Ignite Creation Date:
2024-10-26 @ 3:39 PM
Last Modification Date:
2024-10-26 @ 3:39 PM
Study NCT ID:
NCT06574555
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-08-25
Brief Title:
NE ED90 Bolus in C-Sec
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Determination of the 90 Effective Dose of the Initial Bolus of Norepinephrine in Elective Cesarean Section an Up-Down Study
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
We are aiming to determine what is the effective intravenous dose required of an initial bolus of norepinephrine prior to a maintenance infusion to prevent a 20 decrease in maternal blood pressure from baseline following the administration of spinal anesthesia for elective cesarean section in healthy parturients
Detailed Description:
Previous studies have focused on determining the most appropriate doses for infusion administration of norepinephrine and although current data allows us to conclude that the optimal initial dose would be around 005 mcgkgmin there are still reasonable doubts regarding the initial bolus dose prior to an infusion
Our primary outcome is to determine the 90 effective dose ED90 of an initial bolus of norepinephrine in elective cesarean section under spinal anesthesia to prevent arterial hypotension
We hypothesize that the bolus ED90 of norepinephrine will be in the vicinity of 015 μgkg taking as reference the lower limit of a previous study Lyu et al and the dose used in equipotency studies with phenylephrine
After approval by the Ethics Committee of Pontificia Universidad Católica de Chile and obtaining written informed consent full-term pregnant patients ASA II or III scheduled for elective cesarean section will be prospectively included The study will be registered in Clinical Trials and will be guided by the guidelines of the Helsinki declaration
Inclusion criteria will be age between 18 and 40 years elective caesarean section and singleton term pregnancy Exclusion criteria will be hypertensive disorders of pregnancy cardiovascular disease baseline systolic BP lt100 mmHg height less than 145 cm or greater than 180 cm weight less than 40 kg or greater than 100 kg need for uterine exteriorization during surgery or coagulation disorders The study will follow the 2010 Consolidated Standards for Reporting Trials CONSORT guidelines
Patients will be randomly assigned to two sequences A and B who receive the study drug norepinephrine The initial bolus doses of norepinephrine will be 015 and 013 µgkg
Patients the anesthesiologist involved in the patient39s care surgeons data collectors and outcome adjudicators will be blinded to the initial dose of norepinephrine administered
Anesthetic care will be according to institutional standards which include preoperative fasting and non-invasive hemodynamic monitoring After arrival in the operating room patients will be positioned supine with left lateral tilt to measure baseline blood pressure BP and heart rate after a brief resting period and averaging 3 consecutive measurements in which systolic BP varies lt10
A peripheral intravenous IV line caliber 18G will be placed into an upper extremity vein under local anesthesia Continuous low-rate fluids will be administered for patency purposes but without prior hydration pre-hydration The patients will then be positioned in the left lateral decubitus position for the anesthetic puncture
After skin disinfection and infiltration of the skin with 2 wv lidocaine subarachnoid anesthesia will be performed A 25G Whitacre spinal needle Pencan Braun Germany will be inserted through an introducer at the estimated intervertebral level L3-4 or L4-5 After confirming spontaneous cerebrospinal fluid reflux 14 ml of hyperbaric bupivacaine 075 wv 105 mg fentanyl 04 ml 20 μg and morphine 01 ml 50 μg will be injected intrathecally The patient will then be returned to the supine position with left lateral tilt for uterine displacement Rapid intravenous cohydration will be started up to a total of 15 mlkg after which the infusion rate will be reduced to a maintenance rate The upper sensory block level will be assessed using discrimination with ice For comparison purposes the upper dermatomal level of the blockade at 10 minutes after intrathecal injection will be recorded for each patient for warm discrimination and touch The decision to allow surgery to commence will be based on the clinical judgment of the treating anesthesiologist
Once the intrathecal anesthetic dose has been administered and the patient is positioned in the supine position the study dose of norepinephrine will be administered as a rapid intravenous bolus The first patients in each sequence receive a dose of 015 or 013 µgkg depending on the sequence they were randomised the latter two levels lower than reported in a previous study in which the initial dose was calculated under these conditions9 which is recommended for this type of design11 This will be followed by a continuous infusion of norepinephrine at a dose of 005 µgkgmin and titrating according to hemodynamic parameters
