Ignite Creation Date:
2024-05-06 @ 8:14 PM
Last Modification Date:
2024-10-26 @ 3:23 PM
Study NCT ID:
NCT06302257
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-03-12
First Post:
2024-03-04
Brief Title:
Randomized Controlled Trial of Combined Lidocaine - Chlorprocaine in Labor Epidural Analgesia
Sponsor:
Hadassah Medical Organization
Organization:
Hadassah Medical Organization
Study Overview
Official Title:
Randomized Controlled Trial of Combined Lidocaine - Chlorprocaine in Labor Epidural Analgesia
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Abstract Background The current gold standard epidural analgesia involves some undesirable side effects such as motor and sympathetic blockade Here the investigators suggest a new approach for inducing prolonged differential pain blockade during labor by selectively targeting local anesthetic chloroprocaine to the pain-related peripheral nociceptive fibers The investigators approach involves nociceptor-selective anesthesia by selective targeting of ionized local anesthetics into nociceptive fibers via activation of nociceptor-specific TRPV1 channels The authors demonstrated that activation of these channels by specific TRPV1-agonists capsaicin or the local anesthetic lidocaine allows entry of a polarized membrane-impermeable lidocaine derivative QX-314 specifically into nociceptive neurons inhibiting their activity and pain blockade without causing other neural effects Capsaicin and QX-314 are not suitable for clinical use as capsaicin causes severe injection pain and QX-314 is neurotoxic Here the investigators use lidocaine as the TRPV1 agonist and use the high pKa chloroprocaine as the ionized local anesthetic instead of the toxic QX-314 Both drugs are in routine clinical use but have not been described in co-administration before The investigators preclinical results show that co-administration of chloroprocaine with TRPV1 agonists leads to prolonged nociceptor-specific analgesia KKK Hypothesis The investigators hypothesize that co-administration of epidural lidocaine to activate TRPV1 channels and chloroprocaine as a polarized local anesthetic which can gain preferential access to nociceptors via opened TRPV1 pores will elicit selective nociceptive-anesthesia Methodology This study assess epidural local analgesia in nulliparous labor There are 2 stages Stage 1 Prior to direct comparison of lidocaine Group L chloroprocaine Group C and a lidocaine-chloroprocaine combination Group L-C the investigators first determine equipotential doses of epidural chloroprocaine and lidocaine using double-blinded up-down sequential analysis using the well-established minimum local anesthetic concentration MLAC or ED50 design ED50 is estimated using Dixon-Massey analysis and Wilcoxon and Litchfield probit regression Stage 2 The main phase of the study involves a randomized double-blinded comparison between Groups L C and L-C where all drug concentrations are based on the ED50MLAC from the Stage 1 The primary endpoint is a composite measure of selective nociceptive analgesia VAS pain score modified Bromage motor score Secondary outcomes are 1 pain VAS 0-100 2 modified Bromage motor score 3 thermal imaging of feet and hands 4 sensory assessment to cold sensation using ice 5 anesthesia requirement from the PCEA pump 6 maternal blood pressure 7 ambulation and pushing ability in labor Primary endpoint is assessed using repeated measures ANOVA first 30-min and mixed models ANOVA until first analgesic request Implications Positive findings will be the first evidence in humans of nociceptor-specific local anesthesia will provide a more effective neuraxial analgesia protocol for labor and will lead to future studies of systemic nociceptor-specific local anesthesia
Detailed Description:
There are two stages to this study The first stage requires the determination of equipotential doses of lidocaine and chlorprocaine The second stage requires randomizing patients to one of three groups - lidocaine alone chlorprocaine alone or a mixture of lidocaine and chlorprocaine in order to assess adequacy of analgesia the anesthetic dose required and the presence of non-analgesic effects such as motor blockade sensory blockade and sympathetic blockade
First Stage Determining equipotential doses of lidocaine and chlorprocaine
Patients are enrolled early in labor prior to the request for epidural anesthesia Epidural analgesia is performed exactly as in routine cases not in the study Prior to the epidural patient consent for the epidural is obtained the patient is placed in the sitting position the epidural inserted at the L34 interspace and a multiport epidural catheter is threaded 3-5 cm into the epidural space As for routine epidurals in our institution oxytocin infusions are discontinued during the epidural and are restarted once the patient is comfortable
