Pain, Postoperative
Conditions
Keywords
analgesic adjunct, acetaminophen, spine fusion surgery, opiate reduction, pain management after elective surgical operation
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).
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.
Interventions
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.
OTHERPlacebo
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).
Sponsors
Children's Hospital of Philadelphia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Years to 18 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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). |
| 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). |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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).
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). | 28 |
| 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).
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. | 29 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Met protocol-specific stopping criteria | 2 | 1 |
Baseline characteristics
| Characteristic | Intravenous Acetaminophen | Total | Saline Placebo |
|---|---|---|---|
| Age, Continuous | 14.17 years STANDARD_DEVIATION 1.87 | 14.30 years STANDARD_DEVIATION 1.77 | 14.43 years STANDARD_DEVIATION 1.69 |
| Estimated Blood Loss (EBL) | 600 milliliter (ml) | 700 milliliter (ml) | 775 milliliter (ml) |
| Intra-operative methadone | 0.1 milligrams/kilograms (mg/kg) | 6.0 milligrams (mg) | 0.1 milligrams/kilograms (mg/kg) |
| Region of Enrollment United States | 29 participants | 57 participants | 28 participants |
| Sex: Female, Male Female | 25 Participants | 44 Participants | 19 Participants |
| Sex: Female, Male Male | 4 Participants | 13 Participants | 9 Participants |
| Surgery Duration | 5.09 hours (hr) STANDARD_DEVIATION 1.14 | 5.15 hours (hr) STANDARD_DEVIATION 1.08 | 5.21 hours (hr) STANDARD_DEVIATION 1.03 |
| Weight | 53.44 kilograms (kg) STANDARD_DEVIATION 11.32 | 56.56 kilograms (kg) STANDARD_DEVIATION 12.83 | 59.79 kilograms (kg) STANDARD_DEVIATION 13.69 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 28 | 0 / 29 |
| serious Total, serious adverse events | 0 / 28 | 0 / 29 |
Outcome results
Primary
Total Opiate Requirement
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saline Placebo | Total Opiate Requirement | 1.19 mg/kg | Standard Deviation 0.43 |
| Intravenous Acetaminophen | Total Opiate Requirement | 1.01 mg/kg | Standard Deviation 0.32 |
Secondary
Average Nausea Score
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Saline Placebo | Average Nausea Score | 1.2 units on a scale |
| Intravenous Acetaminophen | Average Nausea Score | 1.0 units on a scale |
Secondary
Average Pain Score
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Saline Placebo | Average Pain Score | 4.53 units on a scale | Standard Deviation 2.02 |
| Intravenous Acetaminophen | Average Pain Score | 4.62 units on a scale | Standard Deviation 1.99 |
Secondary
Average Pruritus Score
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Saline Placebo | Average Pruritus Score | 1.0 units on a scale |
| Intravenous Acetaminophen | Average Pruritus Score | 1 units on a scale |