The infusion syringe will contain 20 ml of norepinephrine solution 8 μgml to be administered by a preprogrammed syringe pump at 005 µgkgmin The syringe for the initial bolus will be 20 ml and will contain norepinephrine at 1 µgml allowing the dose corresponding to 013 or 015 µgkg to be administered rounded to the nearest whole number eg for 67 kg it is 1005 µg ie 10 ml 10 µg will be administered
Maternal blood pressure and heart rate will be recorded noninvasively every 1 minute immediately after spinal anesthesia until delivery after which it will be monitored every 3 minutes
The primary outcome will be the presence of arterial hypotension within 10 minutes of anesthesia administration Post-spinal arterial hypotension will be defined as systolic BP decreasing to less than 80 of baseline Norepinephrine 8 μg bolus will be administered if the patient develops arterial hypotension despite study treatment Severe post-spinal arterial hypotension will be defined if systolic BP decreases to lt60 of baseline Bradycardia will be defined as a heart rate below 50 beats per minute where 03 mg of atropine will be administered A rescue bolus will be re-administered if arterial hypotension or bradycardia is not corrected within one minute
Arterial hypertension will be defined as a greater than 20 increase in baseline systolic BP and norepinephrine infusion will be discontinued
Successive doses will be determined with the up-and-down k-in-row design method for ED90 determination
Failure the dose should be increased in one level 002 µgkg after failure to respond arterial hypotension
Success decrease in one level -002 µgkg upon successful response no arterial hypotension but only after observing at least k-consecutive positive responses at the same dose in this case k7 otherwise remain at the same dose11
Reject Any problem during the execution of the protocol that prevents the evaluation of the intervention failure in spinal anesthesia drug error withdrawal from the study etc will be considered as a reject which will condition the administration of the same dose to the next patient randomized to that group
The sequences will be run in parallel until the total sample size of each is reached
Systolic BP and heart rate values will be recorded at the end of each BP measurement cycle Oxygen will not be routinely administered The attending anesthesiologist will be free to override the protocol and administer alternative or additional medications at any time if deemed clinically indicated based on hisher clinical judgment This could include administration of additional bolus norepinephrine 8 µg ephedrine 10 mg or atropine 03 mg intravenously for the treatment of bradycardia associated with arterial hypotension Treatment of bradycardia not associated with arterial hypotension will be managed expectantly by discontinuing all study medications
After fetal delivery and umbilical cord sample will be taken for blood gas and glycaemia After placental separation a uterotonic will be administered according to standard institutional management
Any manifestations secondary to the use of norepinephrine will be recorded such as headache hypertension pain on injection site or changes in skin colour Nausea or vomiting during the study period shall also be recorded
Cesarean delivery will be performed using a traditional Pfannenstiel technique with no uterine exteriorization
Statistical analysis The primary outcome of the study will be the incidence of arterial hypotension in the first 10 minutes after spinal anesthesia
For the sample size calculation a total of 60 patients will be considered which is the general recommendation to be used to determine the 90 effective dose ED90 which balances the minimum number of subjects and would still provide a useful estimate11 In addition sample sizes Ngt40 will give an exact lower 95 confidence interval 95CI limit for probability of response of 076 for an estimate at ED90
Data will be summarized descriptively using mean standard difference SD median interquartiles and count as appropriate Gaussian distribution will be assessed using the DAgostino Omnibus Kolmogorov-Smirnov and normality plot methods
We will use the up-and-down k-in-a-row design method The confidence intervals obtained can guarantee sufficient coverage for 95 in this type of design We will estimate the 90 effective dose and 95 CI of norepinephrine to prevent arterial hypotension The dose-response will be modelled using isotonic and probit regression with and without the pooled adjacent violators algorithm PAVA as sensitivity analyses in addition to the Firth penalised maximum likelihood estimation regression Firth PMLE Regression Probabilities of response 95CI will be estimated for all doses tested
For secondary outcomes comparisons will be made between groups and between patients with arterial hypotension versus those without using Student t- Mann-Whitney U- and Fisher exact statistics as appropriate Nominal data shall be compared using the χ2 test A p-valuelt005 will be considered significant Bonferroni and Tukey-Kramer corrections will be applied to keep the type I error α at 005 so that the significance criterion is plt0017 0053 for blood pressure measurements that are repeated over time
Statistical analyses will be performed in R RStudio v 2021090 Build 351 jamovi httpswwwjamoviorg Stata 170 Stata Inc College Station TX and Number Cruncher Statistical Systems NCSS 2024 NCSS Inc Kaysville UT
Our primary outcome is to determine the 90 effective dose ED90 of an initial bolus of norepinephrine in elective cesarean section under spinal anesthesia to prevent arterial hypotension
We hypothesize that the bolus ED90 of norepinephrine will be in the vicinity of 015 μgkg taking as reference the lower limit of a previous study Lyu et al and the dose used in equipotency studies with phenylephrine
After approval by the Ethics Committee of Pontificia Universidad Católica de Chile and obtaining written informed consent full-term pregnant patients ASA II or III scheduled for elective cesarean section will be prospectively included The study will be registered in Clinical Trials and will be guided by the guidelines of the Helsinki declaration
Inclusion criteria will be age between 18 and 40 years elective caesarean section and singleton term pregnancy Exclusion criteria will be hypertensive disorders of pregnancy cardiovascular disease baseline systolic BP lt100 mmHg height less than 145 cm or greater than 180 cm weight less than 40 kg or greater than 100 kg need for uterine exteriorization during surgery or coagulation disorders The study will follow the 2010 Consolidated Standards for Reporting Trials CONSORT guidelines
Patients will be randomly assigned to two sequences A and B who receive the study drug norepinephrine The initial bolus doses of norepinephrine will be 015 and 013 µgkg
Patients the anesthesiologist involved in the patient39s care surgeons data collectors and outcome adjudicators will be blinded to the initial dose of norepinephrine administered
Anesthetic care will be according to institutional standards which include preoperative fasting and non-invasive hemodynamic monitoring After arrival in the operating room patients will be positioned supine with left lateral tilt to measure baseline blood pressure BP and heart rate after a brief resting period and averaging 3 consecutive measurements in which systolic BP varies lt10
A peripheral intravenous IV line caliber 18G will be placed into an upper extremity vein under local anesthesia Continuous low-rate fluids will be administered for patency purposes but without prior hydration pre-hydration The patients will then be positioned in the left lateral decubitus position for the anesthetic puncture
After skin disinfection and infiltration of the skin with 2 wv lidocaine subarachnoid anesthesia will be performed A 25G Whitacre spinal needle Pencan Braun Germany will be inserted through an introducer at the estimated intervertebral level L3-4 or L4-5 After confirming spontaneous cerebrospinal fluid reflux 14 ml of hyperbaric bupivacaine 075 wv 105 mg fentanyl 04 ml 20 μg and morphine 01 ml 50 μg will be injected intrathecally The patient will then be returned to the supine position with left lateral tilt for uterine displacement Rapid intravenous cohydration will be started up to a total of 15 mlkg after which the infusion rate will be reduced to a maintenance rate The upper sensory block level will be assessed using discrimination with ice For comparison purposes the upper dermatomal level of the blockade at 10 minutes after intrathecal injection will be recorded for each patient for warm discrimination and touch The decision to allow surgery to commence will be based on the clinical judgment of the treating anesthesiologist
Once the intrathecal anesthetic dose has been administered and the patient is positioned in the supine position the study dose of norepinephrine will be administered as a rapid intravenous bolus The first patients in each sequence receive a dose of 015 or 013 µgkg depending on the sequence they were randomised the latter two levels lower than reported in a previous study in which the initial dose was calculated under these conditions9 which is recommended for this type of design11 This will be followed by a continuous infusion of norepinephrine at a dose of 005 µgkgmin and titrating according to hemodynamic parameters
The infusion syringe will contain 20 ml of norepinephrine solution 8 μgml to be administered by a preprogrammed syringe pump at 005 µgkgmin The syringe for the initial bolus will be 20 ml and will contain norepinephrine at 1 µgml allowing the dose corresponding to 013 or 015 µgkg to be administered rounded to the nearest whole number eg for 67 kg it is 1005 µg ie 10 ml 10 µg will be administered
Maternal blood pressure and heart rate will be recorded noninvasively every 1 minute immediately after spinal anesthesia until delivery after which it will be monitored every 3 minutes