Once the epidural is successfully placed no inadvertent intravascular placement or inadvertent spinal and if the pre-epidural VAS pain score is 30mm the patient may be randomized The patient is assigned to one of the two study drugs lidocaine or chlorprocaine using opaque envelopes previously prepared using computer-generated random allocation As this study is an up-down sequential allocation study once the drug group is identified then the specific concentration to be administered is identified from the study log determined by the success or the failure of the analgesia in the previous patient in the same drug group to the dose of that drug
Twenty mL cof the study drug is administered as an incremental test dose over the course of 5 minutes No other test doses are used
After the final assessment of the study patients are connected to the standard protocol for epidural maintenance and the study is terminated
Determination of MLACAs with previous applications of the up-down sequential analysis design in similar studies the three possible outcomes are success failure and reject
1 Success Pain during a uterine contraction is measured as either
1 VAS 10mm achieved by 30 minutes from the time of completion of the 20-mL induction dose or b VAS at least 70 mm less than the VAS immediately prior to the epidural The consequence of a success is that the next patient in that drug group would have a 005 wtvol reduction in the local anesthetic concentration for the epidural bolus
2 FailureFailure is defined as pain during a uterine contraction measured as VAS 10mm achieved by 30 minutes from the time of completion of the 20mL induction dose or patient request for supplemental analgesia at that same time point even if VAS was 10 mm The consequence of a failure is that the next patient in that drug group would have a 005 wtvol increase in the local anesthetic concentration for the epidural bolus The patient will be supplemented with 10 ml or up to 15 ml if needed of 1 lidocaine for analgesia
3 Reject As for failure above but where one of three conditions exist
1 rapid progress in labor repeat vaginal examination at the time of failure assessment reveals a cervical dilation of 8cm
2 top-up doses up to 15 ml of 1 lidocaine fail to relieve labor pain within a further 20 min presumably due to failed epidural
3 progression to cesarean delivery prior to the 30 min assessment time The consequence of a reject is that the next patient in that group receives the same drug concentration for the epidural bolus
Measurements The visual analogue pain score VAPS is measured during uterine contraction The anchors for the VAPS are 0 no pain and 100 worst pain imaginable
The following demographic variables are recorded upon enrollment in the study age height weight gestational age induction mode and indication augmentation premature rupture of membranes PROM and artificial rupture of membranes AROM The following obstetric outcome variables are recorded following delivery 1st stage duration 2nd stage duration baby weight instrumental delivery Cesarean section for dystocia Cesarean section for other indications
The treating anesthesiologist obstetrician and midwife are blinded to the study group The patient and all medical personnel including the anesthesiologist making the assessments are blinded to the drug group allocation and the drug doses used
Second phase The next phase of the study is a randomized controlled study to randomly allocate patients to one of three groups lidocaine alone chlorprocaine alone or a 5050 mixture of both drugs - where all drugs are administered in concentrations based on their ED50 doses together with epidural opioids fentanyl
Patients are enrolled early in labor prior to the request for epidural anesthesia Epidural analgesia is performed exactly as in routine cases not in the study
Prior to the epidural patient consent for the epidural is obtained the VAS pain score is obtained and the temperature of the feet and hands bilaterally are recorded using a FLIR thermal imaging camera Flir C3
The patient is then placed in the sitting position the epidural inserted at the L34 interspace and a multiport epidural catheter is threaded 3-5 cm into the epidural space As for all routine epidurals in our institution oxytocin infusions are discontinued during the epidural and are restarted once the patient is comfortable
As above once the epidural is successfully placed no inadvertent intravascular placement or inadvertent spinal the patient is randomized
The patient is allocated to one of the three study drug regimes lidocaine or chlorprocaine or lidocaine-chlorprocaine combination using opaque envelopes previously prepared using computer-generated random allocation The concentration to be administered is determined by the ED50 of the previous study see below
