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出境医 / 临床实验 / Drug Concentration and Volume on Adequate Labor Analgesia With PIEB (CADD2)

Drug Concentration and Volume on Adequate Labor Analgesia With PIEB (CADD2)

Study Description
Brief Summary:

Neuraxial labor analgesia is performed by the administration of a local anesthetic/opioid mixture in the epidural space. The delivery method is a combination of continuous infusion, provider-administered boluses and patient-administered boluses (patient controlled epidural analgesia [PCEA]) via epidural catheter. Pain during the first stage of labor is primarily due to lower uterine segment and cervical stretching. The pain signals enter the spinal cord through sensory nerves at the T10 through L1 dermatomes. Pain signals from the late first state and second stage of labor also arise from the vagina and perineum. These signals travel with the pudendal nerve and enter the spinal cord at S2-S4. Thus, the anesthetic solution administered through the lumbar epidural catheter must spread cephalad in the epidural space to reach the T10 nerve roots and spinal cord, and must spread caudad to reach the caudal nerve roots in the epidural space.

The optimal method for maintaining labor analgesia is unknown. Several studies have demonstrated that PIEB, in combination with PCEA, provide superior maintenance of labor analgesia (less need and longer time to provider intervention, lower local anesthetic consumption, less motor block, and improved patient satisfaction scores) than maintenance with a continuous infusion with PCEA.The mechanism for this difference is not known; however, one suggested mechanism is improved spread of the local anesthetic within the epidural space. Kaynar et al. injected methylene blue dye through a multi-orifice catheter using either a continuous infusion or intermittent bolus and the area of diffusion was measured on a piece of paper. The authors found that intermittent boluses were associated with a greater surface area of diffusion than continuous infusion. In a cadaver study, dye was injected into the lumbar epidural space, and cryomicrotome sections were taken.Dye flowed in rivulets through small channels in the epidural space, as opposed to moving as a unified front. The authors found dye injected at high pressures had more uniform spread through the epidural space, supporting the concept of intermittent epidural injection providing superior analgesia.

Epidural infusion pumps capable of delivering PIEB of local anesthetic with PCEA have become commercially available and many studies have attempted to assess the optimal parameter settings (including volume of programmed bolus, bolus interval, rate of bolus administration) to provide superior labor analgesia. Recently we completed a double-blinded randomized control trial evaluating two bolus delivery rates, hypothesizing that those patients randomized to receive higher bolus delivery rates would have improved labor analgesia. However, no difference was found between groups.What is more, both groups had a mean cephalad sensory level to cold of T6. This sensory level is higher than the traditional goal of T10 (upper dermatome level of uterine innervation), but despite the adequate sensory level, a large number of patients required supplemental physician-delivered boluses of local anesthetic during labor. Forty percent of the women in the high-rate group and 36% of the low-rate group required a manual re-dose during labor. This suggests that either a higher volume, or higher concentration of local anesthetic (i.e., higher dose) is needed to maintain adequate labor analgesia.

Traditionally higher concentration local anesthetic solutions have been associated with increased motor blockade leading to a higher incidence of instrumental vaginal delivery. Several local anesthetic solutions with varying drug concentrations are available for labor analgesia and are used clinically in the United States. We plan to perform a randomized, controlled, double-blind study to test the hypothesis that patients whose labor analgesia is maintained using PIEB with low-volume bolus (6.25 mL) of a higher local anesthetic concentration solution (0.1% bupivacaine with fentanyl 2.0 mcg/mL) will require less supplemental analgesia (manual provider re-doses) than patients whose PIEB is delivered with a high-volume bolus (10 mL) of lower density local anesthetic solution (0.0625% bupivacaine with fentanyl 2.0 mcg/mL).

The aim of this study is to evaluate the association between bolus volume and concentration of local anesthetic during maintenance of labor analgesia with programmed intermittent epidural bolus (PIEB) analgesia.

