Effect IV Ibuprofen and Inflammatory Responses

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

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.

Study Overview

• Status: Completed
• Conditions: Gallbladder Disease
• Intervention / Treatment: Drug: ibuprofen; Other: sugar water/placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Newark, New Jersey, United States, 07101
      • University Hospital
  • New York
    • Brooklyn, New York, United States, 11215
      • New York Methodist Hospital
    • New York, New York, United States, 10016
      • New York University Hospital
    • New York, New York, United States, 10029
      • Mt. Sinai Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Ibuprofen; 800mg administered IV in 100cc of normal saline over 5 minutes	Drug: ibuprofen; single preoperative dose prior to surgery; Other Names: caldolor
Placebo Comparator: Sugar water; 100mL of normal saline to be administered over 5 minutes	Other: sugar water/placebo; single preoperative dose prior to surgery; Other Names: 100mL. intravenous sugar water administered over 5 minutes

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Stress Response Inflammation Markers :Cortisol and C Reactive Protein (CRP)	Serum concentration of cortisol, CRP, drawn in Post Anesthesia Care unit at 2 hours following surgery were compared with those same levels drawn preoperatively and intraoperatively.	2 hours following end of surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune Response IL-6		2 hours postoperatively in PACU
Quality of Recovery-40	Quality of Recovery-40 has been used to assess postoperative recovery from anesthesia where higher score correlate with improved recovery and well being. The survey has 5 domains: comfort scale ranges 1-60 with higher value indicating greater comfort, emotions scale ranges 1-45 with higher value indicating best emotional state, physical independence scale ranges 1-25 with higher value indicating best independence, patient support scale ranges 1-35 with a higher score indicating greater support and pain scale 1-35 with higher number indicating greater relief from pain. Scoring is done for PART A on a scale of 1-5 (1=very poor=none of the time, worst score, 5=excellent=all of the time, best possible score).PART B on a scale of 1-5 (1=very poor or all the time worse score), 5=excellent or none of the time, best score) Perfect score=200.	preoperatively and -postoperative days 1 and 3
Modified Fatigue Severity Scale	This questionnaire contains 9 statements that rate severity of fatigue symptoms. Score 1 indicates strong disagreement with the statement and 7= strong agreement. i.e (I am easily fatigued).Total lowest possible score indicating no fatigue is 9. Total highest possible score is 63 which correlates to severe fatigue, interfering with all activities of daily living.	preoperative-postoperative day 1 and day 3
Immune Response:Serum Concentration of IL-10,	.drawn in PACU 2 hours following arrival and compared to preoperative and intraoperative values	2 hours post arrival in PACU
Cognitive Recovery.	Digits span forward subject is asked to repeat a series of numbers with increasing number of digits forward. Digit span backward subject is asked to repeat a series of numbers backward with increasing number of digits. Correct response is worth 1 point. Maximum of 14 points for each sub score with a total of 28 points for total score	preoperatively- 2 hours in PACU, Post op day #1, post op day#3
Geriatric Depression Scale	15 questions. Score 1 point for each answer selected which indicates depression. Score of 0-5 is normal. A score >5 suggests depression.	Preoperatively, post operative day 1 and post op day3

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cytokine Concentrations	IFN y, IL-1B IL-2 were below the limit of detection and no assessments could be made. The lower limit for all cytokine detection was 3.2pg/mL	preoperative-intraoperative-postopoperative

Collaborators and Investigators

• Sponsor: University of Medicine and Dentistry of New Jersey
• Investigators: Principal Investigator: Alex Bekker, MD, PhD, Rutgers/NJMS

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): August 1, 2014
• Study Completion (Actual): August 1, 2014

Study Registration Dates

• First Submitted: May 24, 2013
• First Submitted That Met QC Criteria: September 4, 2013
• First Posted (Estimate): September 10, 2013

Study Record Updates

• Last Update Posted (Estimate): December 21, 2016
• Last Update Submitted That Met QC Criteria: October 28, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Keywords: laparoscopic cholecystectomy
• Additional Relevant MeSH Terms: Digestive System Diseases; Biliary Tract Diseases; Gallbladder Diseases; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Ibuprofen
• Other Study ID Numbers: 2012001793

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO