Postoperative Pain
Conditions
Brief summary
Some patients have respiratory depression (decreased breaths per minute) after surgery. Acetaminophen, an FDA approved pain medication, may prevent this problem. The purpose of this study is to determine if acetaminophen decreases respiratory depression after surgery. The investigators will also evaluate the cost effectiveness of acetaminophen. Patients having elective major abdominal surgery are being asked to participate in this research study. If eligible, a patient will have their baseline tidal volume (amount of air moved into or out of the lungs) and vital capacity (how much air the lungs are capable of holding) measured using a spirometer (apparatus for measuring the volume of air inspired and expired by the lungs) measured before surgery. Three questionnaires will also need to be completed before surgery. The patient will then be randomized, like flipping a coin, to receive either Acetaminophen or placebo (inactive substance) as an infusion throughout surgery and for the first two days thereafter. Neither the patient nor his or her physician will know if the patient is assigned to study drug or placebo. Regardless of study assignment, both groups will receive standard pain management medications and sedation. After surgery, the patient's blood pressure, activity, posture, respiratory rate, the electrical activity of the heart, oxygen saturation, tidal volume, minute ventilation and respiratory rate will be continuously monitored and recorded for 48 hours using a wireless pulse-oximeter and a respiratory volume monitor. 48 hours after surgery the patient will be asked to complete a patient satisfaction questionnaire, which will allow the patient to rate the satisfaction with the treatment received for pain. The patient will also be asked to complete a questionnaire about recovery. At discharge, the patient will be given two questionnaires about pain and quality of life.
Interventions
Sponsors
The Cleveland Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
* Written informed consent * 18-85 years old * above 50 kg * American Society of Anaesthesiologists Physical Status 1-3 * Scheduled for elective open or laparoscopic abdominal surgery, including colorectal, prostate, and hysterectomy surgeries * Patients with anticipated hospitalization of two nights * Expected to require parenteral opioids for at least 48 hours for postoperative pain * Able to use IV Patient-Controlled Analgesia systems
Exclusion criteria
* Hepatic disease, e.g. twice the normal levels of liver enzymes * Kidney disease, e.g. twice the normal level of serum creatinine * Epidural analgesia or regional blocks (including Transverse abdominis plane block) * Acetaminophen sensitivity or known allergy * Female patients who are pregnant or breastfeeding * Patients taking warfarin
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Hypoxemia | the initial 48 hours of postoperative monitoring or for the duration of hospitalization, if shorter. | Hypoxemia is measured as minutes with hypoxemia (Spo2 \<90%) per hour of successful Spo2 monitoring. Patients will have nearly continuous pulseoximeter monitoring and recording. Data from the monitor will be downloaded daily for 48 hours postoperatively. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time Weighted Pain Score in Post Anesthesia Care Unit | Initial 48 postoperative hours or duration of hospitalization (whichever comes first) | Pain scores were calculated on a visual analog scale of 0 to 10, with 0 being no pain and 10 being the most pain imaginable; time-weighted mean was calculated as the area under the curve of the pain score measurements divided by total measurement time. |
| Fatigue Score on Morning of Postoperative Day 1 | Postoperative day 1 | Fatigue scores were calculated on a scale of 1 to 10, with 1 being no fatigue and 10 being the worst fatigue imaginable. |
| Lowest RASS Score During Initial 48 Postoperative Hours | Initial 48 postoperative hours or duration of hospitalization (whichever comes first) | Sedation was estimated by the RASS score and recorded at 2-hour intervals by ward nurses per clinical routine during the initial 48 postoperative hours. The Richmond Agitation-Sedation Scale (RASS) is scored from -5 to +4, with -5 being unarousable, 0 being alert and calm, and +4 being combative. |
| Time Spent in Sitting or Upright Position | Initial 48 postoperative hours or duration of hospitalization (whichever comes first) | Treatment effect data are reported as ratios of geometric means |
| Time-weighted Pain Score During Initial 48 Postoperative Hours | Initial 48 postoperative hours or duration of hospitalization (whichever comes first) | Pain scores were calculated on a visual analog scale of 0 to 10, with 0 being no pain and 10 being the most pain imaginable; time weighted mean was calculated as the area under the curve of the pain score measurements divided by total measurement time. Pain was recorded at roughly 15-minute intervals in the postanesthesia care unit and at 4-hour intervals on surgical wards |
| Incidence of Postoperative Nausea and Vomiting | Initial 48 postoperative hours or duration of hospitalization (whichever comes first) | Patients were asked about postoperative nausea and vomiting in the postanesthesia care unit, at 4-hour intervals while awake through the remaining initial day of surgery, and on the first and second postoperative mornings. |
| Incidence of Low Respiratory Function Event | Initial 48 postoperative hours or duration of hospitalization (whichever comes first) | A low respiratory function event was defined as an episode of less than 40% of predicted minute ventilation for 2 minutes. |
| Total Anesthetic Dose From Induction to Extubation | Induction to extubation (3 hours on average) | Total anesthetic dose is measured in minimal alveolar concentration hours. |
| Opioid Consumption - Intravenous Morphine Equivalents | Initial 48 postoperative hours | Total opioid consumption over the initial 48 postoperative hours was extracted from patients' medical records and converted to intravenous morphine equivalents |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Intravenous 0.9% Sodium Chloride 0.9% sodium chloride infusion will be initiated before the surgical incision with 100 ml and repeated every 6 hours for the earlier of 48 postoperative hours of hospital discharge.
