Clinical trial NCT03993314
Conditions: Pregnancy Related
Sponsor: University of Alabama at Birmingham
Start date: 2019-08-13; Completion date: 2020-12-03
Enrollment: 15 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this study, the investigators will compare CLOROTEKAL® (1% spinal chloroprocaine) to low-dose isobaric bupivacaine using the epidural volume extension (EVE) technique in patients undergoing post-partum tubal ligation (PPBTL). This will be a randomized, double-blinded study. Patients scheduled for PPBTL at the Women and Infants Center (WIC) will be eligible for enrollment in this study. Outcomes measured will include: ability to achieve an adequate level required for surgery (T6), rate of epidural activation, and duration of the block. The investigators hope to determine the usefulness of each drug using the EVE technique in the setting of PPBTL.

Detailed description:

Arms: arm 1: 1 ml 0.5% isobaric bupivacaine (5 mg) + 15 mcg fentanyl intrathecal plus epidural volume extension (EVE) arm 2: 5 ml 1% spinal chloroprocaine (50 mg) intrathecal plus epidural volume extension (EVE)
Interventions: intervention 1: Chloroprocaine intervention 2: Bupivacaine
Intervention descriptions: intervention 1: Adding 5 cc 1% Chloroprocaine with 10 cc sterile saline in the epidural intervention 2: 1 cc of 0.5% bupivacaine with 15 mcg fentanyl 10 cc of sterile saline in the epidural

Protocol documents:
Prot_SAP_000.pdf: 
Optimizing Anesthesia for Postpartum Tubal Ligations 
 
 
     Study Protocol & Statistical Analysis Plan  
 
 
 
 
   
 
 
 
 
        NCT03993314 
 
 
 
 
 
 
 
 
 
 
 
    November 18, 2021 
 
 
 
 
Mark Powell, M.D., Principal Investigator 
 
 
  University of Alabama at Birmingham 
 
 
 
 
Birmingham, AL 35294 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


STUDY SUMMARY 
 
1 ...................................................................................................................... BACKGROUND 
2 .......................................................................................................... STUDY OBJECTIVES 
3 ..................................................................................................................... STUDY DESIGN 
4 ......................................................... SUBJECT SELECTION AND WITHDRAWAL 
5 ……………………………………………………………………...……….…….. STUDY DRUG 
6 ………………………………………………………………………. STUDY PROCEDURES  
7 ............................................................................................................ STATISTICAL PLAN 
8 ............................................................................... SAFETY AND ADVERSE EVENTS 
9 .......................................................... DATA HANDLING AND RECORD KEEPING 
10 ……………………… STUDY MONITORING, AUDITING, AND INSPECTING 
11 ............................................................................................................ STUDY FINANCES 
12 ..................................................................................................................... REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


BACKGROUND 
Although a short surgical procedure, postpartum bilateral tubal ligation (PPBTL) can pose a 
significant challenge to the anesthesiologist. Due to concerns with the obstetric airway, neuraxial 
anesthesia remains the preferred method of anesthesia.[1] However, providing neuraxial anesthesia for 
these cases can be difficult. Labor epidural reactivation for PPTL has been examined; however, this 
technique has an unacceptably high failure rate.[2] Spinal lidocaine, a short-acting local anesthetic, has 
fallen out of favor due to the increased risk of transient neurologic symptoms (TNS).[3] The most 
common local anesthetic used for spinal anesthesia, bupivacaine, provides appropriate coverage, but 
has a very long duration of action and will significantly outlast the PPBTL. This prolonged duration leads 
to a prolonged post-anesthesia care unit (PACU) length of stay.[4] 
 
We recently demonstrated a significant reduction in recovery time for patients undergoing short 
obstetric procedures using low-dose bupivacaine with epidural volume extension (EVE) when compared 
to our traditional bupivacaine dose.[5] At the time of our study, there was no FDA-approved short-acting 
local anesthetic for us to use as a comparison. Peer reviewers at the time noted the need to compare 
our technique to a short-acting local anesthetic in the future. In 2017, that the FDA approved 
chloroprocaine 1% (short-acting local anesthetic) for spinal anesthesia for short surgical procedures. The 
package insert reports reliable coverage for lower abdominal procedures at the T10 level. PPBTL, due to 
sympathetic innervation of the fallopian tubes and uterus, routinely requires a T6 level for an adequate 
surgical block.[6] 
The EVE technique can increase the spread of local anesthetic to higher dermatome levels. The 
leading hypothesis, supported by radiographic evidence, is thecal sac compression from epidural 
injection (typically normal saline), which effectively reduces spinal CSF and thus drives local anesthetic 
to higher dermatomal levels in an active fashion rather than allowing for passive flow.[7] We have 
shown similar dermatome coverage using half the dose of bupivacaine when the EVE technique is 
employed.[5] With the understanding of how the EVE technique works, we believe that EVE will be able 
to adequately increase the surgical block of the 1% chloroprocaine from the T10 to the T6 dermatome 
that is required for PPBTL. 
 
Now that there is an FDA-approved local anesthetic for short obstetric procedures, and the fact 
that this drug can reliably anesthetize fibers up to the T10 dermatome, we wanted to revisit our EVE 
study and compare our low-dose isobaric bupivacaine to 1% spinal chloroprocaine utilizing the EVE 
technique in an effort to determine if either medication provides an advantage for patients undergoing 
PPBTL. 
 
STUDY OBJECTIVES AND HYPOTHESIS 
 
The purpose of this study was to determine if spinal 1% chloroprocaine with EVE or low dose 
spinal 0.5% isobaric bupivacaine with EVE confer a significant clinical advantage over the other. We 
hypothesized that there will be no difference in the block height at 10 minutes after spinal 
injection (𝑇10), comparing 0.5% isobaric bupivacaine to spinal 1% chloroprocaine. If confirmed, 
our results suggest that spinal 1% chloroprocaine is a suitable alternative to 0.5% isobaric 
intrathecal bupivacaine. 
 


STUDY DESIGN 
Design: Randomized, Controlled Trial 
Comparison groups:  
1. 1 ml 0.5% isobaric bupivacaine + 15 mcg fentanyl intrathecal plus EVE 
2. 5 ml 1% spinal chloroprocaine intrathecal plus EVE 
 
EVE = 10 ml sterile normal saline injected into epidural space after intrathecal 
injection of study medication 
Primary Outcomes:  
1. Number of patients who achieve a T6 dermatome level or greater within 10 minutes of spinal 
injection. 
2. Dermatome level achieved. 
Secondary Outcomes:  
1. Number of patients who required epidural activation during the surgery. 
2. Number of patients who required intravenous (IV) sedation or general anesthesia during 
surgery. 
3. Motor blockade as defined by the modified Bromage score at 10 minutes after spinal injection. 
4. Motor blockade as defined by the modified Bromage score at 60 minutes after spinal injection. 
5. Time required to meet post-anesthesia care unit (PACU) discharge criteria. 
SUBJECT SELECTION AND WITHDRAWAL 
Inclusion criteria: 
1. Any patient scheduled for PPBTL at our Women and Infants Center (WIC) age 18 and above. 
Exclusion criteria: 
1. Patients less than 18 years of age. 
2. Documented allergy to either local anesthetic class (ester or amide). 
3. Any documented contraindication to neuraxial block. 
Recruitment and Screening: 
Any patient scheduled for PPBTL at the WIC will be screened for eligibility. The 
inclusion/exclusion criteria described above will be used to screen each patient. Because PPBTL occur 
within 24 hours of delivery, all patients will be screened and enrolled on the day of surgery. If a patient 
is eligible for the study, a member of the study team will approach the patient and discuss the study 
including all risks and benefits. If the patient agrees to participate in the study, informed written consent 
will be obtained. Patients do not receive any compensation for this study. 
 
Because there is no long-term follow up to this study, participant withdrawal should be minimal. 
If withdrawal does occur, the patient will continue to receive standard of care treatment for the PPBTL. 


The patient will still be included in the overall number of patients enrolled; however, the data will not be 
included in the analysis. 
STUDY DRUGS 
Drug Name: Chloroprocaine 
Other Names:  Clorotekal; Nesacaine; Nesacaine-MPF  
Classification: Local Anesthetic, ester-type 
Mode of Action: Prevents both the initiation and conduction of nerve impulses by decreasing the 
neuronal membrane's permeability to sodium ions, which results in inhibition of depolarization with 
resultant blockade of conduction 
Storage and Stability: Store at 20°C to 25°C (68°F to 77°F) in original container; protect from freezing. 
Protect from light. Discard Clorotekal and Nesacaine-MPF following single use. Solution in vials may 
become discolored with prolonged exposure to light; do not administer discolored solutions. Crystals of 
chloroprocaine may develop when exposed to low temperatures; when the vial is returned to room 
temperature, the crystals will redissolve with shaking; do not use solutions that contain undissolved 
matter. Do not heat before use; do not autoclave. Use immediately after initial puncture of vial or after 
ampule opening 
Metabolism: Rapidly hydrolyzed by plasma enzymes to 2-chloro-4-aminobenzoic acid and beta-
diethylaminoethanol (80% conjugated before elimination) 
Preparation: Solution, Intrathecal, as hydrochloride [preservative free]:  Clorotekal: 1% (5 mL)   
Administration: Subarachnoid block: Do not use solutions containing preservatives. Use a filter needle to 
draw up solution from ampule when using Clorotekal. Do not puncture areas of the skin with signs of 
infection/inflammation. Intravascular injections should be avoided; aspiration should be performed 
prior to administration; the needle must be repositioned until no return of blood can be elicited by 
aspiration; however, absence of blood in the syringe does not guarantee that intravascular injection has 
been avoided. Clorotekal is intended for intrathecal administration only; the manufacturer recommends 
against using for epidural administration. Use of Clorotekal via continuous spinal catheters is not 
recommended (safety has not been established). 
 
Drug Name: Bupivacaine 
Other Names:  Bupivacaine Spinal; Marcaine; Marcaine Preservative Free; Marcaine Spinal; P-Care M; 
Sensorcaine; Sensorcaine-MPF  
Classification: Local anesthetic, amide-type 
Mode of Action: Prevents both the initiation and conduction of nerve impulses by decreasing the 
neuronal membrane's permeability to sodium ions, which results in inhibition of depolarization with 
resultant blockade of conduction 


Storage and Stability: Store at 20° to 25°C (68° to 77°F). Discard unused portions of single-dose ampuls 
and vials. Solutions containing epinephrine should be protected from light 
Metabolism: Hepatic; forms metabolite (pipecoloxylidine [PPX]) 
Preparation: Solution, Injection, as hydrochloride [preservative free]:  Generic: 0.5% (30 mL)    
Administration: Spinal: free flow of cerebrospinal fluid during the performance of spinal anesthesia is 
indicative of entry into the subarachnoid space.  Do not inject during uterine contractions because spinal 
fluid current may carry the drug further cephalad than desired. 
STUDY PROCEDURES 
Computer-generated randomized cards were created, placed in envelopes, and sealed prior to 
the start of the study. Once a patient is enrolled, the next card in the sealed envelope is selected for the 
randomization process. As this is a double-blinded study, the researcher will hand the card to the 
qualified anesthesia provider performing the combined spinal epidural (CSE) procedure. Once the 
patient is ready for surgery, she will be moved to the operating room (OR). Standard care will be 
provided to the patient in the OR – basic monitors, routine nursing care, etc. The anesthesia provider 
caring for the patient will then open the envelope and see what group the patient is randomized to – 
either 1% chloroprocaine group (C) or low-dose bupivacaine group (B). [The two study drug groups are 
discussed in detail at the bottom of this section.] The anesthesia provider will then provide standard of 
care and perform a CSE technique. The provider will administer the study drug via the spinal, place 10 ml 
of sterile saline in the epidural space for the EVE, then thread the epidural catheter. This will be marked 
as time 0 (T0). The investigator will then be called into the room to begin data collection. The 
investigator will assess an anesthetic level by taking a blunt-tip needle and lightly scratching the skin 
until the patient feels a sharp sensation. The investigator will also have the patient lift her legs to 
determine the degree of motor blockade. Motor blockade is determined by the modified Bromage score 
where: 0 = ability to maintain leg lift for prolonged period; 1 = ability to lift legs briefly; 2 = ability to 
bend knees; 3 = ability to wiggle toes; 4 = no movement of lower extremities. The first data point will 
occur 10 minutes after the block was placed. Once an adequate surgical level is obtained – T6 bilaterally 
– the surgery will begin. Standard of care will occur throughout the surgery. If the spinal level is not 
adequate, the patient will receive standard medications through the epidural catheter in order to 
provide adequate anesthesia. If this additional medication is required, it will be documented by the 
investigator. At the end of the procedure, another sensory level to pinprick and motor level (having the 
patient lift her legs) will occur. The patient will then be taken to the recovery room where standard care 
will be provided. The time the patient enters the recovery room until the time they are ready for 
discharge will be documented. Once the patient is discharged from the recovery room, the study will be 
complete.  
The two study groups are: 1) (C) 5 ml of 1% spinal chloroprocaine (50mg) plus the 10 ml of 
sterile saline for the EVE; 2) (B) 1 ml of 0.5% isobaric bupivacaine (5mg) plus 15 mcg spinal fentanyl plus 
the 10 ml of sterile saline for the EVE. It is important to note that we are only placing the fentanyl in the 
bupivacaine spinal for these reasons: 1) fentanyl is a common additive to bupivacaine spinals to help 
with the quality of the block; 2) fentanyl will not be added to the chloroprocaine spinal because the 
chloroprocaine is a newly-approved FDA drug, and currently, the FDA recommends against placing any 
additive into the solution. We understand that routinely we should try to make the groups have similar 


additives; however, given the fact that it is standard clinical practice to add fentanyl to bupivacaine and 
currently the FDA doesn’t allow drugs added to chloroprocaine, we felt this was an appropriate clinical 
design to the study. 
STATISTICAL PLAN 
General Data Analysis Plan: The study design is a prospective randomized parallel arm design. The 
primary outcome variable is block height 10 minutes, 𝑇10 after spinal injection.  
Statistical Power and Sample Size Estimates: Using an independent group t-test assuming unequal 
variances, a clinically meaningful mean difference of Δ𝑇10 = 2.5 dermatomes to detect, a standard 
deviation of the mean block height at 10 min, 𝜎𝑇10 = 2.46, we calculate that we require 22 subject per 
group to achieve 90% power at an type I error rate of 0.05. We propose a total sample size of 𝑁 = 50 
subjects to account for some inaccuracy of our assumptions. 
SAFETY AND ADVERSE EVENTS 
Adverse events are similar to the risks involved with placement of CSE and administration of 
local anesthetic. These are standard practice. For the study, breach of confidentiality is a rare but 
potential adverse event. Any adverse event will be documented and immediately reported to the 
departmental human studies research committee and institutional review board.  
DATA HANDLING AND RECORD KEEPING 
All data collected is stored electronically in the HIPAA-compliant, password-protected REDCap 
system. Only study personnel on the stud protocol have access to the data stored in this system.  
STUDY MONITORING, AUDITING, AND INSPECTING 
The PI of the study is responsible for oversight of the study and all co-investigators. The research 
division within the department tracks and ensures all investigators of the study maintain appropriate 
credentialing to participate in research. The research division within the department also reviews and 
approves all protocols. For this study, a yearly progress report is submitted to the IRB that includes all 
patients screened and enrolled, study update, and any adverse events. The study is also subject to audit 
by the IRB at any point during the time it is open. 
STUDY FINANCES 
No external funding was received for this study. All resources for this study were provided by 
the department. 
REFERENCES 
1. McDonnell NJ, Paech MJ, Clavisi OM, Scott KL. Difficult and failed intubation in obstetric 
anaesthesia: an observational study of airway management and complications associated with 
general anaesthesia for caesarean section. Int J Obstet Anesth 2008;17:292-97. 


2. Powell MF, Wellons DD, Tran SF, Zimmerman JM, Froelich MA. Risk factors for failed 
reactivation of a labor epidural for postpartum tubal ligation: a prospective, observational 
study. J Clin Anesth 2016;35:221-24. 
3. Zaric D, Pace NL. Transient neurologic symptoms (TNS) following spinal anaesthesia with 
lidocaine versus other local anesthetics. Cochrane Database Syst Rev. 2009;2:CD003006. 
4. Waddle JP, Evers AS, Piccirillo JF. Postanesthesia care unit length of stay: quantifying and 
assessing dependent factors. Anesth Analg 1998;87:628-33. 
5. Powell MF, Blakely CM, Sakawi Y, Froelich MA. Comparing low-dose bupivacaine with epidural 
volume extension to standard bupivacaine dosing for short obstetric procedures: a prospective, 
randomized study. Minerva Anestesiologica 2018 [epub ahead of print].  
6. Chestnut DH, Wong CA, Tsen LC, Ngan Kee WD, Beilin Y, Mhyre JM, editors. Chestnut’s obstetric 
anesthesia: principles and practice. Philadelphia: Elsevier Saunders: 2014. 
7. Higuchi H, Adachi Y, Kazama T. Effects of epidural saline injection on cerebrospinal fluid volume 
and velocity waveform: a magnetic resonance imaging study. Anesthesiology 2005;102:285-92.