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IV Acetaminophen as an Adjunct Analgesic in Cardiac Surgery (CarDolMev)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01544062
Recruitment Status : Completed
First Posted : March 5, 2012
Results First Posted : June 21, 2016
Last Update Posted : June 21, 2016
Sponsor:
Collaborator:
Mallinckrodt
Information provided by (Responsible Party):
Srdjan Jelacic, University of Washington

Tracking Information
First Submitted Date  ICMJE February 28, 2012
First Posted Date  ICMJE March 5, 2012
Results First Submitted Date  ICMJE November 30, 2015
Results First Posted Date  ICMJE June 21, 2016
Last Update Posted Date June 21, 2016
Study Start Date  ICMJE July 2012
Actual Primary Completion Date December 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 24, 2014)
24 Hour Postoperative Opioid Consumption [ Time Frame: 24 hours after arriving in ICU ]
The 24 hour postoperative opioid consumption will be obtained from the electronic medication administration record and expressed in morphine equivalents.
Original Primary Outcome Measures  ICMJE
 (submitted: March 2, 2012)
Consumption of hydromorphone PCA in mg at 24hs after cardiac surgery [ Time Frame: 24h after cardiac surgery ]
Consumption of iv hydromorphone will be read on the PCA pump the patient will use postoperatively
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 12, 2016)
  • 48 Hour Postoperative Opioid Consumption [ Time Frame: 48 hours after arriving in ICU ]
    48 hour postoperative opioid consumption will be obtained from the electronic medication administration record and expressed in morphine equivalents.
  • 24 Hour Postoperative Pain Scores at Rest [ Time Frame: 24 hours after arriving in ICU ]
    Pain scores at rest will be recorded on Numeric Rating Scale by nursing staff. The Numeric Rating Scale ranges from 0 to 10 (0 - no pain, 1-2-3 - mild pain, 4-5-6 - moderate pain, 7-8-9 - severe pain, 10 - worst pain imaginable).
  • 48 Hour Postoperative Pain Scores at Rest [ Time Frame: 48 hours after arriving in ICU ]
    Pain scores at rest will be recorded on Numeric Rating Scale by nursing staff. The Numeric Rating Scale ranges from 0 to 10 (0 - no pain, 1-2-3 - mild pain, 4-5-6 - moderate pain, 7-8-9 - severe pain, 10 - worst pain imaginable).
  • 24 Hour Postoperative Pain Scores With Movement [ Time Frame: 24 hours after arriving in ICU ]
    Pain scores at rest will be recorded on Numeric Rating Scale by nursing staff. The Numeric Rating Scale ranges from 0 to 10 (0 - no pain, 1-2-3 - mild pain, 4-5-6 - moderate pain, 7-8-9 - severe pain, 10 - worst pain imaginable).
  • 48 Hour Postoperative Pain Scores With Movement [ Time Frame: 48 hours after arriving in ICU ]
    Pain scores at rest will be recorded on Numeric Rating Scale by nursing staff. The Numeric Rating Scale ranges from 0 to 10 (0 - no pain, 1-2-3 - mild pain, 4-5-6 - moderate pain, 7-8-9 - severe pain, 10 - worst pain imaginable).
  • 24 Hour Wound Hyperalgesia [ Time Frame: 24 hours after arriving in ICU ]
    Wound hyperalgesia will be determined by testing the right side of the chest along five horizontal lines vertically separated by 2 cm at right angles to the incision using 180 gram von Frey filament (# 6.45).
  • 48 Hour Wound Hyperalgesia [ Time Frame: 48 hours after arriving in ICU ]
    Wound hyperalgesia will be determined by testing the right side of the chest along five horizontal lines vertically separated by 2 cm at right angles to the incision using 180 gram von Frey filament (# 6.45).
  • Length of Mechanical Ventilation [ Time Frame: From the time of arrival in ICU until extubation ]
    The length of mechanical ventilation will be determined based on the "Extubation Criteria" checklist that will be completed by nursing staff every 2 hours until extubation.
  • Length of ICU Stay [ Time Frame: From the time of arrival in ICU until ICU discharge ]
    The length of ICU stay will be determined based on the "ICU Discharge Criteria" checklist that will be completed by nursing staff every 4 hours until ICU discharge.
  • 48 Hour Patient Satisfaction [ Time Frame: 48 hours after arriving in ICU ]
    "The extent to which subjects overall pain experience met their expectations" question responses were converted to the Likert scale with the following values: not at all (1), a little (2), a fair amount (3), very much (4) and extremely well (5).
  • 24 Hour Nausea [ Time Frame: 24 hours after arriving in ICU ]
    Opioid related adverse effects were recorded using a numeric scale (0 = no adverse effects, 1 = mild adverse effects not requiring treatment, 2 = moderate adverse effects requiring treatment and 3 = severe adverse effects refractory to treatment). Presence of nausea was defined as numeric scale response 2 (moderate adverse effects requiring treatment) or 3 (severe adverse effects refractory to treatment).
  • 48 Hour Nausea [ Time Frame: 48 hours after arriving in ICU ]
    Opioid related adverse effects were recorded using a numeric scale (0 = no adverse effects, 1 = mild adverse effects not requiring treatment, 2 = moderate adverse effects requiring treatment and 3 = severe adverse effects refractory to treatment). Presence of nausea was defined as numeric scale response 2 (moderate adverse effects requiring treatment) or 3 (severe adverse effects refractory to treatment).
  • 24 Hour Pruritus [ Time Frame: 24 hours after arriving in ICU ]
    Opioid related adverse effects were recorded using a numeric scale (0 = no adverse effects, 1 = mild adverse effects not requiring treatment, 2 = moderate adverse effects requiring treatment and 3 = severe adverse effects refractory to treatment). Presence of pruritus was defined as numeric scale response 1 (mild adverse effects not requiring treatment), 2 (moderate adverse effects requiring treatment) or 3 (severe adverse effects refractory to treatment).
  • 48 Hour Pruritus [ Time Frame: 48 hours after arriving in ICU ]
    Opioid related adverse effects were recorded using a numeric scale (0 = no adverse effects, 1 = mild adverse effects not requiring treatment, 2 = moderate adverse effects requiring treatment and 3 = severe adverse effects refractory to treatment). Presence of pruritus was defined as numeric scale response 1 (mild adverse effects not requiring treatment), 2 (moderate adverse effects requiring treatment) or 3 (severe adverse effects refractory to treatment).
  • 24 Hour Sedation [ Time Frame: 24 hours after arriving in ICU ]
    Opioid related adverse effects were recorded using a numeric scale (0 = no adverse effects, 1 = mild adverse effects not requiring treatment, 2 = moderate adverse effects requiring treatment and 3 = severe adverse effects refractory to treatment). Presence of sedation was defined as numeric scale response 1 (mild adverse effects not requiring treatment), 2 (moderate adverse effects requiring treatment) or 3 (severe adverse effects refractory to treatment).
  • 48 Hour Sedation [ Time Frame: 48 hours after arriving in ICU ]
    Opioid related adverse effects were recorded using a numeric scale (0 = no adverse effects, 1 = mild adverse effects not requiring treatment, 2 = moderate adverse effects requiring treatment and 3 = severe adverse effects refractory to treatment). Presence of sedation was defined as numeric scale response 1 (mild adverse effects not requiring treatment), 2 (moderate adverse effects requiring treatment) or 3 (severe adverse effects refractory to treatment).
  • 24 Hour Respiratory Depression [ Time Frame: 24 hours after arriving in ICU ]
    Opioid related adverse effects were recorded using a numeric scale (0 = no adverse effects, 1 = mild adverse effects not requiring treatment, 2 = moderate adverse effects requiring treatment and 3 = severe adverse effects refractory to treatment). Presence of respiratory depression was defined as numeric scale response 1 (mild adverse effects not requiring treatment), 2 (moderate adverse effects requiring treatment) or 3 (severe adverse effects refractory to treatment).
  • 48 Hour Respiratory Depression [ Time Frame: 48 hours after arriving in ICU ]
    Opioid related adverse effects were recorded using a numeric scale (0 = no adverse effects, 1 = mild adverse effects not requiring treatment, 2 = moderate adverse effects requiring treatment and 3 = severe adverse effects refractory to treatment). Presence of respiratory depression was defined as numeric scale response 1 (mild adverse effects not requiring treatment), 2 (moderate adverse effects requiring treatment) or 3 (severe adverse effects refractory to treatment).
  • 24 Hour Dizziness [ Time Frame: 24 hours after arriving in ICU ]
    Opioid related adverse effects were recorded using a numeric scale (0 = no adverse effects, 1 = mild adverse effects not requiring treatment, 2 = moderate adverse effects requiring treatment and 3 = severe adverse effects refractory to treatment). Presence of dizziness was defined as numeric scale response 1 (mild adverse effects not requiring treatment), 2 (moderate adverse effects requiring treatment) or 3 (severe adverse effects refractory to treatment).
  • 48 Hour Dizziness [ Time Frame: 48 hours after arriving in ICU ]
    Opioid related adverse effects were recorded using a numeric scale (0 = no adverse effects, 1 = mild adverse effects not requiring treatment, 2 = moderate adverse effects requiring treatment and 3 = severe adverse effects refractory to treatment). Presence of dizziness was defined as numeric scale response 1 (mild adverse effects not requiring treatment), 2 (moderate adverse effects requiring treatment) or 3 (severe adverse effects refractory to treatment).
Original Secondary Outcome Measures  ICMJE
 (submitted: March 2, 2012)
  • Pain scores [ Time Frame: Every 6 hours for 48hs ]
    VAS, NRS scores
  • Hyperalgesia area [ Time Frame: 24, 48h ]
    Mesure of hyperalgesia area around the sternotomy wound with von Frey filament 180g of pressure
  • Hydromorphone consuption in mg [ Time Frame: 48h ]
    Read on PCA pump
  • Intraoperative pain level [ Time Frame: During Anesthesia ]
    The physiodoloris device (giving to the anesthesia team a ANI index which is a measure of intraoperative pain)will be used during anesthesia. It will not be used to guide intraoperative analgesic administration. ANI index values will just be recorded and analyzed after surgery between the 2 groups.
  • Side effects of opioids [ Time Frame: 24, 48, 72h ]
    post-operative nausea and vomiting (PONV), pruritus, constipation, urinary retention, dizziness, sedation, respiratory depression and de-ambulation. Scale 0-1-2-3-4 will be used.
  • Chronic pain and rehabilitation at 6 months after surgery [ Time Frame: 6 months after surgery ]
    6 months post-surgery by phone with the 40-item Quality of Recovery (QoR-40) Questionnaire and the Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2)
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE IV Acetaminophen as an Adjunct Analgesic in Cardiac Surgery
Official Title  ICMJE Efficacy of Perioperative Intravenous Acetaminophen as an Adjunct Analgesic in Cardiac Surgery Patients
Brief Summary Patients undergoing cardiac surgery experience significant postoperative pain, which may impact postoperative outcomes. The aim of this single center, double-blind, randomized, placebo controlled trial is to determine if intravenous (IV) acetaminophen will significantly decrease 24 hour postoperative opioid consumption.
Detailed Description

Subjects will be randomized to a placebo or treatment group in a 1:1 ratio in blocks of 10 using an online randomization tool. The randomization table numbers for the subjects who are randomized, but subsequently withdrew consent after enrollment or had their case cancelled will be also included. Only the research pharmacists will have access to the securely-stored randomized group allocation list, which will remain blinded until statistical analysis is completed. A research pharmacist will prepare 100 mL normal saline infusion bags, which contain either 1,000 mg IV acetaminophen or placebo. Identical in appearance, the bags will be then delivered to either the operating room satellite pharmacy or ICU.

The subjects will receive a total of 6 doses of 1,000 mg IV acetaminophen or placebo at the following time points: (1) immediately after anesthesia induction, but prior to the incision, (2) at the end of surgery with (3) four additional doses administered postoperatively in the ICU every 6 hours for the first 24 hours. The first ICU dose will be administered 6 hours after the arrival in the ICU. The intraoperative study drug doses will be administered by one of the investigators (SJ or PR) and postoperative ICU study drug doses will be administered by nursing staff.

Anesthesia and Pain Management All of the study subjects will undergo cardiac surgery under general anesthesia. The cardiac surgery procedures will include standard midline sternotomy and in cases involving coronary artery bypass grafting, harvesting of saphenous vein and internal mammary artery grafts. Cardiopulmonary bypass will be conducted using membrane oxygenation. All subjects will undergo standardized induction per current practice at our institution with lidocaine (1-1.5 mg/kg), fentanyl (5-10 μg/kg), etomidate (0.2 mg/kg) and either rocuronium (1 mg/kg) or vecuronium (0.1 mg/kg). Succinylcholine (1-1.5 mg/kg) will be used when rapid sequence induction is appropriate. The anesthesia will be maintained with isoflurane. The intraoperative analgesia will consist of fentanyl or hydromorphone boluses, which will be administered at the discretion of the anesthesia provider. Postoperative pain management will consist of nursing fentanyl boluses while patients were sedated and mechanically ventilated. Following extubation, patients will receive oral oxycodone (5 to 10 mg orally every 3 hours as needed) with intravenous hydromorphone or morphine boluses for breakthrough pain.

Opioid Consumption At the end of the surgery, subjects will be transferred to the ICU while intubated and sedated on a propofol infusion. The time of arrival to the ICU will be considered time 0 for the purpose of postoperative study drug dosing and further evaluations. The 24 hour opioid consumption will be obtained from the electronic medication administration record and will be expressed in morphine equivalents per standard opioid conversions.

Secondary Outcomes The secondary outcomes will include 48 hour postoperative opioid consumption. The ICU nursing staff will be trained to use pain diaries containing an eleven point (0 to 10) Numeric Rating Scale (NRS). Pain assessments at rest and with movement will be recorded by the nursing staff at 6, 12, 18 and 24 hours postoperatively while one of the investigators will record pain assessments at 48 hours postoperatively. At the same times postoperatively, patients will be also assessed for opioid related adverse effects including nausea and vomiting, pruritus, respiratory depression, dizziness and sedation using a numeric scale (0 = no adverse effects, 1 = mild adverse effects not requiring treatment, 2 = moderate adverse effects requiring treatment and 3 = severe adverse effects refractory to treatment).

In addition, the ICU nursing staff will be instructed to complete the "Extubation Criteria" checklist for each 2-hour time period until extubation and the "ICU Discharge Criteria" checklist for each 4-hour time period until discharge from the ICU. A short "Patient Satisfaction Survey" will be also completed during the 24 and 48 hour follow up visits. The extent to which subjects overall pain experience met their expectations will be converted to the Likert scale with the following values: not at all (1), a little (2), a fair amount (3), very much (4) and extremely well (5).

Wound hyperalgesia at 24 and 48 hours postoperatively will be measured using a method previously described by Stubhaug et al. In brief, the lateral right chest area will be first stimulated where no pain sensation is experienced using a 180 gram von Frey filament (# 6.45). The filament will be then moved toward the incision in 1 cm steps until a distinct change in perception (painful, sore, or sharp feeling) is reported and the remaining distance to the incision will be noted. If no change in sensation appears, stimulation will be stopped at 4 cm from the incision. Wound hyperalgesia will be determined by testing the right side of the chest along five horizontal lines vertically separated by 2 cm at right angles to the incision. Only the right side of the chest will be chosen to avoid confounding skin sensation changes from the left internal mammary artery harvesting. The distance (in cm) from the incision to the point where sensations changed will be measured 5 times and the average distance will be used as wound hyperalgesia.

Data and Statistical Analysis A power analysis determined that 35 patients in each group will be needed to have an 80% chance to detect a 30% difference in mean 24 hour cumulative opioid consumption for the first 24 hour period after surgery using 2-sided t-tests with a set α level of 0.05, and an anticipated dropout rate of less than 15%.

Fisher's exact or Chi-squared and t-tests will be used to compare patient characteristics and intraoperative variables between the placebo and treatment group. Outcome variables will be compared between groups using t-tests and analysis of covariance controlling for age, sex, body mass index (BMI) and intraoperative hydromorphone. Scatter plots will be used to display the data to look for interactions, outliers and skewed distributions. The best fit line will be assessed by the F-test on the interaction between age and treatment group in an analysis of covariance. The analyses will be performed using SPSS software, version 15 (SPSS Inc., Chicago, IL). All reported P values will be 2-sided, and a significance level of P < 0.05 will be used.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Acute Pain
  • Hyperalgesia
Intervention  ICMJE
  • Drug: IV acetaminophen
    Total of 6 doses of 1,000 mg IV acetaminophen at the following time points: (1) immediately after anesthesia induction, but prior to the incision, (2) at the end of surgery with (3) four additional doses administered postoperatively in the ICU every 6 hours for the first 24 hours.
    Other Name: Ofirmev
  • Drug: Placebo
    Total of 6 doses of 100 mL of normal saline at the following time points: (1) immediately after anesthesia induction, but prior to the incision, (2) at the end of surgery with (3) four additional doses administered postoperatively in the ICU every 6 hours for the first 24 hours.
Study Arms  ICMJE
  • Experimental: IV acetaminophen
    Study subjects receiving IV acetaminophen
    Intervention: Drug: IV acetaminophen
  • Placebo Comparator: Normal saline
    Study subjects receiving placebo
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 12, 2016)
68
Original Estimated Enrollment  ICMJE
 (submitted: March 2, 2012)
70
Actual Study Completion Date  ICMJE August 2014
Actual Primary Completion Date December 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • (1) subjects who clinically consented to elective sternotomy for coronary artery bypass grafting (CABG), heart valve repair or replacement under general anesthesia, and (2) ages between 18 and 75 years

Exclusion Criteria:

  • (1) subject refusal, (2) non-English speaking, (3) previous chronic or neuropathic pain, (4) previous chronic use of opioids, (5) history of psychiatric disorder, (6) allergy to acetaminophen, (7) severely impaired liver and kidney function and (8) previous sternotomy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01544062
Other Study ID Numbers  ICMJE 42204-D
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Srdjan Jelacic, University of Washington
Study Sponsor  ICMJE University of Washington
Collaborators  ICMJE Mallinckrodt
Investigators  ICMJE
Study Director: Lisa Flint, BS University of Washington
Principal Investigator: Srdjan Jelacic, MD University of Washington
PRS Account University of Washington
Verification Date May 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP