Intravenous Acetaminophen in Craniotomy

• Sponsor: The University of Texas Health Science Center, Houston (Other)
• Overall Status: Completed
• CT.gov ID: NCT01598701
• Collaborator: Mallinckrodt (Industry)
• Enrollment: 100
• Location: 1
• Arms: 2
• Actual Duration (Months): 46.9
• Patients Per Site Per Month: 2.1

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the use of intravenous Acetaminophen (OFIRMEV) as an effective adjunct therapeutic agent in patients undergoing craniotomy.

Condition or Disease	Intervention/Treatment	Phase
Postoperative Pain	Drug: Acetaminophen; Drug: Placebo	Phase 4

Detailed Description

General anesthesia will be induced by bolus administration of propofol (1.5-2.5 mg/kg IV), and fentanyl (2-3 µg/kg IV). Neuromuscular blockade will be achieved with bolus administration of rocuronium, vecuronium, or succinylcholine. Once the endotracheal tube is secured in place, the patient will be mechanically ventilated to an end-tidal CO2 of 35 mmHg. Additional procedures will include radial arterial line placement for invasive arterial blood pressure monitoring, as well as additional large-bore peripheral IV placements, or central line placement, if indicated. Anesthesia will be maintained with desflurane, propofol, and remifentanil.

Once general anesthesia has been induced, but prior to the first surgical incision, the first dose of the interventional agent will be administered. Repeat doses will be administered every 6 hours until 24 hours from the time that the patient enters the PACU, for a total of up to 6 doses. Once the patient has been positioned and prepped for surgery, the surgeon will infiltrate the scalp with bupivacaine 0.5% with epinephrine 1:200,000 (15-20 ml) before skin incision.

No other opioids or agents with analgesic properties (e.g., ketorolac, dexmedetomidine, ketamine) will be administered at any time during the operation. Additional medications that will be routinely administered for this procedure include dexamethasone 8-12mg IV prior to incision, and ondansetron 4mg IV at skin closure. Anticonvulsant drugs will be administered at the surgeon's request.

Emergence and extubation will occur at the completion of the case per standard guidelines. The time of remifentanil infusion discontinuation and time of extubation will be noted. If necessary, extubation may occur in the post anesthesia recovery unit (PACU); otherwise, extubation will occur in the operating room.

The patient will then be taken directly to the PACU. Inability to extubate a patient within two hours of completion of surgery will result in their withdrawal from the study. Once in the PACU, immediate postoperative vital signs will be recorded, including blood pressure, heart rate, respiratory rate, oxygen saturation, and RASS score.

Pain scores will be assessed using the visual analog scale (VAS) upon entering the PACU or upon extubation in PACU (0 hours), and then again at 1, 2, 4, 8, 12, 16, 20, and 24 hours post-operatively. The VAS will be a 10 cm scale on a numerical scale of 0 (no pain) to 10 (severe pain) that the patient will point to in order to indicate their current level of pain. Pain scores will be measured while the patient is at rest. Post-operative nausea will also be recorded on a 10 cm numeric rating scale (NRS) at the same time intervals, with 0 indicating no nausea and 10 indicating severe nausea. All day-time VAS and NRS measurements will be made by a research assistant. Night-time measurements will be made by the nurse on the unit.

While in the PACU, the time until the patient receives their first dose of analgesic medicine will be recorded. Patients will be given a 2mg nurse-administered dose of morphine upon request or if they report a pain score of ≥4/10, and will continue to be given morphine doses based on clinical assessment by the PACU/intensive care nurse, who will be blind to patient group allocation. The nurse will objectively assess the patient's pain score at least once an hour using the VAS pain scale, and an assessment of pain ≥4/10 will warrant an additional 2mg dose of morphine. Morphine dosage requirements will be recorded for 24 hours post-operatively. If morphine requirement is greater than 10mg in a 30 minute period or the patient develops an allergic reaction, pruritus, renal insufficiency, drowsiness, nausea/vomiting, or clinically relevant reason to change medication, the PACU supervising physician or ICU physician may use their clinical discretion to change the opioid rescue medication to hydromorphone (0.3mg doses). The reason for changing medication will be reported by the physician and recorded. The morphine equivalent of hydromorphone will be estimated to be 7 times the hydromorphone dose. The PACU/ICU nurses will also record any episodes of emesis, use of rescue anti-emetic medicine, and the occurrence of any other side effects.

A post-operative neurologic examination will take place in the PACU. Criteria for a neurological exam to be complete is the patient's ability to successfully lift each leg off of the bed for more than two seconds on command, and to be able to hold up two fingers on each hand on command. If these criteria are not met prior to transferring the patient from the PACU to the ICU, a post-operative neurologic complication will be considered and the patient will be withdrawn from the study.

The time until the patient is ready to be discharged from the PACU will also be noted. Patients with a modified Aldrete score of ≥ 8 (see Appendix 1) will be considered ready for discharge. These criteria will be assessed by either the research assistant or PACU staff.

At the end of the 24 hour post-operative time period, a patient interview will be conducted. At this interview the patient will asked about their subjective satisfaction with their analgesic protocol, as well as any adverse effects they may have noticed. The 24 hour morphine consumption will also be recorded at this time.

After the study is completed, patients may receive IV or oral acetaminophen therapy at the discretion of the primary physician.

Study Design

• Study Type: Interventional
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: The Opioid-Sparing and Analgesic Effects of IV Acetaminophen in Craniotomy: A Prospective, Randomized, Placebo-Controlled, Double-Blind Study
• Actual Study Start Date: May 2, 2012
• Actual Primary Completion Date: Mar 30, 2016
• Actual Study Completion Date: Mar 30, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Intravenous Acetaminophen Patients will be receive doses of 1000 mg/100 mL of IV Acetaminophen (OFIRMEV). The drug will be infused over 15 minutes.	Drug: Acetaminophen; Intravenous Acetaminophen, 1000 mg/100mL, Every 6 hours, Infused over 15 minutes.; Other Names: OFIRMEV
Placebo Comparator: Placebo Patients will be given 100 mL normal saline placebos at scheduled time intervals in place of IV acetaminophen.	Drug: Placebo; 100 mL 0.9% Sodium Chloride; Other Names: 0.9% Sodium Chloride

Outcome Measures

Primary Outcome Measures

1. Post-Operative Opioid Requirement [24 hours post-operatively]

   Opioid Consumption will be monitored in the first 24 post-operative hours. All non-opioid analgesics are disallowed. Total opioid consumption was calculated based on morphine equivalents (MEs), where 1 mg of IV morphine was equivalent to 1 ME, and 1 mg IV hydromorphone was calculated as 7 MEs.

Secondary Outcome Measures

1. Post-Operative Pain [24 Hours Post-Operatively]

   Patients will be assessed for pain using a Visual Analogue Scale (VAS) Scale at set time points after surgery (0,1,2,4,8,12,16,20,24 hours post-operatively). The Visual Analogue Scale (VAS) scale was measured on a scale of 0 - 10 (0 = no pain, 1-3 = mild, 4-6 = moderate, 7-10 = severe). Higher values on the VAS represent a worse outcome. The two rows below report: 1. the average VAS score for the least amount of pain reported per group and 2. the average VAS score of the worst amount of pain reported per group.

2. Post-Operative Side Effects [24 Hours Post-Operatively]

   Patients will be monitored for 24 hours post-operatively to detect the incidence of any drug or opioid-related side effects. These side effects were not considered to be adverse events.

3. Time to Extubation at Emergence From Anesthesia [Time from of discontinuation of anesthetic to time of extubation, an average of 7 minutes]

4. Time for Patient to Meet Post-anesthesia Care Unit (PACU) Discharge Criteria [From time of entry to PACU to time to meet PACU discharge criteria, an average of 12 minutes]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adults

• Undergoing Craniotomy for Supratentorial Tumor Resection

• Weight between 50 and 120 kilograms

• ASA Physical Status I-III

• Be able to communicate verbally

• Be able to use Visual Analog Score

Exclusion Criteria:

• Allergies to acetaminophen, morphine or any of the anesthetic agents required by the protocol.

• Use of opioids, tramadol, benzodiazepines, or gabapentin on a daily basis for > 7 days prior to the day of surgery.

• Use of acetaminophen, NSAIDs, or any other analgesic medication in the 12 hours immediately prior to study enrollment.

• Hepatic insufficiency (elevated transaminases > 1.5 times the upper limit of normal) or renal insufficiency (plasma creatinine > 2mg/dl).

• Known or suspected history of alcohol or illicit drug abuse.

• Pregnant or breast-feeding.

• Surgical plan for infratentorial (suboccipital) craniotomy.

• Plan for neurophysiologic monitoring that precludes the use of neuromuscular blockade.

• Inability to communicate due to a language barrier, impaired consciousness, cognitive defect or intellectual disability.

• Uncontrolled Hypertension

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Hermann Hospital - Texas Medical Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• The University of Texas Health Science Center, Houston
• Mallinckrodt

Investigators

• Principal Investigator: Carlos A. Artime, MD, University of Texas Health Sciences Center at Houston
• Principal Investigator: Sam D. Gumbert, MD, University of Texas Health Sciences Center at Houston

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Carlos Artime, Assistant Professor - Anesthesiology, The University of Texas Health Science Center, Houston
• ClinicalTrials.gov Identifier: NCT01598701
• Other Study ID Numbers: HSC-MS-12-0055
• First Posted: May 15, 2012
• Last Update Posted: Jun 19, 2018
• Last Verified: May 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Carlos Artime, Assistant Professor - Anesthesiology, The University of Texas Health Science Center, Houston: Acetaminophen; Intravenous Acetaminophen; Opioid Requirement; Pain; Post-Operative Pain; Craniotomy; Post-Craniotomy Pain
• Additional relevant MeSH terms: Pain, Postoperative; Acetaminophen

Study Results

Participant Flow

Arm/Group Title	Intravenous Acetaminophen	Placebo
Arm/Group Description	Patients will be receive doses of 1000 mg/100 mL of IV Acetaminophen (OFIRMEV). The drug will be infused over 15 minutes. Acetaminophen: Intravenous Acetaminophen, 1000 mg/100mL, Every 6 hours, Infused over 15 minutes.	Patients will be given 100 mL normal saline placebos at scheduled time intervals in place of IV acetaminophen. Placebo: 100 mL 0.9% Sodium Chloride
Period Title: Overall Study
STARTED	50	50
COMPLETED	45	41
NOT COMPLETED	5	9

Baseline Characteristics

Arm/Group Title	Intravenous Acetaminophen	Placebo	Total
Arm/Group Description	Patients will be receive doses of 1000 mg/100 mL of IV Acetaminophen (OFIRMEV). The drug will be infused over 15 minutes. Acetaminophen: Intravenous Acetaminophen, 1000 mg/100mL, Every 6 hours, Infused over 15 minutes.	Patients will be given 100 mL normal saline placebos at scheduled time intervals in place of IV acetaminophen. Placebo: 100 mL 0.9% Sodium Chloride	Total of all reporting groups
Overall Participants	50	50	100
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	50.0 (16.3)	51.5 (14.4)	50.75 (15.35)
Sex: Female, Male (Count of Participants)
Female	24 48%	31 62%	55 55%
Male	26 52%	19 38%	45 45%

Outcome Measures

1. Primary Outcome

Title	Post-Operative Opioid Requirement
Description	Opioid Consumption will be monitored in the first 24 post-operative hours. All non-opioid analgesics are disallowed. Total opioid consumption was calculated based on morphine equivalents (MEs), where 1 mg of IV morphine was equivalent to 1 ME, and 1 mg IV hydromorphone was calculated as 7 MEs.
Time Frame	24 hours post-operatively

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravenous Acetaminophen	Placebo
Arm/Group Description	Patients will be receive doses of 1000 mg/100 mL of IV Acetaminophen (OFIRMEV). The drug will be infused over 15 minutes. Acetaminophen: Intravenous Acetaminophen, 1000 mg/100mL, Every 6 hours, Infused over 15 minutes.	Patients will be given 100 mL normal saline placebos at scheduled time intervals in place of IV acetaminophen. Placebo: 100 mL 0.9% Sodium Chloride
Measure Participants	45	41
Median (Inter-Quartile Range) [Morphine Equivalents]	11.0	10.1

2. Secondary Outcome

Title	Post-Operative Pain
Description	Patients will be assessed for pain using a Visual Analogue Scale (VAS) Scale at set time points after surgery (0,1,2,4,8,12,16,20,24 hours post-operatively). The Visual Analogue Scale (VAS) scale was measured on a scale of 0 - 10 (0 = no pain, 1-3 = mild, 4-6 = moderate, 7-10 = severe). Higher values on the VAS represent a worse outcome. The two rows below report: 1. the average VAS score for the least amount of pain reported per group and 2. the average VAS score of the worst amount of pain reported per group.
Time Frame	24 Hours Post-Operatively

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Intravenous Acetaminophen	Placebo
Arm/Group Description	Patients will be receive doses of 1000 mg/100 mL of IV Acetaminophen (OFIRMEV). The drug will be infused over 15 minutes. Acetaminophen: Intravenous Acetaminophen, 1000 mg/100mL, Every 6 hours, Infused over 15 minutes.	Patients will be given 100 mL normal saline placebos at scheduled time intervals in place of IV acetaminophen. Placebo: 100 mL 0.9% Sodium Chloride
Measure Participants	45	41
Least amount of pain reported	1.4 (1.8)	2.6 (2.7)
Worst amount of pain reported	6.3 (2.5)	6.4 (3.2)

3. Secondary Outcome

Title	Post-Operative Side Effects
Description	Patients will be monitored for 24 hours post-operatively to detect the incidence of any drug or opioid-related side effects. These side effects were not considered to be adverse events.
Time Frame	24 Hours Post-Operatively

Outcome Measure Data

Analysis Population Description

The # analyzed does not match the # who completed or the overall # analyzed because data on all side effects was not collected for all participants who completed, either due to lack of collection of data by research/nursing staff (for emesis) or due to lack of reporting by participants on a questionnaire(for itching, dizziness, and drowsiness).

Arm/Group Title	Intravenous Acetaminophen	Placebo
Arm/Group Description	Patients will be receive doses of 1000 mg/100 mL of IV Acetaminophen (OFIRMEV). The drug will be infused over 15 minutes. Acetaminophen: Intravenous Acetaminophen, 1000 mg/100mL, Every 6 hours, Infused over 15 minutes.	Patients will be given 100 mL normal saline placebos at scheduled time intervals in place of IV acetaminophen. Placebo: 100 mL 0.9% Sodium Chloride
Measure Participants	45	40
Emesis	23 46%	20 40%
Itching	8 16%	5 10%
Dizziness	14 28%	14 28%
Drowsiness	24 48%	19 38%

4. Secondary Outcome

Title	Time to Extubation at Emergence From Anesthesia
Time Frame	Time from of discontinuation of anesthetic to time of extubation, an average of 7 minutes

Outcome Measure Data

Analysis Population Description

The number analyzed is greater than the number completed because this data was collected for more patients than completed the study, and all data that was collected is reported here.

Arm/Group Title	Intravenous Acetaminophen	Placebo
Arm/Group Description	Patients will be receive doses of 1000 mg/100 mL of IV Acetaminophen (OFIRMEV). The drug will be infused over 15 minutes. Acetaminophen: Intravenous Acetaminophen, 1000 mg/100mL, Every 6 hours, Infused over 15 minutes.	Patients will be given 100 mL normal saline placebos at scheduled time intervals in place of IV acetaminophen. Placebo: 100 mL 0.9% Sodium Chloride
Measure Participants	48	45
Median (Inter-Quartile Range) [minutes]	6	8

5. Secondary Outcome

Title	Time for Patient to Meet Post-anesthesia Care Unit (PACU) Discharge Criteria
Time Frame	From time of entry to PACU to time to meet PACU discharge criteria, an average of 12 minutes

Outcome Measure Data

Analysis Population Description

The number analyzed is greater than the number completed because this data was collected for more patients than completed the study, and all data that was collected is reported here.

Arm/Group Title	Intravenous Acetaminophen	Placebo
Arm/Group Description	Patients will be receive doses of 1000 mg/100 mL of IV Acetaminophen (OFIRMEV). The drug will be infused over 15 minutes. Acetaminophen: Intravenous Acetaminophen, 1000 mg/100mL, Every 6 hours, Infused over 15 minutes.	Patients will be given 100 mL normal saline placebos at scheduled time intervals in place of IV acetaminophen. Placebo: 100 mL 0.9% Sodium Chloride
Measure Participants	46	43
Mean (Standard Deviation) [minutes]	11.4 (7.2)	13.5 (8.4)

Adverse Events

Arm/Group Title	Intravenous Acetaminophen		Placebo
Arm/Group Description	Patients will be receive doses of 1000 mg/100 mL of IV Acetaminophen (OFIRMEV). The drug will be infused over 15 minutes. Acetaminophen: Intravenous Acetaminophen, 1000 mg/100mL, Every 6 hours, Infused over 15 minutes.		Patients will be given 100 mL normal saline placebos at scheduled time intervals in place of IV acetaminophen. Placebo: 100 mL 0.9% Sodium Chloride
All Cause Mortality
	Intravenous Acetaminophen		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Intravenous Acetaminophen		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/50 (0%)		0/50 (0%)
Other (Not Including Serious) Adverse Events
	Intravenous Acetaminophen		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/50 (0%)		1/50 (2%)
Cardiac disorders
Bradycardia	0/50 (0%)	0	1/50 (2%)	1

Limitations/Caveats

Not powered to detect differences in pain score. Patients were not given a patient-controlled analgesia device; rather, administration of morphine was dependent on nurse administration.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.