Multi-dose Acetaminophen for Patients Undergoing General Anesthesia

A Multi-center, Randomized, Double-blind, Pilot Study on the Effect of Intravenous Multi-dose Acetaminophen on Readiness for Discharge in Patients Undergoing Surgery With General Anesthesia

Study Objective The aim of the proposed study is to examine the effect of Q4 hour multidose IV acetaminophen on patients' readiness for discharge. In doing so the investigators will also investigate the various factors that could potentially contribute to a patient's readiness for discharge such as overall opioid consumption, time to rescue medication, incidence of postoperative nausea and vomiting, pain scores, and perioperative stress markers and their overall correlation with IV acetaminophen intake.

Study Overview

• Status: Terminated
• Conditions: Recovery Following Cholecystectomy
• Intervention / Treatment: Drug: normal saline; Drug: Acetaminophen

Detailed Description

This is a randomized, double-blind, placebo-controlled, two-arm parallel study.. Patients 50kg or more will receive either 1000mg IV acetaminophen or placebo with the first dose given preoperatively in the holding area followed by re-dosing every four hours from that point up to a maximum of 4 doses or 4000mg in 24 hours. Patients <50 kg will receive 12.5mg/kg to a maximum of 75 mg /per kg/per day as per the label dose with repeat dosing Q4 hours.

After pre-oxygenation, general anesthesia will be induced with lidocaine (1 mg/kg Ideal Body Weight), propofol (1-2 mg/kg Actual Body Weight), and fentanyl (up to 5 mcg/kg Actual Body Weight). Additionally all subjects with receive 2 mg midazolam. Tracheal intubation will be facilitated with rocuronium (0.6 - 1.2 mg/kg Actual Body Weight). Anesthesia will be maintained with air/oxygen (60%/40%) and desflurane. A remifentanyl infusion (0.05-2mcg/kg/min Ideal Body Weight) will be continued throughout the entire case with no further analgesics being administered. All patients will receive ondansetron 4 mg prior to the end of operation as well as additional antiemetics in the PACU as judged by the attending anesthesiologist. Patients will be awakened and extubated in the OR meeting standard extubation criteria. Once extubated all patients will then be transferred to the PACU where they will be assessed via the SPEEDs criteria 5 minutes after arrival and then every 15 minutes for the duration of their PACU stay. While in the PACU, all patients will be assessed for pain using the Visual Analog Scale. Pain will be treated as per our protocol with 0.2mg IV hydromorphone for mild pain (VAS 1-3), 0.4 mg IV hydromorphone for moderate pain (VAS 4-6), and 0.6 mg IV hydromorphone (VAS 7-10). As soon as a patient meets all the SPEEDs criteria he/she will be transferred to phase II of the recovery. In phase II, if need be, pain will be managed according to the following orders: 0.2mg intravenous hydromorphone for mild pain (VAS 1-3), 0.4 mg intravenous hydromorphone for moderate pain (VAS 4-6) and 0.6mg intravenous hydromorphone for severe pain (VAS 7-10).

The patient's readiness for discharge will be our primary outcome. Each patient will be assessed within 5 minutes of arriving in the PACU and then every 15 minutes thereafter until subject reaches maximum score. The assessment will be done using the SPEEDs criteria, which has recently been shown to be as specific and more sensitive for phase 1 nursing interventions and therefore more accurate in predicting which patients are fast-track eligible as compared to the standard Modified Aldrete 2 and Fast-Track criteria (38).

The secondary outcomes will include:

1. Post-operative pain scores a. Assessed every 15 minutes during the recovery period using the Visual and Numerical Analog Scales for 2 hours and then every 4 hours thereafter until discharge.
2. Time to first rescue medication a. 0.2mg intravenous hydromorphone for mild pain (VAS 1-3) b. 0.4mg intravenous hydromorphone for moderate pain (VAS 4-6) c. 0.6 mg intravenous hydromorphone for severe pain (VAS 7-10)
3. Total dosage of post-operative opioids given.
4. Incidence of post operative nausea and vomiting and need for additional antiemetics.
5. Phase II satisfaction survey:

a. This will focus on three of the following factors rated on a scale of 1 to 5, with 1 being dissatisfied/unlikely while 5 being most satisfied/very likely.

i. How satisfied are you with the overall experience? ii. How likely are you to recommend this anesthetic and analgesic to others? iii. How likely would you ask for a similar anesthetic and analgesic in the future if need be? f) Concentration of the plasma stress markers including cortisol, norepinephrine, epinephrine, and C Reactive Protein (CRP).

a. Changes in mediator levels in the IV acetaminophen versus placebo groups will be compared. Plasma samples will be collected before administration of any drug (after placement of IV lines), before incision, and 60 minutes after arrival in PACU. Blood [15millLiters] will be collected at the time points described above from an additional intravenous catheter placed in the patient's arm. These specimens will be placed in vacutainer tubes with no anti-coagulant. Blood will be drawn with a syringe attached directly to the angiocatheter which has been placed intravenously. To prevent hemolysis, blood will be transferred without a needle, to a vacutainer whose top has been removed. The vacutainer top will be replaced and specimens labeled with study name, subject's study IDentification number, sample number (1, 2, 3,), and dated. Bloods from the first two time points will be kept refrigerated until the final sample is obtained postoperatively. They will be centrifuged, serum removed, aliquoted and stored at -80 degrees C until analysis. All samples will be run in duplicate on with plates and reagents of the same lot. Any samples varying greater than 15% between duplicates

