The Maternal CLIMB Trial: Chloroprocaine to Reduce the Impact of Motor Block on Patient Recovery After Short Obstetric Surgery
Phase: PHASE4
Conditions: Anesthesia, Spinal
Sponsor: Oregon Health and Science University

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
The Maternal CLIMB Trial: 
ChLoroprocaine to Reduce the Impact of 
Motor Block on Patient Recovery After 
Short Obstetric Surgery 
Principal Investigator:  Brandon M. Togioka, M.D. 
 
Co-Investigator: N David Yanez, MS, PhD 
Co-Investigator: Miriam Treggiari, MD, PhD, MPH 
 
Medical Monitor: Ryan Ivie, M.D. 
Submission Date:  February 21, 2019 
Protocol Update: September 19, 2019 
Tax ID:  931176109 
Trial Registration: clinicaltrials.gov Identifier: NCT03967288 
IRB#: OHSU 19846 
PI Contact Information:  
Address: Oregon Health & Science University School of Medicine 
 
 
Department of Anesthesiology & Perioperative Medicine 
 
 
Mail Code UHS-2 
 
 
3181 SW Sam Jackson Park Road 
 
 
Portland, OR 97239 
Office Number: 503-494-4572 
Mobile Number: 503-569-3064 
Email Address: togioka@ohsu.edu 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
1 
 
STATEMENT OF COMPLIANCE 
 
The study will be conducted in accordance with the International Conference on 
Harmonisation guidelines for Good Clinical Practice (ICH E6), the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46), and the B. Braun 
Terms of Award. All personnel involved in the conduct of this study have completed 
human subjects protection training. 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
2 
 
SIGNATURE PAGE 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable US federal 
regulations and ICH guidelines. 
Principal Investigator or Clinical Site Investigator: 
 
Signed: 
 
 
Date: 
 
2/21/2019 
 
Name: Brandon M. Togioka, M.D. 
 
Title: Assistant Professor in Anesthesiology & Perioperative Medicine 
          Obstetric, Fertility, and Gender Identity Anesthesia Medical Director 
          Oregon Health & Science University 
 
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
3 
 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
PAGE 
STATEMENT OF COMPLIANCE ................................................................................................. 1 
SIGNATURE PAGE ...................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 3 
1 
LIST OF ABBREVIATIONS ................................................................................................. 5 
2 
PROTOCOL SUMMARY ..................................................................................................... 7 
3 
SCHEMATIC OF STUDY DESIGN: ................................................................................... 10 
4 
KEY ROLES AND CONTACT INFORMATION ................................................................. 11 
5 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ...... 12 
5.1 
Background Information ......................................................................................... 12 
5.2 
Rationale ................................................................................................................ 13 
5.3 
Potential Risks and Benefits .................................................................................. 14 
5.3.1 
Potential Risks ............................................................................................ 14 
5.3.2 
Potential Benefits ....................................................................................... 17 
6 
OBJECTIVES ..................................................................................................................... 18 
6.1 
Study Objectives .................................................................................................... 18 
6.1.1 
Primary Objective: ...................................................................................... 18 
6.1.2 
Secondary Objectives: ............................................................................... 18 
6.1.3 
Tertiary Objectives: .................................................................................... 18 
6.1.4 
Safety Objectives: ...................................................................................... 18 
6.2 
Study Outcome Measures ...................................................................................... 19 
6.2.1 
Primary Outcome Measure ........................................................................ 19 
6.2.2 
Secondary Outcome Measures .................................................................. 19 
6.2.3 
Tertiary Outcome Measures ....................................................................... 20 
6.2.4 
Safety Outcome Measures ......................................................................... 21 
7 
STUDY DESIGN ................................................................................................................ 22 
8 
STUDY ENROLLMENT AND WITHDRAWAL ................................................................... 23 
8.1 
Subject Inclusion Criteria ....................................................................................... 23 
8.2 
Subject Exclusion Criteria ...................................................................................... 23 
8.3 
Strategies for Recruitment and Retention .............................................................. 24 
8.4 
Treatment Assignment Procedures ........................................................................ 24 
8.4.1 
Randomization Procedures ........................................................................ 24 
8.4.2 
Masking Procedures ................................................................................... 25 
8.5 
Subject Withdrawal ................................................................................................ 25 
8.5.1 
Reasons for Withdrawal ............................................................................. 25 
8.5.2 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention ................................................................................................. 25 
8.6 
Premature Termination or Suspension of Study .................................................... 26 
9 
STUDY INTERVENTION ................................................................................................... 27 
9.1 
Study Product Description ...................................................................................... 27 
9.1.1 
Acquisition .................................................................................................. 27 
9.1.2 
Formulation, Packaging, and Labeling ....................................................... 27 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
4 
 
9.1.3 
Product Storage and Stability ..................................................................... 27 
9.2 
Study Procedures ................................................................................................... 27 
10 
STUDY SCHEDULE .......................................................................................................... 31 
10.1 
Screening ............................................................................................................... 31 
10.2 
Enrollment/Baseline ............................................................................................... 31 
10.3 
Outcome Assessor Visits ....................................................................................... 31 
11 
ASSESSMENT OF SAFETY ............................................................................................. 32 
11.1 
Reporting Procedures ............................................................................................ 32 
11.2 
Halting Rules .......................................................................................................... 32 
12 
STUDY OVERSIGHT ......................................................................................................... 33 
13 
CLINICAL SITE MONITORING ......................................................................................... 34 
14 
STATISTICAL CONSIDERATIONS ................................................................................... 35 
14.1 
Study Hypotheses .................................................................................................. 35 
14.2 
Sample Size Considerations .................................................................................. 35 
14.3 
Planned Interim Analyses ...................................................................................... 35 
14.3.1 Safety Review ............................................................................................ 35 
14.3.2 Efficacy Review .......................................................................................... 35 
14.4 
Final Analysis Plan ................................................................................................. 35 
15 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS .................. 37 
16 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................. 38 
16.1 
Ethical Standard ..................................................................................................... 38 
16.2 
Institutional Review Board ...................................................................................... 38 
16.3 
Informed Consent Process ..................................................................................... 38 
16.4 
Exclusion of Women, Minorities, and Children (Special Populations) .................... 39 
16.5 
Subject Confidentiality ............................................................................................ 39 
17 
HANDLING OF DATA AND SPECIMENS ......................................................................... 40 
18 
PUBLICATION/DATA SHARING POLICY ......................................................................... 43 
19 
LITERATURE REFERENCES ........................................................................................... 44 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
5 
 
1 LIST OF ABBREVIATIONS 
 
AE 
Adverse Event/Adverse Experience 
ALT 
Alanine Transaminase 
APOM 
Anesthesia and Perioperative Medicine 
ASA 
American Society of Anesthesiologists 
AST 
Aspartate Transaminase 
CFR 
Code of Federal Regulations 
CRF 
Case Report Forms 
CSF 
Cerebrospinal Fluid 
EDC 
Electronic Data Capture 
EKG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice Guidelines 
HCAHPS 
Hospital Consumer Assessment of Healthcare Providers and 
Systems 
Hg 
Mercury 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
kg 
kilograms 
LAST 
Local Anesthetic Systemic Toxicity 
m 
meters 
mg 
milligrams 
min 
minutes 
mL 
milliliters 
mm 
millimeters 
NIH 
National Institutes of Health 
OCEAN 
Outcomes and Clinical Epidemiology in Anesthesia 
OHSU 
Oregon Health and Science University 
PACU 
Post-Anesthesia Care Unit 
PDPH 
Post-Dural Puncture Headache 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
6 
 
PI 
Principal Investigator 
PTT 
Partial Thromboplastin Time 
SAE 
Serious Adverse Events/Serious Adverse Experience 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SUSAR 
Suspected, Unanticipated, Serious Adverse Reactions  
UP 
Unanticipated Problems 
US 
United States 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
7 
 
2 PROTOCOL SUMMARY 
 
Title: 
Comparison of Clorotekal® and Bupivacaine for Short 
Obstetric Surgery 
 
Précis: 
This will be a single-blind, randomized, controlled, single 
center clinical trial assessing the efficacy of Clorotekal® on 
resolution of motor block and associated patient flow through 
the PACU.   
 
Masking:  
 
 
 
1. 
Subject 
2. 
Obstetric provider 
3. 
Investigator 
4. 
Outcomes assessor 
 
The anesthesia provider will be unblinded because of the 
large difference in volume between Clorotekal® (5 mL) and 
hyperbaric bupivacaine (1.4 mL).  The block characteristics 
and safety profile of a dilution of 10.5 mg hyperbaric 
bupivacaine to a volume of 5 mL are unknown.   
 
Fifty patients will be equally randomized to receive either 
Clorotekal® or hyperbaric bupivacaine.  
 
Objectives: 
Primary Objective:  
 
1. To compare duration of motor block, defined as the 
number of 5-minute intervals since completion of spinal 
injection to achievement of a Bromage scale score of 2 
(able to flex knees), between patients randomly 
assigned to receive Clorotekal® or hyperbaric 
bupivacaine.    
 
Secondary Objectives:   
 
1. To compare duration of motor block, defined by patient 
report since completion of spinal injection to 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
8 
 
achievement of a Bromage score of 2 (able to flex 
knees), between patients randomly assigned to receive 
Clorotekal® or hyperbaric bupivacaine.    
2. To compare Phase 1 PACU length of stay between 
patients randomly assigned to Clorotekal® or hyperbaric 
bupivacaine. 
3. To compare PACU time (Phase 1 + Phase 2) between 
patients randomly assigned to Clorotekal® or hyperbaric 
bupivacaine. 
4. To compare time to first ambulation between patients 
randomly assigned to receive Clorotekal® or hyperbaric 
bupivacaine. 
5. To compare incidence of bladder catheterization (Foley 
or straight catheter insertion) between patients randomly 
assigned to receive Clorotekal® or hyperbaric 
bupivacaine. 
 
 
Population: 
Patients will be ASA category 1-3 women, 18 years old or 
greater, undergoing one of the following obstetric procedures: 
bilateral tubal ligation, external cephalic version, cerclage 
insertion, cerclage removal, minimally invasive fetal surgery, or 
evacuation of retained products of conception at Oregon 
Health and Science University in Portland, Oregon. 
 
Number of Sites: 
Single center trial 
 
Treatment Arms: 
Experimental: Intrathecal injection of Clorotekal® 50 mg (5 ml 
of 1% chloroprocaine)  
 
Active Comparator: Intrathecal injection of hyperbaric 
bupivacaine 10.5 mg (1.4 ml of 0.75% bupivacaine 
hydrochloride in 8.25% dextrose)  
 
Study Duration: 
The study duration including initiation, enrollment, data 
collection, and close out is expected to be 24 months.  In 
addition, IRB submission and obtaining IRB approval is 
expected to take 3 months.  Data analysis, writing, editing and 
submission to a peer-reviewed journal is expected to take 6 
months.   

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
9 
 
 
In summary, the study should be completed within 3 years of 
obtaining approval for funding. 
 
Subject 
Participation 
Duration: 
Individual subjects will be included the study for three days or 
until discharge, whichever comes first.   
 
 
Estimated Time to 
Complete 
Enrollment: 
Estimated time from enrollment into study of the first subject to 
enrollment into study of the last subject is 18 months. 
 
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
10 
 
3 SCHEMATIC OF STUDY DESIGN: 
 
Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
Visit 1 
Preoperative  
 
 
 
Visit 2 
Intraoperative 
  
 
 
 
Visit 3 
PACU  
 
 
 
Visit 4 
Surgical Ward 
 
 
 
 
Record Review 
After Discharge 
 
Screen potential subjects by inclusion and exclusion criteria.  Call to introduce the 
study.  Meet to complete history and obtain informed consent (n = 50). 
Perform baseline assessments. 
Educate anesthesia providers, obstetricians, and labor and delivery nurses on the 
study protocol. 
 
Daily visits to assess for time of first ambulation, requirement for bladder 
catheterization, and adverse events. 
Determine the patient’s Bromage score at 5-minute increments.  Document PACU 
Phase 1 and Phase 2 time.  Assess for adverse events. 
 
Data collection for outcome 
measures 
Randomize 
Arm 2 
25 subjects 
Arm 1 
25 subjects 
Administer intrathecal Clorotekal® or hyperbaric bupivacaine.  
Measure highest sensory block achieved. 
Assess for adverse events. 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
11 
 
4 KEY ROLES AND CONTACT INFORMATION 
 
Principal 
Investigator:   
Brandon M. Togioka, MD 
Obstetric, Fertility, and Gender Identity Anesthesia Medical 
Director in the OHSU School of Medicine 
Director of Clinical Research 
Department of Anesthesiology & Perioperative Medicine 
Mail Code UHS-2 
3181 SW Sam Jackson Park Road 
Portland, OR 97239 
Office Number: 503-494-4572 
Mobile Number: 503-569-3064 
Email Address: togioka@ohsu.edu  
 
 
 
Co-Investigator: 
N. David Yanez, MS, PhD 
Co-Director of the OHSU Biostatistics and Design Program 
within the Oregon Clinical and Translational Research Institute 
Email Address: yanezn@ohsu.edu  
 
Co-Investigator: 
Miriam M. Treggiari, MD, PhD, MPH 
Vice Chair for Clinical Research 
Email Address: treggiar@ohsu.edu  
 
Medical Monitor: 
Ryan Ivie, MD 
Director of Regional Anesthesia at OHSU 
Email Address: ivie@ohsu.edu  
 
Research 
Coordinator: 
Janna Higgins, MSW 
Senior Research Associate 
Email Address: higginsj@ohsu.edu  
 
Institution: 
Oregon Health and Science University 
Portland, OR 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
12 
 
5 INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE  
 
5.1 
Background Information 
 
The standard anesthetic for surgical procedures on labor and delivery is a spinal.  
Gastrointestinal and airway changes during pregnancy increase maternal risk for 
aspiration, difficult mask ventilation, and failed endotracheal intubation1.  Furthermore, 
spinal anesthesia exposes the fetus to less anesthesia and allows for maternal 
involvement in labor and delivery procedures.  General anesthesia is so rarely 
performed on labor and delivery floors that many nurses are not trained or credentialed 
to recovery patients after general anesthesia.  This is true at Oregon Health and 
Science University where the policy is to relocate a main operating room nurse to the 
labor and delivery Post-Anesthesia Care Unit (PACU) each time a general anesthetic is 
performed.  This can impact patient safety, hospital cost, and perioperative patient 
throughput. 
 
The following obstetric procedures are commonly performed with spinal anesthesia on 
labor and delivery: bilateral tubal ligation2-4, external cephalic version5-7, cerclage 
insertion8,9, cerclage removal, minimally invasive fetal surgery10, and evacuation of 
retained products of conception1.  These procedures are typically completed within 30 
minutes.  Patients prefer rapid PACU discharge to facilitate getting back to their 
families; short PACU recovery times are associated with improved mother-baby 
bonding11 and less interruption with breastfeeding11.  Not surprisingly, a short PACU 
stay is associated with higher Hospital Consumer Assessment of Healthcare Providers 
and Systems (HCAHPS) survey scores12 and a more favorable impression of hospital 
staff12,  
 
Shorter labor and delivery PACU recovery times are also preferred by anesthesiologists 
and labor and delivery nurses.  Labor and delivery units are typically not staffed with 
dedicated PACU nurses or multiple anesthesia teams.  Longer PACU times increase 
nursing burden and can impact nursing-associated hospital costs13.  In addition, nursing 
and anesthesia time spent in the PACU is time that these providers are not available for 
laboring patients or for responding to urgent or emergent unit needs.  This staffing 
model has been suggested as a contributor to the high rate of unfulfilled requests for 
bilateral tubal ligation—half of requests for immediate postpartum bilateral tubal ligation 
go unfulfilled14,15.  
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
13 
 
Patients must achieve the following in order to be discharged from the PACU: 
hemodynamic stability, return to baseline oxygen saturation, stable electrocardiogram 
rhythm that is consistent with baseline, independent maintenance of airway, respiratory 
rate greater than or equal to 10 breaths per minute, temperature greater than 36 
degrees Celsius, return to baseline level of consciousness, surgical hemostasis, pain 
less than or equal to 4/10 or for chronic pain patients less than or equal to 2 points 
above baseline, either no nausea or mild nausea without vomiting, and either full return 
of sensory or motor function (discharge home) or evidence that motor block is receding 
(discharge to the ward)16.  After spinal anesthesia, the rate limiting criterion for most 
patients is return of motor function.   
 
Bupivacaine is currently the standard spinal medication on labor and delivery.  It is 
favored because of its long history of safe use, its low incidence of transient neurologic 
symptoms (a temporary sensation of radiating pain down the buttock and thighs 
associated with spinal anesthesia)17, and its ability to provide a dependable, dense 
block with a high degree of maternal satisfaction1. While bupivacaine has the 
aforementioned advantages, it unfortunately has a long duration of action, up to 240-
380 minutes18, which far exceeds the time necessary to complete most obstetric 
procedures.  Low-dose bupivacaine, with a shorter duration of action, has been 
suggested as a potential alternative.  Unfortunately, low-dose bupivacaine has been 
associated with inadequate anesthesia, urinary retention, and prolonged discharge 
times19. 
 
5.2 
Rationale 
 
Clorotekal®, the first FDA approved chloroprocaine solution created for spinal injection, 
is a potential alternative that can address bupivacaine’s shortcomings. Clorotekal® 
carries a FDA indication for intrathecal injection to provide spinal anesthesia for adults 
undergoing short duration lower extremity and lower abdominal surgical procedures.  A 
vial of Clorotekal® includes 50 mg of preservative-free 1% chloroprocaine in 5 mL (10 
mg/mL). Clorotekal® has been shown to provide well tolerated, rapid onset, reliable 
spinal anesthesia for surgeries of short duration20. When compared with bupivacaine 
spinals, chloroprocaine spinals have been shown to facilitate clinically significant shorter 
times to resolution of motor and sensory block18,21-23, first ambulation18,22,23, 
micturition22,23, and discharge readiness18,22-24. Importantly, the incidence of transient 
neurologic symptoms with chloroprocaine appears to be very low25,26. Therefore, 
chloroprocaine can have significant advantages to allow the performance of short 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
14 
 
obstetric procedure on labor and delivery, while affording a safety profile similar to 
bupivacaine.  
 
We designed a randomized, controlled, single-blind trial to test the hypothesis that 
administering Clorotekal® has shorter resolution time of motor block, which is typically 
the rate limiting step for moving patients from the PACU to the postpartum ward or to 
home, compared with equivalent block with hyperbaric bupivacaine21.     
 
5.3 
Potential Risks and Benefits 
5.3.1 
Potential Risks 
 
As with all studies, breach of confidentiality is a common risk.  In addition, there is the 
possibility of slightly increased anxiety on the day of surgery for patients approached for 
inclusion in the study.  There is also likely to be a loss of free time in the preoperative 
area as consent and study education will take 15 minutes to complete. As data 
collection will continue to occur throughout the patient’s surgery and postoperative care, 
inconvenience is possible. 
 
Spinal anesthesia is generally very safe, but all anesthetic interventions are associated 
with some risk.  The side effects associated with spinal anesthesia with local 
anesthetics (chloroprocaine and bupivacaine) include1:  
• Hypotension 
• Nausea 
• Vomiting 
• Urinary retention 
• Motor block 
• Shivering 
 
Complications associated with spinal anesthesia include1:  
• Inadequate anesthesia 
• High block which can cause anxiety, breathing problems, and cardiac arrest 
• Post-dural puncture headache (PDPH) 
• Bleeding 
• Infection 
• Nerve injury 
• Fetal heart rate changes  
• Local anesthetic systemic toxicity (LAST) 
 
The following steps will be taken to mitigate the aforementioned risks: 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
15 
 
• Hypotension:  All patients will receive a co-load of 1 liter lactated Ringer’s 
solution, vasopressors will be drawn up and ready for administration, all patients 
greater than 20 weeks gestational age will have left uterine displacement 
• Nausea and vomiting: Hypotension will be treated if present and ondansetron will 
be available for administration. 
• Urinary retention: Patients will be managed according to the “OB Urinary 
Retention Guide,” which is attached as Supplement 1.  The “OB Urinary 
Retention Guide” was recently approved by the Perinatal Best Practice 
Committee. The Algorithm was created to balance the avoidance of unnecessary 
Foley insertion because of infection risk and patient discomfort against risks 
associated with urinary retention.   
• Motor block: Patients will be assessed by labor and delivery nurses prior to 
allowing ambulation. 
• Shivering: Warm blankets and upper body convective warmers will be used. 
• Inadequate anesthesia: Intravenous opioid administration will be used to 
supplement spinal anesthesia.  If this is inadequate, general endotracheal 
anesthesia will be considered. 
• High block: Strict adherence to the doses described in this protocol will be 
mandated.  
• PDPH: Patients will be assessed for a PDPH daily and if present, treated with 
fluid resuscitation, acetaminophen, butalbital, and caffeine. Patients that do not 
respond to conservative treatment will be offered a blood patch. 
• Bleeding: Only patients will platelet counts higher than 80,000, INR > 1.2, or PTT 
> 36 seconds will be offered spinal anesthesia. 
• Infection: Strict aseptic technique will be followed with hand washing, use of 
sterile gloves, mask, cap, and skin preparation with chlorhexidine gluconate. 
• Nerve injury: Only trained MD anesthesia personnel will be allowed to place the 
spinal.  Patients will be assessed for nerve injury daily.  Patients with nerve 
injuries that do not resolve on their own will be referred for neurology consult. 
• Fetal heart rate changes: Hypotension will be mitigated as described above.  
Fetal bradycardia will be treated with discontinuation of intravenous oxytocin if 
applicable, changes in patient position, administration of supplemental oxygen, 
and for recalcitrant uterine hypertonus tocolytic medications will be administered. 
• LAST: The dose of bupivacaine (10.5 mg) and chloroprocaine (50 mg) that will 
be administered will be far below the maximum recommended dosage for 
bupivacaine (3 mg/kg)27 and chloroprocaine (11 mg/kg)28. 
 
Chloroprocaine has a long history of safe use and is assumed to have a low potential 
for systemic toxicity because of its very short maternal (mean 11.2 seconds, SD 2.8)28 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
16 
 
and fetal (mean 15.4 seconds, SD 5.2)28 plasma half-life and relatively high maximum 
recommended dosage (11 mg/kg without epinephrine).  
 
The clinical presentation of local anesthetic systemic toxicity is quite variable29.  Most 
case reports describe local anesthetic systemic toxicity after administration of local 
anesthetics with a much longer duration of action than chloroprocaine29,30.  In general, 
local anesthetics first cause central nervous system excitation (e.g. anxiety, agitation, 
muscle twitching, seizures) followed by central nervous system depression (e.g. 
sedation, respiratory depression) and then cardiovascular effects (e.g. bradycardia, 
hypotension, arrhythmias, cardiac arrest)29.    
 
In a review of reported cases of local anesthetic systemic toxicity published in 2015 
there were no cases of local anesthetic systemic toxicity attributed to chloroprocaine29.  
A search of PubMed and Google revealed 3 articles that describe systemic toxicity from 
chloroprocaine31-33.  Cladis et al33 described a 30 second self-limited wide complex 
bradycardia after a 30 mg/kg inadvertent vascular injection through a caudal catheter in 
a 2 month old infant.  Hernandez et al32 described a 40 second self-limited seizure after 
a 28.7 mg/kg inadvertent vascular injection through a paravertebral catheter in a 9 
month old infant.  Marsch et al31 described 34 patients with non-life threatening 
symptoms of local anesthetic systemic toxicity after direct intravenous injection of 200 to 
400 mg of chloroprocaine into patients with an average weight of 70 kg (2.8-5.7 mg/kg).  
Symptoms lasted 3 to 11 minutes and included the following: dizziness (34 patients), 
tinnitus (13 patients), metallic taste (10 patients), nausea or vomiting (4 patients), and 
slight bradycardia (2 patients).  None of the patients described in any of the 3 articles 
had any long term morbidity or mortality31-33.  
 
Chloroprocaine has been touted as the preferred local anesthetic for providing epidural 
anesthesia to laboring women with a decompensating fetus because it does not 
participate in ion trapping like other local anesthetics. Local anesthetics are weak bases 
which become ionized when exposed to acidotic environments. Ionized particles cannot 
cross the lipid membrane of the placenta. Ion trapping occurs when non-ionized local 
anesthetics cross the placenta, become ionized in relatively acidotic fetal blood, 
compared to maternal blood, and get stuck in fetal circulation.  This creates a cycle in 
which accumulating local anesthetic causes the fetus to become more acidotic which 
results in more ion trapping.  Because only non-ionized local anesthetic equilibrates 
across the placenta and the ratio of ionized to non-ionized local anesthetic is higher in 
fetal blood, a sink is created driving local anesthetic into fetal circulation.  Placental 
transfer of chloroprocaine has not been shown to be influenced by the degree of fetal 
acidosis.34  

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
17 
 
 
Literature describing intrathecal chloroprocaine administration in pregnant women is 
sparse.  Accordingly, there is a possibility of local anesthetic systemic toxicity in this 
study.  To this extent, adverse experience reporting will include monitoring for and 
publishing the occurrence of any of the following adverse events associated with 
chloroprocaine administration:  
 
• Seizures 
• Tinnitus 
• Metallic taste 
• Anxiety 
• Agitation 
• Muscle twitching 
• Sedation 
• Respiratory depression with desaturation (oxygen saturation < 88%) 
• Dizziness 
• Nausea 
• Vomiting 
• Vision changes 
• Paresthesias 
• Perioral numbness 
• Hypotension (drop in systolic blood pressure >20% within 5 minutes of 
chloroprocaine administration) 
• Arrhythmias defined as a change in EKG rhythm 
• Cardiac arrest 
 
Participants will not incur any additional cost for participating in this study 
 
5.3.2 
Potential Benefits 
We are performing this study because the duration of anesthesia provided by 
hyperbaric bupivacaine exceeds the time necessary to complete short obstetric 
procedures.  Intrathecal chloroprocaine may shorten the duration of motor block after 
spinal placement, compared to hyperbaric bupivacaine.  Shorter motor block may 
translate to a shorter duration of PACU Phase 1 recovery, a shorter PACU stay, earlier 
ambulation, and less required bladder catheterization procedures.  Patient satisfaction 
may improve with short PACU times, earlier ambulation, and less bladder 
catheterizations.  
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
18 
 
6 OBJECTIVES 
6.1 
Study Objectives 
 
6.1.1 
Primary Objective:  
 
1. To compare duration of motor block, defined as the number of 5-minute intervals 
since completion of spinal injection to achievement of a Bromage scale score of 
2 (able to flex knees), between patients randomly assigned to receive 
Clorotekal® or hyperbaric bupivacaine.    
 
6.1.2 
Secondary Objectives:   
 
1. To compare duration of motor block, defined by patient report since completion of 
spinal injection to achievement of a Bromage score of 2 (able to flex knees), 
between patients randomly assigned to receive Clorotekal® or hyperbaric 
bupivacaine.    
2. To compare Phase 1 PACU length of stay between patients randomly assigned 
to Clorotekal® or hyperbaric bupivacaine. 
3. To compare total PACU time (Phase 1 + Phase 2) between patients randomly 
assigned to Clorotekal® or hyperbaric bupivacaine. 
4. To compare time to first ambulation between patients randomly assigned to 
receive Clorotekal® or hyperbaric bupivacaine. 
5. To compare incidence of bladder catheterization (Foley or straight 
catheterization) between patients randomly assigned to receive Clorotekal® or 
hyperbaric bupivacaine. 
 
6.1.3 
Tertiary Objectives:   
 
1. To compare IV opioid consumption, in milligram morphine equivalents, between 
patients randomly assigned to Clorotekal® or hyperbaric bupivacaine. 
2. To compare highest sensory block level achieved, measured by pinprick, 
between patients randomly assigned to Clorotekal® or hyperbaric bupivacaine. 
 
6.1.4 
Safety Objectives:   
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
19 
 
1. To compare incidence of intraoperative hypotension (systolic blood pressure 
<100 mm Hg or > 20% drop from baseline systolic blood pressure requiring 
intervention) between patients randomly assigned to Clorotekal® or hyperbaric 
bupivacaine. 
2. To compare intraoperative vasopressor requirement between patients randomly 
assigned to Clorotekal® or hyperbaric bupivacaine. 
3. To evaluate the safety of Clorotekal® comparing the occurrence of adverse 
events including perioperative respiratory depression, new postoperative 
neurologic deficits, nausea or vomiting between patients randomly assigned to 
Clorotekal® or hyperbaric bupivacaine, and any other serious adverse events. 
 
6.2 
Study Outcome Measures 
6.2.1 
Primary Outcome Measure 
 
Motor Block (interval assessment): Bromage scale score at 5 minute intervals, 
since spinal injection.  Interval assessment motor block will be defined as the 
number of 5-minute intervals since completion of spinal injection to achieve a 
Bromage score of 2 (able to flex knees).   
 
Definition: Bromage scale: 
Bromage score 1: Free movement of legs and feet (no block) 
Bromage score 2: Able to flex knees and move feet (partial block) 
Bromage score 3: Unable to flex knees, but able to move feet (near complete 
block) 
Bromage score 4: Unable to move legs or feet (complete block) 
6.2.2 
Secondary Outcome Measures 
 
Motor block (patient report): The patient will be instructed to notify the outcomes 
assessor when they are able to flex their knees (Bromage score 2).  Patient 
report motor block will be defined as the time interval in minutes since completion 
of spinal injection to achieve a Bromage score of 2 (able to flex knees). 
 
 
Phase 1 PACU time: Phase 1 PACU time will be defined as the interval between 
“out of operating room” and “end of Phase 1” as documented by the PACU 
nurse.  Patients must achieve the following after spinal anesthesia in order to 
complete Phase 1 of PACU recovery:  
• Hemodynamic stability defined as a systolic blood pressure and heart rate 
within 20% of baseline  

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
20 
 
• Safe oxygen saturation defined by an oxygen saturation > 94% on room 
air or for patients with low baseline saturation an oxygen saturation within 
2% of baseline 
• Stable electrocardiogram rhythm that is consistent with baseline 
• Independent maintenance of airway 
• Respiratory rate greater than or equal to 10 breaths per minute 
• Temperature greater than 36 degrees Celsius 
• Return to baseline level of consciousness  
• Surgical hemostasis 
• Pain less than or equal to 4/10 or for chronic pain patients, less than or 
equal to 2 points above baseline 
• Either no nausea or mild nausea without vomiting 
• Bromage score of 2 or less 
 
PACU time (Phase 1 + Phase 2): PACU time will be defined as the interval 
between “out of operating room” and “end of Phase 2” as documented by the 
labor and delivery nurse for patients discharged home and as mutually agreed 
upon by the outcomes assessor and nurse for patients discharged to the ward.  
In addition to meeting Phase 1 criteria, patients must be able to ambulate, 
micturate, and tolerate food intake in order to exit Phase 2 of PACU recovery.  
Completing Phase 2 of PACU recovery is also requires that a responsible adult 
can escort the patient out of the hospital and remain with the patient for the first 
24 hours. 
 
Time to ambulation: Defined as the time interval in minutes between intrathecal 
medication administration and time to first ambulation.  Ambulation requires a 
Bromage score of 1 and a standard nursing assessment that is already in 
practice at Oregon Health and Science University (OHSU).   
 
Bladder Catheterization:  Defined as the insertion of a Foley catheter or a 
Straight catheterization within 24 hours of spinal insertion.   
6.2.3 
Tertiary Outcome Measures 
 
Opioid consumption:  Defined as the total intraoperative opioid consumption in 
milligram morphine equivalents.   
 
Peak block sensory level:  Defined as the most caudal dermatome with sensation 
to pinprick at the time of “anesthesia ready.” 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
21 
 
6.2.4 
Safety Outcome Measures 
 
Incidence of hypotension:  Defined by the proportion of patients given 
intraoperative vasopressor (phenylephrine or ephedrine) for a systolic blood 
pressure drop greater than 20% below baseline or any SBP < 100 mm Hg.   
 
Vasopressor requirement: Defined by the total intraoperative quantity of 
phenylephrine administered in mcg. 
 
Respiratory depression:  Defined by a respiratory rate less than 10 breaths per 
minute. 
 
New neurologic deficits:  Defined as a new, persistent sensory deficit, motor 
deficit, or dysesthesia diagnosed during the patient’s hospitalization. 
 
Nausea:  Defined by a self-report of intraoperative nausea by the patient, yes or 
no.   
 
Vomiting:  Defined by an observed intraoperative vomiting episode by the 
outcomes assessor, yes or no.   
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
22 
 
7 STUDY DESIGN 
Study Design: 
 
 
 
This will be a single-blind, randomized, controlled, single center clinical trial assessing 
the efficacy of Clorotekal® on resolution of motor block and associated patient flow 
through the PACU.  Fifty patients will be equally randomized to receive either 
Clorotekal® or hyperbaric bupivacaine.  
 
Masking:  
 
 
 
1. Subject 
2. Obstetric provider 
3. Investigator 
4. Outcomes assessor 
 
The anesthesia provider will be unblinded because of the large difference in volume 
between Clorotekal® (5 mL) and hyperbaric bupivacaine (1.4 mL).  The block 
characteristics and safety profile of a dilution of 10.5 mg hyperbaric bupivacaine to a 
volume of 5 mL are unknown.   
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
23 
 
8 STUDY ENROLLMENT AND WITHDRAWAL 
8.1 
Subject Inclusion Criteria 
 
1. Women 18 years old or greater 
2. ASA category 1-3 
3. Undergoing one of the following obstetric procedures: bilateral tubal ligation, 
external cephalic version, cerclage insertion, cerclage removal, minimally 
invasive fetal surgery, or evacuation of retained products of conception.  
8.2 
Subject Exclusion Criteria 
 