Intravenous Acetaminophen | 287 |
| Intravenous Acetaminophen Acetaminophen infusion will be initiated before the surgical incision with 1 g and repeated every 6 hours for the earlier of 48 postoperative hours of hospital discharge.
Intravenous Acetaminophen | 283 |
| Total | 570 |
Baseline characteristics
| Characteristic | Intravenous 0.9% Sodium Chloride | Intravenous Acetaminophen | Total |
|---|---|---|---|
| Age, Continuous | 48.4 years STANDARD_DEVIATION 15.1 | 50.3 years STANDARD_DEVIATION 15.3 | 49.3 years STANDARD_DEVIATION 15.2 |
| Body mass index (BMI) | 26.7 kg/m^2 STANDARD_DEVIATION 4.8 | 26.7 kg/m^2 STANDARD_DEVIATION 4.7 | 26.7 kg/m^2 STANDARD_DEVIATION 4.8 |
| Race/Ethnicity, Customized Black | 15 Participants | 14 Participants | 29 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 6 Participants | 7 Participants | 13 Participants |
| Race/Ethnicity, Customized White | 265 Participants | 261 Participants | 526 Participants |
| Region of Enrollment United States | 287 participants | 283 participants | 570 participants |
| Sex: Female, Male Female | 136 Participants | 140 Participants | 276 Participants |
| Sex: Female, Male Male | 151 Participants | 143 Participants | 294 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 283 | 0 / 287 |
| other Total, other adverse events | 0 / 283 | 0 / 287 |
| serious Total, serious adverse events | 0 / 283 | 0 / 287 |
Outcome results
Primary
Duration of Hypoxemia
Hypoxemia is measured as minutes with hypoxemia (Spo2 \<90%) per hour of successful Spo2 monitoring. Patients will have nearly continuous pulseoximeter monitoring and recording. Data from the monitor will be downloaded daily for 48 hours postoperatively.
Time frame: the initial 48 hours of postoperative monitoring or for the duration of hospitalization, if shorter.
Population: Patients were analyzed according to their randomized group, excluding patients who did not receive study intervention. 28 patients (5%) did not have any data recorded due to unexpected technical issues.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intravenous Acetaminophen | Duration of Hypoxemia | 0.7 min/h |
| Intravenous 0.9% Sodium Chloride | Duration of Hypoxemia | 1.1 min/h |
Comparison: A total of 28 patients (5%) were missing monitoring data (14 patients in each group). Values for these patients were obtained using multivariable imputation with 5 imputation data sets. The imputation regression model included all of the baseline, intraoperative, surgical, and postanesthesia care unit variables and all of the secondary outcomesp-value: 0.2995% CI: [-0.18, 0.11]Wilcoxon (Mann-Whitney)
Secondary
Fatigue Score on Morning of Postoperative Day 1
Fatigue scores were calculated on a scale of 1 to 10, with 1 being no fatigue and 10 being the worst fatigue imaginable.
Time frame: Postoperative day 1
Population: Data on the outcome could not be collected for 12 patients in the IV acetaminophen group and 15 patients in the IV sodium chloride group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravenous Acetaminophen | Fatigue Score on Morning of Postoperative Day 1 | 5 score on a scale | Standard Deviation 2.6 |
| Intravenous 0.9% Sodium Chloride | Fatigue Score on Morning of Postoperative Day 1 | 4.9 score on a scale | Standard Deviation 2.7 |
p-value: 0.5699.4% CI: [-0.49, 0.76]t-test, 2 sided
Secondary
Incidence of Low Respiratory Function Event
A low respiratory function event was defined as an episode of less than 40% of predicted minute ventilation for 2 minutes.
Time frame: Initial 48 postoperative hours or duration of hospitalization (whichever comes first)
Population: Data on the outcome could not be collected for 95 patients in the IV acetaminophen group and 124 patients in the IV sodium chloride group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravenous Acetaminophen | Incidence of Low Respiratory Function Event | 52 Participants |
| Intravenous 0.9% Sodium Chloride | Incidence of Low Respiratory Function Event | 50 Participants |
p-value: 0.5399.4% CI: [0.57, 1.43]Chi-squared
Secondary
Incidence of Postoperative Nausea and Vomiting
Patients were asked about postoperative nausea and vomiting in the postanesthesia care unit, at 4-hour intervals while awake through the remaining initial day of surgery, and on the first and second postoperative mornings.
