The Efficacy of Intravenous Acetaminophen During Perioperative Neurosurgery Period

• Sponsor: NorthShore University HealthSystem (Other)
• Overall Status: Completed
• CT.gov ID: NCT01739699
• Collaborator: Cadence Pharmaceuticals (Industry)
• Enrollment: 140
• Location: 1
• Arms: 2
• Duration (Months): 60.6
• Patients Per Site Per Month: 2.3

Study Details

Study Description

Brief Summary

This is a prospective randomized double blinded trial study involving 128 patients undergoing any craniotomy procedure at Evanston Hospital. The patients will be randomized by the sealed envelope technique. The anesthesiologist and nurses who will be administering the placebo or intravenous acetaminophen will be blinded to the group in which patients are assigned.

The following general perioperative data will be recorded: patient information/preoperative data, procedural information, postoperative information, and overall satisfaction of pain management at 24 hours after surgery.

Based on a pilot study (N-20) we expect that 25% of the placebo treated patients will require no opioids in the first 24 hour postoperative period. With the use of intravenous acetaminophen, it is hypothesized that the number of patients that do not require opioids in the first 24 hours after surgery will double.

Condition or Disease	Intervention/Treatment	Phase
Craniotomy; Brain Surgery	Drug: Acetaminophen; Drug: Placebo	Phase 4

Detailed Description

This is a prospective randomized double blinded trial study involving 128 patients undergoing any craniotomy procedure at Evanston Hospital. The patients will be randomized by the sealed envelope technique. The anesthesiologist and nurses who will be administering the placebo or intravenous acetaminophen will be blinded to the group in which patients are assigned.

The following information will be recorded for each patient enrolled in this study:

• Patient information/Preoperative Data

• Age, sex, height, weight,

• Disease specific information

• Primary diagnosis

• Pertinent medical history

• Medications

• Pertinent changes in patient status

• Procedural information

• Operation type

• Preoperative anesthetic medications

• Induction meds, intra-operative anesthetic meds, and post-operative anesthetic meds

• Duration of Surgery and Intubation

• Amount of dilaudid equivalent narcotics

• Postoperative Information

• Amount of narcotics administered in the PACU

• Amount of narcotics administered in the first 24 hour postoperative period

• Amount of non-narcotic analgesics administered in the first 24 hour postoperative period

• Time to first rescue analgesic in the PACU

• Amount of first rescue medication recorded

• Assessment of Pain Intensity at T0.5 (30min into PACU stay) and T24 (24 hours after end of surgery) (A 10-cm VAS scale will be used and labeled no pain at its left terminus and worst pain imaginable at its right terminus)

• Temperature in degrees centigrade every 8 hours for 24hours.

• CAM-ICU is performed by ICU nurses to detect delirium in patients every 8 hours and will be documented on a data collection sheet for the first 24 hours

• RASS is a sedation scoring system that is used in our ICU and is documented every 8 hours by ICU nursing. We will record the RASS score for the first 24 hours on a data collection sheet as documented by the ICU nurse.

• Overall satisfaction score at 24 hrs. "Overall satisfaction with pain management" (verbal rating score: scale 1 - 100)

Based on a pilot study (N-20) we expect that 25% of the placebo treated patients will require no opioids in the first 24 hour postoperative period. With the use of intravenous acetaminophen, it is hypothesized that the number of patients that do not require opioids in the first 24 hours after surgery will double.

Study Design

• Study Type: Interventional
• Actual Enrollment: 140 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Efficacy of Intravenous Acetaminophen During The Perioperative Period Of Neurosurgical Patients Undergoing Craniotomies
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Aug 1, 2016
• Actual Study Completion Date: Jan 20, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Acetaminophen Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure.	Drug: Acetaminophen; Other Names: Tylenol
Other: Placebo Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure.	Drug: Placebo; Other Names: normal saline

Outcome Measures

Primary Outcome Measures

1. Opioid Requirement After Surgery [during first 24 hours after surgery]

   The purpose of the study was to determine whether more patients undergoing craniotomies would not require any opioids (i.e., opioid consumption reduced to zero) during the first 24 postoperative hours when receiving intravenous (IV) acetaminophen during that time compared to those receiving placebo (normal saline).

Secondary Outcome Measures

1. Time to Rescue Medication in Both Groups [0 to 24 hours after surgery]

   Time (minutes) from end of procedure to first rescue dose in either PACU or ICU

2. Amount of Rescue Medication in PACU in Both Groups [0 to 24 hours after surgery]

3. Median Difference in ICU Length of Stay/Hospital Length of Stay Between Both Groups [from 0 to estimated 24 hours after surgery]

4. Number of Participants Who Had a Successful Neurologic Exams Between Intervention and Placebo Group as Determined by a Neurosurgical Provider by Answering Either Yes or No [from 0 to estimated maximum of 24 hours after surgery]

   Successful neurologic exams are performed by neurosurgical team during the first 24 hour period. Successful neurologic exams will be provided by a neurosurgical professional and they will answer Yes or No if the exam is appropriate.

5. Median Difference in Temperature Between Intervention and Placebo Groups [from 0 to estimated maximum 24 hours after surgery]

   Temperature measure in degrees celcius during the first 24hours postoperatively in increments of 8 hours.

6. Sedation Scores Measured by Richmand-Agitation-Sedation Scale (RASS) Every 8 Hours for 24 Hours in Both Groups [during first 24 hours after surgery]

   Sedation scores will be evaluated by providers through the Richmand-Agitation-Sedation Scale (RASS) system every 8 hours for the first 24hour postoperatively. The RASS is a 10 point scale with four levels for anxiety or agitation (+1 to +4 (indicates more agitation and alertness the higher number you have)), one level to indicate a calm and alert state (0), and 5 levels of deeper sedation (-1 to -5 ( the more negative number indicating a deeper level of sedation)) patients. It helps guide sedation therapy at the bedside. There are no worse outcomes with different levels of sedation scores. However, typically, we try to keep the scores in the range of 0-+1 to be able to appropriately assess patients and allow them to be mobile in a safe fashion.

7. Pain VAS Scores (1-100) Every 8 Hours for 24 Hours in Both Groups [during first 24 hours after surgery]

   Pain was measured using the Visual Analog Scale (VAS) for each patient at the time of arrival and every eight hours after arrival for the first 24 hours of ICU stay. A VAS score of 1 indicates little or no pain and a VAS score of 100 indicates severe pain.

8. # of Participants With Delirium Measured by a Positive CAM-ICU Every 8 Hours for 24 Hours in Both Groups- [during first 24 hours after surgery]

   Delirium was assessed in each of the participants upon arrival to the ICU using the Confusion Assessment Method for the ICU (CAM-ICU). The CAM-ICU was performed for each participant every 8 hours following admission for the first 24 hours The CAM ICU scoring is based on a scale of 0-7, 0-2=no delirium, 3-5=miild delirium, 6-7=severe delirium. The positive CAM ICU consists of features 1 and 2 and either 3 or 4: Features 1: Acute onset or fluctuating course Features 2: Inattention Features 3: Disorganized thinking Features 4: Altered level of consciousness

9. Median Satisfaction Scores on a Verbal Score From 1(Not Satisfied at All) to 100 (Very Satisfied) [During first 24 hours after surgery]

   on a verbal score 1-100, 1 would mean that the patient is not satisfied at all and 100 would mean that the patient was very satisfied.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject are able to provide informed consent prior to participation in the study

• Subjects must be scheduled to undergo elective open craniotomy procedure of > 2 hour duration

• Subjects must be >18 years old but less than 90 years old

• Subjects must have an American Society of Anesthesiologists (ASA) class I-IV

• Subjects must have the ability to communicate meaningfully with the investigator staff and read/understand the study procedures and the use of pain scales

Exclusion Criteria:

• Subjects used opioids or tramadol daily for >7 days before study medication administration

• Subjects had been treated with any of the following within 14 days of surgery: chaparral, comfrey, germander, jin bu huan, kava, pennyroyal, skullcap, St. John's wort, or valerian

• Subjects who have a chronic pain condition, significant medical disease or laboratory abnormality that in the investigator's judgment could compromise the subject's welfare

• Subjects with known hypersensitivity to opioids, acetaminophen or the inactive ingredients

• Subjects with known or suspected history of alcohol or drug abuse or dependence in the previous 2 years prior to the proposed surgery

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	NorthShore University HealthSystem	Evanston	Illinois	United States	60201

Sponsors and Collaborators

• NorthShore University HealthSystem
• Cadence Pharmaceuticals

Investigators

• Principal Investigator: Steven Greenberg, MD, NorthShore University Health Sytem - Evanston Hospital Department of Anesthesia

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Steven Greenberg, MD, NorthShore University HealthSystem
• ClinicalTrials.gov Identifier: NCT01739699
• Other Study ID Numbers: EH11-380
• First Posted: Dec 3, 2012
• Last Update Posted: Nov 4, 2021
• Last Verified: Oct 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Steven Greenberg, MD, NorthShore University HealthSystem: craniotomy; brain surgery; acetaminophen; Tylenol
• Additional relevant MeSH terms: Acetaminophen

Study Results

Participant Flow

Arm/Group Title	Acetaminophen	Placebo
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen	Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo
Period Title: Overall Study
STARTED	70	70
COMPLETED	66	65
NOT COMPLETED	4	5

Baseline Characteristics

Arm/Group Title	Acetaminophen	Placebo	Total
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen	Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo	Total of all reporting groups
Overall Participants	70	70	140
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	46 65.7%	45 64.3%	91 65%
>=65 years	24 34.3%	25 35.7%	49 35%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58 (15)	56 (13)	57 (14)
Sex: Female, Male (Count of Participants)
Female	41 58.6%	36 51.4%	77 55%
Male	29 41.4%	34 48.6%	63 45%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
United States	70 100%	70 100%	140 100%

Outcome Measures

1. Primary Outcome

Title	Opioid Requirement After Surgery
Description	The purpose of the study was to determine whether more patients undergoing craniotomies would not require any opioids (i.e., opioid consumption reduced to zero) during the first 24 postoperative hours when receiving intravenous (IV) acetaminophen during that time compared to those receiving placebo (normal saline).
Time Frame	during first 24 hours after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acetaminophen	Placebo
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen	Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo
Measure Participants	66	65
Count of Participants [Participants]	10 14.3%	4 5.7%

2. Secondary Outcome

Title	Time to Rescue Medication in Both Groups
Description	Time (minutes) from end of procedure to first rescue dose in either PACU or ICU
Time Frame	0 to 24 hours after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acetaminophen	Placebo
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen	Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo
Measure Participants	66	65
Median (Inter-Quartile Range) [minutes]	22	37

3. Secondary Outcome

Title	Amount of Rescue Medication in PACU in Both Groups
Time Frame	0 to 24 hours after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acetaminophen	Placebo
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen	Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo
Measure Participants	66	65
Median (Inter-Quartile Range) [mg]	0.5	0.5

4. Secondary Outcome

Title	Median Difference in ICU Length of Stay/Hospital Length of Stay Between Both Groups
Time Frame	from 0 to estimated 24 hours after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acetaminophen	Placebo
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen	Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo
Measure Participants	66	65
Hospital Length of stay	71.75	75.5
ICU length of stay	26	28

5. Secondary Outcome

Title	Number of Participants Who Had a Successful Neurologic Exams Between Intervention and Placebo Group as Determined by a Neurosurgical Provider by Answering Either Yes or No
Description	Successful neurologic exams are performed by neurosurgical team during the first 24 hour period. Successful neurologic exams will be provided by a neurosurgical professional and they will answer Yes or No if the exam is appropriate.
Time Frame	from 0 to estimated maximum of 24 hours after surgery

Outcome Measure Data

Analysis Population Description

As length of stay increased in ICU, the likelihood of discharge increased for the patients. This lowered the total amount of analyzed patients as the time increased.

Arm/Group Title	Acetaminophen	Placebo
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen	Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo
Measure Participants	66	65
ICU arrival	57 81.4%	61 87.1%
8 Hours	63 90%	64 91.4%
16 Hours	60 85.7%	60 85.7%
24 Hours	53 75.7%	55 78.6%

6. Secondary Outcome

Title	Median Difference in Temperature Between Intervention and Placebo Groups
Description	Temperature measure in degrees celcius during the first 24hours postoperatively in increments of 8 hours.
Time Frame	from 0 to estimated maximum 24 hours after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acetaminophen	Placebo
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen	Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo
Measure Participants	66	65
ICU Arrival	36.6	36.7
8 Hours	36.7	36.8
16 Hours	36.7	36.8
24 Hours	36.8	36.7

7. Secondary Outcome

Title	Sedation Scores Measured by Richmand-Agitation-Sedation Scale (RASS) Every 8 Hours for 24 Hours in Both Groups
Description	Sedation scores will be evaluated by providers through the Richmand-Agitation-Sedation Scale (RASS) system every 8 hours for the first 24hour postoperatively. The RASS is a 10 point scale with four levels for anxiety or agitation (+1 to +4 (indicates more agitation and alertness the higher number you have)), one level to indicate a calm and alert state (0), and 5 levels of deeper sedation (-1 to -5 ( the more negative number indicating a deeper level of sedation)) patients. It helps guide sedation therapy at the bedside. There are no worse outcomes with different levels of sedation scores. However, typically, we try to keep the scores in the range of 0-+1 to be able to appropriately assess patients and allow them to be mobile in a safe fashion.
Time Frame	during first 24 hours after surgery

Outcome Measure Data

Analysis Population Description

The amount of participants analyzed decreased as length of stay in the ICU increased as patients were likely discharged from the ICU. The median number indicates the RASS score and not the number of participants.

Arm/Group Title	Acetaminophen	Placebo
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen	Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo
Measure Participants	66	65
ICU arrival	0	0
8 hours	0	0
16 hours	0	0
24 hours	0	0

8. Secondary Outcome

Title	Pain VAS Scores (1-100) Every 8 Hours for 24 Hours in Both Groups
Description	Pain was measured using the Visual Analog Scale (VAS) for each patient at the time of arrival and every eight hours after arrival for the first 24 hours of ICU stay. A VAS score of 1 indicates little or no pain and a VAS score of 100 indicates severe pain.
Time Frame	during first 24 hours after surgery

Outcome Measure Data

Analysis Population Description

The median number below indicates the median VAS score.

Arm/Group Title	Acetaminophen	Placebo
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen	Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo
Measure Participants	66	65
ICU Arrival	35	50
8 Hours	30	45
16 Hours	30	30
24 Hours	30	20

9. Secondary Outcome

Title	# of Participants With Delirium Measured by a Positive CAM-ICU Every 8 Hours for 24 Hours in Both Groups-
Description	Delirium was assessed in each of the participants upon arrival to the ICU using the Confusion Assessment Method for the ICU (CAM-ICU). The CAM-ICU was performed for each participant every 8 hours following admission for the first 24 hours The CAM ICU scoring is based on a scale of 0-7, 0-2=no delirium, 3-5=miild delirium, 6-7=severe delirium. The positive CAM ICU consists of features 1 and 2 and either 3 or 4: Features 1: Acute onset or fluctuating course Features 2: Inattention Features 3: Disorganized thinking Features 4: Altered level of consciousness
Time Frame	during first 24 hours after surgery

Outcome Measure Data

Analysis Population Description

As the time post surgery increased, the amount of individual participants discharged from the ICU increased.

Arm/Group Title	Acetaminophen	Placebo
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen	Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo
Measure Participants	66	65
ICU Arrival	1 1.4%	0 0%
8 Hours	0 0%	0 0%
16 Hours	0 0%	0 0%
24 Hours	0 0%	0 0%

10. Secondary Outcome

Title	Median Satisfaction Scores on a Verbal Score From 1(Not Satisfied at All) to 100 (Very Satisfied)
Description	on a verbal score 1-100, 1 would mean that the patient is not satisfied at all and 100 would mean that the patient was very satisfied.
Time Frame	During first 24 hours after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acetaminophen	Placebo
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen	Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo
Measure Participants	66	65
Median (Inter-Quartile Range) [units on a scale]	87.5	80

Adverse Events

Time Frame	Any adverse events were noted for 7 days following completion of the procedure.
Arm/Group Title	Acetaminophen		Placebo
Arm/Group Description	Subjects will receive 1000mg of intravenous acetaminophen every 6 hours for 24 hours beginning with dural closure. Acetaminophen		Subjects will receive 100cc of normal saline every 6 hours for 24 hours beginning at dural closure. Placebo
All Cause Mortality
	Acetaminophen		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/66 (0%)		0/65 (0%)
Serious Adverse Events
	Acetaminophen		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/66 (0%)		0/65 (0%)
Other (Not Including Serious) Adverse Events
	Acetaminophen		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/66 (0%)		0/65 (0%)

Limitations/Caveats

Underpowered. Nurses used the local standard order sets. Dexamethasone dose was not standardized Long acting opioids or NSAIDS of any type were not administered. Patients observed every 8 hours for 24 hours postoperatively.

More Information

Certain Agreements

Principal Investigators are NOT 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.