The hypothesis of this study is: patients whose labor analgesia is maintained using PIEB with low-volume bolus (6.25 mL) of higher local anesthetic concentration solution (0.1% bupivacaine with fentanyl 2.0 mcg/mL) will have a longer duration of adequate analgesia (time to first manual re-dose request) than patients whose PIEB is delivered with a high-volume bolus (10 mL) of lower concentration local anesthetic solution (0.0625% bupivacaine with fentanyl 2.0 mcg/mL).


Condition or disease Intervention/treatment Phase
Pain Anesthesia Labor Pain Drug: Low volume bolus Drug: High volume bolus Phase 4

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 400 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Two group randomized controlled trial
Masking: Double (Participant, Outcomes Assessor)
Masking Description: The participant and outcomes assessor will be blinded to the assigned randomization.
Primary Purpose: Treatment
Official Title: The Relationship Between Local Anesthetic Concentration and Volume on Adequate Labor Analgesia With Programmed Intermittent Epidural Bolus
Actual Study Start Date : January 9, 2020
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : January 15, 2024
Arms and Interventions
Arm Intervention/treatment
Experimental: Low volume bolus
6.25 mL administration at 250 ml per hour of a greater density solution (0.1% bupivacaine with fentanyl 2.0 mcg/mL)
Drug: Low volume bolus
Administration of a low-volume bolus (6.25 mL) of greater density solution (0.1% bupivacaine with fentanyl 2.0 mcg/mL) at 250 mL per hour given by CADD pump.

Experimental: High volume bolus
10 mL administration of a lower density local anesthetic (0.0625% bupivacaine with fentanyl 2.0 mcg/mL).
Drug: High volume bolus
Administration of a high-volume bolus (10 mL) of lower density local anesthetic (0.0625% bupivacaine with fentanyl 2.0 mcg/mL) at 250 mL per hour given by CADD pump.

Outcome Measures
Primary Outcome Measures :
  1. Need for supplemental physician-delivered bolus of local anesthetic [ Time Frame: Time of delivery of baby ]
    The amount of supplemental physician delivered boluses of local anesthetic administered prior to the delivery of the baby.


Secondary Outcome Measures :
  1. Time to first request for supplemental analgesia [ Time Frame: delivery (Minutes to first request) ]
    Time elapsed in minutes from epidural set up to time to request supplemental analgesia

  2. Total hourly bupivacaine consumption [ Time Frame: Delivery of baby ]
    Total amount of bupivacaine in milligrams used by the patient from start time of epidural placement to the delivery of the baby

  3. Mode of delivery [ Time Frame: Delivery of baby ]
    Mode of delivery identified as: normal vaginal delivery, instrumental vaginal delivery, cesarean delivery or emergency cesarean delivery

  4. Motor block throughout labor (0-9 cm dilation) [ Time Frame: delivery (From 0 cm to 9 cm dilation of the cervix) ]
    The level of neuraxial blockade assessed by touch from 0-9 cm dilation.

  5. Motor block throughout labor (10cm dilation) [ Time Frame: delivery (At 10 cm dilation of the cervix) ]
    The level of neuraxial blockade assessed by touch at 10 cm cervical width.

  6. Sensory level of block throughout labor (0-9 cm) [ Time Frame: delivery (To 9 cm dilation of cervix) ]
    The level of sensory loss reported by the subject by touch 0-9 cm cervical width assessed every 2 hours

  7. Sensory level at 10 cm [ Time Frame: delivery (At 10 cm dilation of cervix) ]
    The level of sensory loss reported by the subject by touch at 10 cm cervical width.

  8. Pain burden [ Time Frame: Delivery of baby ]
    Pain burden as defined as area under the pain-time curve

  9. Patient Satisfaction [ Time Frame: delivery (After removal of epidural catheter) ]
    Overall satisfaction of labor is measured using a 100 mm unmarked line (the left end labeled "not satisfied at all (o=no satisfaction) " and the right end labeled "extremely satisfied" (100=extremely satisfied)


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Pregnant female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 18 years and above
  • Nulliparous parturients
  • Present to the labor and delivery unit for an induction of labor or who are in spontaneous labor
  • Request neuraxial labor analgesia at ≤5 cm cervical dilation

Exclusion Criteria:

  • Patients who are not eligible to receive a combined spinal epidural (CSE) technique with 25 mcg of intrathecal fentanyl
  • Non-English speaking
  • Failed initiation of CSE analgesia (VAS pain score >10 15 minutes after intrathecal dose)
  • Need to have the epidural catheter replaced during labor
  • Who deliver within 90 minutes of initiation of labor analgesia
  • Require re-dose within 90 minutes of initiation of labor analgesia.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Elizabeth Lange, M.D 312-472-3585 elizabeth.lange@northwestern.edu
Contact: Paul C Fitzgerald, MS 312-695-1064 p-fitzgerald2@northwestern.edu

Locations
Layout table for location information
United States, Illinois
Prentice Women's Hospital Recruiting
Chicago, Illinois, United States, 60611
Contact: Paul Fitzgerald, RN, MS    313-695-1064    p-fitzgerald2@northwestern.edu   
Sponsors and Collaborators
Northwestern University
Investigators
Layout table for investigator information
Principal Investigator: Elizabeth Lange, MD Northwestern University
Tracking Information
First Submitted Date  ICMJE May 30, 2018
First Posted Date  ICMJE June 12, 2018
Last Update Posted Date February 1, 2021
Actual Study Start Date  ICMJE January 9, 2020
Estimated Primary Completion Date December 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 11, 2018)
Need for supplemental physician-delivered bolus of local anesthetic [ Time Frame: Time of delivery of baby ]
The amount of supplemental physician delivered boluses of local anesthetic administered prior to the delivery of the baby.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 11, 2018)
  • Time to first request for supplemental analgesia [ Time Frame: delivery (Minutes to first request) ]
    Time elapsed in minutes from epidural set up to time to request supplemental analgesia
  • Total hourly bupivacaine consumption [ Time Frame: Delivery of baby ]
    Total amount of bupivacaine in milligrams used by the patient from start time of epidural placement to the delivery of the baby
  • Mode of delivery [ Time Frame: Delivery of baby ]
    Mode of delivery identified as: normal vaginal delivery, instrumental vaginal delivery, cesarean delivery or emergency cesarean delivery
  • Motor block throughout labor (0-9 cm dilation) [ Time Frame: delivery (From 0 cm to 9 cm dilation of the cervix) ]
    The level of neuraxial blockade assessed by touch from 0-9 cm dilation.
  • Motor block throughout labor (10cm dilation) [ Time Frame: delivery (At 10 cm dilation of the cervix) ]
    The level of neuraxial blockade assessed by touch at 10 cm cervical width.
  • Sensory level of block throughout labor (0-9 cm) [ Time Frame: delivery (To 9 cm dilation of cervix) ]
    The level of sensory loss reported by the subject by touch 0-9 cm cervical width assessed every 2 hours
  • Sensory level at 10 cm [ Time Frame: delivery (At 10 cm dilation of cervix) ]
    The level of sensory loss reported by the subject by touch at 10 cm cervical width.
  • Pain burden [ Time Frame: Delivery of baby ]
    Pain burden as defined as area under the pain-time curve
  • Patient Satisfaction [ Time Frame: delivery (After removal of epidural catheter) ]
    Overall satisfaction of labor is measured using a 100 mm unmarked line (the left end labeled "not satisfied at all (o=no satisfaction) " and the right end labeled "extremely satisfied" (100=extremely satisfied)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Drug Concentration and Volume on Adequate Labor Analgesia With PIEB
Official Title  ICMJE The Relationship Between Local Anesthetic Concentration and Volume on Adequate Labor Analgesia With Programmed Intermittent Epidural Bolus
Brief Summary

