Pregnancy Related
Conditions
Keywords
Pregnancy, Vaginal Delivery, Epidural Labor Analgesia
Brief summary
The purpose of this randomized controlled trial is to compare the effectiveness of epidural clonidine, dexmedetomidine, or fentanyl adjuncts for labor analgesia.
Detailed description
Adjuncts for epidural labor analgesia have remained unchanged for decades, whereas changes in patient population and the opioid epidemic have created an increased demand for non-opioid alternative adjuncts to limit peripartum opioid exposure. This study aims to identify effective alternative and non-opioid adjunctive agents for epidural labor analgesia. The opioid crisis in the United States has translated to an increasing number of pregnant women requiring care for labor and delivery. These trends have resulted in new questions about alternative epidural analgesia adjuncts besides lipophilic opioids (e.g., fentanyl and sufentanil) because: 1) many people with opioid or substance use disorder desire to avoid opioids in all formulations and routes of administration; and 2) epidural fentanyl or sufentanil administration for labor can potentially interfere with the accuracy of urine drug screening in the postpartum period, which has implications for postpartum social services considerations. Some existing literature suggests that dexmedetomidine and clonidine are viable adjuncts to local anesthetics that offer a faster onset and a better quality of analgesia for patients requiring labor analgesia. However, the relative effectiveness of these adjunctive agents for labor analgesia have not been compared head-to-head. Better data on how these adjuncts compare with each other for labor analgesia efficacy, can result in more informed clinical care strategies. This trial was initially initiated as a superiority design. After further scientific input, it was decided that a non-inferiority design would be more informative for the clinical question at hand. The hypothesis is that clonidine (Group C) and dexmedetomidine (Group D) are non-inferior to fentanyl (Group F) (usual care) as adjuncts for epidural labor analgesia. The null hypothesis is that clonidine and dexmedetomidine are inferior to fentanyl as adjuncts for epidural labor analgesia. Clinical Protocol specific methodology did not change throughout the trial and the full trial protocol document can be found in the relevant section below. An updated statistical analysis plan includes updated sample size calculations and has been reported to account for the noninferiority analysis plan. No data was analyzed prior to the completion of all data collection procedures.
Interventions
DRUGClonidine
Clonidine belongs to the drug classification of antihypertensives
DRUGDexmedetomidine
Dexmedetomidine belongs to the drug classification of sedatives
DRUGFentanyl
Fentanyl belongs to the drug classification of analgesic opioid agonists and is used as the standard of care
DRUGRopivacaine
Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care
Sponsors
Grace Lim, MD, MS
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
This study is designed as a randomized, quadruple blinded, parallel arm, controlled, non-inferiority trial in 3 groups allocated in a 1:1:1 ratio
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
Pregnant minors were not enrolled in this trial. Inclusion Criteria: * Pregnant women greater than 18 years of age * American Society of Anesthesiologists (ASA) Physical Status 2 or 3 * Term pregnancy (greater than 37 gestational weeks) * Planning epidural labor analgesia * Singleton pregnancy * Vertex presentation * Planned vaginal delivery
Exclusion criteria
* Pre-eclampsia with or without severe features * New initiation of antihypertensive agent within 24 hours prior to enrollment * Uncontrolled systemic comorbidities \[i.e., diabetes, hepatic, renal or cardiac\] * Known or suspected fetal abnormalities * Allergy to study agents * Contra-indication to neuraxial anesthesia * Inability to communicate or participate in study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain Burden, AUC (30 Minutes) | First 30 minutes of analgesia | Pain score AREA UNDER THE CURVE (AUC), which is a calculated area under curve using the trapezoidal rule, where pain scores measured from 0 (no pain) to 10 (worst imaginable pain) are on the y axis, and time is on the x axis (pain scores were measured at 5 minutes, 10 minutes,15 minutes, 30 minutes after epidural initiation for the primary outcome assessment). The scale for AUC is not 0-10 but rather is completely dependent upon the area generated under the curve created by pain scores for the first 30 minutes of epidural analgesia (primary outcome time frame): in this case, the scale is 0-250 pain units\*minute, given maximum pain score possibility of 10 and time period of 30 minutes. The units of AUC are the units of Y axis times units of X axis, in this case, pain score units \* minutes. Pain AUC was compared between Fentanyl, Clonidine and Dexmedetomidine groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nausea | 0-120 min after study drug administration | Patient self-report of nausea at any time between 0-120 min after study drug administration |
| Vomiting | 0-120 min after study drug administration | Patient self-report of vomiting at any time between 0-120 min after study drug administration |
| Shivering | 0-120 min after study drug administration | Patient self-report of shivering at any time between 0-120 min after study drug administration |
| Pruritus | 0-120 min after study drug administration | Patient self-report of pruritus at any time between 0-120 min after study drug administration |
| Hypotension | Between 0-120 min after study drug administration | This is measured as any hypotensive event occurring any time between 0-120 min after study drug administration. |
| Pain Scores | 15 minutes after initiation of epidural analgesia | Pain as defined by the Numeric Rating Score (NRS) in which the minimum score of 0 indicates no pain at all and the maximum score of 10 indicates the worst pain imaginable. |
| Cesarean Delivery | At the time of delivery | This will be measured by yes/no response to cesarean delivery mode of delivery outcome. We report the raw numbers of patients who did receive a cesarean delivery according to group. |
| Patient Treatment Satisfaction | Immediately after delivery | Patient self-report regarding satisfaction with analgesia on a scale of 1-10; 1 = not satisfied, 10 = the most satisfied. |
| Newborn Apgar Score | 1 minute after delivery | The Apgar score is a method of assessing newborn health at the time of delivery. Score range 0 to 10 where 0 is poor health and 10 is the best health. |
| Pain Burden, AUC (120 Minutes) | First 120 minutes of analgesia | Pain score AREA UNDER THE CURVE (AUC), which is a calculated area under curve using the trapezoidal rule, where pain scores measured from 0 (no pain) to 10 (worst imaginable pain) are on the y axis, and time is on the x axis (pain scores were measured at 5 minutes, 10 minutes,15 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes after epidural initiation). The scale for AUC is not 0-10 but rather is completely dependent upon the area generated under the curve created by pain scores for the first 120 minutes of epidural analgesia: in this case, the scale is 0-850 pain units\*minute, given maximum pain score possibility of 10 and time period of 120 minutes. The units of AUC are the units of Y axis times units of X axis, in this case, pain score units \* minutes. Pain AUC was compared between Fentanyl, Clonidine and Dexmedetomidine groups. |
Countries
United States
Participant flow
Recruitment details
Participant flow numbers reflect mother-fetus dyads (1 mother + 1 infant per dyad). Intervention groups were assigned at the maternal level.
Pre-assignment details
Pregnant subjects were enrolled at the time of admission to labor and delivery. Both mothers and infants were considered enrolled for the purpose of capturing specific infant information from the infant medical record after delivery (i.e., Apgar scores, cord gases). However, only mothers received the study medication for labor pain control. All other outcomes were assessed on maternal subjects only. Enrollment number & number of subjects started/completed represents the number of dyads enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Clonidine (Maternal) Bolus dose at epidural initiation, through the epidural catheter:
10 ml Ropivacaine 0.1 % combined with a single dose of Clonidine 60 mcg
Clonidine: Clonidine belongs to the drug classification of antihypertensives
Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care | 24 |
| Dexmedetomidine (Maternal) Bolus dose at epidural initiation, through the epidural catheter:
10 ml Ropivacaine 0.1 % combined with a single dose of Dexmedetomidine 30 mcg
Dexmedetomidine: Dexmedetomidine belongs to the drug classification of sedatives
Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care | 22 |
| Ropivacaine + Fentanyl (Maternal) Bolus dose at epidural initiation, through the epidural catheter:
10 ml Ropivacaine 0.1 % combined with a single dose of Fentanyl 100mcg
Fentanyl: Fentanyl belongs to the drug classification of analgesic opioid agonists and is used as the standard of care
Ropivacaine: Ropivacaine belongs to the drug classification of local or regional anesthesia for surgery and is used as standard of care | 23 |
| Total | 69 |
Baseline characteristics
