Cytokine Concentrations
timeFrame: preoperative-intraoperative-postopoperative
Locations:
city: Newark
country: United States
facility: University Hospital
state: New Jersey
city: Brooklyn
country: United States
facility: New York Methodist Hospital
state: New York
city: New York
country: United States
facility: New York University Hospital
state: New York
city: New York
country: United States
facility: MT. Sinai Medical Center
state: New York
Study officials:
affiliation: Rutgers/NJMS
name: Alex Bekker, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Le V, Kurnutala L, SchianodiCola J, Ahmed K, Yarmush J, Daniel Eloy J, Shapiro M, Haile M, Bekker A. Premedication with Intravenous Ibuprofen Improves Recovery Characteristics and Stress Response in Adults Undergoing Laparoscopic Cholecystectomy: A Randomized Controlled Trial. Pain Med. 2016 Jun;17(6):1163-1173. doi: 10.1093/pm/pnv113. Epub 2016 Feb 18.