The primary outcome will be the presence of arterial hypotension within 10 minutes of anesthesia administration Post-spinal arterial hypotension will be defined as systolic BP decreasing to less than 80 of baseline Norepinephrine 8 μg bolus will be administered if the patient develops arterial hypotension despite study treatment Severe post-spinal arterial hypotension will be defined if systolic BP decreases to lt60 of baseline Bradycardia will be defined as a heart rate below 50 beats per minute where 03 mg of atropine will be administered A rescue bolus will be re-administered if arterial hypotension or bradycardia is not corrected within one minute
Arterial hypertension will be defined as a greater than 20 increase in baseline systolic BP and norepinephrine infusion will be discontinued
Successive doses will be determined with the up-and-down k-in-row design method for ED90 determination
Failure the dose should be increased in one level 002 µgkg after failure to respond arterial hypotension
Success decrease in one level -002 µgkg upon successful response no arterial hypotension but only after observing at least k-consecutive positive responses at the same dose in this case k7 otherwise remain at the same dose11
Reject Any problem during the execution of the protocol that prevents the evaluation of the intervention failure in spinal anesthesia drug error withdrawal from the study etc will be considered as a reject which will condition the administration of the same dose to the next patient randomized to that group
The sequences will be run in parallel until the total sample size of each is reached
Systolic BP and heart rate values will be recorded at the end of each BP measurement cycle Oxygen will not be routinely administered The attending anesthesiologist will be free to override the protocol and administer alternative or additional medications at any time if deemed clinically indicated based on hisher clinical judgment This could include administration of additional bolus norepinephrine 8 µg ephedrine 10 mg or atropine 03 mg intravenously for the treatment of bradycardia associated with arterial hypotension Treatment of bradycardia not associated with arterial hypotension will be managed expectantly by discontinuing all study medications
After fetal delivery and umbilical cord sample will be taken for blood gas and glycaemia After placental separation a uterotonic will be administered according to standard institutional management
Any manifestations secondary to the use of norepinephrine will be recorded such as headache hypertension pain on injection site or changes in skin colour Nausea or vomiting during the study period shall also be recorded
Cesarean delivery will be performed using a traditional Pfannenstiel technique with no uterine exteriorization
Statistical analysis The primary outcome of the study will be the incidence of arterial hypotension in the first 10 minutes after spinal anesthesia
For the sample size calculation a total of 60 patients will be considered which is the general recommendation to be used to determine the 90 effective dose ED90 which balances the minimum number of subjects and would still provide a useful estimate11 In addition sample sizes Ngt40 will give an exact lower 95 confidence interval 95CI limit for probability of response of 076 for an estimate at ED90
Data will be summarized descriptively using mean standard difference SD median interquartiles and count as appropriate Gaussian distribution will be assessed using the DAgostino Omnibus Kolmogorov-Smirnov and normality plot methods
We will use the up-and-down k-in-a-row design method The confidence intervals obtained can guarantee sufficient coverage for 95 in this type of design We will estimate the 90 effective dose and 95 CI of norepinephrine to prevent arterial hypotension The dose-response will be modelled using isotonic and probit regression with and without the pooled adjacent violators algorithm PAVA as sensitivity analyses in addition to the Firth penalised maximum likelihood estimation regression Firth PMLE Regression Probabilities of response 95CI will be estimated for all doses tested
For secondary outcomes comparisons will be made between groups and between patients with arterial hypotension versus those without using Student t- Mann-Whitney U- and Fisher exact statistics as appropriate Nominal data shall be compared using the χ2 test A p-valuelt005 will be considered significant Bonferroni and Tukey-Kramer corrections will be applied to keep the type I error α at 005 so that the significance criterion is plt0017 0053 for blood pressure measurements that are repeated over time
Statistical analyses will be performed in R RStudio v 2021090 Build 351 jamovi httpswwwjamoviorg Stata 170 Stata Inc College Station TX and Number Cruncher Statistical Systems NCSS 2024 NCSS Inc Kaysville UT
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None