| Characteristic | Clonidine (Maternal) | Dexmedetomidine (Maternal) | Ropivacaine + Fentanyl (Maternal) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 22 Participants | 23 Participants | 69 Participants |
| Age, Continuous | 30.5 years STANDARD_DEVIATION 4.1 | 32 years STANDARD_DEVIATION 3.5 | 31.5 years STANDARD_DEVIATION 3.9 | 31.33 years STANDARD_DEVIATION 3.83 |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Sex: Female, Male Female | 24 Participants | 22 Participants | 23 Participants | 69 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 29 | 0 / 29 | 0 / 30 | 0 / 29 | 0 / 29 |
| other Total, other adverse events | 18 / 30 | 10 / 29 | 19 / 29 | 1 / 30 | 0 / 29 | 0 / 29 |
| serious Total, serious adverse events | 0 / 30 | 0 / 29 | 0 / 29 | 0 / 30 | 0 / 29 | 0 / 29 |
Outcome results
Primary
Pain Burden, AUC (30 Minutes)
Pain score AREA UNDER THE CURVE (AUC), which is a calculated area under curve using the trapezoidal rule, where pain scores measured from 0 (no pain) to 10 (worst imaginable pain) are on the y axis, and time is on the x axis (pain scores were measured at 5 minutes, 10 minutes,15 minutes, 30 minutes after epidural initiation for the primary outcome assessment). The scale for AUC is not 0-10 but rather is completely dependent upon the area generated under the curve created by pain scores for the first 30 minutes of epidural analgesia (primary outcome time frame): in this case, the scale is 0-250 pain units\*minute, given maximum pain score possibility of 10 and time period of 30 minutes. The units of AUC are the units of Y axis times units of X axis, in this case, pain score units \* minutes. Pain AUC was compared between Fentanyl, Clonidine and Dexmedetomidine groups.
Time frame: First 30 minutes of analgesia
Population: Maternal only
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clonidine | Pain Burden, AUC (30 Minutes) | 101 pain units*minutes |
| Dexmedetomidine | Pain Burden, AUC (30 Minutes) | 67 pain units*minutes |
| Ropivacaine + Fentanyl | Pain Burden, AUC (30 Minutes) | 39 pain units*minutes |
p-value: 0.226ANOVA
Secondary
Cesarean Delivery
This will be measured by yes/no response to cesarean delivery mode of delivery outcome. We report the raw numbers of patients who did receive a cesarean delivery according to group.
Time frame: At the time of delivery
Population: Maternal only
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clonidine | Cesarean Delivery | 3 Participants |
| Dexmedetomidine | Cesarean Delivery | 1 Participants |
| Ropivacaine + Fentanyl | Cesarean Delivery | 3 Participants |
p-value: 0.28Fisher Exact
Secondary
Hypotension
This is measured as any hypotensive event occurring any time between 0-120 min after study drug administration.
Time frame: Between 0-120 min after study drug administration
Population: Maternal only
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clonidine | Hypotension | 13 Participants |
| Dexmedetomidine | Hypotension | 10 Participants |
| Ropivacaine + Fentanyl | Hypotension | 11 Participants |
p-value: 0.83Fisher Exact
Secondary
Nausea
Patient self-report of nausea at any time between 0-120 min after study drug administration
Time frame: 0-120 min after study drug administration
Population: Maternal only
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clonidine | Nausea | 5 Participants |
| Dexmedetomidine | Nausea | 4 Participants |
| Ropivacaine + Fentanyl | Nausea | 5 Participants |
p-value: 0.01Fisher Exact
Secondary
Newborn Apgar Score
The Apgar score is a method of assessing newborn health at the time of delivery. Score range 0 to 10 where 0 is poor health and 10 is the best health.
Time frame: 1 minute after delivery
Population: Neonatal only
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Clonidine | Newborn Apgar Score | 9 score on a scale |
| Dexmedetomidine | Newborn Apgar Score | 8 score on a scale |
| Ropivacaine + Fentanyl | Newborn Apgar Score | 8.5 score on a scale |
p-value: 0.98Kruskal-Wallis
Secondary
Pain Burden, AUC (120 Minutes)
Pain score AREA UNDER THE CURVE (AUC), which is a calculated area under curve using the trapezoidal rule, where pain scores measured from 0 (no pain) to 10 (worst imaginable pain) are on the y axis, and time is on the x axis (pain scores were measured at 5 minutes, 10 minutes,15 minutes, 30 minutes, 60 minutes, 90 minutes and 120 minutes after epidural initiation). The scale for AUC is not 0-10 but rather is completely dependent upon the area generated under the curve created by pain scores for the first 120 minutes of epidural analgesia: in this case, the scale is 0-850 pain units\*minute, given maximum pain score possibility of 10 and time period of 120 minutes. The units of AUC are the units of Y axis times units of X axis, in this case, pain score units \* minutes. Pain AUC was compared between Fentanyl, Clonidine and Dexmedetomidine groups.
Time frame: First 120 minutes of analgesia
Population: Maternal only
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clonidine | Pain Burden, AUC (120 Minutes) | 133 pain units*minutes |
| Dexmedetomidine | Pain Burden, AUC (120 Minutes) | 67 pain units*minutes |
| Ropivacaine + Fentanyl | Pain Burden, AUC (120 Minutes) | 45 pain units*minutes |
p-value: 0.16ANOVA
Secondary
Pain Scores
Pain as defined by the Numeric Rating Score (NRS) in which the minimum score of 0 indicates no pain at all and the maximum score of 10 indicates the worst pain imaginable.
Time frame: 15 minutes after initiation of epidural analgesia
Population: Maternal only
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clonidine | Pain Scores | 2.8 score on a scale | Standard Deviation 2.7 |
| Dexmedetomidine | Pain Scores | 1.9 score on a scale | Standard Deviation 2.5 |
| Ropivacaine + Fentanyl | Pain Scores | 1.0 score on a scale | Standard Deviation 1.5 |
p-value: 0.03ANOVA
Secondary
Pain Scores
Pain as defined by the Numeric Rating Score (NRS) in which the minimum score of 0 indicates no pain at all and the maximum score of 10 indicates the worst pain imaginable.
Time frame: 30 minutes after initiation of epidural analgesia
Population: Maternal only
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clonidine | Pain Scores | 2.0 score on a scale | Standard Deviation 2.4 |
| Dexmedetomidine | Pain Scores | 0.9 score on a scale | Standard Deviation 2 |
| Ropivacaine + Fentanyl | Pain Scores | 0.8 score on a scale | Standard Deviation 1.2 |
p-value: 0.07ANOVA
Secondary
Pain Scores
Pain as defined by the Numeric Rating Score (NRS) in which the minimum score of 0 indicates no pain at all and the maximum score of 10 indicates the worst pain imaginable.
Time frame: Immediately after delivery
Population: Maternal only
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Clonidine | Pain Scores | 1.7 score on a scale | Standard Deviation 2.8 |
| Dexmedetomidine | Pain Scores | 0.8 score on a scale | Standard Deviation 2.3 |
| Ropivacaine + Fentanyl | Pain Scores | 0.5 score on a scale | Standard Deviation 0.9 |
p-value: 0.22ANOVA
Secondary
Patient Treatment Satisfaction
Patient self-report regarding satisfaction with analgesia on a scale of 1-10; 1 = not satisfied, 10 = the most satisfied.
Time frame: Immediately after delivery
Population: Maternal only
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Clonidine | Patient Treatment Satisfaction | 10 score on a scale |
| Dexmedetomidine | Patient Treatment Satisfaction | 10 score on a scale |
| Ropivacaine + Fentanyl | Patient Treatment Satisfaction | 10 score on a scale |
p-value: 0.58Kruskal-Wallis
Secondary
Pruritus
Patient self-report of pruritus at any time between 0-120 min after study drug administration
Time frame: 0-120 min after study drug administration
Population: Maternal only
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clonidine | Pruritus | 3 Participants |
| Dexmedetomidine | Pruritus | 0 Participants |
| Ropivacaine + Fentanyl | Pruritus | 5 Participants |
p-value: 0.54Fisher Exact
Secondary
Shivering
Patient self-report of shivering at any time between 0-120 min after study drug administration
Time frame: 0-120 min after study drug administration
Population: Maternal only
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clonidine | Shivering | 6 Participants |
| Dexmedetomidine | Shivering | 4 Participants |
| Ropivacaine + Fentanyl | Shivering | 7 Participants |
p-value: 0.36Fisher Exact
Secondary
Vomiting
Patient self-report of vomiting at any time between 0-120 min after study drug administration
Time frame: 0-120 min after study drug administration
Population: Maternal only
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Clonidine | Vomiting | 1 Participants |
| Dexmedetomidine | Vomiting | 0 Participants |
| Ropivacaine + Fentanyl | Vomiting | 1 Participants |
p-value: 0.36Fisher Exact