Neuraxial labor analgesia is performed by the administration of a local anesthetic/opioid mixture in the epidural space. The delivery method is a combination of continuous infusion, provider-administered boluses and patient-administered boluses (patient controlled epidural analgesia [PCEA]) via epidural catheter. Pain during the first stage of labor is primarily due to lower uterine segment and cervical stretching. The pain signals enter the spinal cord through sensory nerves at the T10 through L1 dermatomes. Pain signals from the late first state and second stage of labor also arise from the vagina and perineum. These signals travel with the pudendal nerve and enter the spinal cord at S2-S4. Thus, the anesthetic solution administered through the lumbar epidural catheter must spread cephalad in the epidural space to reach the T10 nerve roots and spinal cord, and must spread caudad to reach the caudal nerve roots in the epidural space.

The optimal method for maintaining labor analgesia is unknown. Several studies have demonstrated that PIEB, in combination with PCEA, provide superior maintenance of labor analgesia (less need and longer time to provider intervention, lower local anesthetic consumption, less motor block, and improved patient satisfaction scores) than maintenance with a continuous infusion with PCEA.The mechanism for this difference is not known; however, one suggested mechanism is improved spread of the local anesthetic within the epidural space. Kaynar et al. injected methylene blue dye through a multi-orifice catheter using either a continuous infusion or intermittent bolus and the area of diffusion was measured on a piece of paper. The authors found that intermittent boluses were associated with a greater surface area of diffusion than continuous infusion. In a cadaver study, dye was injected into the lumbar epidural space, and cryomicrotome sections were taken.Dye flowed in rivulets through small channels in the epidural space, as opposed to moving as a unified front. The authors found dye injected at high pressures had more uniform spread through the epidural space, supporting the concept of intermittent epidural injection providing superior analgesia.

Epidural infusion pumps capable of delivering PIEB of local anesthetic with PCEA have become commercially available and many studies have attempted to assess the optimal parameter settings (including volume of programmed bolus, bolus interval, rate of bolus administration) to provide superior labor analgesia. Recently we completed a double-blinded randomized control trial evaluating two bolus delivery rates, hypothesizing that those patients randomized to receive higher bolus delivery rates would have improved labor analgesia. However, no difference was found between groups.What is more, both groups had a mean cephalad sensory level to cold of T6. This sensory level is higher than the traditional goal of T10 (upper dermatome level of uterine innervation), but despite the adequate sensory level, a large number of patients required supplemental physician-delivered boluses of local anesthetic during labor. Forty percent of the women in the high-rate group and 36% of the low-rate group required a manual re-dose during labor. This suggests that either a higher volume, or higher concentration of local anesthetic (i.e., higher dose) is needed to maintain adequate labor analgesia.

Traditionally higher concentration local anesthetic solutions have been associated with increased motor blockade leading to a higher incidence of instrumental vaginal delivery. Several local anesthetic solutions with varying drug concentrations are available for labor analgesia and are used clinically in the United States. We plan to perform a randomized, controlled, double-blind study to test the hypothesis that patients whose labor analgesia is maintained using PIEB with low-volume bolus (6.25 mL) of a higher local anesthetic concentration solution (0.1% bupivacaine with fentanyl 2.0 mcg/mL) will require less supplemental analgesia (manual provider re-doses) than patients whose PIEB is delivered with a high-volume bolus (10 mL) of lower density local anesthetic solution (0.0625% bupivacaine with fentanyl 2.0 mcg/mL).

The aim of this study is to evaluate the association between bolus volume and concentration of local anesthetic during maintenance of labor analgesia with programmed intermittent epidural bolus (PIEB) analgesia.

The hypothesis of this study is: patients whose labor analgesia is maintained using PIEB with low-volume bolus (6.25 mL) of higher local anesthetic concentration solution (0.1% bupivacaine with fentanyl 2.0 mcg/mL) will have a longer duration of adequate analgesia (time to first manual re-dose request) than patients whose PIEB is delivered with a high-volume bolus (10 mL) of lower concentration local anesthetic solution (0.0625% bupivacaine with fentanyl 2.0 mcg/mL).

