Estimation of the ED95 of Intrathecal Hyperbaric Prilocaine 2% With Sufentanyl for Scheduled Cesarean Delivery

Study Overview
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Brief Summary
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Hyperbaric bupivacaine 0.5% associated with opioids is the local anesthetic the most commonly used for spinal injection in cesarean section. Nevertheless, its use often results in a long duration of motor nerve block and a haemodynamical instability. Recently developped, the Prilocaine, with its new 2% hyperbaric formulation, seems to offer a good alternative for hyperbaric bupivicaine. A first study has determined the ED95 of hyperbaric prilocaine 2% for intrathecal anesthesia in scheduled cesarean delivery. As opioid adjuvants potentiate the effect of the local anesthetics while decreasing their dose-related side effects, the aim of this study is to determine the ED95 of hyperbaric prilocaine 2% with sufentanyl for scheduled cesarean delivery under spinal anesthesia,by using the Continual Reassessment Method (CRM)

Official Title
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Estimation of the ED95 of Intrathecal Hyperbaric Prilocaine 2% With Sufentanyl for Scheduled Cesarean Delivery : a Dose-finding Study Bases on the Continual Reassessment Method (CRM)

Conditions
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Pregnant Women

Intervention / Treatment
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* Drug: HB Prilocaine 2% (varying dose)
* Drug: HB Prilocaine 2%
* Drug: Sufentanil
* Drug: Morphine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: American Society of Anesthesiologists physical status (ASA) < III Age 18-40 year Body Weight <100 kg Height between 155 and 175 cm Gestational age>37 SA Elective cesarean delivery Singleton pregnancy Non complicated pregnancy Signed informed consent obtained prior to any study specific assessments and procedures Exclusion Criteria: Twin pregnancy History of 2 cesarean section or more Diabetes and gestational diabetes Placenta praevia Congenital foetal abnormality Patient in labour Membrane rupture Known allergy to local anaesthetics Disagreement of the patient Pregnancy-induced hypertension Pre eclampsia and eclampsia

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 : HB prilocaine 2%, 45mg<br>Dose-finding study with 4 subjects per dose and a maximum of 40 parturients.To identify the dose to give for reaching the ED95 (effective dose for 95% subjects), Hyperbaric prilocaine 2%, associated with sufentanyl, will be administrated at the dose initial of 45 mg in the cohort 1 (4 subjects), then the dose will be adjusted in the next cohorts using the Continual Reassessment Method (CRM). Possible dose levels are 30, 35, 40, 45, 50, 55mg. | Drug: HB Prilocaine 2%<br>* The dose of 45mg of hyperbaric (HB) prilocaine 2% will be administrated intrathecally with 100µg of morphine and 2.5µg of sufentanyl<br>* Other names: Tachipri;Drug: Sufentanil<br>* 2.5µg sufentanyl<br>Drug: Morphine<br>* 100 µg Morphine<br>|
| Experimental: Cohort 2 : HB prilocaine 2%, (30-55mg)<br>Dose-finding study with 4 subjects per dose and a maximum of 40 parturients.To identify the dose to give for reaching the ED95 (effective dose for 95% subjects), Hyperbaric prilocaine 2%, associated with sufentanyl, will be administrated at the dose initial of 45 mg in the cohort 1 (4 subjects), then the dose will be adjusted in the next cohorts using the Continual Reassessment Method (CRM). Possible dose levels are 30, 35, 40, 45, 50, 55mg. | Drug: HB Prilocaine 2% (varying dose)<br>* Varying dose of hyperbaric (HB) prilocaine 2% according to sensitive response of previous subjects. The dose of hyperbaric prilocaine 2% will be administrated intrathecally with 100µg of morphine and 2.5µg of sufentanyl<br>* Other names: Tachipri;Drug: Sufentanil<br>* 2.5µg sufentanyl<br>Drug: Morphine<br>* 100 µg Morphine<br>|
| Experimental: Cohort 3 : HB prilocaine 2%, (30-55mg)<br>Dose-finding study with 4 subjects per dose and a maximum of 40 parturients.To identify the dose to give for reaching the ED95 (effective dose for 95% subjects), Hyperbaric prilocaine 2%, associated with sufentanyl, will be administrated at the dose initial of 45 mg in the cohort 1 (4 subjects), then the dose will be adjusted in the next cohorts using the Continual Reassessment Method (CRM). Possible dose levels are 30, 35, 40, 45, 50, 55mg. | Drug: HB Prilocaine 2% (varying dose)<br>* Varying dose of hyperbaric (HB) prilocaine 2% according to sensitive response of previous subjects. The dose of hyperbaric prilocaine 2% will be administrated intrathecally with 100µg of morphine and 2.5µg of sufentanyl<br>* Other names: Tachipri;Drug: Sufentanil<br>* 2.5µg sufentanyl<br>Drug: Morphine<br>* 100 µg Morphine<br>|
| Experimental: Cohort 4 : HB prilocaine 2%, (30-55mg)<br>Dose-finding study with 4 subjects per dose and a maximum of 40 parturients.To identify the dose to give for reaching the ED95 (effective dose for 95% subjects), Hyperbaric prilocaine 2%, associated with sufentanyl, will be administrated at the dose initial of 45 mg in the cohort 1 (4 subjects), then the dose will be adjusted in the next cohorts using the Continual Reassessment Method (CRM). Possible dose levels are 30, 35, 40, 45, 50, 55mg. | Drug: HB Prilocaine 2% (varying dose)<br>* Varying dose of hyperbaric (HB) prilocaine 2% according to sensitive response of previous subjects. The dose of hyperbaric prilocaine 2% will be administrated intrathecally with 100µg of morphine and 2.5µg of sufentanyl<br>* Other names: Tachipri;Drug: Sufentanil<br>* 2.5µg sufentanyl<br>Drug: Morphine<br>* 100 µg Morphine<br>|
| Experimental: Cohort 5 : HB prilocaine 2%, (30-55mg)<br>Dose-finding study with 4 subjects per dose and a maximum of 40 parturients.To identify the dose to give for reaching the ED95 (effective dose for 95% subjects), Hyperbaric prilocaine 2%, associated with sufentanyl, will be administrated at the dose initial of 45 mg in the cohort 1 (4 subjects), then the dose will be adjusted in the next cohorts using the Continual Reassessment Method (CRM). Possible dose levels are 30, 35, 40, 45, 50, 55mg. | Drug: HB Prilocaine 2% (varying dose)<br>* Varying dose of hyperbaric (HB) prilocaine 2% according to sensitive response of previous subjects. The dose of hyperbaric prilocaine 2% will be administrated intrathecally with 100µg of morphine and 2.5µg of sufentanyl<br>* Other names: Tachipri;Drug: Sufentanil<br>* 2.5µg sufentanyl<br>Drug: Morphine<br>* 100 µg Morphine<br>|
| Experimental: Cohort 6 : HB prilocaine 2%, (30-55mg)<br>Dose-finding study with 4 subjects per dose and a maximum of 40 parturients.To identify the dose to give for reaching the ED95 (effective dose for 95% subjects), Hyperbaric prilocaine 2%, associated with sufentanyl, will be administrated at the dose initial of 45 mg in the cohort 1 (4 subjects), then the dose will be adjusted in the next cohorts using the Continual Reassessment Method (CRM). Possible dose levels are 30, 35, 40, 45, 50, 55mg. | Drug: HB Prilocaine 2% (varying dose)<br>* Varying dose of hyperbaric (HB) prilocaine 2% according to sensitive response of previous subjects. The dose of hyperbaric prilocaine 2% will be administrated intrathecally with 100µg of morphine and 2.5µg of sufentanyl<br>* Other names: Tachipri;Drug: Sufentanil<br>* 2.5µg sufentanyl<br>Drug: Morphine<br>* 100 µg Morphine<br>|
