ED90 of 3% Chloroprocaine for Cervical Cerclage

Cervical cerclage is a procedure performed on pregnant women with cervical incompetence to
reduce the risk of second trimester spontaneous abortion and preterm labor. This outpatient
procedure is performed commonly under both general and regional anesthesia. In an effort to
ensure rapid discharge some institutions prefer the use of general anesthesia; however, this
has the disadvantage of exposing the fetus to general anesthetic drugs, increased risk of
aspiration and a higher requirement for opioid analgesia post operatively. The benefits of
neuraxial anesthesia for cerclage placement includes rapid onset of a dense sensory block,
reduced fetus exposure to medications, and maintenance of maternal airway reflexes.
Successful analgesia for cerclage placement requires a sensory block from S4-T10 dermatomes.
Inadequate sensory coverage with a spinal anesthetic typically necessitates the conversion to
general anesthesia adding risk to the mother and fetus while increasing intraoperative times
and resources. Currently there are no studies determining optimum dose of spinal
chloroprocaine for cervical cerclage. The investigators propose a dose determining study to
determine the ED90 of intrathecal lidocaine and chloroprocaine which will help decrease
incidence of inadequate anesthesia for cervical cerclage.

This is a multicenter, double blinded, dose ranging, biased-coin design study. Usual practice
for regional anesthesia for cerclage placement consists of a mixture of 3% chloroprocaine and
fentanyl. The exact dosing of the local anesthetic mixture used is dependent on the
anesthesiologist's preference. Chloroprocaine provides a rapid onset of surgical anesthesia
with little need for intraoperative analgesic supplementation. If there are contraindications
for spinal anesthesia or patient refusal than general anesthesia is offered as an
alternative.

The aim of this study is to assess the anesthetic quality of various doses chloroprocaine and
in elective cerclage placement. Chloroprocaine is licensed and commonly administered
intrathecally for cerclage placement.

To mitigate against the occurrence of inadequate analgesia in this ED90 study, a combined
spinal-epidural technique will be utilized in order to provide supplemental analgesia via
epidural top up if needed.

The investigators propose testing the hypothesis in patients scheduled for elective cervical
cerclage placement. Participants will receive standard of care for anesthesia but in the
context of a clinical trial with the addition of randomization, blinding, and more
comprehensive evaluation of the trial outcomes (see outcomes objectives below).

The proposed study will be conducted over a 2 year period from January 2019 to September
2020.

Spinal Study Solutions The solutions and their administration procedures are identical to
those used outside this research and are almost exclusively used for patients requiring
spinal anesthesia for cervical cerclage. The only deviation involves diluting the
chloroprocaine with saline so that study solutions are of equal volume to maintain blinding.

Initial Patient (A#X) 45mg (1.5mL) of Chloroprocaine 3% (Nesacaine — Fresenius Kabi), will be
drawn up into a 3 ml syringe (a 1 ml 'TB syringe' will be used to aspirate the drug in
aliquots to ensure accuracy). The following additive will be added: 10 mcg (0.2ml) of
fentanyl (50 mcg/ml) 0.3 ml of sterile 0.9% sodium chloride Thus the total volume in the
syringe will be 2 ml. Study drugs will be prepared by one anesthesiologist (un-blinded) and
administered by another anesthesiologist (blinded).

Subsequent Patient (A#X+1) The dose of Chloroprocaine 3% based on outcome from prior subject
and calculations mentioned previously will be added to 10 mcg (0.2ml) of fentanyl (50
mcg/ml). Sterile 0.9% sodium chloride will be added until the total volume in the syringe is
2 ml.

Rescue If the subject has discomfort and requests analgesia, then 5 ml of 3% chloroprocaine
via the epidural route will be given, alternatively the anesthesiologist can treat the
discomfort at his discretion. Other alternatives include intravenous fentanyl, ketamine,
inhalational nitrous oxide and conversion to general anesthesia.

Riks/Benefit Risks of the procedure include the following: discomfort during placement (10%
or 1 in 10), drop in blood pressure (1% or 1 in 100), headache (1% or 1 in 100), allergic
reactions (0.001% or 1 in 100,000), bleeding or infection (0.001% or 1 in 100,000), damage to
nerves (0.001% or 1 in 100,000), failure of the anesthetic or inadequate anesthesia and need
for general anesthesia (0.1% or 1 in 1,000). The benefit of participating in the study is
that perceived pain may be better controlled, however this cannot be guaranteed.

This study will be conducted at two study sites, the University of Arkansas for Medical
Sciences in Little Rock, Arkansas and Duke University in Durham, North Carolina.

Inclusion Criteria:

- ≥ 18 years of age

- Singleton pregnancy

- ASA class II or III

- Cervical cerclage 1st or 2nd trimester of pregnancy

- Simple prophylactic cervical cerclage

Exclusion Criteria:

- Patient refusal

- Abdominal and complex cervical cerclage (e.g. bulging bag)

- BMI ≥ 50 kg/m2

- ASA class IV or above

- Contraindication to neuraxial anesthesia

- Allergy to chloroprocaine