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Two group randomized controlled trial
Masking: Double (Participant, Outcomes Assessor)
Masking Description:
The participant and outcomes assessor will be blinded to the assigned randomization.
Primary Purpose: Treatment
Condition  ICMJE
  • Pain
  • Anesthesia
  • Labor Pain
Intervention  ICMJE
  • Drug: Low volume bolus
    Administration of a low-volume bolus (6.25 mL) of greater density solution (0.1% bupivacaine with fentanyl 2.0 mcg/mL) at 250 mL per hour given by CADD pump.
  • Drug: High volume bolus
    Administration of a high-volume bolus (10 mL) of lower density local anesthetic (0.0625% bupivacaine with fentanyl 2.0 mcg/mL) at 250 mL per hour given by CADD pump.
Study Arms  ICMJE
  • Experimental: Low volume bolus
    6.25 mL administration at 250 ml per hour of a greater density solution (0.1% bupivacaine with fentanyl 2.0 mcg/mL)
    Intervention: Drug: Low volume bolus
  • Experimental: High volume bolus
    10 mL administration of a lower density local anesthetic (0.0625% bupivacaine with fentanyl 2.0 mcg/mL).
    Intervention: Drug: High volume bolus
Publications *
  • Wong CA, Ratliff JT, Sullivan JT, Scavone BM, Toledo P, McCarthy RJ. A randomized comparison of programmed intermittent epidural bolus with continuous epidural infusion for labor analgesia. Anesth Analg. 2006 Mar;102(3):904-9.
  • Lim Y, Sia AT, Ocampo C. Automated regular boluses for epidural analgesia: a comparison with continuous infusion. Int J Obstet Anesth. 2005 Oct;14(4):305-9.
  • Chua SM, Sia AT. Automated intermittent epidural boluses improve analgesia induced by intrathecal fentanyl during labour. Can J Anaesth. 2004 Jun-Jul;51(6):581-5.
  • Kaynar AM, Shankar KB. Epidural infusion: continuous or bolus? Anesth Analg. 1999 Aug;89(2):534.
  • Hogan Q. Distribution of solution in the epidural space: examination by cryomicrotome section. Reg Anesth Pain Med. 2002 Mar-Apr;27(2):150-6.
  • Comparative Obstetric Mobile Epidural Trial (COMET) Study Group UK. Effect of low-dose mobile versus traditional epidural techniques on mode of delivery: a randomised controlled trial. Lancet. 2001 Jul 7;358(9275):19-23.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 11, 2018)
400
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 15, 2024
Estimated Primary Completion Date December 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 18 years and above
  • Nulliparous parturients
  • Present to the labor and delivery unit for an induction of labor or who are in spontaneous labor
  • Request neuraxial labor analgesia at ≤5 cm cervical dilation

Exclusion Criteria:

  • Patients who are not eligible to receive a combined spinal epidural (CSE) technique with 25 mcg of intrathecal fentanyl
  • Non-English speaking
  • Failed initiation of CSE analgesia (VAS pain score >10 15 minutes after intrathecal dose)
  • Need to have the epidural catheter replaced during labor
  • Who deliver within 90 minutes of initiation of labor analgesia
  • Require re-dose within 90 minutes of initiation of labor analgesia.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Gender Based Eligibility: Yes
Gender Eligibility Description: Pregnant female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Elizabeth Lange, M.D 312-472-3585 elizabeth.lange@northwestern.edu
Contact: Paul C Fitzgerald, MS 312-695-1064 p-fitzgerald2@northwestern.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03553576
Other Study ID Numbers  ICMJE STU00206113
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Elizabeth Lange, Northwestern University
Study Sponsor  ICMJE Northwestern University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Elizabeth Lange, MD Northwestern University
PRS Account Northwestern University
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP