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

• 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: University of Washington
• Collaborator: Mallinckrodt
• Information provided by (Responsible Party): Srdjan Jelacic, University of Washington

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Acute Pain; Hyperalgesia	Drug: IV acetaminophen; Drug: Placebo	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 68 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy of Perioperative Intravenous Acetaminophen as an Adjunct Analgesic in Cardiac Surgery Patients
• Study Start Date: July 2012
• Actual Primary Completion Date: December 2013
• Actual Study Completion Date: August 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: IV acetaminophen; Study subjects receiving IV acetaminophen	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
Placebo Comparator: Normal saline; Study subjects receiving placebo	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.

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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).
3. 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).
4. 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).
5. 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).
6. 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).
7. 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).
8. 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.
9. 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.
10. 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).
11. 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).
12. 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).
13. 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).
14. 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).
15. 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).
16. 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).
17. 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).
18. 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).
19. 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).
20. 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).

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Washington

University of Washington Medical Center, Department of ANesthesiology and Pain Medicine

Seattle, Washington, United States, 98195

Sponsors and Collaborators

University of Washington

Mallinckrodt

Investigators

• Study Director: Lisa Flint, BS; University of Washington
• Principal Investigator: Srdjan Jelacic, MD; University of Washington

More Information

• Responsible Party: Srdjan Jelacic, Assistant Professor, University of Washington
• ClinicalTrials.gov Identifier: NCT01544062
• Other Study ID Numbers: 42204-D
• First Posted: March 5, 2012
• Results First Posted: June 21, 2016
• Last Update Posted: June 21, 2016
• Last Verified: May 2016

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Srdjan Jelacic, University of Washington:

Cardiac surgery; Acute Pain; Wound Hyperalgesia; Intravenous Acetaminophen; Patient Satisfaction

Additional relevant MeSH terms:

Hyperalgesia; Acute Pain; Pain; Neurologic Manifestations; Somatosensory Disorders; Sensation Disorders; Nervous System Diseases; Acetaminophen; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Antipyretics