Time frame: Initial 48 postoperative hours or duration of hospitalization (whichever comes first)
Population: Data on the outcome could not be collected for 3 patients in the IV acetaminophen group and 7 patients in the IV sodium chloride group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Intravenous Acetaminophen | Incidence of Postoperative Nausea and Vomiting | 140 Participants |
| Intravenous 0.9% Sodium Chloride | Incidence of Postoperative Nausea and Vomiting | 124 Participants |
p-value: 0.1899.4% CI: [0.88, 1.45]Chi-squared
Secondary
Lowest RASS Score During Initial 48 Postoperative Hours
Sedation was estimated by the RASS score and recorded at 2-hour intervals by ward nurses per clinical routine during the initial 48 postoperative hours. The Richmond Agitation-Sedation Scale (RASS) is scored from -5 to +4, with -5 being unarousable, 0 being alert and calm, and +4 being combative.
Time frame: Initial 48 postoperative hours or duration of hospitalization (whichever comes first)
Population: Data on the outcome could not be collected for 91 patients in the IV acetaminophen group and 86 patients in the IV sodium chloride group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravenous Acetaminophen | Lowest RASS Score During Initial 48 Postoperative Hours | -0.96 score on a scale | Standard Deviation 0.75 |
| Intravenous 0.9% Sodium Chloride | Lowest RASS Score During Initial 48 Postoperative Hours | -0.89 score on a scale | Standard Deviation 0.76 |
p-value: 0.399.4% CI: [-0.29, 0.13]t-test, 2 sided
Secondary
Opioid Consumption - Intravenous Morphine Equivalents
Total opioid consumption over the initial 48 postoperative hours was extracted from patients' medical records and converted to intravenous morphine equivalents
Time frame: Initial 48 postoperative hours
Population: Data on the outcome could not be collected for 3 patients in the IV acetaminophen group and 7 patients in the IV sodium chloride group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intravenous Acetaminophen | Opioid Consumption - Intravenous Morphine Equivalents | 50 mg |
| Intravenous 0.9% Sodium Chloride | Opioid Consumption - Intravenous Morphine Equivalents | 58 mg |
p-value: 0.2299.4% CI: [0.61, 1.21]t-test, 2 sided
Secondary
Time Spent in Sitting or Upright Position
Treatment effect data are reported as ratios of geometric means
Time frame: Initial 48 postoperative hours or duration of hospitalization (whichever comes first)
Population: Data on the outcome could not be collected for 31 patients in the IV acetaminophen group and 37 patients in the IV sodium chloride group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intravenous Acetaminophen | Time Spent in Sitting or Upright Position | 2.2 hours |
| Intravenous 0.9% Sodium Chloride | Time Spent in Sitting or Upright Position | 2.2 hours |
p-value: 0.6599.4% CI: [0.63, 1.39]t-test, 2 sided
Secondary
Time-weighted Pain Score During Initial 48 Postoperative Hours
Pain scores were calculated on a visual analog scale of 0 to 10, with 0 being no pain and 10 being the most pain imaginable; time weighted mean was calculated as the area under the curve of the pain score measurements divided by total measurement time. Pain was recorded at roughly 15-minute intervals in the postanesthesia care unit and at 4-hour intervals on surgical wards
Time frame: Initial 48 postoperative hours or duration of hospitalization (whichever comes first)
Population: Data on the outcome could not be collected for 7 patients in the IV acetaminophen group and 5 patients in the IV sodium chloride group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravenous Acetaminophen | Time-weighted Pain Score During Initial 48 Postoperative Hours | 4.2 score on a scale | Standard Deviation 1.8 |
| Intravenous 0.9% Sodium Chloride | Time-weighted Pain Score During Initial 48 Postoperative Hours | 4.4 score on a scale | Standard Deviation 1.8 |
p-value: 0.0799.4% CI: [-0.71, 0.15]t-test, 2 sided
Secondary
Time Weighted Pain Score in Post Anesthesia Care Unit
Pain scores were calculated on a visual analog scale of 0 to 10, with 0 being no pain and 10 being the most pain imaginable; time-weighted mean was calculated as the area under the curve of the pain score measurements divided by total measurement time.
Time frame: Initial 48 postoperative hours or duration of hospitalization (whichever comes first)
Population: Data on the outcome could not be collected for 2 patients in the IV acetaminophen group and 6 patients in the IV sodium chloride group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Intravenous Acetaminophen | Time Weighted Pain Score in Post Anesthesia Care Unit | 4.3 score on a scale | Standard Deviation 1.7 |
| Intravenous 0.9% Sodium Chloride | Time Weighted Pain Score in Post Anesthesia Care Unit | 4.4 score on a scale | Standard Deviation 1.8 |
p-value: 0.4699.4% CI: [-0.51, 0.29]t-test, 2 sided
Secondary
Total Anesthetic Dose From Induction to Extubation
Total anesthetic dose is measured in minimal alveolar concentration hours.
Time frame: Induction to extubation (3 hours on average)
Population: Data on the outcome could not be collected for 1 patient in the IV acetaminophen group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Intravenous Acetaminophen | Total Anesthetic Dose From Induction to Extubation | 2.9 minimal alveolar concentration hours |
| Intravenous 0.9% Sodium Chloride | Total Anesthetic Dose From Induction to Extubation | 2.9 minimal alveolar concentration hours |
p-value: 0.9999.4% CI: [-0.39, 0.36]Wilcoxon (Mann-Whitney)