| Experimental: Cohort 7 : HB prilocaine 2%, (30-55mg)<br>Dose-finding study with 4 subjects per dose and a maximum of 40 parturients.To identify the dose to give for reaching the ED95 (effective dose for 95% subjects), Hyperbaric prilocaine 2%, associated with sufentanyl, will be administrated at the dose initial of 45 mg in the cohort 1 (4 subjects), then the dose will be adjusted in the next cohorts using the Continual Reassessment Method (CRM). Possible dose levels are 30, 35, 40, 45, 50, 55mg. | Drug: HB Prilocaine 2% (varying dose)<br>* Varying dose of hyperbaric (HB) prilocaine 2% according to sensitive response of previous subjects. The dose of hyperbaric prilocaine 2% will be administrated intrathecally with 100µg of morphine and 2.5µg of sufentanyl<br>* Other names: Tachipri;Drug: Sufentanil<br>* 2.5µg sufentanyl<br>Drug: Morphine<br>* 100 µg Morphine<br>|
| Experimental: Cohort 8 : HB prilocaine 2%, (30-55mg)<br>Dose-finding study with 4 subjects per dose and a maximum of 40 parturients.To identify the dose to give for reaching the ED95 (effective dose for 95% subjects), Hyperbaric prilocaine 2%, associated with sufentanyl, will be administrated at the dose initial of 45 mg in the cohort 1 (4 subjects), then the dose will be adjusted in the next cohorts using the Continual Reassessment Method (CRM). Possible dose levels are 30, 35, 40, 45, 50, 55mg. | Drug: HB Prilocaine 2% (varying dose)<br>* Varying dose of hyperbaric (HB) prilocaine 2% according to sensitive response of previous subjects. The dose of hyperbaric prilocaine 2% will be administrated intrathecally with 100µg of morphine and 2.5µg of sufentanyl<br>* Other names: Tachipri;Drug: Sufentanil<br>* 2.5µg sufentanyl<br>Drug: Morphine<br>* 100 µg Morphine<br>|
| Experimental: Cohort 9 : HB prilocaine 2%, (30-55mg)<br>Dose-finding study with 4 subjects per dose and a maximum of 40 parturients.To identify the dose to give for reaching the ED95 (effective dose for 95% subjects), Hyperbaric prilocaine 2%, associated with sufentanyl, will be administrated at the dose initial of 45 mg in the cohort 1 (4 subjects), then the dose will be adjusted in the next cohorts using the Continual Reassessment Method (CRM). Possible dose levels are 30, 35, 40, 45, 50, 55mg. | Drug: HB Prilocaine 2% (varying dose)<br>* Varying dose of hyperbaric (HB) prilocaine 2% according to sensitive response of previous subjects. The dose of hyperbaric prilocaine 2% will be administrated intrathecally with 100µg of morphine and 2.5µg of sufentanyl<br>* Other names: Tachipri;Drug: Sufentanil<br>* 2.5µg sufentanyl<br>Drug: Morphine<br>* 100 µg Morphine<br>|
| Experimental: Cohort 10 : HB prilocaine 2%, (30-55mg)<br>Dose-finding study with 4 subjects per dose and a maximum of 40 parturients.To identify the dose to give for reaching the ED95 (effective dose for 95% subjects), Hyperbaric prilocaine 2%, associated with sufentanyl, will be administrated at the dose initial of 45 mg in the cohort 1 (4 subjects), then the dose will be adjusted in the next cohorts using the Continual Reassessment Method (CRM). Possible dose levels are 30, 35, 40, 45, 50, 55mg. | Drug: HB Prilocaine 2% (varying dose)<br>* Varying dose of hyperbaric (HB) prilocaine 2% according to sensitive response of previous subjects. The dose of hyperbaric prilocaine 2% will be administrated intrathecally with 100µg of morphine and 2.5µg of sufentanyl<br>* Other names: Tachipri;Drug: Sufentanil<br>* 2.5µg sufentanyl<br>Drug: Morphine<br>* 100 µg Morphine<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Success of Anesthesia | The nerve blockade will be considered as success when a bilateral T4 level will reach in 15 minutes after intrathecal injection without additional epidural injection needed within 45 minutes peri-operative ; no pain at the skin incision, no pain during 45 minutes after the skin incision | during surgery (average 1 hour) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensitive Block Duration | Level of Sensory block assessed as loss of sensation to cold, every 2 minutes after spinal anesthesia during 15 minutes, then every 5 minutes until the end of surgery, thereafter, once 30 minutes until total regression of sensory block (T12-S1). | Until complete release of sensory block (T12-S1) (average 4 hours) | 