1. Refusal of consent 
2. Multiple gestations 
3. History of ester local anesthetic or para-aminobenzoic acid allergy 
4. Height less than 5 feet or greater than 6 feet 
5. Body mass index less than 18.5 kg/m2 or greater than 45 kg/m2 
6. Any coagulopathy defined by platelets < 80k/microliter, INR > 1.2, or PTT > 
36 seconds 
7. Signs of hypovolemia that is not corrected by routine management including 
hypotension (systolic blood pressure <90 mm Hg) at the time of evaluation 
8. Liver disease including jaundice and ascites, with elevated liver function tests, 
AST > 2x institutional normal, ALT > 2x institutional normal 
9. Renal disease including history of dialysis, with elevated renal function tests 
on admission labs, glomerular filtration rate <60 ml/min/1.73 m2 
10. Infection at the site of potential spinal insertion 
11. Neurologic condition that contraindicates spinal anesthesia, tethered spinal 
cord or multiple sclerosis 
12. Known atypical plasma cholinesterase activity 
13. Other contraindications to receive a spinal anesthetic  
14. Vulnerable populations including prisoners and decisionally impaired adults 
 
Due to the nature of the study, pregnant subjects will have to be enrolled to obtain the 
medical knowledge that we seek.  A very small quantity of drug may possibly be 
transferred to the fetus through the placenta, but we believe the risk to the fetus is not 
greater than minimal.  Chloroprocaine has a long history of safe use in pregnant women 
and the maternal half-life is very short (mean 11.2 seconds, SD 2.8 seconds).  In this 
manner, the drug concentration can be considered to be negligible after 45 seconds (4 
half-lives). 
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
24 
 
8.3 
Strategies for Recruitment and Retention 
 
Most subject recruitment is expected to occur by approved study staff as early as two 
months prior to a potential subject’s scheduled operation via a review of the OHSU 
Labor and Delivery surgical schedule as posted in Epic (Verona, Wisconsin). The study 
staff will work with obstetricians to identify and screen for potential eligible subjects. We 
will review all the inclusion/exclusion criteria as early as two months prior to a potential 
subject’s scheduled surgery.  If a potential subject has been identified as meeting all 
inclusion criteria and none of the exclusion criteria, an approved member of the study 
team will call the subject, using an approved phone script to introduce the study. If the 
subject is amenable to the study, study staff will make arrangements to meet with the 
subject to provide formal consent materials and signature at their pre-op visit or day of 
surgery. If the subject is not interested in participating in the study, the 
inclusion/exclusion criteria and any other information related to this subject will be 
destroyed. 
 
The study will be listed on ClinicalTrials.gov to provide subjects, family members, and 
the public background information on the study. 
 
Other than posting this study on OHSU Study Participation Opportunities, we do not 
expect to create advertisements for the study.   
 
Subjects will not be offered remuneration as incentive for completing the study protocol. 
 
8.4 
Treatment Assignment Procedures 
8.4.1 
Randomization Procedures 
 
Subjects will be randomly assigned to either the intervention (chloroprocaine) or control 
(hyperbaric bupivacaine) arm. Before initiation of the clinical portion of the study, 50 
opaque sealed envelopes will be prepared by a researcher not involved in subject 
recruitment or enrollment: 25 for the intervention arm and 25 for the control arm.  These 
envelopes will be randomized without stratification via a computer generated random 
allocation sequence and numbered in ascending order from 1 to 50.  Subjects enrolled 
in the study will be assigned to the next free envelope and given the corresponding 
treatment contained therein.  All researchers involved in patient recruitment, allocation, 
and assessment will be kept blind to the allocation sequence. 
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
25 
 
8.4.2 
Masking Procedures 
 
Assessment of outcomes will be conducted by a researcher blind to treatment 
allocation. The subject and the obstetric providers will also be blinded to treatment 
allocation. To blind the outcome assessor and obstetric provider they will remain 
outside of the operating room while the spinal is being placed. The anesthesia provider 
will be unblinded because of the large difference in volume between Clorotekal® (5 
mL) and hyperbaric bupivacaine (1.4 mL).  The block characteristics and safety profile 
of a dilution of 10.5 mg hyperbaric bupivacaine to a volume of 5 mL are unknown.  The 
anesthesia provider will be strongly inculcated not to disclose the treatment allocation 
to the subject, outcomes assessor, or obstetric providers after spinal placement.  A 
member of the research team not involved in patient recruitment, allocation, or 
assessment will feed collected data into the APOM OCEAN, a 21 CFR Part 11-
compliant electronic data capture system provided by the Department of 
Anesthesiology and Perioperative Medicine, so that data analysis can occur without 
disclosing information about allocation. 
 
The medical safety monitor will not be blinded. 
 
8.5 
Subject Withdrawal 
 
8.5.1 
Reasons for Withdrawal 
 
Subjects enrolled that do not receive a spinal anesthetic, for any reason, may be 
withdrawn from the study.  In addition, a subject may be removed from the study if the 
investigator or funder stops the study, a member of the care team feels like the study is 
no longer in the best interest of the subject. In the event that such a situation occurs the 
subject would be informed at the earliest reasonable time. 
8.5.2 
Handling of Subject Withdrawals or Subject Discontinuation of Study 
Intervention 
 
The study will follow a modified intention-to-treat approach. Subjects that enroll in the 
study and then decide to withdraw before spinal placement will be excluded from further 
data collection and analysis. 
 
Subjects that decide they no longer want to participate in research after completion of 
the study protocol, data will be collected up to the time of withdrawal. 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
26 
 
8.6 
Premature Termination or Suspension of Study 
 
There is no planned interim analysis, but the study may be suspended or prematurely 
terminated by the medical monitor for safety concerns after discussion with the study PI 
and the sponsor. 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
27 
 
9 STUDY INTERVENTION 
9.1 
Study Product Description 
9.1.1 
Acquisition 
The product for the intervention arm (Clorotekal®) has been acquired from B. Braun 
Medical Inc.   
The active comparer (hyperbaric bupivacaine) is available in all operating rooms at 
OHSU. 
9.1.2 
Formulation, Packaging, and Labeling 
Clorotekal® is a 1% formulation of chloroprocaine indicated for intrathecal injection.  
Each mL of Clorotekal® contains 10 mg chloroprocaine HCL, equivalent to 8.81 mg 
chloroprocaine base, sodium chloride 1 N, water for injection.  Clorotekal® comes in 
single dose 5 mL glass ampules.  
Hyperbaric bupivacaine is a 0.75% formulation of bupivacaine that contains 8.25% 
dextrose for intrathecal injection.  Each mL of solution contains 7.5 mg bupivacaine.  
Hyperbaric bupivacaine comes in 2 mL glass ampules. 
9.1.3 
Product Storage and Stability 
Clorotekal® is stored in cartons containing ten single-dose 5 mL glass ampules.  The 
product will be stored at room temperature in the cartons.  The product acquired has an 
expiration date of April 2020 when kept in unbroken vials. 
Hyperbaric bupivacaine is stored in the drug trays of all labor and delivery operating 
room equipment carts.  The product will be stored at room temperature.  Due to the high 
quantity of hyperbaric bupivacaine used at OHSU vials with different expiration dates 
are available.  Only unexpired hyperbaric bupivacaine will be used.   
9.2 
Study Procedures 
 
Before starting the surgery, the following baseline demographic data will be collected: 
 
• Age 
• Height 
• Weight at time of surgery 
• Body mass index at time of surgery 
• Gestational age 
• Parity 
• History of previous neuraxial anesthesia 
• Type of surgery 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
28 
 
 
Before study activation a sample of 50 sequentially numbered opaque envelopes will be 
prepared by a researcher not involved in patient recruitment, allocation, consent, or 
assessment: 25 for the Clorotekal® arm and 25 for the bupivacaine arm.  Patient 
allocation will occur in the operating room when the anesthesia provider responsible for 
patient care opens the lowest remaining numbered free envelope.  Group assignment 
will be determined by a computer generated random number sequence [Excel, 
Redmond WA]).  The random number sequence will be generated by a researcher not 
involved in either patient enrollment or patient assignment.  The medication for 
intrathecal injection (i.e. Clorotekal® or bupivacaine) will be defined in the opened 
opaque envelope.  Once a study subject signs a consent form, a unique number 
corresponding to the opened opaque envelope will be assigned to that subject.  This 
subject number will never be reused and will remain with the subject for the entirety of 
the study.  No subject will ever be allowed to have more than one unique subject 
number.  The envelope will not be opened until the anesthesia provider is ready to 
prepare and administer the spinal anesthetic.  The envelope will not be opened in the 
presence of the outcomes assessor or a member of the obstetric team.  The patient will 
have their back to the envelope when it is opened.  The envelope will be disposed of 
prior to the outcomes assessor entering the operating room. 
 
Subjects will receive a 1 liter co-load of crystalloid (Ringer’s Lactate or Normal Saline) 
solution during spinal placement. All patients will have standard ASA monitors plus five 
lead EKG applied.  Additional monitoring needs will be left up the anesthesia team 
directing patient care.   
 
Subjects will be allocated to either intrathecal injection of 50 mg Clorotekal® or 10.5 mg 
(1.4 mL) hyperbaric bupivacaine.  The intrathecal space will be accessed with a 25 
gauge Whitacre needle. Upon obtaining CSF, the syringe of study solution will be 
attached the end of the Whitacre needle.  The syringe will be pulled back to reveal 
aspiration of CSF.  The study solution will then be administered over approximately 5 
seconds. The Whitacre needle and spinal introducer needle will be removed from the 
patient’s back.  The patient will be placed supine on the operating room table.  The 
outcomes assessor will then be allowed to enter the operating room. 
 
Decisions on when to administer additional sedative and analgesic medications will be 
left to the discretion of the anesthesia team.  The level of block will be initially assessed 
by the anesthesia team.  When the block is felt to be at peak height the outcomes 
assessor will test with pinprick to determine the peak block height.   
 
In accordance with standard of practice at our institution all patients will have convective 
warmers used during the case and patient temperature will be monitored.  Non-invasive 
blood pressures will be obtained every 2.5 minutes after spinal placement.  The 
frequency of blood pressure measurement will be changed to every 5 minutes, 15 
minutes after spinal placement.  Anesthesia providers will administer phenylephrine via 
intravenous bolus to maintain maternal blood pressure within 20% of baseline or for a 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
29 
 
SBP < 100 mm Hg.  Anesthesia providers will be allowed to add ephedrine or 
glycopyrrolate to phenylephrine for maternal hypotension with co-existent bradycardia.   
 
A research coordinator will remain with the patient throughout their time in the operating 
room and the PACU.  Active, non-standard of care, monitoring for the following signs 
and symptoms of local anesthetic toxicity will occur in the operating room and PACU at 
the following time intervals after spinal placement: 5 minutes, 10 minutes, 15 minutes, 
upon PACU arrival, upon completing Phase 1 of PACU recovery, and upon discharge 
from the PACU: 
• 
Seizures 
• 
Tinnitus 
• 
Metallic taste 
• 
Agitation 
• 
Sedation 
• 
Respiratory depression (respiratory rate < 10 breaths per minute) 
• 
Dizziness 
• 
Nausea 
• 
Vomiting 
• 
Vision changes 
• 
Paresthesia 
• 
Perioral numbness 
• 
Hypotension (drop in MAP > 20% or SBP < 100 mm Hg) 
• 
Arrhythmias 
 
The dose of chloroprocaine and bupivacaine used in the study are very unlikely to 
cause symptoms of local anesthetic systemic toxicity.  However, patients that exhibit 
seizures, arrhythmias, or cardiac arrest will be immediately administered intralipid.  
Intralipid is already available on labor and delivery in the epidural cart.  Intralipid would 
be dosed according to the American Society of Regional Anesthesia guideline (i.e. initial 
bolus of 1.5 ml/kg followed by 0.25 ml/kg/minute).  The intralipid infusion would be 
continued for 10 minutes after restoration of hemodynamic stability.  All patients that 
require intralipid will have telemetry monitoring on the floor. 
The research coordinator will obtain from anesthesia, upon arrival to the PACU, the total 
dose of intraoperative opioids administered, whether the patient had intraoperative 
hypotension, and the total dose of intraoperative phenylephrine administered.  In the 
PACU, the research coordinator will determine the patient’s Bromage scale score at 5-
minute increments.  The research coordinator will also ask the patient to notify them 
when they have a Bromage scale score of 2 (able to flex knees).  While in the PACU, 
the research coordinator will also document the time of PACU arrival, the end of Phase 
1 of PACU recovery, and the time that the patient leaves the PACU (end of Phase 2).   
The research coordinator will meet with the patient on the evening of their surgery as 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
30 
 
well as daily for the duration of their hospitalization to assess for time of first ambulation, 
whether a Foley or Straight catheter was inserted into the bladder, and for adverse 
events including, new postoperative neurologic deficits and any other potential adverse 
events.   
To gather information on the incidence of new postoperative neurologic deficits all 
patients will be called 1 week after spinal insertion.  A telephone script will be used to 
obtain this information. 
The subject’s status in the research project will show up clearly in their electronic 
medical record problem list, until the subject’s participation is complete.  A progress 
note will be placed in the subject’s chart to allow other providers to easily contact study 
investigators.   
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
31 
 
10 STUDY SCHEDULE 
Study initiation including IRB submission and obtaining IRB approval is expected to take 
6 months.  Assuming we can enroll one patient per week, study enrollment should take 
approximately 50 weeks (12 months).  Data collection will occur during the study 
enrollment period.  Data analysis, writing, editing and submission to a peer-reviewed 
journal is expected to take 6 months.   
 
In summary, the study should be completed within 2 years of obtaining approval for 
funding. 
 
10.1 
Screening 
Patients will be screened weekly by the PI for the duration of the enrollment period (12 
months). 
10.2 
Enrollment/Baseline 
Subject enrollment and collection of baseline characteristics are expected to occur in 
the preoperative area on the morning of surgery.  Patients arrive to the preoperative 
area 2 hours before their scheduled surgery.  There is a significant amount of research 
that occurs on labor and delivery at OHSU.  Accordingly, built into this 2 hour time 
period is time for patients to meet with research coordinators. 
10.3 
Outcome Assessor Visits 
After enrolling the patient, the outcome assessor will remain outside of the operating 
room while the intrathecal injection is completed.  This will keep the outcome assessor 
blinded.  The outcome assessor will then enter the operating room and remain with the 
patient for the duration of their surgery.  The outcome assessor will go with the patient 
to the PACU and remain with the patient until discharge to the surgical ward or home.  
The outcome assessor will visit the patient daily on the surgical ward until discharge.  
 
 
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
32 
 
11 ASSESSMENT OF SAFETY 
11.1 
Reporting Procedures 
 
Serious adverse events will be reported to the study medical monitor within 48 hours of 
learning of the event and followed up until resolution. Serious, unanticipated adverse 
events will be reported to the sponsor and to regulatory authorities within 5 business 
days, in accordance with Federal Regulations. Listings of adverse events will be 
generated quarterly to assess for trends, and examined for possible patterns between 
the groups and over time. If potential trends or unexpected events are noted, a 
summary will be provided to the Institutional Review Board and to the sponsor for 
further review and evaluation. 
 
11.2 
Halting Rules 
 
Significant clinical manifestations of local anesthetic systemic toxicity will halt the study 
and prompt immediate (within two working days) notification of the IRB.  In addition, all 
medical teams involved in the patient’s care will be notified and the patient will receive a 
detailed summary of the event upon resolution of the event.  In the scenario that the 
patient lacks the ability to comprehend the adverse event the patient’s family will be 
notified.  For purposes of this study significant clinical manifestations will include the 
following: 
• Seizures 
• Respiratory depression with desaturation (oxygen saturation < 88%) 
• Any arrhythmias associated with hypotension 
• Cardiac arrest 
 
The study will also be halted and the IRB notified if two or more patients in the 
Clorotekal® group are unable to complete their surgery under spinal anesthesia, 
requiring general endotracheal anesthesia.  Only a few patients a year require general 
endotracheal anesthesia to complete the surgeries included in this study.  In this 
manner, two failed spinals would constitute enough concern to halt the study and 
prompt investigation.  
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
33 
 
12 STUDY OVERSIGHT 
In addition to the PI’s responsibility for oversight, an independent Medical Monitor will 
be assigned to review serious adverse events (SAEs) and unanticipated problems 
(UPs). The PI will review a listing of serious adverse events, unanticipated problems 
and adverse events every 3 months. If an unexpectedly high incidence of SAEs 
(Suspected, Unanticipated, Serious Adverse Reactions related to the study drug - 
SUSARs), UPs or unusual trends in AEs is observed, the PI will discuss with the 
Sponsor if the trial should be terminated early, in accordance to a predefined Data 
Safety Monitoring Plan. If necessary, additional steps may be taken to ensure data 
integrity and protocol compliance.  
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
34 
 
13 CLINICAL SITE MONITORING 
Clinical site monitoring is conducted to ensure that the rights of human subjects are 
protected, that the study is implemented in accordance with the protocol and/or other 
operating procedures, and that the quality and integrity of study data and data collection 
methods are maintained.  Medical Monitoring for this study will be performed by Dr. 
Ryan Ivie.  Dr. Ivie is the Director of Regional Anesthesia at OHSU and has significant 
experience and expertise providing spinal anesthesia. Dr. Ivie will evaluate the study 
SAEs and UPs in accordance with the International Conference on Harmonisation 
(ICH), E6: Good Clinical Practice guidelines (GCP), and local regulations. The 
Institutional Review Board will have oversight on the study conduct.  
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
35 
 
14 STATISTICAL CONSIDERATIONS 
14.1 
Study Hypotheses 
We hypothesize that subjects administered Clorotekal® will have a shorter duration of 
motor block than subjects administered hyperbaric bupivacaine, defined as the number 
of 5-minute intervals since completion of spinal injection to achievement of a Bromage 
scale score of 2. 
 
14.2 
Sample Size Considerations 
 
We plan to enroll 50 patients. A sample of 50 patients will provide at least 90% power to 
detect a 40-minute reduction in the duration of motor block, assuming a standard 
deviation of 40 minutes and a two-sided alpha level of 5%18.   
 
14.3 
Planned Interim Analyses 
14.3.1 Safety Review 
 
For the safety endpoints, we will compare the pre-specified adverse events and any 
additional adverse events reported between the two groups. In addition, safety will be 
monitored on an ongoing basis throughout the trial by an independent Medical Monitor. 
The Medical Monitor will not be an investigator, but will have experience providing 
neuraxial anesthesia for the surgical procedures being studied.  There will not be an a 
priori planned interim safety or tolerability review, however, the study can be stopped 
anytime for safety concerns.  
14.3.2 Efficacy Review 
There is no planned interim efficacy review. 
 
14.4 
Final Analysis Plan 
 
Data analysis will be completed by N. David Yanez, co-director of the OHSU 
Biostatistics and Design Program within the Oregon Clinical and Translational Research 
Institute, upon conclusion of enrollment and follow up for patient #50. 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
36 
 
The main analysis will use an intention-to-treat approach. Descriptive statistics will be 
used to describe the distribution of baseline characteristics using two-sample Student’s 
t-test or chi-square statistic, as appropriate. The primary endpoint, number of 
assessments at 5-min intervals from spinal injection to Bromage score of 2, will be 
compared using an independent two-sample Student’s t-test with assumption of 
unequal variances. We will also evaluate the number of minutes from spinal injection to 
Bromage score of 2 based on participant’s report to return of knee flection. This test will 
also be used for other secondary endpoints with symmetric distribution. A test of 
homogeneity using the chi-square statistic will be performed for dichotomous or 
categorical variables. A two-sided level of significance of .05 will be considered for all 
analyses. The analyses will be performed using the statistical software STATA (Stata 
Corp, College Station, TX). 
 
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
37 
 
15 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
Study staff will maintain appropriate medical and research records for this study, in 
compliance with ICH E6, Section 4.9 and regulatory and institutional requirements for 
the protection of confidentiality of subjects.  Study staff will permit authorized 
representatives of B. Braun and regulatory agencies to examine (and when required by 
applicable law, to copy) research records for the purposes of quality assurance reviews, 
audits, and evaluation of the study safety, progress and data validity.   
 
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
38 
 
16 ETHICS/PROTECTION OF HUMAN SUBJECTS 
16.1 
Ethical Standard 
The investigator will ensure that this study is conducted in full conformity with the 
principles set forth in The Belmont Report: Ethical Principles and Guidelines for the 
Protection of Human Subjects of Research, as drafted by the US National Commission 
for the Protection of Human Subjects of Biomedical and Behavioral Research (April 18, 
1979) and codified in 45 CFR Part 46 and/or the ICH E6.  
 
16.2 
Institutional Review Board 
The protocol, informed consent form(s), recruitment materials, and all subject materials 
will be submitted to the IRB for review and approval.  Approval of both the protocol and 
the consent form must be obtained before any subject is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are 
implemented in the study.   
 
16.3 
Informed Consent Process 
Informed consent is a process that is initiated prior to the individual agreeing to 
participate in the study and continues throughout study participation.  Extensive 
discussion of risks and possible benefits of study participation will be provided to 
subjects and their families, if applicable.  A consent form describing in detail the study 
procedures and risks will be given to the subject.  Consent forms will be IRB-approved, 
and the subject is required to read and review the document or have the document read 
to him or her.  The investigator or designee will explain the research study to the subject 
and answer any questions that may arise.  The subject will sign the informed consent 
document prior to any study-related assessments or procedures.  Subjects will be given 
the opportunity to discuss the study with their surrogates or think about it prior to 
agreeing to participate.  They may withdraw consent at any time throughout the course 
of the study.  A copy of the signed informed consent document will be given to subjects 
for their records.  The rights and welfare of the subjects will be protected by 
emphasizing to them that the quality of their clinical care will not be adversely affected if 
they decline to participate in this study. 
The consent process will be documented in the clinical or research record.   
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
39 
 
16.4 
Exclusion of Women, Minorities, and Children (Special Populations) 
The study will only include women because obstetric procedures are being studied.  
Women of all racial/ethnic groups may participate.  Children will be excluded from this 
study as that is our institutional standard for clinical trials on labor and delivery. 
 
16.5 
Subject Confidentiality 
 
Subject confidentiality is strictly held in trust by the investigators, study staff, and the 
sponsor and their agents.  This confidentiality is extended to cover testing of biological 
samples and genetic tests (not applicable to this study) in addition to any study 
information relating to subjects. 
 
The study protocol, documentation, data, and all other information generated will be 
held in strict confidence.  No information concerning the study or the data will be 
released to any unauthorized third party without prior written approval of the sponsor. 
 
The study monitor or other authorized representatives of the sponsor may inspect all 
study documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) for the study subjects.  The 
clinical study site will permit access to such records. 
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
40 
 
17 HANDLING OF DATA AND SPECIMENS 
The investigators are responsible for ensuring the accuracy, completeness, legibility, 
and timeliness of the data reported.  All source documents should be completed in a 
neat, legible manner to ensure accurate interpretation of data.  The investigators will 
maintain adequate case histories of study subjects, including accurate case report 
forms (CRFs), and source documentation. 
Study subjects will be assigned a unique study number after enrollment in the study.  All 
data points, procedure related data, and electronic files for data analysis will be linked 
only to this unique study number.  This study number will not contain any of the 18 
HIPAA identifiers such as: geographic location, dates related to the individual, medical 
record number, account numbers, etc.  The key linking study subjects to study code will 
be kept in an OHSU approved cloud location with special protection for confidential and 
restricted health information (the OHSU Box).  Only the principal investigator and other 
study staff will have access to this key.  The key will be maintained for 3 years after 
publication in accordance with the US Department Office of Research Integrity 
guidelines for responsible data management in scientific research.   
 
The results of the study as well as all other information collected on the data collection 
sheet will be stored in the locked office of the research coordinator.  The office requires 
a key for entry.  Only research personnel are allowed access to the office. No protected 
health information or other data collected during the completion of this randomized 
controlled trial will be taken off campus.  All data gathered for this study will be coded 
before any analysis or publication occurs. 
 
Clinical data will be entered into APOM OCEAN, a 21 CFR Part 11-compliant Electronic 
Data Capture (EDC) system provided by the Department of Anesthesiology and 
Perioperative Medicine. The EDC system includes password protection. Secure data 
will be stored in APOM OCEAN for 3 years after publication.  Data in the EDC will be 
linked only to subject study code, not to any of the 18 HIPAA identifiers.   
 
The following clinical data will be entered into APOM OCEAN: 
 
• 
Baseline demographic and surgical parameters 
 
o Age 
o Height 
o Weight at time of surgery 
o Body mass index at time of surgery 
o Gestational age 
o Parity 
o History of previous neuraxial anesthesia 
o Type of surgery 
o Level of intrathecal injection 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
41 
 
 
• 
Signs and symptoms of local anesthetic toxicity at the following time intervals 
after spinal placement: 5 minutes, 10 minutes, 15 minutes, upon PACU arrival, 
upon completing Phase 1 of PACU recovery, and upon discharge from the 
PACU: 
 
o Seizures 
o Tinnitus 
o Metallic taste 
o Agitation 
o Sedation 
o Respiratory depression (respiratory rate < 10 breaths per minute) 
o Dizziness 
o Nausea 
o Vomiting 
o Vision changes 
o Paresthesias 
o Perioral numbness 
o Arrhythmias 
 
• 
Primary, secondary and tertiary endpoints 
 
o Duration of motor block, defined as the number of 5-minute intervals since 
completion of spinal injection to achievement of a Bromage scale score of 
2  
o Duration of motor block, defined by patient report since completion of 
spinal injection to achievement of a Bromage scale score of 2 
o PACU Phase 1 length 
o PACU length of stay 
o Time to first ambulation 
o Bladder catheterization 
o Intraoperative opioid consumption in parenteral morphine equivalents 
o Highest sensory block achieved 
o Incidence of hypotension (drop in MAP > 20% or SBP < 100 mm Hg) 
o Intraoperative phenylephrine requirement in mcg 
o Occurrence of adverse events including perioperative respiratory 
depression, new postoperative neurologic deficits, or any other potential 
adverse events 
 
Any data that is shared will be transmitted in an encrypted manner over a secure 
network.  Transmitted data will be labeled only with the study code, none of the 18 
HIPAA identifiers.  When data is transmitted, the transmitter (research personnel with 
access to APOM OCEAN EDC) will be responsible for sending the data in a protected 
manner.   Any person receiving data will then assume responsibility for patient 
confidentiality and data integrity.   

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
42 
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
43 
 
18 PUBLICATION/DATA SHARING POLICY 
The current plan is to present the study results at a future American Society of 
Anesthesiologists annual meeting.  The manuscript will be submitted to a peer-reviewed 
journal. 
 
Study results will not be available to subjects at the time of participation.  All subjects 
will be given the contact information of the principal investigator and told that they may 
contact him to obtain their individual data once analysis is complete.  Patients will also 
be able to obtain a free copy of any published data should they indicate interest.  This 
study will not generate genetic information or imaging studies. 
 
 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
44 
 
19 LITERATURE REFERENCES 
1. 
Palmer CM, D'Angelo R, Paech MJ. Obstetric anesthesia. Oxford ; New York: 
Oxford University Press; 2011. 
2. 
Huffnagle SL, Norris MC, Huffnagle HJ, Leighton BL, Arkoosh VA. Intrathecal 
hyperbaric bupivacaine dose response in postpartum tubal ligation patients. Reg 
Anesth Pain Med. 2002;27(3):284-288. 
3. 
McKenzie C, Akdagli S, Abir G, Carvalho B. Postpartum tubal ligation: A 
retrospective review of anesthetic management at a single institution and a 
practice survey of academic institutions. J Clin Anesth. 2017;43:39-46. 
4. 
Viscomi CM, Rathmell JP. Labor epidural catheter reactivation or spinal 
anesthesia for delayed postpartum tubal ligation: a cost comparison. J Clin 
Anesth. 1995;7(5):380-383. 
5. 
Chalifoux LA, Bauchat JR, Higgins N, et al. Effect of Intrathecal Bupivacaine 
Dose on the Success of External Cephalic Version for Breech Presentation: A 
Prospective, Randomized, Blinded Clinical Trial. Anesthesiology. 
2017;127(4):625-632. 
6. 
Weiniger CF, Ginosar Y, Elchalal U, Sela HY, Weissman C, Ezra Y. Randomized 
controlled trial of external cephalic version in term multiparae with or without 
spinal analgesia. Br J Anaesth. 2010;104(5):613-618. 
7. 
Weiniger CF, Sultan P, Dunn A, Carvalho B. Survey of external cephalic version 
for breech presentation and neuraxial blockade use. J Clin Anesth. 2016;34:616-
622. 
8. 
Lee GY, Kim CH, Chung RK, Han JI, Kim DY. Spread of subarachnoid sensory 
block with hyperbaric bupivacaine in second trimester of pregnancy. J Clin 
Anesth. 2009;21(7):482-485. 
9. 
Lee MH, Son HJ, Lee SH, et al. Comparison of spread of subarachnoid sensory 
block and incidence of hypotension in early and late second trimester of 
pregnancy. Korean J Anesthesiol. 2013;65(4):322-326. 
10. 
Van de Velde M, De Buck F. Fetal and maternal analgesia/anesthesia for fetal 
procedures. Fetal Diagn Ther. 2012;31(4):201-209. 
11. 
Maes S, Laubach M, Poelaert J. Randomised controlled trial of spinal 
anaesthesia with bupivacaine or 2-chloroprocaine during caesarean section. Acta 
Anaesthesiol Scand. 2016;60(5):642-649. 
12. 
Maher DP, Wong W, Woo P, et al. Perioperative factors associated with 
HCAHPS responses of 2,758 surgical patients. Pain Med. 2015;16(4):791-801. 
13. 
Dexter F, Tinker JH. Analysis of strategies to decrease postanesthesia care unit 
costs. Anesthesiology. 1995;82(1):94-101. 
14. 
Zite N, Wuellner S, Gilliam M. Failure to obtain desired postpartum sterilization: 
risk and predictors. Obstet Gynecol. 2005;105(4):794-799. 
15. 
Committee on Health Care for Underserved W. Committee opinion no. 530: 
access to postpartum sterilization. Obstet Gynecol. 2012;120(1):212-215. 
16. 
Marshall SI, Chung F. Discharge criteria and complications after ambulatory 
surgery. Anesth Analg. 1999;88(3):508-517. 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
45 
 
17. 
Zaric D, Pace NL. Transient neurologic symptoms (TNS) following spinal 
anaesthesia with lidocaine versus other local anaesthetics. Cochrane Database 
Syst Rev. 2009(2):CD003006. 
18. 
Saporito A, Ceppi M, Perren A, et al. Does spinal chloroprocaine 
pharmacokinetic profile actually translate into a clinical advantage in terms of 
clinical outcomes when compared to low-dose spinal bupivacaine? A systematic 
review and meta-analysis. J Clin Anesth. 2019;52:99-104. 
19. 
Gupta A, Axelsson K, Thorn SE, et al. Low-dose bupivacaine plus fentanyl for 
spinal anesthesia during ambulatory inguinal herniorrhaphy: a comparison 
between 6 mg and 7. 5 mg of bupivacaine. Acta Anaesthesiol Scand. 
2003;47(1):13-19. 
20. 
Prescribing Information: Clorotekal. In: Inc. BBM, ed2018. 
21. 
Camponovo C, Wulf H, Ghisi D, et al. Intrathecal 1% 2-chloroprocaine vs. 0.5% 
bupivacaine in ambulatory surgery: a prospective, observer-blinded, randomised, 
controlled trial. Acta Anaesthesiol Scand. 2014;58(5):560-566. 
22. 
Lacasse MA, Roy JD, Forget J, et al. Comparison of bupivacaine and 2-
chloroprocaine for spinal anesthesia for outpatient surgery: a double-blind 
randomized trial. Can J Anaesth. 2011;58(4):384-391. 
23. 
Teunkens A, Vermeulen K, Van Gerven E, Fieuws S, Van de Velde M, Rex S. 
Comparison of 2-Chloroprocaine, Bupivacaine, and Lidocaine for Spinal 
Anesthesia in Patients Undergoing Knee Arthroscopy in an Outpatient Setting: A 
Double-Blind Randomized Controlled Trial. Reg Anesth Pain Med. 
2016;41(5):576-583. 
24. 
Yoos JR, Kopacz DJ. Spinal 2-chloroprocaine: a comparison with small-dose 
bupivacaine in volunteers. Anesth Analg. 2005;100(2):566-572. 
25. 
Forster JG. Short-acting spinal anesthesia in the ambulatory setting. Curr Opin 
Anaesthesiol. 2014;27(6):597-604. 
26. 
Goldblum E, Atchabahian A. The use of 2-chloroprocaine for spinal anaesthesia. 
Acta Anaesthesiol Scand. 2013;57(5):545-552. 
27. 
Thiele R, Nemergut E. Local anesthetics: systemic toxicity. Open Anesthesia. 
Accessed Febrary 15th, 2019, 2019. 
28. 
Kuhnert BR, Kuhnert PM, Philipson EH, Syracuse CD, Kaine CJ, Yun CH. The 
half-life of 2-chloroprocaine. Anesth Analg. 1986;65(3):273-278. 
29. 
Vasques F, Behr AU, Weinberg G, Ori C, Di Gregorio G. A Review of Local 
Anesthetic Systemic Toxicity Cases Since Publication of the American Society of 
Regional Anesthesia Recommendations: To Whom It May Concern. Reg Anesth 
Pain Med. 2015;40(6):698-705. 
30. 
Di Gregorio G, Neal JM, Rosenquist RW, Weinberg GL. Clinical presentation of 
local anesthetic systemic toxicity: a review of published cases, 1979 to 2009. 
Reg Anesth Pain Med. 2010;35(2):181-187. 
31. 
Marsch SC, Sluga M, Studer W, Barandun J, Scharplatz D, Ummenhofer W. 
0.5% versus 1.0% 2-chloroprocaine for intravenous regional anesthesia: a 
prospective, randomized, double-blind trial. Anesth Analg. 2004;98(6):1789-
1793, table of contents. 

Maternal CLIMB 
19 September 2019 
 
 
 ________________________________________________________________________________________________________  
 
 _____________________________________________________________________________________________  
 
46 
 
32. 
Hernandez MA, Boretsky K. Chloroprocaine: local anesthetic systemic toxicity in 
a 9-month infant with paravertebral catheter. Paediatr Anaesth. 2016;26(6):665-
666. 
33. 
Cladis FP, Litman RS. Transient cardiovascular toxicity with unintentional 
intravascular injection of 3% 2-chloroprocaine in a 2-month-old infant. 
Anesthesiology. 2004;100(1):181-183. 
34. 
Philipson EH, Kuhnert BR, Syracuse CD. Fetal acidosis, 2-chloroprocaine, and 
epidural anesthesia for cesarean section. Am J Obstet Gynecol. 
1985;151(3):322-324.