Inflammation, Pain
Conditions
Keywords
biomarkers
Brief summary
The investigators hypothesize that perioperative administration of anakinra will reduce incisional pain by lowering the concentration of inflammatory mediators in surgical wounds. This knowledge is important because it suggests a new, previously unexplored pharmacological target for the control of postoperative incisional pain.
Detailed description
This study will test whether administration of anakinra, an IL-1 receptor antagonist, will decrease pain and improve wound healing in patients undergoing vascular or orthopedic surgical procedures. The investigators will administer two doses of Anakinra via an injection under the skin, one dose one hour before surgery and a second dose on the first postoperative day (24 hours after surgery). The investigators will remove fluid from the surgical incisions using a small plastic catheter placed under skin during surgery and measure the amounts of pain- causing inflammatory mediators. The investigators will also measure the amount of pain the participant is experiencing using questions about pain intensity and by gently touching the incision to determine sensitivity of the incision site.
Interventions
DRUGAnakinra
An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery.
OTHERNormal Saline
An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery.
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
-Patients 18 years of age and older presenting to the Stanford Preoperative Evaluation Clinic prior to elective orthopedic surgical procedures or elective vascular surgical procedures not involving the abdominal aorta or carotid arteries.
Exclusion criteria
Patients will be excluded from participation if they have one or more of the following conditions: 1. Evidence of active local or systemic infection as demonstrated by fever, leukocytosis (white blood cell count \> 11,000/ul), productive cough, new infiltrate on chest x-ray, or purulent drainage from any source 2. End-stage renal disease 3. A history of diabetic neuropathy 4. A malignancy other than basal cell carcinoma of the skin or in situ carcinoma of the cervix within the previous 5 years 5. Leukopenia (white blood cell count \< 2,000/ul) 6. Thrombocytopenia (platelet count \< 100,000/ul) 7. Abnormal liver function test result (aspartate aminotransferase or alanine aminotransferase level ≥1.5-fold the upper limit of normal) 8. A history or infection with tuberculosis, hepatitis B, hepatitis C, or human immunodeficiency virus 9. Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Concentration Levels of Inflammatory Mediators IL-1 Receptor Antagonist (IL-1ra) Present in Human Wounds Following Surgery With and Without the Use of Anakinra. | Up to 72 hours following surgery | Tissue samples were collected at the surgical wound site at 3 time points during the 1st 72 hours following surgery. Tissue samples from subjects receiving placebo, and subjects receiving anakinra injections pre, and post op were analyzed for IL-1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | Up to 72 hours following surgery | Analgesic consumption is reported as the count of participants receiving each analgesic type. Comparisons between the placebo and active drug groups were made at the conclusion of the study. PCA/IV: Patient controlled Analgesia/ Intravenous |
| Count of Participants Experiencing Wound Infection in the Study From Surgery Till the Time of Discharge From the Hospital | Up to 72 hours following surgery plus 3 weeks follow-up | Evaluation of the surgical wound for symptoms of wound infection was made every day during hospitalization. Records from the first post-operative clinic visit were also evaluated for evidence of wound infection. |
| Post-operative Pain Intensity | Up to 72 hours following surgery | Pain was measured on Day 1 and day 2 following surgery using a VAS scale at rest and on stimulation with Visual Analog Scale (VAS) of 1-10 (1=no pain and 10=worst pain) |
| Assess Rates of Wound Dehiscence | Up to 72 hours following surgery plus 3 weeks follow-up | Evaluation of the surgical wound for symptoms of wound dehiscence was made every day during hospitalization. Records from the first post-operative clinic visit were also evaluated for evidence of wound dehiscence. |
| Total Length of Hospital Stay | Up to approximately 5 days maximum (admittance to discharge) | Total length of hospital stay for patients enrolled in the study. |
| Count of Participants With Venous Thrombosis After Surgery During Hospitalization | Up to 72 hours following surgery plus 3 weeks follow-up | Evaluation of the surgical wound for symptoms of venous thrombosis was made every day during hospitalization. Records from the first post-operative clinic visit were also evaluated for evidence of venous thrombosis. |
Countries
United States
Participant flow
Pre-assignment details
13 were enrolled and 3 participants withdrew prior to randomization
Participants by arm
| Arm | Count |
|---|---|
| Anakinra Two subcutaneous injections of anakinra (IL-1ra) were given, the first one hour prior to surgery and the second 24 hours after surgery.
Anakinra: An injection of 100 mg Anakinra was administered 1 hour prior to surgery and again 24 hours following surgery. | 5 |
| Saline Injection Two subcutaneous injections of normal saline (same volume as the anakinra group injection) were given, the first one hour prior to surgery and the second 24 hours after surgery.
Normal Saline: An injection of normal saline was administered 1 hour prior to surgery and again 24 hours following surgery. | 5 |
| Total | 10 |
Baseline characteristics
| Characteristic | Anakinra | Saline Injection | Total |
|---|---|---|---|
| Age, Continuous | 71.4 years | 74 years | 73 years |
| Region of Enrollment United States | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 5 |
| other Total, other adverse events | 0 / 5 | 0 / 5 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 |
Outcome results
Primary
Concentration Levels of Inflammatory Mediators IL-1 Receptor Antagonist (IL-1ra) Present in Human Wounds Following Surgery With and Without the Use of Anakinra.
Tissue samples were collected at the surgical wound site at 3 time points during the 1st 72 hours following surgery. Tissue samples from subjects receiving placebo, and subjects receiving anakinra injections pre, and post op were analyzed for IL-1
Time frame: Up to 72 hours following surgery
Population: IL-1ra measurements were invalid due to cross-reaction with the assay platform.
Secondary
Assess Rates of Wound Dehiscence
Evaluation of the surgical wound for symptoms of wound dehiscence was made every day during hospitalization. Records from the first post-operative clinic visit were also evaluated for evidence of wound dehiscence.
Time frame: Up to 72 hours following surgery plus 3 weeks follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anakinra | Assess Rates of Wound Dehiscence | 0 Participants |
| Saline Injection | Assess Rates of Wound Dehiscence | 0 Participants |
Secondary
Count of Participants Experiencing Wound Infection in the Study From Surgery Till the Time of Discharge From the Hospital
Evaluation of the surgical wound for symptoms of wound infection was made every day during hospitalization. Records from the first post-operative clinic visit were also evaluated for evidence of wound infection.
Time frame: Up to 72 hours following surgery plus 3 weeks follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anakinra | Count of Participants Experiencing Wound Infection in the Study From Surgery Till the Time of Discharge From the Hospital | 0 Participants |
| Saline Injection | Count of Participants Experiencing Wound Infection in the Study From Surgery Till the Time of Discharge From the Hospital | 0 Participants |
Secondary
Count of Participants With Venous Thrombosis After Surgery During Hospitalization
Evaluation of the surgical wound for symptoms of venous thrombosis was made every day during hospitalization. Records from the first post-operative clinic visit were also evaluated for evidence of venous thrombosis.
Time frame: Up to 72 hours following surgery plus 3 weeks follow-up
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Anakinra | Count of Participants With Venous Thrombosis After Surgery During Hospitalization | 0 Participants |
| Saline Injection | Count of Participants With Venous Thrombosis After Surgery During Hospitalization | 0 Participants |
Secondary
Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery
Analgesic consumption is reported as the count of participants receiving each analgesic type. Comparisons between the placebo and active drug groups were made at the conclusion of the study. PCA/IV: Patient controlled Analgesia/ Intravenous
Time frame: Up to 72 hours following surgery
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Anakinra | Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | PCA/IV - Morphine | 4 Participants |
| Anakinra | Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | PO - Oxycontin(tab) | 5 Participants |
| Anakinra | Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | PO - Percocet(tab) | 1 Participants |
| Anakinra | Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | PCA/IV - Dilaudid (mg) | 5 Participants |
| Anakinra | Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | PO - Acetaminophen(tab) | 3 Participants |
| Anakinra | Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | PCA/IV - Fentanyl (mcg) | 3 Participants |
| Saline Injection | Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | PO - Acetaminophen(tab) | 2 Participants |
| Saline Injection | Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | PCA/IV - Morphine | 4 Participants |
| Saline Injection | Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | PCA/IV - Fentanyl (mcg) | 1 Participants |
| Saline Injection | Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | PO - Oxycontin(tab) | 4 Participants |
| Saline Injection | Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | PO - Percocet(tab) | 1 Participants |
| Saline Injection | Number of Participants With Analgesic Consumption During the 72 Hours Following Surgery | PCA/IV - Dilaudid (mg) | 4 Participants |
Secondary
Post-operative Pain Intensity
Pain was measured on Day 1 and day 2 following surgery using a VAS scale at rest and on stimulation with Visual Analog Scale (VAS) of 1-10 (1=no pain and 10=worst pain)
Time frame: Up to 72 hours following surgery
Population: Participants with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Anakinra | Post-operative Pain Intensity | Pain Intensity on Stimulation Day One | 7 units on a Visual Analog scale |
| Anakinra | Post-operative Pain Intensity | Pain Intensity at Rest Day Two | 2.25 units on a Visual Analog scale |
| Anakinra | Post-operative Pain Intensity | Pain Intensity on Stimulation Day Two | 3.3 units on a Visual Analog scale |
| Anakinra | Post-operative Pain Intensity | Pain Intensity at Rest Day One | 2.25 units on a Visual Analog scale |
| Saline Injection | Post-operative Pain Intensity | Pain Intensity on Stimulation Day Two | 6.2 units on a Visual Analog scale |
| Saline Injection | Post-operative Pain Intensity | Pain Intensity on Stimulation Day One | 6.4 units on a Visual Analog scale |
| Saline Injection | Post-operative Pain Intensity | Pain Intensity at Rest Day One | 2.8 units on a Visual Analog scale |
| Saline Injection | Post-operative Pain Intensity | Pain Intensity at Rest Day Two | 3.6 units on a Visual Analog scale |
Secondary
Total Length of Hospital Stay
Total length of hospital stay for patients enrolled in the study.
Time frame: Up to approximately 5 days maximum (admittance to discharge)
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Anakinra | Total Length of Hospital Stay | 75.06 hours | Standard Deviation 17.37 |
| Saline Injection | Total Length of Hospital Stay | 87.76 hours | Standard Deviation 13.8 |