IV APAP SF: Analgesic Efficacy of Repeated Doses of Intravenous (IV) Acetaminophen in Post-operative Pediatric Spine Fusion Patients

• Sponsor: Children's Hospital of Philadelphia (Other)
• Overall Status: Completed
• CT.gov ID: NCT01394718
• Collaborator: (none)
• Enrollment: 67
• Location: 1
• Arms: 2
• Duration (Months): 48
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

This is a prospective, randomized, double-blinded, placebo controlled trial Potential subjects will be identified from the Pre-Surgical Anesthesia Clinic visit. Parents/legal guardians will be approached about study participation at the Anesthesia outpatient pre-visit. Attending Anesthesiologist will receive e-mail notification about potential subject participation the day before the scheduled surgery. Study lab (hepatic function panel) will be collected as soon as possible after anesthesia induction by anesthesia. Results will be reviewed by study team member and study drug will be ordered by study team if patient does not meet exclusion criteria. Study drug (IV acetaminophen or placebo) will be administered at the time of skin closure by anesthesia on completion of the surgical procedure (after randomization). Study drug will be administered every 6 hours for 2 days. Subjects will continue to receive standard of care with patient controlled analgesia (PCA) opiate therapy (morphine or hydromorphone) for analgesia as per the Pain Management Service. Pain scores, opiate (morphine equivalent) administered, requirements for treatment of opiate related side effects (treatment for nausea and itching), and certain post-operative characteristics will be measured for up to 4 days post-operatively (time to mobilization, time to diet advancement, time to discharge).

Condition or Disease	Intervention/Treatment	Phase
Pain, Postoperative	Drug: Intravenous Acetaminophen; Other: Placebo	Phase 3

Detailed Description

An ideal drug as an opiate-sparing analgesic adjunct, acetaminophen, unlike some other drugs, is platelet function sparing, and thus particularly useful in the post-operative orthopedic patient population. In part because of its well established safety profile, as well as minimal drug interactions, acetaminophen is considered a cornerstone of a multimodal analgesic approach. Several studies have described the clinically significant beneficial effects of a multimodal drug approach to analgesia, citing improved pain control and a shorter recovery time. Reduced adverse events and improved pain control with multimodal analgesia drug approaches may result in shorter hospitalizations, improved recovery and function, and reduced health care costs. Opiate therapy, while effective analgesia, is associated with a variety of potential adverse side effects, including pruritus, nausea, emesis, ileus, respiratory depression, tolerance, addiction and sedation. These adverse effects may limit post-operative mobility, postpone return of bowel function, cause feeding intolerance, prolong hospitalization, and postpone post-operative recovery.

While oral acetaminophen is useful as an opiate-sparing therapy, the oral route of drug administration may not be feasible in the early post-operative period. Enteral drug absorption in the initial post-operative period may be erratic, with negative impacts on therapeutic effect. Intravenous acetaminophen may a particularly useful analgesic in these circumstances. At present, there are no pediatric studies in the United States examining the efficacy of multiple- dose IV acetaminophen in the post-operative surgical population. This study will compare analgesic efficacy, nausea and pruritus scores, time to recovery, and length of hospital stay in two subject groups who are status post spine fusion surgery: those who receive schedule IV acetaminophen and opiate for 48 hours, and those who are treated with standard opiate therapy without IV acetaminophen.

Study Design

• Study Type: Interventional
• Actual Enrollment: 67 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Analgesia Efficacy of Repeated Doses of Intravenous Acetaminophen (Paracetamol) in the Pediatric Spinal Fusion Population
• Study Start Date: Jul 1, 2011
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Jul 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Saline Placebo Control subjects will receive saline as placebo at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses).	Other: Placebo; Saline placebo will be given at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses).
Experimental: Intravenous Acetaminophen Subjects will receive the first dose of intravenous (IV) acetaminophen (at 15 mg/kg, with maximum doses based on patient age and weight) at the time of skin closure intra-operatively and will continue to receive IV acetaminophen for 42 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses).	Drug: Intravenous Acetaminophen; Scheduled doses of 15 mg/kg of IV acetaminophen will be administered to the treatment arm of the study for a total of 8 doses over a 48 hour period post-operatively.

Outcome Measures

Primary Outcome Measures

1. Total Opiate Requirement [24 hours]

   Total opiate requirement was monitored 24 hours post-operatively. Morphine and hydromorphone measurements were totaled and recorded in mg/kg/day of morphine equivalents.

Secondary Outcome Measures

1. Average Pain Score [24 hours]

   Pain Scores were monitored using the numeric pain assessment scale in both treatment arms of the study and recorded and averaged for the first 24 hours after initial intra-operative dose of study drug. The numeric pain assessment scale is a verbal self-reported pain assessment that ranges between 1 (no pain) to 10 (worst pain imaginable).

2. Average Nausea Score [24 hours]

   Nausea scores were recorded by the nursing staff approximately 4 times over the first 24 hours and then averaged for the 24 hour period. Nausea Scores range from 1 (none) to 4 (severe).

3. Average Pruritus Score [24 hours]

   Pruritus scores were recorded by the nursing staff approximately 4 times over the first 24 hours and then averaged for the 24 hour period. Pruritus scores range from 1 (none) to 3 (intolerable).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 10 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Subjects 10-18 years who are status post anterior or posterior spine fusion surgery

Exclusion Criteria:

1. All patients requiring mechanical ventilation post-operatively, continuous infusions of sedative, or continuous infusions of alternate opiates (i.e. fentanyl)

2. Patients with hepatic dysfunction

3. Patients with chronic opiate requirements

4. Pregnant or lactating females

5. Patients placed on opiates other than morphine or hydromorphone

6. Patients with opiate or acetaminophen allergies

7. Patients placed on alternate analgesic adjuncts (i.e. ketamine, etc)

8. Patients who receive intrathecal opiates

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Children's Hospital of Philadelphia

Investigators

• Principal Investigator: Athena Zuppa, MD, Children's Hospital of Philadelphia

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Hospital of Philadelphia
• ClinicalTrials.gov Identifier: NCT01394718
• Other Study ID Numbers: 11-08095
• First Posted: Jul 14, 2011
• Last Update Posted: Apr 18, 2016
• Last Verified: Mar 1, 2016

• Keywords provided by Children's Hospital of Philadelphia: analgesic adjunct; acetaminophen; spine fusion surgery; opiate reduction; pain management after elective surgical operation
• Additional relevant MeSH terms: Pain, Postoperative; Acetaminophen

Study Results

Participant Flow

Recruitment Details	All children of ages 10-18 undergoing posterior spine fusion surgery for idiopathic or neuromuscular scoliosis between July 2011 and May 2014 were eligible for inclusion.
Pre-assignment Detail	281 subjects were screened, 125 approached for consent/assent and 67 consented/assented. Of the initial 67 subjects, 1 was withdrawn by the clinical team, 1 patient's surgery was cancelled, 2 were withdrawn by the family, and 3 were deemed ineligible after consent were removed from the study.

Arm/Group Title	Saline Placebo	Intravenous Acetaminophen
Arm/Group Description	Control subjects will receive saline as placebo at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Placebo: Saline placebo will be given at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses).	Subjects will receive the first dose of intravenous (IV) acetaminophen (at 15 mg/kg, with maximum doses based on patient age and weight) at the time of skin closure intra-operatively and will continue to receive IV acetaminophen for 42 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Intravenous Acetaminophen: Scheduled doses of 15 mg/kg of IV acetaminophen will be administered to the treatment arm of the study for a total of 8 doses over a 48 hour period post-operatively.
Period Title: Overall Study
STARTED	30	30
COMPLETED	28	29
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Saline Placebo	Intravenous Acetaminophen	Total
Arm/Group Description	Control subjects will receive saline as placebo at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Placebo: Saline placebo will be given at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses).	Subjects will receive the first dose of intravenous (IV) acetaminophen (at 15 mg/kg, with maximum doses based on patient age and weight) at the time of skin closure intra-operatively and will continue to receive IV acetaminophen for 42 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Intravenous Acetaminophen: Scheduled doses of 15 mg/kg of IV acetaminophen will be administered to the treatment arm of the study for a total of 8 doses over a 48 hour period post-operatively.	Total of all reporting groups
Overall Participants	28	29	57
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.43 (1.69)	14.17 (1.87)	14.30 (1.77)
Sex: Female, Male (Count of Participants)
Female	19 67.9%	25 86.2%	44 77.2%
Male	9 32.1%	4 13.8%	13 22.8%
Region of Enrollment (participants) [Number]
United States	28 100%	29 100%	57 100%
Weight (kilograms (kg)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms (kg)]	59.79 (13.69)	53.44 (11.32)	56.56 (12.83)
Surgery Duration (hours (hr)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [hours (hr)]	5.21 (1.03)	5.09 (1.14)	5.15 (1.08)
Estimated Blood Loss (EBL) (milliliter (ml)) [Median (Full Range) ]
Median (Full Range) [milliliter (ml)]	775	600	700
Intra-operative methadone (milligrams (mg)) [Median (Full Range) ]
Median (Full Range) [milligrams (mg)]	6.3	6.0	6.0
Intra-operative methadone (milligrams/kilograms (mg/kg)) [Median (Full Range) ]
Median (Full Range) [milligrams/kilograms (mg/kg)]	0.1	0.1	0.1

Outcome Measures

1. Primary Outcome

Title	Total Opiate Requirement
Description	Total opiate requirement was monitored 24 hours post-operatively. Morphine and hydromorphone measurements were totaled and recorded in mg/kg/day of morphine equivalents.
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

Subjects were deemed evaluable if a minimum of 24 hours of data was collected post-operatively, with receipt of at least four doses of study drug, prior to study withdrawal or unblinding, with T0 (time zero) being time of administration of first dose of either treatment drug or placebo.

Arm/Group Title	Saline Placebo	Intravenous Acetaminophen
Arm/Group Description	Control subjects will receive saline as placebo at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Placebo: Saline placebo will be given at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses).	Subjects will receive the first dose of intravenous (IV) acetaminophen (at 15 mg/kg, with maximum doses based on patient age and weight) at the time of skin closure intra-operatively and will continue to receive IV acetaminophen for 42 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Intravenous Acetaminophen: Scheduled doses of 15 mg/kg of IV acetaminophen will be administered to the treatment arm of the study for a total of 8 doses over a 48 hour period post-operatively.
Measure Participants	28	29
Mean (Standard Deviation) [mg/kg]	1.19 (0.43)	1.01 (0.32)

2. Secondary Outcome

Title	Average Pain Score
Description	Pain Scores were monitored using the numeric pain assessment scale in both treatment arms of the study and recorded and averaged for the first 24 hours after initial intra-operative dose of study drug. The numeric pain assessment scale is a verbal self-reported pain assessment that ranges between 1 (no pain) to 10 (worst pain imaginable).
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

Subjects were deemed evaluable if a minimum of 24 hours of data was collected post-operatively, with receipt of at least four doses of study drug, prior to study withdrawal or unblinding, with T0 (time zero) being time of administration of first dose of either treatment drug or placebo

Arm/Group Title	Saline Placebo	Intravenous Acetaminophen
Arm/Group Description	Control subjects will receive saline as placebo at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Placebo: Saline placebo will be given at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses).	Subjects will receive the first dose of intravenous (IV) acetaminophen (at 15 mg/kg, with maximum doses based on patient age and weight) at the time of skin closure intra-operatively and will continue to receive IV acetaminophen for 42 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Intravenous Acetaminophen: Scheduled doses of 15 mg/kg of IV acetaminophen will be administered to the treatment arm of the study for a total of 8 doses over a 48 hour period post-operatively.
Measure Participants	28	29
Mean (Standard Deviation) [units on a scale]	4.53 (2.02)	4.62 (1.99)

3. Secondary Outcome

Title	Average Nausea Score
Description	Nausea scores were recorded by the nursing staff approximately 4 times over the first 24 hours and then averaged for the 24 hour period. Nausea Scores range from 1 (none) to 4 (severe).
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

Subjects were deemed evaluable if a minimum of 24 hours of data was collected post-operatively, with receipt of at least four doses of study drug, prior to study withdrawal or unblinding, with T0 (time zero) being time of administration of first dose of either treatment drug or placebo

Arm/Group Title	Saline Placebo	Intravenous Acetaminophen
Arm/Group Description	Control subjects will receive saline as placebo at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Placebo: Saline placebo will be given at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses).	Subjects will receive the first dose of intravenous (IV) acetaminophen (at 15 mg/kg, with maximum doses based on patient age and weight) at the time of skin closure intra-operatively and will continue to receive IV acetaminophen for 42 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Intravenous Acetaminophen: Scheduled doses of 15 mg/kg of IV acetaminophen will be administered to the treatment arm of the study for a total of 8 doses over a 48 hour period post-operatively.
Measure Participants	28	29
Median (Full Range) [units on a scale]	1.2	1.0

4. Secondary Outcome

Title	Average Pruritus Score
Description	Pruritus scores were recorded by the nursing staff approximately 4 times over the first 24 hours and then averaged for the 24 hour period. Pruritus scores range from 1 (none) to 3 (intolerable).
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

Subjects were deemed evaluable if a minimum of 24 hours of data was collected post-operatively, with receipt of at least four doses of study drug, prior to study withdrawal or unblinding, with T0 (time zero) being time of administration of first dose of either treatment drug or placebo

Arm/Group Title	Saline Placebo	Intravenous Acetaminophen
Arm/Group Description	Control subjects will receive saline as placebo at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Placebo: Saline placebo will be given at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses).	Subjects will receive the first dose of intravenous (IV) acetaminophen (at 15 mg/kg, with maximum doses based on patient age and weight) at the time of skin closure intra-operatively and will continue to receive IV acetaminophen for 42 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Intravenous Acetaminophen: Scheduled doses of 15 mg/kg of IV acetaminophen will be administered to the treatment arm of the study for a total of 8 doses over a 48 hour period post-operatively.
Measure Participants	28	29
Median (Full Range) [units on a scale]	1.0	1

Adverse Events

Time Frame	96 Hours
Arm/Group Title	Saline Placebo		Intravenous Acetaminophen
Arm/Group Description	Control subjects will receive saline as placebo at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Placebo: Saline placebo will be given at the time of skin closure intra-operatively and will continue to receive IV saline for 44 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses).		Subjects will receive the first dose of intravenous (IV) acetaminophen (at 15 mg/kg, with maximum doses based on patient age and weight) at the time of skin closure intra-operatively and will continue to receive IV acetaminophen for 42 hours post-operatively. Doses will be administered every 6 hours (total of 8 doses). Intravenous Acetaminophen: Scheduled doses of 15 mg/kg of IV acetaminophen will be administered to the treatment arm of the study for a total of 8 doses over a 48 hour period post-operatively.
All Cause Mortality
	Saline Placebo		Intravenous Acetaminophen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Saline Placebo		Intravenous Acetaminophen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/29 (0%)
Other (Not Including Serious) Adverse Events
	Saline Placebo		Intravenous Acetaminophen
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/29 (0%)

Limitations/Caveats

This is a single center study with subjects confined to a single surgical procedure with a small sample size, possibly limiting generalizability of results.

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.