Clinical trial NCT04037085
Conditions: Obstetric Pain Postpartum Depression Breastfeeding Pain, Acute Pain, Chronic Obstetric Anesthesia Problems Drug Effect Opioid Use
Sponsor: Grace Lim, MD, MS
Start date: 2019-10-09; Completion date: 2021-08-01
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this study is evaluate the breastmilk transfer and pharmacokinetics (Part 1) and effectiveness (Part 2) of a post-cesarean delivery intravenous ketamine bolus-and-infusion strategy, as a preventive analgesic modality to reduce pain and opioid requirements.

In Part 1, physiochemical analysis of pharmacokinetic/pharmacodynamic (PK/PD) and breastmilk transfer of ketamine and its metabolites will be assessed. Additionally calculated estimations for neonatal and infant exposure will be assessed.

In Part 2, PK/PD assessments will continue in a larger cohort; endpoints will also include postpartum pain, depression scores, central sensitization measures, patient-reported postpartum recovery scores, breastfeeding, and parent-infant bonding, assessed in the acute post-cesarean period and up to 12 weeks postpartum in a randomized controlled trial.

Detailed description:
Postpartum pain management strategies currently permit opioids for breakthrough pain, but strategies focused on minimizing or eliminating opioids are lacking. In the non-obstetric surgical population, modalities such as intravenous ketamine are well-recognized as effective adjuncts in opioid-reduction strategies for postoperative pain. Although there have been some studies of ketamine exposure in postpartum women without deleterious outcomes noted, these studies in pregnant and lactating women are limited by a lack of information on maternal pharmacokinetics, breastmilk secretion, and clinical effectiveness when used with standard multimodal analgesic approaches. There is also a lack of information on intermediate and long-term outcomes in this setting. This two-part trial will address these knowledge gap by advancing understanding of the safety and efficacy of ketamine and its metabolites in peripartum populations.

Arms: arm 1: Ketamine - IV after cord clamping; IV infusion for 12 hours OR in the weaning population IV Ketamine infusion for 12 hours in the Montefiore CTRC
Interventions: intervention 1: Ketamine
Intervention descriptions: intervention 1: Subjects in the intervention arm will receive infusion dosing as noted in arm/group descriptions at the time of cord clamping. Duration of infusion will be 12 hours. Concentrations of ketamine and ketamine metabolites (nor-ketamine, NKET; and dehydro-nor-ketamine, DHNK) are measured in maternal plasma and urine as well as breastmilk. Maternal side effects, adverse events, and efficacy endpoints will be measured over the 12 hour infusion and over 15 hours after infusion discontinuation.

Protocol documents:
ICF_005.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ketamine to Improve Recovery After Cesarean 
Delivery – Part 1 (KINETIC) 
 
NCT04037085 
 
 
 
IRB: STUDY18120046 
 
IRB DOCUMENT DATE: 04/27/2021 


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Magee Womens Hospital of UPMC
300 Halket Street, Suite 3510
Pittsburgh, Pennsylvania 15213
UPMC |
University of Pittsburgh
Medical Center
Department of Anesthesiology
CONSENT TO ACT AS A PARTICIPANT IN A RESEARCH STUDY
Ketamine to Improve Recovery After Cesarean Delivery (KINETIC Trial):
PART 1: Lactation Studies
KEY INFORMATION
You are being asked to take part in a research study. Research studies include only people who 
choose to take part. The study team members will explain the study to you and will answer any 
questions you might have. You should take your time to make your decision.
The purpose of this research is study if low doses of ketamine, a pain killer that is not an opioid, 
is safe and effective for controlling pain after women have had a c-section birth or who are 
weaning off of breastfeeding.
In this first part of the study, any of the following groups of women can be enrolled: 
-
women who are planning not to breastfeed their infants
-
women who are withholding breastfeeding during the first 27 hours after birth
-
women who are weaning their baby off of breastfeeding. 
For the first 24 hours (weaning participants) to 36 hours (c-section participants) after your baby 
is born or after the scheduled start time, we will collect breast milk, blood, urine, and ask you to 
do computerized surveys about your pain and mood. You will receive the usual pain 
medications given to women who have had c-sections, according to your doctor’s care, in 
addition to the ketamine. You will be in the study only while you are in the hospital (c-section 
participants) or while you are staying in a research unit in Montefiore Hospital called the 
Clinical Translational Research Center or “CTRC” (weaning participants).
The risks of participating include: 
Study Drug: dizziness, lightheadedness, nausea, vomiting, itching, hallucinations, bad dreams, 
and sleepiness. 
Other risks include minor discomforts related to study procedures.
If you are a participant getting a c-section, you may benefit by having better pain control, 
helping you recover from your c-section. If you decide not to participate in this research, your 
other choices include getting your usual pain care regimen that your doctor prescribes.


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PRINCIPAL INVESTIGATOR:
Grace Lim MD, MS
Assistant Professor of Anesthesiology
300 Halket Street, Suite 3510
Pittsburgh PA 15213
Phone 412-641-4260 Fax 412-641-4766
CO- INVESTIGATORS:
Steve N. Caritis, MD
Professor
Department of Obstetrics, Gynecology & 
Reproductive Sciences
300 Halket Street
Pittsburgh, PA 15213
Telephone: 412-641-5403
Stacy Beck, MD
Assistant Professor
Department of Obstetrics, Gynecology & 
Reproductive Sciences
300 Halket Street, Suite 0610
Pittsburgh PA 15213
Telephone: 412-641-2252
Raman Venkataramanan, PharmD
Professor of Pharmaceutical Sciences
Professor of Pathology
Director of the Clinical Pharmacokinetics Lab
4103 PTC Building, 700 Technology Drive
Pittsburgh, PA 15219
Telephone: 412-648-7671
Ajay Wasan MD, MA, MSc 
Professor of Anesthesiology and 
Psychiatry
Vice Chair for Pain Medicine
Department of Anesthesiology 
and Psychiatry
5750 Centre Avenue, Suite 400
Pittsburgh, PA 15206 
Telephone: 412-665-8049
Jill Demirci, PhD, RN, IBCLC
Assistant Professor
Health Promotion & 
Development
School of Nursing
3500 Victoria Street
Pittsburgh, PA 15261
412-383-9236
Jacques Chelly, MD, PhD, MBA
UPMC Shadyside
5230 Centre Avenue
Pittsburgh, Pennsylvania 15232
412.623.6904
SOURCE(S) OF SUPPORT:
Clinical and Translational Science Institute (CTSI) Pain Research Challenge
Why is this research being done?
This research is being done to explore a new medication for controlling pain for women who 
have had cesarean sections. It is part of research to find medications other than opioids to 
control pain. Opioids are effective pain killers but have negative side effects including addiction.


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In this research study, we are testing if ketamine given during and after cesarean sections along 
with routine care will be transferred into breast milk. 
Who is being asked to take part in this research study?
You are being invited to take part in this research study because you are going to have a baby at 
Magee Women's Hospital, you are having a cesarean delivery, and you are not planning to 
breastfeed or are willing to withhold breastfeeding for 27 hours after delivery. If you are not 
having a cesarean delivery, you are being invited to take park in this research study because 
you are going to be weaning from breastfeeding. Procedures will occur in person and within 
normal clinical care as much as possible.
What procedures will be performed for research purposes?
If you decide to take part in this research study, you will undergo the following procedures that 
are not part of your standard medical care:
Experimental Procedures: 
If you qualify and agree to take part in this research study, you will participate in the following 
things listed below. These procedures will take place electronically, or at Magee Women's 
Hospital, or UPMC Montefiore CTRC if you are a subject who is weaning.
During your stay at the hospital or CTRC clinic, you will be given a 12-hour infusion of ketamine 
through your IV. The medicine will start right after your baby is delivered or at the scheduled 
time in the CTRC clinic. During the infusion, and for 15 hours after the infusion has ended, we 
will provide you with counseling and support to express samples of your breastmilk. Hand 
expression and/or breast pumps will be used to express samples. We will help you with these 
steps. We will enroll 6 women. The results from this study will be used to for a study with many 
more women. 
If you are having a cesarean delivery, after 15 hours, you may nurse your infant but we will do 1 
more breast milk collection for the study at 24 hours after the drug infusion ends. 
There will be several encounters between you and our study team. In the chart below, where it 
says ‘Breastmilk’ or ‘Whole blood’, it means those samples will be collected from you. The 
blood will be drawn from an IV that is in place.  Up to 3 mL of blood will be drawn for each of 
these samples. 24 mL of blood total may be drawn over the course of the study. The study team 
will assist you in learning how to hand express or use a breast pump to obtain the breast milk 
sample. 
Study Visit
Where
Activity
Time


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1
Hospital
Breastmilk - T0-T2 (0-2hrs after infusion start, at 
earliest opportunity)
15-30 min
2
Hospital
Vital Signs - T0.5 (30min into study drug infusion)
5 min
3
Electronically
Side Effect Diary - T1 (1hr into study drug infusion)
5-10 min
4
Hospital
Vital signs - T1 (60min into study drug infusion)
5 min
5
Hospital
Vital Signs - T2  (2hr into study drug infusion)
5 min
6
Hospital
Vital Signs - T3 (3hr into study drug infusion)
5 min
7
Hospital
Breastmilk - T4 (4 hours)
15-30 min
8
Electronically
Side Effect Diary - T4 (4hr into study drug infusion)
5-10 min
9
Hospital
Vital Signs - T4 (4hr into study drug infusion)
5 min
10
Hospital
Breastmilk - T8 (8 hours)
15-30 min
11
Hospital
Whole blood - T8 (8-10 hours into study drug infusion)
5-10 min
12
Electronically
Side Effect Diary - T8 (8hr into study drug infusion)
5-10 min
13
Hospital
Vital Signs - T8 (8hr into study drug infusion)
5 min
14
Hospital
Breastmilk - T12 (12 hours)
15-30 min
15
Hospital
Whole blood - T12 (12 hours into study drug infusion)
5-10 min
16
Electronically
Side Effect Diary - T12 (12hr into study drug infusion)
5-10 min
17
Hospital
Vital Signs - T12 (12hr into study drug infusion)
5 min
18
Hospital
Whole blood - T12.5 (0.5hr after infusion end)
5-10 min
19
Hospital
Whole blood - T13 (1hr after infusion end)
5-10 min
20
Hospital
Vital Signs - T13 (1hr after infusion end)
5 min
21
Hospital
Breastmilk - T14 (2 hrs after infusion end)
15-30 min
22
Hospital
Whole blood - T14 (2hr after infusion end)
5-10 min
23
Hospital
Vital Signs - T14 (2hr after infusion end)
5 min
24
Hospital
Vital Signs - T15 (3hr after infusion end)
5 min
25
Hospital
Vital Signs – T16 (4hr after infusion end)
5 min
26
Hospital
Breastmilk - T16 (4 hours after infusion end)
15-30 min
27
Hospital
Whole blood - T16 (4 hrs after infusion end)
5-10 min
28
Electronically
Side Effect Diary - T16 (4hr after infusion end)
5-10 min
29
Hospital
Breastmilk - T20 (8 hours after infusion end)
15-30 min
30
Hospital
Whole blood - T20 (8hrs after infusion end)
5-10 min
31
Electronically
Side Effect Diary - T20 (8hr after infusion end)
5-10 min
32
Hospital
Vital Signs – T20 (8hr after infusion end)
5 min
33
Hospital
Urine - T24 (total volume of urine at 24hrs after 
infusion start)
(passively 
collected)
34
Electronically
Side Effect Diary - T24 (12hr after infusion end)
5-10 min
35
Hospital
Vital Signs – T24 (12hr after infusion end)
5 min
36 (weaning 
participants 
skip this step)
Hospital
Breastmilk - T36 (24 hours after infusion end)
15-30 min


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37 (weaning 
participants 
skip this step)
Hospital
Whole blood - T36 (24hrs after infusion end)
5-10 min
Your blood, breastmilk and urine samples will be stored in a lab in Magee Women’s Hospital 
and then transferred to a facility in the Pittsburgh Technology Center. It will also be stored in 
the Montefiore CTRC. They will have anything that identifies you removed. The samples will be 
analyzed for the amount of ketamine in them. The leftover will be stored frozen for future 
research use. The results of the analyses will not be shared with you – as they will not affect 
your clinical care and are for research.
The Side Effect diaries will ask you questions about your mood, stress level, amount of pain you 
are experiencing.
We will ask you to provide us with your email address and a phone number so that we can keep 
in touch with you about the study. Although every reasonable effort has been taken, 
confidentiality during Internet communication activities cannot be guaranteed and it is possible 
that additional information beyond that collected for research purposes may be captured and 
used by others not associated with this study.
If you are unable to provide an e-mail address, we will contact you by phone.
Your participation in the study would also permit us to re-contact you at a future date for 
follow-up questions, if necessary.
For the weaning population, a urine pregnancy test will be done before drug infusion or any 
other study procedures. If you are in the weaning population and have a positive pregnancy 
test, the PI or Co-I will re-evaluate your eligibly.
What are the possible risks, side effects, and discomforts of this research study?
You will be asked to answer questions regarding your pain and comfort before, during, and 
after you have your baby. Answering these questions may be viewed as an inconvenience to 
you.
Risks of Experimental Drug: Some common side effects of ketamine are dizziness, 
lightheadedness, nausea, vomiting, itching, hallucinations, bad dreams, and sedation. Rarely 
there can be changes in vital signs, like blood pressure and heart rate. These risks are minimized 
as much as possible by using doses that are well below the doses that we typically see these 
side effects. If you are a subject who is weaning and not currently experiencing pain, it is 
possible though unlikely, that you could experience side effects different from women who take 


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ketamine who are having pain. The overall risk of side effects with this dose is thought to be 
low.
Risk of breach of confidentiality: There is a possible risk of a breach of confidentiality. However, 
we will take all possible steps to prevent this from happening.
Risk of blood draw from existing IV line: There is a low risk of infection from blood draws 
conducted in the study. However, we will take all possible steps to prevent this from 
happening.
Risk of Withholding Breastfeeding. Due to potential, yet unknown risks of ketamine exposure 
through breastmilk, breastfeeding will be withheld for the duration of study drug infusion and 
for 15 hours after the infusion is stopped. The potential negative implications of withholding 
breastfeeding over the study period (first 24 hours after delivery) include 1) missed feedings of 
colostrum (the first milk/substance excreted from the breast after birth, typically 1-4 teaspoons 
per day) which is high in nutrients, antibodies and white blood cells; and 2) need to assist 
newborn to transition back to breastfeeding, and 3) possibility for breast discomfort if lactation 
is stopped. Any participant who withholds breastfeeding, and/or then wishes to breastfeed 
afterward, will be referred to a lactation consultant for breastfeeding support, to cope with any 
discomfort if lactation is stopped, and as there are coaxing techniques that can be used to help 
the newborn make the transition back to the breast.
Risk of answering survey questions. There is a risk that you will be inconvenienced by answering 
our survey questions. However, we have made sure that our surveys are as brief as possible in 
order to avoid this risk.
Risk of maternal urine collection. There is a risk that you will be inconvenienced by the study 
team collecting a sample of your urine. However, we will make this procedure as unobtrusive as 
possible by using a urine collection hat in your bathroom.
Risk of breastmilk collection. There is a risk that you will be inconvenienced or feel discomfort 
during collection of breastmilk samples. However, we will minimize this risk as much as possible 
by allowing you to pump or express breastmilk without the assistance of the study team if you 
wish, and by having a lactation consultant available to help with obtaining these samples.
Risk of venipuncture with 25g or smaller butterfly needle. If we are unable to get blood draws 
from an existing IV, we may have to use a 25g or smaller butterfly needle to obtain these 
samples. There is a risk of infiltration and discomfort,  and a small risk of vein inflammation and 
injury to local structures. However, we will minimize this risk as much as possible by using 
existing IV’s’ when possible and relying on trained nursing staff to complete these draws.
What are possible benefits from taking part in this study?


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Potential direct benefits of your participation in this study include availability of lactation 
consultants and keeping the breast pump that we give to you to help you express the breast 
milk. There are societal benefits in that there will be increased knowledge about whether 
ketamine administered during cesarean sections is metabolized into breastmilk, and ultimately 
the results of this study, if significant, will enable health care providers to improve the health of 
mothers.
If I agree to take part in this research study, will I be told of any new risks that may be found 
during the course of the study?
You will be promptly notified if, during the conduct of this research study, any new information 
develops which may cause you to change your mind about continuing to participate.
Will my insurance provider or I be charged for the costs of any procedures performed as part 
of this research study?
Neither you, nor your insurance provider, will be charged for the costs of any of the procedures 
performed for this research study (i.e., the Screening Procedures, Experimental Procedures, or 
Monitoring/Follow-up Procedures described above). You will be charged, in the standard 
manner, for any procedures performed for your routine medical care (e.g., the care for 
pregnancy and delivery at Magee Women's Hospital, and the receipt of labor epidural pain 
relief).
Will I be paid if I take part in this research study?
You will be paid for the work you perform in this study in the following schedule:
Participant Payment Schedule
Task
 Amount 
Breastmilk - T0 (infusion start)
 $                                 62.50 
Breastmilk - T4 (4 hours)
 $                                 62.50 
Breastmilk - T8 (8 hours)
 $                                 62.50 
Breastmilk - T12 (12 hours)
 $                                 62.50 
Breastmilk - T14 (2 hrs after infusion end)
 $                                 62.50 
Breastmilk - T16 (4 hours after infusion end)
 $                                 62.50 
Breastmilk - T20 (8 hours after infusion end)
 $                                 62.50 
Breastmilk - T36 (24 hours after infusion end)
 $                                 62.50 
Whole blood - T8 (8-10 hours into study drug infusion)
 $                                 62.50 
Whole blood - T12 (12 hours into study drug infusion)
 $                                 62.50 
Whole blood - T12.5 (0.5hr after infusion end)
 $                                 62.50 
Whole blood - T13 (1hr after infusion end)
 $                                 62.50 
Whole blood - T14 (2hr after infusion end)
 $                                 62.50 
Whole blood - T16 (4 hrs after infusion end)
 $                                 62.50 
Whole blood - T20 (8hrs after infusion end)
$                                  62.50
Whole blood - T36 (24hrs after infusion end)
 $                                 62.50 


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Urine - T24 (24hrs after infusion start)
 $                                   2.50 
Side Effect Diary - T1 (1hr into study drug infusion)
 $                                 62.50 
Side Effect Diary - T4 (4hr into study drug infusion)
 $                                 62.50 
Side Effect Diary - T8 (8hr into study drug infusion)
 $                                 62.50 
Side Effect Diary - T12 (12hr into study drug infusion)
 $                                 62.50 
Side Effect Diary - T16 (4hr after infusion end)
 $                                 62.50 
Side Effect Diary - T20 (8hr after infusion end)
 $                                 62.50 
Side Effect Diary - T24 (12hr after infusion end)
 $                                 62.50 
Vital Signs - T0.5 (30min into study drug infusion)
 $                                   4.62
Vital signs - T1 (60min into study drug infusion)
 $                                   4.62
Vital Signs - T2 (2hr into study drug infusion)
 $                                   4.62
Vital Signs - T3 (3hr into study drug infusion)
 $                                   4.62
Vital Signs - T4 (4hr into study drug infusion)
 $                                   4.62
Vital Signs - T8 (8hr into study drug infusion)
 $                                   4.62 
Vital Signs - T12 (12hr into study drug infusion)
 $                                   4.62
Vital Signs - T13 (1hr after infusion end)
 $                                   4.61
Vital Signs - T14 (2hr after infusion end)
 $                                   4.61
Vital Signs - T15 (3hr after infusion end)
 $                                   4.61
Vital Signs - T16 (4hr after infusion end)
 $                                   4.61
Vital Signs - T20 (8hr after infusion end)
 $                                   4.61
Vital Sings - T24 (12hr after infusion end)
 $                                   4.61
GRAND TOTAL
$                           1,500.00
You will be paid on a reloadable debit card. All compensation is taxable income to the 
participant regardless of the amount.  If a participant receives $600 or more in a calendar year 
from one organization, that organization is required by law to file a Form 1099 – Miscellaneous 
with the IRS and provide a copy to the taxpayer. Individuals who do not provide a social security 
number may still participate in the research, but the IRS requires that 28% of the payment be 
sent by the institution to the IRS for ‘backup withholding;’ thus you would only receive 72% of 
the expected payment.
Your participation may lead, in the future, to new inventions or products.  If the investigators 
can develop new products from the research use of your survey answers, there are currently no 
plans to share with you any money or other rewards that may result from the development of 
these new products.
Compensation for Eligible Referrals:

You might be eligible to receive additional compensation of $100, if you refer eligible 
participants to our study team. To receive compensation, the potential other participant 
you refer to us would need to have been screened by the study team and found eligible 
to participate. That potential participant may then choose to enroll in our study or may 
decline enrollment, but you will still receive the $100 compensation if they were 


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screened as eligible to participate in the study. If you refer a participant that is screened 
ineligible, you will receive no compensation for this referral. 
Who will pay if I am injured because of taking part in this study?
If you believe that the research procedures have resulted in an injury to you, immediately 
contact the Principal Investigator who is listed on the first page of this form. Emergency medical 
treatment for injuries solely and directly related to your participation in this research study will 
be provided to you by the hospitals of UPMC.  Your insurance provider may be billed for the 
costs of this emergency treatment, but none of those costs will be charged directly to you. If 
your research-related injury requires medical care beyond this emergency treatment, you will 
be responsible for the costs of this follow-up care. Currently, there is no plan for any additional 
financial compensation. You waive no legal rights by signing this consent. 
Will information be recorded in my medical record?
The medication infusion will be recorded in your medical record as a medication given to you. 
Medication infusion rates and any adjustments will be recorded in your medication 
administration record in your medical record. A copy of this consent document will be placed in 
your paper medical record.
Who can I reach out to with questions about the breastmilk pumping that occurs during this 
study?
If you have any questions about or issues with lactation following your participation in this 
research, please reach out to the study team. We will will be available to you for evaluation or 
counseling at your request, and there will also be a lactation consultant readily available. 
Who will know about my participation in this research study?
Any information about you obtained from this research will be kept as confidential (private) as 
possible.  All records related to your involvement in this research study will be stored in a 
locked file cabinet in a secured office at Magee-Womens Hospital, or on secure servers behind 
the UPMC firewall. Provided e-mail address will be stored in a file within a secure server and 
will be used strictly for research study purposes. Your identity on these records will be indicated 
by a case number rather than by your name or other personal identifiers, and the information 
linking these case numbers with your identity will be kept separate from the research records.  
You will not be identified by name in any publication of the research results unless you sign a 
separate consent form giving your permission.
Will this research study involve the use or disclosure of my identifiable medical information?
This research study will involve the recording of current and/or future identifiable medical 
information from your hospital and/or other (e.g., physician office) records. This includes things 
like your age, health history, medications you are taking, social history and information about 
your pregnancy and delivery. It will also include information about your labor and delivery, 
including details and duration of your cesarean section and your pain assessment scores and 


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medications during your hospital stay. A copy of this consent form and information from the 
study such as drug dosing, pain control and recovery will be recorded in your medical record.
Who will have access to identifiable information related to my participation in this research 
study?
In addition to the investigators listed on the first page of this authorization (consent) form and 
their research staff, the following individuals will or may have access to identifiable information 
(which may include your identifiable medical information) related to your participation in this 
research study: 
Authorized representatives of the University of Pittsburgh Office of Research Protections may 
review your identifiable research information (which may include your identifiable medical 
information) for the purpose of monitoring the appropriate conduct of this research study. In 
unusual cases, the investigators may be required to release identifiable information (which may 
include your identifiable medical information) related to your participation in this research 
study in response to an order from a court of law.  If the investigators learn that you or 
someone with whom you are involved is in serious danger or potential harm, they will need to 
inform, as required by Pennsylvania law, the appropriate agencies. 
Authorized representatives of the UPMC hospitals or other affiliated health care providers may 
have access to identifiable information (which may include your identifiable medical 
information) related to your participation in this research study for the purpose of (1) fulfilling 
orders, made by the investigators, for hospital and health care services (e.g., laboratory tests, 
diagnostic procedures) associated with research study participation; (2) addressing correct 
payment for tests and procedures ordered by the investigators; and/or (3) for internal hospital 
operations (i.e. quality assurance).  
Representatives from the Food and Drug Administration and the National Institutes of Health 
may access research records with your private information for the purpose of monitoring the 
research and use of study drug.
In the future, the investigators may decide to share data or samples with other investigators 
both within and outside of this institution. If that were to occur, we would de-identify all of 
your information prior to sharing data in this way. There are no plans at the present but future 
research could include genetic or whole genome testing on your samples. 
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, documents, 
or biospecimens that may identify you in any federal, state, or local civil, criminal, 
administrative, legislative, or other action, suit, or proceeding, or be used as evidence, for 
example, if there is a court subpoena, unless you have consented for this use. Information, 
documents, or biospecimens protected by this Certificate cannot be disclosed to anyone else 
who is not connected with the research except, if there is a federal, state, or local law that 


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requires disclosure (such as to report child abuse or communicable diseases but not for federal, 
state, or local civil, criminal, administrative, legislative, or other proceedings; if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other 
scientific research, as allowed by federal regulations protecting research subjects. 
For how long will the investigators be permitted to use and disclose identifiable information 
related to my participation in this research study?  
The investigators may continue to use and disclose, for the purposes described above, 
identifiable information (which may include your identifiable medical information) related to 
your participation in this research study for a minimum of seven years after final reporting or 
publication of a project. Per University of Pittsburgh policy all research records must be 
maintained for at least 7 years following final reporting or publication of a project. For projects 
involving children, records must be maintained for 5 years past age of majority (age 23 per PA 
State law) after study participation ends.
Can I expect to be automatically advised or referred if any survey results show concerns for 
me?
There are no questions in Part 1 of this study that would indicate the need for emergency care. 
Should you, at any time, express any concerns about self-harm or a blue mood, you will be 
given contact information for Magee Behavioral Health (412-624-2000 option 3) or the Resolve 
Crisis Line (1-888-796-8226).
Is my participation in this research study voluntary?
Your participation in this research study, to include the use and disclosure of your identifiable 
information for the purposes described above, is completely voluntary.  If you do not provide 
your consent for the use and disclosure of your identifiable information for the purposes 
described above, you will not be allowed to participate in the research study.  Whether or not 
you provide your consent for participation in this research study will have no effect on your 
current or future relationship with the University of Pittsburgh.  Whether or not you provide 
your consent for participation in this research study will have no effect on your current or 
future medical care at a UPMC hospital or affiliated health care provider or your current or 
future relationship with a health care insurance provider.
May I withdraw, at a future date, my consent for participation in this research study?
You may withdraw, at any time, your consent for participation in this research study, to include 
the use and disclosure of your identifiable information for the purposes described above.  
(Note, however, that if you withdraw your consent for the use and disclosure of your 
identifiable medical record information for the purposes described above, you will also be 
withdrawn, in general, from further participation in this research study.)  Any identifiable 
research or medical information recorded for, or resulting from, your participation in this 
research study prior to the date that you formally withdrew your consent may continue to be 
used and disclosed by the investigators for the purposes described above. 


University of Pittsburgh MODCR18120046-017    Effective: 4/27/2021    Expires: 4/20/2022
                                                                          Page 12 of 13  
  
To formally withdraw your consent for participation in this research study you should provide a 
written and dated notice of your decision to withdraw to the principal investigator of this 
research study at the address listed on the first page of this form.
Your decision to withdraw your consent for participation in this research study will have no 
effect on your current or future relationship with the University of Pittsburgh.  Your decision to 
withdraw your consent for participation in this research study will have no effect on your 
current or future medical care at a UPMC hospital or affiliated health care provider or your 
current or future relationship with a health care insurance provider.
If I agree to take part in this research study, can I be removed from the study without my 
consent?
It is possible that you may be removed from the research study by the researchers if, for 
example, conditions during your pregnancy or delivery render you ineligible. 
A description of this clinical trial will be available on www.clinicaltrials.gov, as required by US 
Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time.
************************************************************************
VOLUNTARY CONSENT
All of the above has been explained to me and all of my current questions have been answered.  
I understand that I am encouraged to ask questions about any aspect of this research study 
during the course of this study, and that such future questions will be answered by the 
researchers listed on the first page of this form.  
Any questions which I have about my rights as a research participant will be answered by the 
Human Subject Protection Advocate of the IRB Office, University of Pittsburgh (1-866-212-
2668).
By signing this form, I agree to participate in this research study, and I authorize the use of my 
medical record for the purpose described above. A copy of this consent form will be given to 
me.
________________________________
Participant’s Signature
____________________
Date and time


University of Pittsburgh MODCR18120046-017    Effective: 4/27/2021    Expires: 4/20/2022
                                                                          Page 13 of 13  
  
Participant Name (printed)
CERTIFICATION of INFORMED CONSENT
I certify that I have explained the nature and purpose of this research study to the above-
named individual(s), and I have discussed the potential benefits and possible risks of study 
participation.  Any questions the individual(s) have about this study have been answered, and 
we will always be available to address future questions as they arise.
I further certify that no research component of this protocol was begun until after this consent 
form was signed.
___________________________________
________________________
Printed Name of Person Obtaining Consent
Role in Research Study
_________________________________
____________
Signature of Person Obtaining Consent
Date and time

SAP_004.pdf: 
Pharmacokinetics and Pharmacodynamic Data 
Analysis Plan PART 1 
For 
PROTOCOL:  NCT04037085 and FDAAA801 
 
STUDY TITLE: 
Ketamine to Improve Recovery After Cesarean 
Delivery – Part 1 
(KINETIC) 
 
VERSION 2.0 
DOCUMENT DATE: 11/20/2022 
 
 
 
 
 


I. Clinical Protocol 
In a prospective, open label, observational design study, women who were weaning from breastfeeding 
were enrolled. Women were included if they were ≥18 years of age, able to provide informed consent, 
weaning from breastfeeding, ASA physical status 1, 2, or 3, and producing a minimum of 2mL breast milk 
every 24 hours. They were excluded if they were allergic to study medications, ASA physical status 4 or 
greater, had a history of psychiatric comorbidity, uncontrolled hyperthyroidism, cardiac disease, fever, 
hypertension, history of hallucinations, alcohol, or illicit substance abuse, were on chronic opioid therapy, 
or had chronic pain disorders.  
II. Dose Administration 
Subjects received a sub-anesthetic ketamine infusion at 0.1 mg/kg/hour for 12 hours (not to exceed 
8mg/hr dose). The justification for intravenous administration for 12 hours of 0.1mg/kg/hr are based on 
pharmacokinetic studies in humans18-20. Ketamine produces analgesia at plasma concentrations of 100-
200ng/mL, which is a fraction of the plasma concentrations associated with general anesthetic doses 
(9000-25,000 ng/mL)18, 19. In longitudinal studies reporting ketamine infusions from 0.05 -1mg/kg/hr, 
significant reductions in pain scores with minimal adverse events and no psychomimetic effects were 
observed over infusions lasting up to 5 days, while the effect of ketamine on pain scores were notably 
varied according to infusion duration21, 22. 
III. PK Sampling Schedule of Treatment Group 
Blood samples (2-3mL each) were collected at 8, 10, 12, 12.5, 13, 14, 16, and 20 hours after ketamine 
infusion start. Plasma was obtained by centrifugation at room temperature and kept frozen until analysis. 
The entire human milk expressed was collected starting at the time of infusion initiation (t0) and ending 
12 hours after the infusion was stopped (t24). Breastmilk was labeled by collection time and weighed to 
estimate the volume (1 gram = 1 mL) and stored at -80oC until analysis. Patient vital signs were 
monitored every hour and continuous pulse oximetry was done for 12 hours during the infusion and for 
12 hours after infusion.  
IV. Analytic Methods: Liquid Chromatography-tandem Mass Spectrometry (LCMS/MS) Assay for 
Ketamine and Metabolites in Breast 
Samples were separated using a Waters UPLC equipped with Acquity UPLC BEH RP18 1.7μm, 2.1 × 100 
mm column combined with a guard filter (Waters # 289002078). The Liquid Chromatography (LC) 
method consisted of a gradient mobile phase of Solvent A (95% 2mM Ammonium Acetate + 5% 


Acetonitrile + 0.1 % Formic Acid) and Solvent B (95% Acetonitrile and 5% Water) for elution of the 
analyte. The gradient started at 100% of Solvent A which was held for 1.0 minute and then changed to 
80% Solvent A and 20% Solvent B which was kept constant for the next 3 minutes. The solvent 
composition then changed to 65% Solvent A and 35% Solvent B over 0.1 min and then immediately to 
30% Solvent A and 70% Solvent B which was maintained for 1 minute. The gradient then returned to the 
initial solvent condition of 100% Solvent A, achieving the initial base line. The total run time was 7 
minutes with a flow rate of 0.3 mL/min.  
Analysis was performed on a Waters TQ-S Mass Spectrometer (Waters, Milford, MA) in positive electron 
spray mode (+ESI) using multiple reaction monitoring (MRM). The following MRM settings were 
employed: Capillary Voltage 1.5kV, de-solvation temperature 500°C, Cone gas flow 150 L/h, de-solvation 
gas flow 1000 L/h; Argon pressure 0.15 mL/min, Nitrogen pressure 7 bar and dwell time was 0.038 sec. 
The extracted ions following MRM transitions monitored were m/z 237.84→124.994 for KET, m/z 
223.9→125.01 for NKET, m/z 221.9→141.83 for DHNK, m/z 241.9→128.91 for KET-D4 (IS for KET 
and DHNK) and m/z 227.9→128.96 for NKET-D4 (IS for NKET). The LC and mass spectrometer were 
controlled, and data collected using Masslynx® software version 4.2 (Waters Corporation, Milford MA). 
Ketamine (KET) and its metabolites (NKET & DHNK) were analyzed in plasma and breast milk samples 
using ultra high-pressure liquid chromatography and mass spectrometric analysis. The developed assay 
was linear between 0.05 - 100 ng/ml and Coefficient of Variability (CV) of the assay was less than 10%. 
V. 
PK Calculations 
The pharmacokinetic parameters were calculated using Phoenix™ WinNonlin 8.3.4 (Certara, Princeton 
NJ). A two compartment PK model was used to estimate PK parameters of ketamine. These parameters 
included Area Under the Curve (AUC) estimates, the elimination half- life (t½), clearance (CL), Area 
Under Moment Curve (AUMC), Mean Residence Time (MRT) and Volume Distribution Steady State 
(Vdss). Statistics will include Mean, Standard deviation (SD), and range where applicable. 
a. Area Under the Curve (AUC) is defined as the area under the concentration-time curve. 
AUC was calculated by linear trapezoidal method.  
b. Elimination half-life (t½) is the time required for drug concentration to decrease by one-
half at the end drug dosing. Elimination half-life was obtained from the slope of terminal 
elimination phase.  
c. Clearance (CL) is calculated as the Dose/𝐴𝑈𝐶0−∞ and calculated by Phoenix 
WinNonlin. 


d. Volume Distribution Steady State (Vdss) is the period of dynamic equilibrium of the 
drug calculated as the amount of drug in the body at time, t divided by the plasma 
concentration of the drug at time, t.  These data were calculated by Phoenix WinNonlin. 
e. Metabolic ratio was calculated for each metabolite using the formula: 
𝑀𝑒𝑡𝑎𝑏𝑜𝑙𝑖𝑐 𝑟𝑎𝑡𝑖𝑜= 𝑀𝑒𝑡𝑎𝑏𝑜𝑙𝑖𝑡𝑒 𝐴𝑈𝐶0−∞
𝑃𝑎𝑟𝑒𝑛𝑡 𝐴𝑈𝐶0−∞
 
VI. Milk to Plasma Ratio 
Milk to plasma ratio for KET, NKET, and DHNK were calculated by dividing the concentration of the 
respective components Ketamine and Ketamine metabolites in human milk by plasma concentration at the 
corresponding times (± 30 min). Ratios higher than 1 indicate breastmilk concentrations of ketamine and 
the metabolites would be higher in breastmilk than in maternal plasma concentrations. 
VII. 
Relative Infant Dose (RID) Calculations 
The relative infant dose was calculated from the concentrations of ketamine and its metabolites in breast 
milk at different times following ketamine administration to the women. The concentration of ketamine 
and its metabolites were converted to amount by multiplying with the volume of breast milk collected at 
various time intervals. The cumulative dose of ketamine and molar equivalents of metabolites was 
calculated and RID was calculated using the formula 23-25:  An RID ≤10% was considered low24. 
𝑅𝐼𝐷 (%) = 𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑖𝑛𝑓𝑎𝑛𝑡 𝑑𝑜𝑠𝑒 𝑣𝑖𝑎 𝑏𝑟𝑒𝑎𝑠𝑡 𝑚𝑖𝑙𝑘 (
𝑚𝑔
𝑘𝑔
𝑑𝑎𝑦) 𝑋 100 ÷ 𝑚𝑎𝑡𝑒𝑟𝑛𝑎𝑙 𝑑𝑜𝑠𝑒 (
𝑚𝑔
𝑘𝑔
𝑑𝑎𝑦) 
VIII. 
Descriptive Statistics  
Descriptive Statistics will include participant characteristics such as maternal age, maternal race, gravida, 
parity, ASA rating, and weight. Means and standard deviations (SD) are calculated for maternal age and 
weight. Medians and range are used for maternal gravida, parity, and ASA rating. Maternal race is noted 
as a proportion of the total sample. 
 
 
 


 
 

Prot_003.pdf: 
 
 
 
Pharmacokinetics and Pharmacodynamic Clinical Protocol  
For 
PROTOCOL:  NCT04037085  
 
STUDY TITLE: 
Ketamine to Improve Recovery After  
Cesarean Delivery – Part 1 
(KINETIC) 
 
VERSION WITH MODIFICATIONS APPROVED BY 
HUMAN SUBJECTS PROTECTION REVIEW BOARD 
(IRB) DATE: 4/28/2021 
 
 


Brief Description 
This is a drug study that will examine the physiochemical, PK/PD properties of ketamine infusion in postpartum 
lactating women and in women weaning from breastfeeding. Part 1 of this study will inform the safety of a 
future planned RCT studying the effect of ketamine vs. placebo administered during scheduled cesarean 
deliveries or in weaning women on pain, opioid use, side effects, breastfeeding, and other outcomes. 
 
15 (goal of 6 complete subjects) mothers will be recruited who are planning to either exclusively bottle-feed or 
to withhold breastfeeding for the first 27 hours after birth (during infusion of 12 hours, plus 15 hours after 
infusion) or they will be women who have been breastfeeding and are planning on weaning their baby off of the 
breastmilk who will be at the CTRC clinic for 24 hours total. For the cesarean population, after cord clamping, 
an intravenous infusion of 0.1mg/kg/hr for 12 hours will be started without a loading dose. If the patient is a 
weaning woman, they will come into the CTRC clinic in Montefiore and will have infusion in the clinic for 12 
hours. Side effects, vital signs, and pain/analgesia endpoints will be monitored and recorded. 
Breastmilk/colostrum, serum, and urine will be collected to measure ketamine and its metabolites. The results 
of part 1 will inform appropriate future trial in Part 2 (the Phase 2 RCT) to either exclude or permit 
breastfeeding mother-infant dyads. 
Study Aims 
The objective of this study is to assess pharmacokinetics of ketamine in the women immediately post 
cesarean delivery or women weaning from breastfeeding. Study Hypotheses: Breastmilk secretion of 
ketamine is low and poses minimal risk for neonatal exposure 
 
Study Aims: 
Aim 1. Evaluate breastmilk secretion of ketamine and its metabolites during and after administration 
of intravenous ketamine infusion in women immediately post C-section or women weaning from 
breastfeeding 
Aim 2. Quantify pharmacokinetics of ketamine infusion in lactating people 
Study Design 
1. Total number of subjects to be enrolled at this site: 
15 (maximum) 
2. Describe and explain the study design: 
Open-label lead-in evaluation of ketamine infusion and breastmilk secretion. 
 
Part 1 is an open-label evaluation in women who are either exclusively bottle-feeding, planning 
to withhold breastfeeding for the first 27 hours after birth, or weaning women. The goal is to get 
6 complete patients (target n=6). Analysis of breastmilk for ketamine and metabolites will be 
done on each patient. The results of this part will inform conducting an additional future open-
label evaluation in breastfeeding mother-infant dyads for ketamine and metabolites. 
 
The patients enrolled will undergo an open-label sub-anesthetic ketamine infusion at 0.1 
mg/kg/hr to assess breastmilk secretion of ketamine and its metabolites. These women will be 
selected for their plan to exclusively bottle-feed or will be weaning; they will then receive the 
ketamine infusion in the trial dosing protocol, and provide blood and breastmilk samples during 
and after ketamine infusion, so that ketamine and its metabolites concentrations can be 
assessed. 
 


Protocol for Study Drug/Intervention: 
Ketamine - 0.1 mg/kg/hr IV infusion for 12 hours, not to exceed 8mg/hr. 
Weight-based dosing will be done on term body weight (kg), minus 41% of ponderal increment 
(for the post-cesarean delivery cohort) 
 
3. Describe the primary and secondary study endpoints: 
Primary outcome: Breastmilk transfer: concentration of ketamine and its metabolites in 
breastmilk 
 
4. List the inclusion criteria: 
Cesarean Section Population: 
Adult female patients (i.e., ≥18 years of age) 
Able to provide informed consent 
Cesarean Delivery, Scheduled or Non-Emergent (delivery within 15 minutes not necessary), 
ASA PS 2 or 3, with or without E designation (delivery within 15 minutes not necessary) 
Spinal anesthesia with intrathecal morphine 
Multimodal postop analgesia with IV ketorolac, PO NSAID, and PO APAP 
Women who do not plan to breastfeed or who want to temporarily withhold breastfeeding 
 
Weaning Women Population: 
Adult female patients (i.e., ≥18 years of age) 
Able to provide informed consent 
Female weaning baby off of breastfeeding 
ASA PS 1, 2 or 3 
Minimum production of 2mL/24 hours breast milk 
5. List the exclusion criteria: 
Cesarean Section Population: 
Cesarean Delivery under General Anesthesia 
Allergies to study medications 
ASA PS 4 or 4E 
ASA PS with E designation because delivery within 15 minutes required 
ASA PS greater than 4 (moribund patients) 
Contraindications to spinal anesthesia 
Contraindications to NSAIDs (gastric bypass, etc.) 
Contraindication to any other multimodal analgesia medicine 
Psychiatric history (depression and anxiety NOT exclusion criteria) 
Uncontrolled hyperthyroidism 
Cardiac disease 
Fever 
Hypertension 
Adverse occurrence during caesarean section such as hemorrhage, need for transfusion, 
hemodynamic instability 
Placenta accreta or previa with large anticipated blood loss 
History of hallucinations, alcohol or illicit substance use/abuse 
History of chronic opioid therapy, or chronic pain (chronic pain - defined by any condition 
requiring consistent follow up with pain specialist or daily administration of pain medications 
that could augment sedative effects) 
Pre-eclampsia with severe features 
 


Weaning Women Population: 
Allergies to study medications 
ASA PS 4 or 4E 
ASA PS greater than 4 (moribund patients) 
Psychiatric history (depression and anxiety NOT exclusion criteria) 
Uncontrolled hyperthyroidism 
Cardiac disease 
Fever 
Hypertension 
History of hallucinations, alcohol or illicit substance use/abuse 
History of chronic opioid therapy, or chronic pain (chronic pain - defined by any condition 
requiring consistent follow up with pain specialist or daily administration of pain medications 
that could augment sedative effects) 
Methods 
1. Provide a detailed description of all research activities  
PART 1: LACTATION STUDY 
Women who are planning not to breastfeed, who are willing to withhold breastfeeding for the 
first 27 hours after delivery, or women who are weaning off of breastfeeding will be 
approached. 
 
After electronic screening and confirming eligibility, approach will be by the clinical anesthesia 
team or by the bedside nurse to assess the patient’s interest in hearing more about the study. 
Interested patients will be provided with a full explanation of study-related goals and 
procedures. The informed consent document will be reviewed in its entirety with the potential 
subject. All questions will be answered to the subjects’ satisfaction. The patient may decide on 
participation in the study at any time during or after the initial encounter, and the desire and 
duration for a potential waiting period will be at the full discretion of the subject. The study 
coordinator or investigators can be contacted after the subject makes a volitional decision to 
participate in the study. The physician investigators will obtain written informed consent. The 
consent will be provided by the patient themselves; no patients will be approached or recruited 
if they are unable to consent for themselves. Subjects will not be informed of the outcome of 
the study at this time except through routine reporting structures available to the public forum 
via ClinicalTrials.gov. 
 
OR Women who are weaning from breastfeeding. We will use multiple recruitment methods 
which are shown in the recruitment section. The women will come into the CTRC in Montefiore 
to provide consent. Interested patients will be provided with a full explanation of study-related 
goals and procedures. The informed consent document will be reviewed in its entirety with the 
potential subject. All questions will be answered to the subjects’ satisfaction. The patient may 
decide on participation in the study at any time during or after the initial encounter. The study 
coordinator or investigators can be contacted after the subject makes a volitional decision to 
participate in the study. The physician investigators will obtain written informed consent. The 
consent will be provided by the patient themselves; no patients will be approached or recruited 
if they are unable to consent for themselves. A study physician will perform a history and 
physical and confirm ASA inclusion criteria after consent on day of study drug administration. 
For this weaning population, a urine pregnancy test will be performed the morning of CTRC 
visit, after informed consent and prior to any study related procedures. A positive test allows 


the PI or CO-Is to re-evaluate the participants eligibility for this study. Subjects will not be 
informed of the outcome of the study at this time except through routine reporting structures 
available to the public forum via ClinicalTrials.gov. The CTRC has 24/7 RN staff and it will be a 
1:1 participant:RN ratio. All staff are trained on IV ketamine protocol. They will be discharged 
after 24 hours after the start of infusion or as seen medically fit by the discharging physician. 
 
Ketamine will be delivered in an open-label fashion as follows: 0.1mg/kg/hr IV infusion after 
cord clamping or at CTRC at a scheduled time with the participant and clinic (maximum 
allowable dose 8mg/hr infusion rate), for a total duration of 12 hours. Pharmacokinetic studies 
will be performed on breastmilk, serum, and urine samples. 
 
Blood samples: 3mL whole blood at each sample from an indwelling intravenous catheter or by 
fresh sample by 25g or smaller butterfly needle. Specimens will be placed on ice and stored 
within 24 hours at -20 to -80C until analysis. Timepoints for collection: 8-10hrs into study drug 
infusion; 12hrs into study drug infusion; after infusion end at the following times: 0.5hrs, 1hr, 
2hr, 4hr, 8hr, 24hr. 
 
Urine: Total volume of maternal urine will be taken in the first 24 hours post-operatively. 
Collected in hat placed in toilet bowl and filled into a urine container. Samples can be 
stored/stable at room temperature and transported to the laboratory for analysis within 24 
hours. 
 
Breastmilk: colostrum/breastmilk samples will be expressed by hand expression or pump to 
get total volume into "snappies (R)" specimen collection devices. Specimens will be placed on 
ice and stored within 24 hours at -20 to -80C until analysis. Timepoints for collection: T0-2hrs 
after infusion start (at first opportunity), during infusion (4hrs, 8hrs, 12hrs), after infusion ends 
(2hrs, 4hrs, 8hrs, 24hrs). Per study team communication, the post c-section and weaning 
samples will undergo the same analysis for assessment of metabolites, confirmed by Co-I, Dr 
Venkataraman, overseeing the analysis. 
 
Pain assessments: During 72 hour hospital stay, medical records will be reviewed to collect 
pain scores during the hospital stay 
 
Side effect electronic diary: a novel app has been developed for the purpose of this study to 
make sound alerts to collect data at appropriate times. Assessments will be made within 1hr 
after start of study drug (at the earliest possible time); every 4 hr thereafter until 12 hr after 
study drug infusion start. Assessments will include: Dizziness, lightheadedness, bad dreams, 
nausea, vomiting, itchiness, hallucinations; LSD short form of Addiction Research Center 
Inventory, ARCI (psychomimetic effects). 
 
Maternal vital signs (blood pressure, pulse rate, temperature, heart rate, respirations, and 
oxygen saturation, Richmond agitation-sedation scale (RASS) score) will be measured after 
infusion start: every 30 min for one hour, then q1hr for 3 hours, then every 4 hours per existing 
clinical standards for the 12-hour duration of infusion (existing clinical standards: blood 
pressure, pulse rate, temperature, heart rate, respirations, and oxygen saturation). If the 
infusion rate is increased by the anesthesiologist investigators, then vitals are rechecked within 
one hour. When the infusion is discontinued at 12 hours, vital signs monitoring will be hourly 
for the first 4 hours, then every 4 hours including blood pressure, pulse rate, temperature, 
heart rate, respirations, and oxygen saturations, until 24 hours after the start of the study drug 
infusion (= 12 hours after study drug discontinuation)