Three study groups
Lidocaine only
Bolus 20mL MLAC of lidocaine administered as incremental test dose over 5 minutes as in all routine epidurals by our hospital protocol the incremental test dose is preferred to using classical surgical test doses which expose the patient to excessive local anesthetic concentrations
Maintenance Epidural is connected to a 250mL bag of lidocaine MLAC 500mcg fentanyl in 250mL 2mcgmL administered as a PCEA regime with 0 mLhr background infusion 10mL bolus dose 10min lockout time
Chlorprocaine only
Bolus 20mL MLAC of chlorprocaine administered as incremental test dose over 5 minutes as above no other test doses are used
Maintenance Epidural connected to a 250mL bag of lidocaine MLAC 500mcg fentanyl in 250mL 2mcgmL administered as PCEA regime with 0 mLhr background infusion 10mL bolus dose 10min lockout time
Lidocaine-chlorprocaine combination
Bolus 10mL MLAC of lidocaine plus 10mL MLAC of chlorprocaine mixed in a 20mL syringe administered as incremental test dose over 5 minutes as above no other test doses are used
Maintenance Epidural connected to a 250mL bag containing 125mL lidocaine MLAC 125mL chlorprocaine MLAC 500mcg fentanyl in 250mL 2mcgmL administered as PCEA regime with 0 mLhr background infusion 10mL bolus dose 10min lockout time
In keeping with policy for walking epidurals written protocol from 2005 and recently revived all patients will be confined to their beds for the first 30 minutes following epidural analgesia and thereafter will be encouraged to ambulate to go to the bathroom and to use ambulatory fetal monitors rather than wired fetal monitors Ambulation as per our hospital protocol requires the presence of a member of staff and the ability to perform knee-bend movements stand - knee-bend - stand
Measurements
The primary endpoint measure at each time point is the composite selective nociceptive analgesia score VAS pain score modified Bromage motor block score
Assessments are made as follows
1 Pain VAS 0-100 where the anchors of the VAS score are 0no pain 100worst pain imaginable
Need to receive additional anesthesia incase of breakthrough pain and insufficient supplemental doses is also noted
2 Modified Bromage motor block score where the scores are determined as follows
1 unable to move legs or feet 2 unable to flex knees free movement of feet 3 just able to flex knees with free movement of feet 4 free movement of legs and feet 5 able to perform partial knee-bend movements while standing
3 Thermal imaging of the feet and hands using a FlirC3 thermal camera Our team have used this technology to identify segmental sympathectomy following spinal anesthesia in mice Xu Z et al
4 Sensory assessment to cold sensation using an ice cube three options - perception of cold perception of touch no perception
5 Anesthesia requirement From the epidural PCEA pump we will record the frequency of epidural PCA self-administered doses the need for any rescue supplemental boluses the numbers of failed attempted self-administered boluses requests were not allowed because the button was pressed within the 10-minute lockout time the total dose administered and the total dose time of labor
6 Pushing ability in labor This will be assessed by the midwife who is blinded to the study group As occasionally the delivery of the fetus is impaired by the large size or malrotation of the fetus this score is assessed not on the successful vaginal delivery but rather on the strength of pushing and the ability to sense the need to push
In the second stage of labor rate the ability to sense the urge to push 0-100 0 complete inability and 100best imaginable
In the second stage of labor rate the ability push strength 0-100 0 complete inability and 100best imaginable
7 Maternal blood pressure Recorded from the fetal heart rate monitor device as per hospital protocol every 5 min for the first 20 minutes and every 30 minutes thereafter Periodicity of assessments VAS pain score is assessed at the peak of uterine contraction Thermal imaging cold sensation and Bromage motor block score are tested in that order between uterine contractions Assessments are made twice at baseline prior to the epidural and at 10 min intervals for the first 30-minutes and at 15-minute intervals thereafter until the first epidural top-up request administered via PCEA
Anesthesia requirement and pushing ability in labor are recorded at the end of delivery This includes top up doses 10-15 of Lidocaine 1 for breakthrough pain
First Stage Determining equipotential doses of lidocaine and chlorprocaine