• Study Type: Interventional
• Enrollment (Actual): 88
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • University Hospital
    • Newark, New Jersey, United States, 07103
      • New Jersey Medical School
  • New York
    • Brooklyn, New York, United States, 11215
      • New York Methodist Hospital

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Undergoing ambulatory laparoscopic cholecystectomy.
• American Society of Anesthesiologists physical status 1, 2 or 3.-

Exclusion Criteria -

• Cognitively impaired (by history) and unable or unwilling to consent
• Chronic steroid or opioid user (as prescribed for a chronic systemic illness)
• Parturient or nursing mother. Patients who have been informed by a physician that they have liver or kidney disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: normal saline; Patients will receive 100 milliliters of normal saline with the first dose given preoperatively in the holding area followed by re-dosing every four hours from that point up to a maximum of 4 doses in 24 hours. Blinded medication will be prepared by research pharmacist.	Drug: normal saline; 100mL of normal saline every 4 hours to a maximum administration of 400mL; Other Names: placebo
Experimental: acetaminophen; Patients 50kg or more will receive either 1000mg IV acetaminophen with the first dose given preoperatively in the holding area followed by re-dosing every four hours from that point up to a maximum of 4 doses or 4000mg in 24 hours. Patients <50 kg will receive 12.5mg/kg to a maximum of 75 mg /per kg/per day as per the label dose with repeat dosing Q4 hours. Blinded medication will be prepared by research pharmacist in 100mL of normal saline	Drug: Acetaminophen; patients 50kg or more receive1000mg in 100milliliters of normal saline every 4 hours to a maximum dose 4000mg/24 hours. <50kg receive 12.5mg/kg to a maximum of 75mg/kg/24 hours.; Other Names: Ofirmev

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Readiness for Discharge	Number (percentage) of Participants with Readiness for Discharge (achieving discharge-readiness status at end of 2- hours post-surgery evaluated using the SPEEDs criteria: oxygen saturation, pain control, emesis control, extremity movement, dialogue, and stable vital signs.	2 hours following surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post Operative Pain Scores	Pain scores every 15 min for 2 hours or until achieving discharge-readiness, whatever comes first, an average of 1 hour. Visual Analogue Scale (VAS) for pain was used: score on a scale from 0 (no pain) to 10 (worst pain) were recorded.	Every 15 min for 2 hours or until achieving discharge-readiness, whatever comes first, an average of 1 hour
Plasma Stress Markers	Concentration of the plasma stress markers including epinephrine, norepinephrine, cortisol, interleukins (IL) 6, 8 and 10.	Before administration of any drug (after placement of intravenous (IV) line), before surgical incision (in operating room (OR)), and 1 h after arrival in post-anesthesia care unit (PACU)
The Level of C-reactive Protein	Concentration of the plasma C-reactive protein (CRP)	Before administration of any drug (after placement of intravenous (IV) line), before surgical incision (in operating room (OR)), and 1 h after arrival in post-anesthesia care unit (PACU)
Time to Rescue Pain Medication	Time to the first dose of pain medication	From arrival in PACU to the first dose of pain medication is given during 2 hours or until achieving discharge-readiness, whatever comes first, an average of 1 hour.
Total Dosage of Post Operative Opioids	Total dosage of post operative opioids (hydromorphone)	From arrival in PACU for 2 hours or until achieving discharge-readiness, whatever comes first, an average of 1 hour.
Patient Satisfaction Survey	Survey asking patients about their satisfaction with the experience, pain control, and anesthetic rated on a 5 point Likert scale, with 1 being dissatisfied/unlikely and 5 being most satisfied/very likely. Subscales were summed to receive total score.	For patients going home the day of surgery the survey is given prior to departing the hospital (approx 5 hours post surgery). For those being admitted, the survey is given once discharge criteria are met in the PACU (approx 3 hours post surgery).
Number of Participants With Post Operative Nausea and Vomiting	Number of Participants with Post Operative Nausea and Vomiting	From arrival in PACU for 2 hours or until achieving discharge-readiness, whatever comes first, an average of 1 hour
Number of Participants Requiring Additional Anti-emetics	Number of Participants Requiring Additional Anti-emetics (anti-vomiting)	From arrival in PACU for 2 hours or until achieving discharge-readiness, whatever comes first, an average of 1 hour

Collaborators and Investigators

• Sponsor: Rutgers, The State University of New Jersey
• Collaborators: Mallinckrodt
• Investigators: Principal Investigator: Michal Gajewski, Do, Rutgers, State University of New Jersey

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2017
• Primary Completion (Actual): September 1, 2020
• Study Completion (Actual): December 31, 2020

Study Registration Dates

• First Submitted: May 24, 2016
• First Submitted That Met QC Criteria: July 11, 2016
• First Posted (Estimate): July 14, 2016

Study Record Updates

• Last Update Posted (Actual): December 9, 2021
• Last Update Submitted That Met QC Criteria: November 10, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: 20150002613

Plan for Individual participant data (IPD)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No