ED90 for Hyperbaric Bupivacaine in Spinal Anesthesia for Cesarean Delivery in Super Obese Parturients
Phase: PHASE4
Conditions: Obesity, Morbid, Spinal Anesthesia, Cesarean Delivery
Sponsor: Duke University

9/22/2023 
1 
ED90 for Hyperbaric Bupivacaine in Spinal Anesthesia for Cesarean Delivery in Super Obese 
Parturients 
 
 
 
NCT03781388 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

9/22/2023 
2 
 
Study Protocol 
Inclusion criteria: 
            American Society of Anesthesiology (ASA) class 2 and 3 
            English speaking 
            Gestational age > 36 weeks 
            Non-emergent cesarean delivery under combined spinal epidural anesthesia 
            18 years or older 
            BMI =/> 50 kg/m2 
  
Exclusion Criteria: 
            History of past or current intravenous drug or chronic opioid abuse 
            Allergy or contraindication to any study medications 
            Intrapartum cesarean delivery under epidural anesthesia 
            Cesarean delivery under general anesthesia 
Interventions: 
After obtaining Duke University Institutional Review Board approval and informed consent, women 
scheduled to undergo a cesarean delivery under combined spinal epidural anesthesia will be approached to 
participate in the study. A peripheral IV will be placed and baseline maternal vitals will be collected (BP, HR, 
SPO2) and fetal heart tones will be assessed as per standard practice.  
  
A combined spinal epidural (CSE) anesthetic technique will be performed by a member of the anesthesia 
team using a 17-g Tuohy needle and 27g pencil-tip spinal needle in a needle through needle technique into 
the L2-3 or L3-4 interspace in the sitting position. The spinal anesthesia administered to the patients will be 
a standardized dose of intrathecal fentanyl (15 mcg), preservative-free morphine (150 mcg) and a pre-
determined dose of hyperbaric bupivacaine. Our standard intrathecal dose of hyperbaric bupivacaine in non-
super morbidly obese parturients is 12mg, and we assume an ED90 of 10.5mg in the super obese 
parturient, which is usually effective in those patients in our practice. We will therefore consider a range of 
7.5mg-12mg in this study. The starting dose of hyperbaric bupivacaine for the first patient in this study will 
be 9.75mg; the dose for the subsequent subject will be based on the response of the preceding subject as 
per the Narayana Rule, a modification of the biased-coin design (BCD) up-down sequential method (UDM).  
  
If the patient did not respond adequately to the current dose (failureoperation or failureinduction), the dose will be 
considered to have failed.  If the current patient responds successfully to the current dose 
(successinduction and success operation), this will be considered a success.  Determination of the dose will rely on 
the outcomes of the preceding 7 patients receiving the same dose, as the number of previous patients to 
consider is a function of the target dose. Among all patients who received a certain dose, a proportion of 
successful outcomes will be determined (P(d)); if P(d) <0.90, and at least one of the previous 7 patients 
who received the same dose had an unsatisfactory outcome, the next patient will receive a pre-determined 
increment of 0.75 mg of bupivacaine. Alternatively, if P(d)  0.90 and the previous 7 patients who received 
the same dose had successful outcomes, the next patient will receive a pre-determined decrement of 
0.75mg of bupivacaine. Otherwise, the dose will remain the same.  In this study, dose of hyperbaric 
bupivacaine is adjusted in 0.75mg increments, with a presumed ED90 of 10.5mg and ED50 of 7.5mg, and a 
ceiling of 12 mg. Blinded study drugs will be prepared by an anesthesia provider not involved in the study. 

9/22/2023 
3 
The anesthesia provider providing care to the patient will be blinded to the dosage of the hyperbaric 
bupivacaine. In order to preserve the blinding of the provider, the total volume of study drug will be 
maintained at a constant of 2mL. The difference in total volume based on the variation of hyperbaric 
bupivacaine dosing will be replaced with preservative free normal saline.  
  
The data collection will be performed by the anesthesia provider or research assistant, who will also be 
blinded to the dosage of the study drug. Block assessment will be determined by sensory dermatome 
evaluation with pinprick at 2, 4, 6, 8, and 10 minutes after drug administration. Successful blocks for 
induction (successinduction) will be defined as bilateral T6 sensory level to pinprick by 10 minutes after 
intrathecal drug administration. A failed block for induction (failureinduction) will be defined as a T6 sensory 
level not obtained within 10 minutes of study drug administration. If a failure of induction is recorded, an 
epidural supplementation of 2% lidocaine in epinephrine 1:200.000 and sodium bicarbonate will be 
administered until the appropriate level is reached. A successful block for operation (successoperation) will be 
defined as a successful initial sensory level without requiring additional epidural anesthetic during surgery up 
to 90 minutes after intrathecal injection.  
  
Intervention for inadequate block/intraoperative pain will include dosing via the epidural catheter as 
described above. A failure of the block in operation (failureoperation) will be defined as an initial T6 sensory 
level that required supplemental epidural analgesia (earlier than 90 minutes after intrathecal injection) to 
complete the operation, based on patient need for additional analgesia. Intraoperative and postoperative 
management of blood pressure, nausea, vomiting and pruritus will be according to our standard practice.  
 
Sta$s$cal Analysis: 
 
Power analysis was conducted by simulation, assuming an ED90 for hyperbaric bupivacaine of 10.5mg and 
an ED50 of 7.5mg.  The simulation assumed assignment of patients to doses according to the Narayana Rule 
for up-down sequential allocation.  A sample size of 40 patients showed good precision, with 80% of 
simulated samples finding a calculated ED90 within approximately 1mg of the true value and 90% having a 
calculated ED90 within approximately 1.5mg of the true value.   
Baseline characteristics of study patients will be examined and reported as mean and standard deviation or 
median and interquartile range, as appropriate.  ED90 will be estimated through logistic regression by using 
the maximum likelihood estimates (MLE) of intercept and slope from the logistic model.  The logistic 
regression model is given by:  log (p/1-p) = a + B * dose, where p is the probability of successful 
block.  The estimated ED90 is given by:  ED90 = (log 9-á/b) where á and b  are the MLEs of a  and B , 
respectively.  
All statistical analysis will be carried out using R (version 3.5.0; http://www.R-project.org/) or SAS (version 
9.4; SAS Institute, Cary, NC).