Patients are enrolled early in labor prior to the request for epidural anesthesia Epidural analgesia is performed exactly as in routine cases not in the study Prior to the epidural patient consent for the epidural is obtained the patient is placed in the sitting position the epidural inserted at the L34 interspace and a multiport epidural catheter is threaded 3-5 cm into the epidural space As for routine epidurals in our institution oxytocin infusions are discontinued during the epidural and are restarted once the patient is comfortable
Once the epidural is successfully placed no inadvertent intravascular placement or inadvertent spinal and if the pre-epidural VAS pain score is 30mm the patient may be randomized The patient is assigned to one of the two study drugs lidocaine or chlorprocaine using opaque envelopes previously prepared using computer-generated random allocation As this study is an up-down sequential allocation study once the drug group is identified then the specific concentration to be administered is identified from the study log determined by the success or the failure of the analgesia in the previous patient in the same drug group to the dose of that drug
Twenty mL cof the study drug is administered as an incremental test dose over the course of 5 minutes No other test doses are used
After the final assessment of the study patients are connected to the standard protocol for epidural maintenance and the study is terminated
Determination of MLACAs with previous applications of the up-down sequential analysis design in similar studies the three possible outcomes are success failure and reject
1 Success Pain during a uterine contraction is measured as either
1 VAS 10mm achieved by 30 minutes from the time of completion of the 20-mL induction dose or b VAS at least 70 mm less than the VAS immediately prior to the epidural The consequence of a success is that the next patient in that drug group would have a 005 wtvol reduction in the local anesthetic concentration for the epidural bolus
2 FailureFailure is defined as pain during a uterine contraction measured as VAS 10mm achieved by 30 minutes from the time of completion of the 20mL induction dose or patient request for supplemental analgesia at that same time point even if VAS was 10 mm The consequence of a failure is that the next patient in that drug group would have a 005 wtvol increase in the local anesthetic concentration for the epidural bolus The patient will be supplemented with 10 ml or up to 15 ml if needed of 1 lidocaine for analgesia
3 Reject As for failure above but where one of three conditions exist
1 rapid progress in labor repeat vaginal examination at the time of failure assessment reveals a cervical dilation of 8cm
2 top-up doses up to 15 ml of 1 lidocaine fail to relieve labor pain within a further 20 min presumably due to failed epidural
3 progression to cesarean delivery prior to the 30 min assessment time The consequence of a reject is that the next patient in that group receives the same drug concentration for the epidural bolus
Measurements The visual analogue pain score VAPS is measured during uterine contraction The anchors for the VAPS are 0 no pain and 100 worst pain imaginable
The following demographic variables are recorded upon enrollment in the study age height weight gestational age induction mode and indication augmentation premature rupture of membranes PROM and artificial rupture of membranes AROM The following obstetric outcome variables are recorded following delivery 1st stage duration 2nd stage duration baby weight instrumental delivery Cesarean section for dystocia Cesarean section for other indications
The treating anesthesiologist obstetrician and midwife are blinded to the study group The patient and all medical personnel including the anesthesiologist making the assessments are blinded to the drug group allocation and the drug doses used
Second phase The next phase of the study is a randomized controlled study to randomly allocate patients to one of three groups lidocaine alone chlorprocaine alone or a 5050 mixture of both drugs - where all drugs are administered in concentrations based on their ED50 doses together with epidural opioids fentanyl
Patients are enrolled early in labor prior to the request for epidural anesthesia Epidural analgesia is performed exactly as in routine cases not in the study
Prior to the epidural patient consent for the epidural is obtained the VAS pain score is obtained and the temperature of the feet and hands bilaterally are recorded using a FLIR thermal imaging camera Flir C3
The patient is then placed in the sitting position the epidural inserted at the L34 interspace and a multiport epidural catheter is threaded 3-5 cm into the epidural space As for all routine epidurals in our institution oxytocin infusions are discontinued during the epidural and are restarted once the patient is comfortable
As above once the epidural is successfully placed no inadvertent intravascular placement or inadvertent spinal the patient is randomized
The patient is allocated to one of the three study drug regimes lidocaine or chlorprocaine or lidocaine-chlorprocaine combination using opaque envelopes previously prepared using computer-generated random allocation The concentration to be administered is determined by the ED50 of the previous study see below
Three study groups
Lidocaine only
Bolus 20mL MLAC of lidocaine administered as incremental test dose over 5 minutes as in all routine epidurals by our hospital protocol the incremental test dose is preferred to using classical surgical test doses which expose the patient to excessive local anesthetic concentrations
Maintenance Epidural is connected to a 250mL bag of lidocaine MLAC 500mcg fentanyl in 250mL 2mcgmL administered as a PCEA regime with 0 mLhr background infusion 10mL bolus dose 10min lockout time
Chlorprocaine only
Bolus 20mL MLAC of chlorprocaine administered as incremental test dose over 5 minutes as above no other test doses are used
Maintenance Epidural connected to a 250mL bag of lidocaine MLAC 500mcg fentanyl in 250mL 2mcgmL administered as PCEA regime with 0 mLhr background infusion 10mL bolus dose 10min lockout time
Lidocaine-chlorprocaine combination
Bolus 10mL MLAC of lidocaine plus 10mL MLAC of chlorprocaine mixed in a 20mL syringe administered as incremental test dose over 5 minutes as above no other test doses are used
Maintenance Epidural connected to a 250mL bag containing 125mL lidocaine MLAC 125mL chlorprocaine MLAC 500mcg fentanyl in 250mL 2mcgmL administered as PCEA regime with 0 mLhr background infusion 10mL bolus dose 10min lockout time
In keeping with policy for walking epidurals written protocol from 2005 and recently revived all patients will be confined to their beds for the first 30 minutes following epidural analgesia and thereafter will be encouraged to ambulate to go to the bathroom and to use ambulatory fetal monitors rather than wired fetal monitors Ambulation as per our hospital protocol requires the presence of a member of staff and the ability to perform knee-bend movements stand - knee-bend - stand
Measurements
The primary endpoint measure at each time point is the composite selective nociceptive analgesia score VAS pain score modified Bromage motor block score
Assessments are made as follows
1 Pain VAS 0-100 where the anchors of the VAS score are 0no pain 100worst pain imaginable
Need to receive additional anesthesia incase of breakthrough pain and insufficient supplemental doses is also noted
2 Modified Bromage motor block score where the scores are determined as follows
1 unable to move legs or feet 2 unable to flex knees free movement of feet 3 just able to flex knees with free movement of feet 4 free movement of legs and feet 5 able to perform partial knee-bend movements while standing
3 Thermal imaging of the feet and hands using a FlirC3 thermal camera Our team have used this technology to identify segmental sympathectomy following spinal anesthesia in mice Xu Z et al
4 Sensory assessment to cold sensation using an ice cube three options - perception of cold perception of touch no perception
5 Anesthesia requirement From the epidural PCEA pump we will record the frequency of epidural PCA self-administered doses the need for any rescue supplemental boluses the numbers of failed attempted self-administered boluses requests were not allowed because the button was pressed within the 10-minute lockout time the total dose administered and the total dose time of labor
6 Pushing ability in labor This will be assessed by the midwife who is blinded to the study group As occasionally the delivery of the fetus is impaired by the large size or malrotation of the fetus this score is assessed not on the successful vaginal delivery but rather on the strength of pushing and the ability to sense the need to push
In the second stage of labor rate the ability to sense the urge to push 0-100 0 complete inability and 100best imaginable
In the second stage of labor rate the ability push strength 0-100 0 complete inability and 100best imaginable
7 Maternal blood pressure Recorded from the fetal heart rate monitor device as per hospital protocol every 5 min for the first 20 minutes and every 30 minutes thereafter Periodicity of assessments VAS pain score is assessed at the peak of uterine contraction Thermal imaging cold sensation and Bromage motor block score are tested in that order between uterine contractions Assessments are made twice at baseline prior to the epidural and at 10 min intervals for the first 30-minutes and at 15-minute intervals thereafter until the first epidural top-up request administered via PCEA
Anesthesia requirement and pushing ability in labor are recorded at the end of delivery This includes top up doses 10-15 of Lidocaine 1 for breakthrough pain
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None