| Sensitive Block at End of Surgery | Level of Sensory block assessed as loss of sensation to cold, every 2 minutes after spinal anesthesia during 15 minutes, then every 5 minutes until the end of surgery, thereafter, once 30 minutes until total regression of sensory block (T12-S1). For this study, dermatome levels are depicted on a scale ranging from 1 to 18. (1 to 12 = T1-T12 thoracic levels; 13 to 17 = L1-L5 lumbar levels; 18 = S1 sacral level) | Until complete release of sensory block (T12-S1) (average 4 hours) | 
| Motor Block Duration | Bromage scale (1 = no motor block; 2 = hip blocked; 3 = hip and knee blocked; and 4 = hip, knee, and ankle blocked) was used to evaluate the motor block every 15 minutes after spinal anaesthesia (T0) and until the end of surgery. Duration was defined from the time of the spinal injection until Bromage scale = 1. | Until complete release of motor block (Bromage scale = 1; average 4 hours) | 
| Bromage Motor Block Level at End of Surgery | Bromage scale (1 = no motor block; 2 = hip blocked; 3 = hip and knee blocked; and 4 = hip, knee, and ankle blocked) was used to evaluate the motor block every 15 min after spinal anaesthesia (T0) and until the end of surgery. | Until complete release of motor block (average 4 hours) | 
| Newborn Apgar Score | Newborn Apgar score assessed at 1, 5, 10 minutes after baby extraction. The Apgar score is determined by evaluating the newborn baby on five simple criteria on a scale from 0 to 2, then summing up the five values thus obtained. The overall resulting score ranges from 0 to 10 ( 0-3 : severely depressed, 4-6 : Moderately depressed and 7-10 : Excellent condition). The five criteria are summarized using words chosen to form an abbreviation (Appearance, Pulse, Grimace, Activity, Respiration). | up to 10 minutes after baby extraction | 
| Newborn Methemoglobinemia (MetHb) | Newborn Methemoglobinemia (MetHb) will be assessed at delivery by cordal blood sample, as a routine control, and expressed as a percentage of total hemoglobinemia. | average 1 hour | 
| Number of Participants Needing Vasopressors | Arterial blood pressure will be measured at every 2.5 minute during surgery, then at every 20 minutes in the PACU (Post Anesthesia Care Unit). Vasopressors were given for patients with low blood pressure. A low blood pressure is defined as a blood pressure lower than 20% or more than the basal blood pressure (Systolic blood pressure before spinal anesthesia). | during surgery (average 1 hour) | 
| Number of Participants With Transient Neurologic Symptoms (TNS) | TNS are defined as pain and/or dysesthesia occurred after complete release of sensory block at the gluteal level, at the thighs and at the legs. At Day 0, Day 1, Day 3 and Day 5 | up to 5 Days | 
| Number of Participants With Nausea or Vomiting | from 15 minutes after spinal anesthesia and every 4 hours for 24 hours (score 0=no symptoms; 1=symptoms with no treatment necessary; 2=symptoms present and treated) | up to 24 hours after surgery | 
| Number of Participants With Pruritus | from 15 minutes after spinal anesthesia and every 4 hours for 24 hours (score 0=no symptoms; 1=symptoms with no treatment necessary; 2=symptoms present and treated) | Up to 24 hours after surgery | 
| Number of Participants With Urinary Retention | All parturients will be questioned for urinary retention (yes or no) | Up to 24 hours after surgery | 
| Number of Participants With Dizziness | All parturients will be questioned for dizziness (yes or no) | Up to 24 hours after surgery | 
| Number of Satisfied Participants | Maternal satisfaction (yes or no) will be assessed 1 hour after surgery in the PACU (Post Anesthesia Care Unit) | up to 1 hour after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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scheduled cesarean delivery, spinal anesthesia, local anesthesia