Clinical trial NCT03733145
Conditions: Hypertension
Keywords: Angiotensin II Angiotensin Converting Enzyme Inhibitors Angiotensin Receptor Blockers Anesthesia-Mediated Hypotension
Sponsor: Wake Forest University Health Sciences
Start date: 2019-10-03; Completion date: 2023-03-21
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Hypotension in adult patients undergoing general anesthesia is common. This can lead to hypoperfusion of vital organs, organ damage, and states of increased metabolic duress. This may be worse in patients with underlying essential hypertension and worse in patients taking Angiotensin Converting Enzyme Inhibitors (ACE) and Angiotensin Receptor Blockers (ARBs). Intravenous (IV) administration of Ang II may be an effective treatment of hypotension in this patient population.

Detailed description:
Hypotension in adult patients undergoing general anesthesia is common. Many of the body's normal mechanisms to maintain adequate blood pressure in the non-anesthetized state are significantly altered by anesthetic agents, which may lead to hypotension. This can lead to hypoperfusion of vital organs, organ damage, and states of increased metabolic duress. In response to this it has become standard of care to attempt to maintain blood pressure levels within 20% of baseline in most patients under anesthesia. Maintaining the baseline blood pressure is important as patients may have pathology such as coronary artery disease, carotid stenosis, and renal artery stenosis, and hypotension may compromise the perfusion of these organs. Vasodilation also plays a key role in hypotension due to general anesthesia. Therefore, the intravenous (IV) administration of Ang II may be an effective treatment of hypotension in this patient population.The objective of this study is to determine the infusion rate of Ang II that is necessary to return systolic blood pressure (SBP) to within 5% of baseline or greater in patients with essential hypertension taking ACE inhibitors, ARBs, or different classes of antihypertensive agents and further to determine the plasma levels of different RAAS components

Arms: arm 1: Participants taking ACE inhibitors (angiotensin-converting enzyme inhibitors)will be placed into this group. Intervention: Drug: Angiotensin II. arm 2: Participants taking ARBs (angiotensin-receptor blockers) will be placed into this group. Intervention: Drug: Angiotensin II. arm 3: Participants taking any other class of Antihypertensive Agents will be placed into this group. Intervention: Drug: Angiotensin II.
Interventions: intervention 1: Angiotensin II
Intervention descriptions: intervention 1: Participants in the ACE inhibitors, angiotensin-receptor blockers (ARBs), and Other Classes of Antihypertensive Agents who's systolic blood pressure (SBP) is less than 80% of the baseline reading is detected, will have Ang II initiated at 2 ng/kg/min through a peripheral IV. The infusion will be increased at the discretion of the clinical team based on the response of the patient until a SBP within 5% of the baseline SBP.

Protocol documents:
ICF_001.pdf: 
Official Title:  A Dose Finding Trial for Angiotensin II in Hypertensive Adults on Angiotensin Converting 
Enzyme Inhibitors and Angiotensin Receptor Blockers with Anesthesia-Mediated Hypotension
NCT03733145
IRB Approval Date:  06/17/2024


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DEPARTMENT OF ANESTHESIOLOGY 
A DOSE FINDING TRIAL FOR ANGIOTENSIN II (GIAPREZA) IN 
HYPERTENSIVE ADULTS ON ANGIOTENSIN CONVERTING ENZYME 
INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS WITH 
ANESTHESIA-MEDIATED HYPOTENSION 
INFORMED CONSENT FORM TO PARTICIPATE IN RESEARCH
ROHESH J. FERNANDO, MD, FASE, PRINCIPAL INVESTIGATOR
SUMMARY
You are invited to participate in a research study. The purpose of this research is to determine the 
dose of a particular drug called Angiotensin II (Giapreza) that is needed to appropriately 
maintain blood pressure in patients who normally take medications to treat high blood pressure 
(hypertension) but experience low blood pressure while under general anesthesia for surgery.  
You are invited to be in this study because you have hypertension (high blood pressure), are 
taking medications for this reason, and are undergoing a planned surgery under general 
anesthesia. 
Your participation in this research will involve zero additional visits, other than the usual visit 
for your planned surgery and the preoperative anesthesia visit that typically accompanies it.  
Participation in this study will involve receiving Angiotensin II intravenously after you are 
asleep under general anesthesia for surgery. However, you will only be given this medication if 
your blood pressure decreases enough to require being treated with medications.  In addition, you 
will have five blood samples drawn.  Two will be at the time that your intravenous line is placed 
in the preoperative holding room and three will be after you are under anesthesia.  All research 
studies involve some risk, however there are no significant risks expected in this study.  If you 
agree to take part in this study, there may or may not be direct benefit to you. We hope the 
information learned from this study will benefit other people in the future. The benefits of 
participating in this study may be: Angiotensin II (Giapreza) could be more effective in 
treating low blood pressure than the medications currently used.
Your participation in this study is voluntary.  You do not have to participate in this study if you 
do not want to.  You will not lose any services, benefits, or rights you would normally have if 
you choose not to participate. 
The remainder of this form contains a more complete description of this study. Please read this 
description carefully. You can ask any questions if you need help deciding whether to join the 
study. The person in charge of this study is Rohesh J. Fernando, MD, FASE. If you have 
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questions, suggestions, or concerns regarding this study or you want to withdraw from the study, 
his contact information is: 
.
If you have any questions, suggestions or concerns about your rights as a volunteer in this 
research, contact the Institutional Review Board at 
 or the Research Subject 
Advocate at Wake Forest at 
.
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you have high blood pressure (hypertension), are taking medications for this 
reason, and are undergoing a planned surgery under general anesthesia. Your participation is 
voluntary. Please take your time in making your decision as to whether or not you wish to 
participate. Ask your study doctor or the study staff to explain any words or information 
contained in this informed consent document that you do not understand. You may also discuss 
the study with your friends and family.
WHY IS THIS STUDY BEING DONE?
The purpose of this research is to determine the dose of a particular drug called Angiotensin II 
(Giapreza) that is needed to appropriately maintain blood pressure in patients who normally 
take medications to treat high blood pressure but experience low blood pressure while 
undergoing general anesthesia for surgery. This is important because the medications used to 
start and maintain anesthesia frequently cause a decrease in blood pressure.  
Currently, Angiotensin II (Giapreza) is approved by the US Food and Drug Administration 
(FDA) to treat low blood pressure associated with shock, but it has not been specifically 
approved for treating low blood pressure during anesthesia. 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
Ninety people will be recruited at Wake Forest Baptist Health in order to enroll sixty people in this 
study.
WHAT IS INVOLVED IN THE STUDY?
You will have five blood samples drawn. Two will be at the time that your intravenous line is 
placed in the preoperative holding room and three will be after you are under anesthesia. You 
will be seen in the holding area prior to your scheduled surgery. An intravenous line will then be 
placed, as is typical for patients having surgery, so that you can be given medications and fluids 
into your vein.  At that time the first two blood will be taken so that we can measure the levels of 
various hormones in your blood stream that your body uses to control your blood pressure. You 
will have your blood pressure and heart rate checked and recorded at that time as well.  
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Meeting Date Approved 6/17/2024          
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Once you are taken back to the operating room for surgery your blood pressure and heart rate 
will again be checked and your anesthesia team will give you medications to put you to sleep for 
surgery.  After you are sleeping your blood pressure will be checked every minute, which is 
typical for patients who have just been put under anesthesia.  If your blood pressure goes down 
below a certain point you will be started on a constant infusion of Angiotensin II (Giapreza) at a 
low dose.  The dose will be increased slowly if needed until your blood pressure returns almost 
back to where it started.  After your blood pressure remains stable on the infusion of medication 
for 5 minutes, the third and fourth blood samples will be drawn and the infusion of medication 
will be stopped.  Your blood pressure will be supported with other medications as needed per 
your anesthesia team.  Finally, a fifth blood sample will be drawn thirty minutes after the 
surgical procedure starts.   
You will have approximately 1-1.5 tablespoons of blood taken for each of the blood sample 
tubes. There will be a total of 5 blood samples that will be withdrawn from a vein at three time 
points. The first two samples will be taken in the holding room, the third and fourth samples will 
be taken 5 minutes after Angiotensin II infusion stabilization, and the fifth and final sample will 
be taken 30 minutes after Angiotensin II infusion.  The total amount of blood withdrawn during 
the study will be approximately 5 tablespoons. 
If your blood pressure does not drop to a level that requires treatment, then the study drug will 
not be administered. However, we may still draw the blood samples mentioned above to test the 
levels of hormones. This will be done for up to 15 patients that did not receive the study drug. 
The study team will call you seven days after your surgical procedure to ask how you have been 
feeling.  
HOW LONG WILL I BE IN THE STUDY?
You will be in the study for only about one week.  The study starts when we place your 
intravenous line in the holding room and ends after our follow up phone call, which will take 
place seven days after your surgical procedure.  If you are not feeling well at the time of the first 
follow up phone call, you may receive additional phone calls to determine whether you are 
experiencing a side effect due to receiving angiotensin II.
You can stop participating at any time. If you decide to stop participating in the study, we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. 
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. Risks and side effects related to the drug we are studying include: blood 
clots, low platelet count, fast heart rate, fungal infection, delirium, and increased blood sugars. 
These risks come from a study of Angiotensin II (Giapreza) that was performed on very sick 
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patients in the intensive care unit so it is unclear how likely these are to happen in a study on 
healthier patients.  
In addition, there is a slight risk of a breach of confidentiality.  We will do our best to protect 
your confidential information.  There also may be other side effects that we cannot predict. You 
should tell the research staff about all the medications, vitamins and supplements you take and 
any medical conditions you have. This may help avoid side effects, interactions and other risks.
You may experience discomfort, bruising and/or bleeding where the needle is inserted for your 
blood draws. Occasionally some people become dizzy, lightheaded, or feel faint. Infection may 
occur on rare occasions.  Frequent donation of blood can result in low iron in your blood (iron 
deficient anemia).  
Reproductive Risks and other Issues to Participating in Research
Due to unknown risks and potential harm from Angiotensin II (Giapreza) to the unborn fetus, 
sexually active women of childbearing potential must use a reliable method of birth control while 
participating in this study. Reliable methods of birth control are: abstinence (not having sex), oral 
contraceptives, intrauterine device (IUD), DepoProvera, tubal ligation, hysterectomy, vasectomy 
of the partner in a monogamous relationship (same partner), or if at least 2 years have passed 
since you experienced menopause. An acceptable, although less reliable, method includes 
“double barrier contraception.” Examples include the careful use of condoms and spermicidal 
foam or gel and/or a cervical cap or sponge. We encourage you to discuss this issue further with 
your physicians if you have any questions.
Pregnant women are excluded from participation in this study. If you are a sexually active 
woman of childbearing potential, we will perform a pregnancy test on the day of surgery to 
check for possible early pregnancy prior to starting treatment.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct benefit to you. We hope the 
information learned from this study will benefit other people in the future. The benefits of 
participating in this study may be: Angiotensin II (Giapreza) could be more effective in treating 
low blood pressure than the medications currently used.
WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment. You should talk to your doctor about all 
the choices you have. Instead of being in this study, you have these options:
You could elect to receive more traditionally used medications if support of your blood pressure 
is needed while you are under anesthesia.  How Angiotensin II (Giapreza) compares to these 
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00054661
Meeting Date Approved 6/17/2024          
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other medications is currently unknown. 
WHAT ARE THE COSTS?
All study costs, including any study medications and procedures related directly to the study, will 
be paid for by the study. Costs for your regular medical care, which are not related to this study, 
will be your own responsibility.
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
in scientific journals.  Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others.  There is always some risk that even de-identified information might be re-identified. 
Participant information may be provided to Federal and other regulatory agencies as required.  
The Food and Drug Administration (FDA), for example, may inspect research records and learn 
your identity if this study falls within its jurisdiction.
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 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, see below); 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. 
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the FDA which is funding this project or for information that must be 
disclosed in order to meet the requirements of the federal Food and Drug Administration 
(FDA).  You should understand that a Certificate of Confidentiality does not prevent you from 
voluntarily releasing information about yourself or your involvement in this research. If you 
want your research information released to an insurer, medical care provider, or any other person 
not connected with the research, you must provide consent to allow the researchers to release it.
The Certificate of Confidentiality will not be used to prevent disclosure for any purpose you 
have consented to in this informed consent document
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IRB Number:IRB00054661
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WILL YOU BE PAID FOR PARTICIPATING?
You will receive no payment or other compensation for taking part in this study.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by Wake Forest University Health Sciences. La Jolla 
Pharmaceutical Company will be providing support to Wake Forest University Health Sciences 
to help conduct this study. The study is also partially funded by the National Institutes of Health. 
The researchers do not, however, hold a direct financial interest in La Jolla Pharmaceutical 
Company or the product being studied.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance coverage 
for the usual and customary medical fees for reasonable and necessary treatment of such injuries 
or illnesses. To the extent research insurance coverage is available under this policy the reasonable 
costs of these necessary medical services will be paid, up to a maximum of $25,000. Wake Forest 
University Baptist Medical Center holds the insurance policy for this coverage. It provides a 
maximum of $25,000 coverage for each claim and is limited to a total of $250,000 for all claims 
in any one year. Wake Forest University Baptist Hospital does not assume responsibility to pay 
for these medical services or to provide any other compensation for such injury or illness. 
Additional information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at 
.
If you are injured, the sponsor may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the sponsor is required 
by law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call Rohesh J. Fernando, MD, FASE at 
 
or 
 after hours. 
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you and/or information we get from 
your medical records or other facilities about your health or behaviors is considered Protected 
Health Information. The information we will collect for this research study includes: information 
about your medical conditions, medications, your age, gender, weight, and vital signs. 
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If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study may be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations. 
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
provide required reports and to get approval for new products.  
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; La Jolla Pharmaceuticals, central laboratories, 
Attoquant Diagnostics GmbH, reading centers or analysis centers; the Institutional Review 
Board; representatives of Wake Forest Baptist Hospital; representatives from government 
agencies such as the Food and Drug Administration (FDA) or the Office of Human Research 
Protections (OHRP), the Department of Health and Human Services (DHHS), the National 
Institutes of Health (NIH),  and similar agencies in other countries. 
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for at least six years after the study is finished. At that time any 
research information not already in your medical record will either be destroyed or it will be de-
identified.  You will not be able to obtain a copy of your Protected Health Information in the 
research records until all activities in the study are completely finished. 
You can tell Rohesh J. Fernando, MD, FASE that you want to take away your permission to use 
and share your Protected Health Information at any time by sending a letter to this address:
Rohesh J. Fernando, MD, FASE
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However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form, you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. 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 Web site at any time. 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences. The investigators also have the right to stop your participation in the study 
at any time. This could be because they feel it is in your best interest, you have an unexpected 
reaction to the medication, or because they believe that an alternative medication to support your 
blood pressure would be better/safer.  
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Rohesh J. Fernando, MD, FASE at 
 or 
after hours. 
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
 or the 
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Research Subject Advocate at 
.
You will be given a copy of this signed consent form. 
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.   By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent (Printed):_____________________________
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
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Prot_SAP_002.pdf: 
Official Title:  A Dose Finding Trial for Angiotensin II in Hypertensive Adults on Angiotensin Converting 
Enzyme Inhibitors and Angiotensin Receptor Blockers with Anesthesia-Mediated Hypotension
NCT03733145
IRB Approval Date:  10/20/2020


Ver 10202020 
1 
Study Title: A Dose Finding Trial for Angiotensin II in Hypertensive Adults on Angiotensin 
Converting Enzyme Inhibitors and Angiotensin Receptor Blockers with Anesthesia-Mediated 
Hypotension  
Principal Investigator, Co-investigator(s): Rohesh J. Fernando, MD, FASE; Wes Templeton, MD; 
Roger Royster, MD; Ashley Talbott, MD; Sarah Kittner, MD; Ben Morris, MD; Chandrika Garner, MD; 
Darryl Henshaw, MD; Leanne Groban, MD; Carlos Ferrario, MD; Ashish Khanna, MD; 
Sponsor or funding source: This study will be primarily funded by the department of anesthesia and will 
be partially funded by the National Institutes of Health. In addition, La Jolla Pharmaceutical 
Company will be supporting the study in the amount of $19,926. 
Background, Rationale and Context 
Hypotension in adult patients undergoing general anesthesia is common. Many of the body’s normal 
mechanisms to maintain adequate blood pressure in the non-anesthetized state are significantly altered by 
anesthetic agents, which may lead to hypotension. In addition, anesthetic agents themselves can 
contribute to hypotension by a variety of mechanisms, including vasodilation.  The resultant hypotension 
can lead to hypoperfusion of vital organs, organ damage, and states of increased metabolic duress. This 
may be worse in patients with underlying essential hypertension and can even be further exacerbated in 
patients taking ACE inhibitors and ARBs.1 In response to this it has become standard of care to attempt to 
maintain blood pressure levels within 20% of baseline in most patients under anesthesia.2 Maintaining the 
baseline blood pressure is important as patients may have pathology such as coronary artery disease, 
carotid stenosis, and renal artery stenosis, and hypotension may compromise the perfusion of these 
organs. 
At this time there are a number of vasopressor agents which are commonly used to increase blood 
pressure in anesthetized patients undergoing surgery. These agents work either directly or indirectly 
through adrenergic receptors present in vascular smooth muscle and are in many ways non-specific 
vasoconstrictive agents. Some also affect contractility of the heart and can impact blood pressure through 
this mechanism as well. Angiotensin II (Ang II) is an endogenous peptide that is part of the renin-
angiotensin-aldosterone system (RAAS). The RAAS plays an integral role in maintaining and regulating 
blood pressure under normal physiologic conditions. In a randomized controlled trial, the ATHOS-3 
investigators found that Ang II was effective in raising blood pressure in patients with refractory 
vasodilatory shock.3   
As stated previously, vasodilation also plays a key role in hypotension due to general anesthesia. 
Therefore, the intravenous (IV) administration of Ang II may also be an effective treatment of 
hypotension in this patient population.  However, the dose or infusion rate that would be most effective at 
treating hypotension in patients under general anesthesia is currently unknown. Additionally, it is 
unknown if patients with essential hypertension taking ACE inhibitors or ARBs will respond differently 
than patients not taking these agents.  
In addition to measuring levels of Ang II (classic RAAS system), we also wish to study other components 
of RAAS. For example, angiotensin 1-7 provides counter regulation to the classic RAAS and increases in 
response to ACE inhibitors and ARBs.4 Bradykinin can also be responsible for hypotension and is 
potentiated by angiotensin 1-7. RAAS sampling could therefore allow a more comprehensive 
understanding of hypotension in our study population and provide a framework to better interpret results. 
RAAS testing can be done using liquid chromatography / mass spectrometry (LC/MS) or 
radioimmunoassay (RIA).  


Ver 10202020 
2 
Objectives 
The primary objective of this study is to determine the infusion rate of Ang II that is necessary to return 
systolic blood pressure (SBP) to within 5% of baseline or greater in patients with essential hypertension 
taking ACE inhibitors, ARBs, or different classes of antihypertensive agents for greater than two months 
and further to determine the plasma levels of different RAAS components (as measured by the Attoquant 
system) in patients preoperatively, following induction, at a steady state infusion level of Ang II, and 30 
minutes after surgical incision. In addition, a secondary objective is to determine how the levels of 
various RAAS components in the blood compare based on the method of analysis (liquid chromatography 
versus radioimmunoassay).  
Methods and Measures 
Design 
Patients scheduled for general surgery who are evaluated in our preoperative assessment clinic 
(PAC) will be recruited for participation. Recruitment and consent for participation in the study 
will be performed prior to day of surgery via telephone screen or in person at the PAC. If patient 
is consented via telephone screen and agrees to participate, a consent form will be electronically 
mailed, or physically mailed to the patient. Patient will be asked to sign consent and return 
electronically or by physical mail. Patient will also sign consent in person on day of, prior to 
surgery. Once initial consent is received, (Giapreza) will be prepared and ready for use during 
surgery. Women of childbearing age will be asked about level of sexual activity and use of birth 
control. Given that the safety of Ang II has not been demonstrated in pregnant patients, the only 
women of childbearing age who will be considered for recruitment are those that (1) are not 
sexually active; or (2) are sexually active and use an acceptable method of birth control; or (3) are 
surgically sterile; or (4) are at least 2 years postmenopausal; or (5) have a monogamous partner 
who is surgically sterile; or (6) are practicing double barrier contraception. Once recruited, we 
will verify on the day of surgery that the patient is still agreeable to participate in the study. 
Women of childbearing age will be asked to undergo a pregnancy test on the day of surgery and 
provide a negative result. The determination of whether the patient takes their anti-hypertensive 
on the day of surgery will be determined by the PAC’s normal practice and will be unaltered by 
this study. Our goal would be to enroll and obtain data on 15 patients for each group: (Arm 1) 
ACE group, (Arm 2) ARB group, and (Arm 3) patients on any other class of antihypertensive 
agent for greater than two months. There will also be a fourth comparison group (Arm 4) 
consisting of up to the first 15 enrolled patients whose SBP does not drop below the 80% baseline 
threshold after intubation.  It would be our intent to continue enrolling patients until a sample size 
of 15 patients for each of the 3 groups (Arms 1,2,3) have completed the protocol and received the 
trial medication. Once each of the three experimental arms of the study (Arms 1,2,3) have 15 
patients, enrollment in the fourth comparison group (Arm 4) will cease regardless of whether or 
not it has met the 15 patient goal. Based on an estimated incidence of hypotension of 40-60% 
following induction of anesthesia, we expect to have to consent approximately 90 patients. This is 
to account for patients who do not meet study criteria, thereby reaching our goal of 45 
experimental patients and the tentative 15 patient comparison group.1 
There will be a total of 5 blood samples taken at three time points throughout the duration of the 
study. Patients will have an IV line placed in the holding area prior to surgery. At this time, we 
will draw the first two 10cc blood samples (one for LC/MS analysis, one for RIA analysis) for 
study purposes while the patient is in the preoperational holding room. The RIA labs will be 
processed at Wake Forest Baptist Medical Center and is sponsored by a grant from the NHLBI of 
the NIH. , and the LC/MS labs will be analyzed through an external contracted laboratory to gain 
information for RAAS component testing. An initial set of vital signs including heart rate (HR), 


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non-invasive blood pressure (BP), and oxygen saturation (SpO2) will be checked in the holding 
room. We will also record all medications taken on the day of surgery. Once in the operating 
room and following placement of vital sign monitors, another non-invasive BP will be checked 
prior to anesthetic induction. This reading will be used as the baseline systolic blood pressure 
(SBP). Sequential Compression Devices (SCD) will be used for venous thromboembolism (VTE) 
prophylaxis during surgery and these will be applied prior to induction of general anesthesia. 
General anesthesia will then be induced with 1.5 mg/kg of propofol followed by 0.8 mg/kg 
rocuronium and the patient will be intubated.  If the dose of propofol is inadequate to achieve loss 
of consciousness, additional propofol may be given at the discretion of the attending 
anesthesiologist. In addition, a rapid sequence induction and intubation may also be allowed if 
clinically indicated for the safety of the patient as determined by the attending anesthesiologist.  
Anesthesia will be maintained with isoflurane in fresh gas such as oxygen and/or air. No 
vasopressors will be administered at induction or during intubation unless the SBP is less than 
80% of baseline for greater than 4 consecutive minutes. In that case, a rescue vasopressor such as 
phenylephrine will be given.  
 
Following intubation and before initial surgical incision, the BP will be checked using a non-
invasive BP cuff every minute for 10 minutes. If a SBP that is less than 80% of the baseline 
reading is detected, the clinical team will immediately cycle the BP cuff in order to confirm the 
presence of hypotension. At this point an infusion of Ang II will be initiated at 2 ng/kg/min 
through a peripheral IV (although the recommended starting dose of Ang II is listed as 
20ng/kg/min, this dosing regimen is based on patients in shock. The package insert also states 
that doses as low as 1.25ng/kg/min may be effective). Starting at a low dose will be important 
since patients taking ACE inhibitors may be more sensitive to Ang II. The BP will be checked 
every minute. The half-life of angiotensin 2 is < 1 minute and time to peak pharmacologic affect 
is less than 30-35 seconds so it will be necessary to monitor the blood pressure once per minute. 
The infusion will be increased at the discretion of the clinical team based on the response of the 
patient until a SBP within 5% of the baseline SBP has been achieved (although the rate will not 
be increased by more than 15ng/kg/min at a time and the rate will not exceed 80ng/kg/min based 
on the package insert dosing instructions). If the patient remains hypotensive despite use of the 
maximum dose of angiotensin II, then angiotensin II will be discontinued, the patient will be 
excluded from the study, and the blood pressure will be treated using conventional vasopressors. 
If a patient experiences SBP < 80% baseline for greater than four consecutive minutes after 
initiating Ang II, then a rescue vasopressor such as phenylephrine will be administered. This will 
be important for patients taking ARBs as they may be less sensitive to Ang II.  
 
We will record the infusion rate of Ang II, anesthetic level (i.e. end tidal agent concentration), 
HR, SBP, diastolic blood pressure, mean arterial pressure, and SpO2 every minute for the 
duration of the study period if an infusion was initiated. Once the SBP is within 5% of baseline or 
greater, the infusion will be continued at that rate for 5 minutes. If the measured SBP significantly 
exceeds the baseline SBP by ≥15%, the infusion will be reduced or halted at the discretion of the 
team taking care of the patient. After 5 minutes of reaching the target pressure of within 5% of 
baseline or greater the final infusion rate will be recorded. At this time the third and fourth blood 
samples (10cc LC/MS blood sample, along with a 10 cc RIA blood sample) will be taken to 
measure the serum levels of different RAAS components associated with normalization of the 
SBP under general anesthesia. The infusion of Ang II will be discontinued. This will mark the 
end of the dose finding trial for the patient. Further vasopressor administration will be at the 
discretion of the team taking care of the patient but will not include Ang II. A fifth and final 10cc 
blood sample for LC/MS RAAS testing will be drawn 30 minutes after incision.  
 


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4 
If the SBP for any enrolled patient does not drop below 80% of baseline in the first 10 minutes 
after intubation, Ang II will not be administered. However, we will still perform LC/MS RAAS 
10 minutes after intubation, and LC/MS RAAS sampling 30 minutes after surgical incision for up 
to 15 previously enrolled patients as a comparison group (Arm 4). Once Arm 4 reaches 15 
patients, any subsequent patients that do not experience a drop in SBP < 80% baseline will be 
excluded from the study and their LC/MS blood samples that were previously drawn will be 
discarded. However, we intend to analyze the RIA blood samples for up to 90 patients and these 
samples will not be discarded.  
 
 
Subjects selection criteria 
The study will recruit adult general surgery patients with underlying essential hypertension undergoing 
general anesthesia for elective general surgery. Patients will be recruited dependent upon their 
antihypertensive medication into the following arms.  
Arm 1: Patients must be on ACE inhibitors, in addition they can also be on other classes of 
antihypertensive medication except for ARB.  
Arm 2: Patients must be on ARBs, in addition they can also be on other classes of antihypertensive 
medication except for ACEi.  
Arm 3: Patients on any other antihypertensive medication, and must not be on an ACEi or ARB. 
Arm 4: Patients who qualify for arm 1, 2, or 3 but whose SBP does not drop below 80% of baseline in the 
first 10 minutes after intubation. 
 
• 
Inclusion Criteria 
o Diagnosis of hypertension and treatment for greater than 2 months and on the 
following medications 
▪ 
ACE inhibitors, in addition they can also be on other classes of 
antihypertensive medication except for ARB 
▪ 
ARBs, in addition they can also be on other classes of antihypertensive 
medication except for ACEi 
▪ 
Any other antihypertensive medication, and must not be on an ACEi or 
ARB 
o Patients undergoing general anesthesia 
o American Society of Anesthesiologists physical status 1-3 
o Age >/= 40 given that hypertension is not prevalent below this age 
 
• 
Exclusion Criteria 
o American Society of Anesthesiologists physical status 4-6 
o BMI > 40 
o History of deep venous thrombosis / thromboembolic disease 
o History of stroke, 
o Baseline SBP of ≥ 160 mmHg, 
o History of myocardial infarction or cardiac stents 
o Difficult airway 
o Asthma 
o Diagnosis of congestive heart failure of any stage, regardless of preserved or 
reduced ejection fraction; this includes both systolic heart failure and diastolic 
heart failure; 
o Diagnosis of chronic obstructive pulmonary disease of any stage; this includes 
diagnoses of chronic bronchitis and emphysema 
o Pregnant patients (safety of Ang II in pregnancy is unknown) 


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o Patients at increased risk for venous thromboembolic events such as current 
diagnosis of cancer and/or diagnosis of blood clotting disorders 
 
• 
Sample Size 
Our goal would be to enroll and obtain data on 15 patients for each group: ACE group, ARB 
group, and patients on any other class of antihypertensive agent for greater than 2 months. In 
addition, we would like to obtain data for up to 15 patients in the comparison group (Arm 4). 
The sample size was chosen due to its similarity to the ATHOS II dose-finding trial.9 It would 
be our intent to continue enrolling patients until a sample size of 15 patients for all 3 
experimental groups has been reached. Based on an estimated incidence of hypotension of 
40-60%, we expect to have to consent approximately 90 patients.1 This is not a multisite 
study. 
 
Interventions and Interactions 
The largest overall commitment of time from the patient will be in the PAC at the time of recruitment. 
One of the PAC attendings, or investigators, or study personnel will interview the patient explain the 
study and attempt to recruit the patient if they are eligible. The study participant will have their questions 
answered. If patient agrees to participate a consent form will be electronically mailed or physically 
mailed, to patient. Patient will be asked to sign consent and return electronically or by physical mail. 
Once initial consent is received, (Giapreza) will be prepared and ready for use during surgery 
 
On the day of surgery, the study participant will be identified in the holding area and a study 
representative will make sure that he or she has not changed their mind about participation and will 
answer any questions the study subject may have thought of since the interview in the PAC. Patient will 
be asked to physically sign consent in person on day of, prior to surgery. Labs will be drawn as described 
in the methods section. 
 
The participant will then be taken to the OR. After appropriate monitors are placed, induction of general 
anesthesia will be accomplished with propofol, rocuronium, and/or succinylcholine.  If there is a decrease 
in SBP greater or equal to 20% (as described in the methods section), Ang II will be administered starting 
at 2ng/kg/min. Ang II will be titrated until the SPB is within 5% of the baseline SBP (see methods section 
for exact details). The duration of Ang II administration will not exceed 20 minutes. 
 
After the surgery, a study representative will see the patient in the post anesthetic recovery room (PACU) 
prior to discharge to evaluate for any adverse events. A follow-up phone call will also be made 7 days 
after the administration of angiotensin II to evaluate for any adverse events. 
 
The LC/MS RAAS laboratory analysis will be performed by placing the patient’s whole blood into a 
special test tube provided by La Jolla Pharmaceuticals (the tube will be identified by the patient study 
number and will not contain any other patient identifiers). This test tube contains an inhibitor to prevent 
the breakdown of some of the angiotensin metabolites, which may only be seconds. The contents of the 
test tube will subsequently be spun down and eventually frozen. The tubes will be sent to a specialized 
laboratory in Austria for analysis (Attoquant Diagnostics GmbH in Österreich, Austria). The Attoquant 
system will allow for quantification of the following components: 
• 
Angiotensin I 
• 
Angiotensin II 
• 
Angiotensin IV 
• 
Angiotensin 1-7 
• 
Angiotensin 1-5 
• 
Angiotensin 1-9 


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6 
• 
Angiotensin 2-10 
• 
Angiotensin 2-7 
• 
Angiotensin 3-7 
• 
Bradykinin 1-8 
• 
Bradykinin 1-7 
• 
Bradykinin 1-5 
• 
Aldosterone 
 
The RIA blood analysis will be performed for the following: 
• 
Angiotensin 1-12 
 
 
 
 
 
 
 
Patient 
identified 
in PAC. 
Patient 
approached 
in PAC and 
questions 
answered 
about. 
Patient to 
sign consent 
for study 
participation 
here.  
Confirmation 
on day of 
surgery and 
blood draw 
sample in 
holding 
room and 
when 
starting IV 
for initial 
RAAS 
mapping 
Intraoperative 
ang II 
administration, 
blood draws, 
and data 
collection 
Patient 
will be 
evaluated 
in PACU 
for 
adverse 
events  
Patient will 
receive a 
follow-up 
phone call 7 
days after 
administration 
of angiotensin 
II to evaluate 
for adverse 
events 
Time 
required 
of 
Patient 
0 min 
20 min 
10-15 min 
15-25 min 
5-10 min 
5 min 
 
 
Outcome Measure(s) 
 
 
Analytical Plan 
The primary outcome will be the mean dose required to increase the SBP in these 3 cohorts with essential 
hypertension (ACE inhibitor, ARB, or those on another class of hypertensive agents) to within 5% of 
baseline or higher. 15 patients will be selected to follow suit with other similar dose finding trials with 
vasopressors.10 The mean dose required to elevate SBP from the nadir to within 5% of baseline for each 
group will be compared for significance using a student’s t-test and Bonferoni correction for multiple 
comparisons to determine if different doses of angiotensin 2 are required in patients chronically on ACE 
or ARB inhibitors. The dose-response data will be analyzed with linear regression to construct a dose 
response curve relating dose and percent increase in SBP from the nadir in the setting of general 
anesthesia. We will perform descriptive statistics on the patient population. Secondary outcomes will be 
the mean value for different components of the RAAS system in all 4 populations at different times prior 
to and during the surgical epoch;  
 


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7 
Human Subjects Protection 
 
Subject Recruitment Methods 
Patients will be identified for participation in the Preoperative Assessment Clinic (PAC) prior to the day 
of surgery. Patients will be recruited by investigators and/or the study coordinator with the participation 
and collaboration of PAC attending and other staff present in the clinic involved in this study. We will 
attempt to recruit qualified subjects in a non-biased manner. Privacy will be protected because subjects 
will be recruited in the process of a confidential preoperative evaluation in the PAC. If they choose not 
participate no research record will be created other than to indicate that they declined to participate and as 
such there will be no contact information to destroy.  
 
 
 
Informed Consent 
Signed informed consent will be obtained from each subject. Research study members involved in the 
study will obtain informed consent. A copy of the signed consent will be given to the subject. 
 
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  To help ensure subject privacy 
and confidentiality, only a unique study identifier will appear on the data collection form and the 
sample test tubes.  Any collected patient identifying information corresponding to the unique study 
identifier will be maintained on a linkage file, store separately from the data.  The linkage file will be 
kept secure, with access limited to designated study personnel.  Following data collection subject 
identifying information will be destroyed six years after closure of the study via shredding, consistent 
with data validation and study design, producing an anonymous analytical data set.  Data access will 
be limited to study staff.  Data and records will be kept locked and secured, with any computer data 
password protected.  No reference to any individual participant will appear in reports, presentations, 
or publications that may arise from the study. 
 
Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety of 
study participants.  The principal investigator will be assisted by other members of the study staff. In 
addition to the evaluation for adverse events in PACU, patients will be contacted seven days after 
their surgical procedure via a phone call by a study team member. The phone call will be based on the 
sample script and is primarily meant to evaluate if they have experienced a venous thromboembolic 
event due to the administration of Ang II during their surgical procedure. Any adverse reactions or 
events experienced by the patient as a result of Ang II administration will be followed through until 
their resolution, or until a determination is made that the adverse reaction is not related to the 
administration of Ang II. 
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes 
will be promptly reported by the principal investigator or designated member of the research team to 
the IRB, La Jolla Pharmaceutical Company, or appropriate government agency if appropriate. 
 
 
 
 


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References 
 
1. 
Comfere T, Sprung J, Kumar MM, et al. Angiotensin system inhibitors in a general surgical 
population. Anesthesia and analgesia 2005;100:636-44, table of contents. 
2. 
Singh A, Antognini JF. Perioperative hypotension and myocardial ischemia: diagnostic and 
therapeutic approaches. Ann Card Anaesth 2011;14:127-32. 
3. 
Khanna A, English SW, Wang XS, et al. Angiotensin II for the Treatment of Vasodilatory Shock. 
The New England journal of medicine 2017;377:419-30. 
4. 
Ferreira AJ, Murca TM, Fraga-Silva RA, Castro CH, Raizada MK, Santos RA. New 
cardiovascular and pulmonary therapeutic strategies based on the Angiotensin-converting enzyme 
2/angiotensin-(1-7)/mas receptor axis. International journal of hypertension 2012;2012:147825. 
5. 
Ferrario CM, Smith RD, Brosnihan B, et al. Effects of omapatrilat on the renin-angiotensin 
system in salt-sensitive hypertension. Am J Hypertens 2002;15:557-64. 
6. 
Luque M, Martin P, Martell N, Fernandez C, Brosnihan KB, Ferrario CM. Effects of captopril 
related to increased levels of prostacyclin and angiotensin-(1-7) in essential hypertension. Journal of 
hypertension 1996;14:799-805. 
7. 
Kobori H, Navar LG. Urinary Angiotensinogen as a Novel Biomarker of Intrarenal Renin-
Angiotensin System in Chronic Kidney Disease. International review of thrombosis 2011;6:108-16. 
8. 
Navar LG. Translational studies on augmentation of intratubular renin-angiotensin system in 
hypertension. Kidney international supplements 2013;3:321-5. 
9. 
Chawla LS, Busse L, Brasha-Mitchell E, et al. Intravenous angiotensin II for the treatment of 
high-output shock (ATHOS trial): a pilot study. Critical Care 2014;18:534. 
10. 
Tallarida RJ, Stone DJ, Jr., Raffa RB. Efficient designs for studying synergistic drug 
combinations. Life sciences 1997;61:Pl 417-25. 
 
Appendix 
1. Data Collection Form 
2. Angiotensin II (Giapreza) Follow Up Telephone Questionnaire 
 
 
 
 
 
 


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Appendix 1: Data Collection Form
 
 
 
 
 
 
 
 
 
 
Study ID: ______________ 
 
 
 
 
 
A dose finding trial for angiotensin II (Giapreza) in hypertensive adults on 
angiotensin converting enzyme inhibitors and angiotensin receptor blockers 
with anesthesia-mediated hypotension 
 
 
 
 
 
DATA COLLECTION SHEET 
 
 
 
 
 
 
 
 
 
 
 
 


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A dose finding trial for angiotensin II (Giapreza) in hypertensive adults on angiotensin converting enzyme inhibitors and angiotensin receptor blockers 
with anesthesia-mediated hypotension 
 
 
 
 
 
 
 
Study ID: ___________________________          Age: ____________         ASA PS: ___________ 
 
 
Gender:  M   /   F                                                    UPT: +  /  -  / NA 
 
 
 
 
Surgery date: _______________  Surgical procedure: ____________________________________ 
 
 
Attending Anesthesiologist: ____________________________
 
 
 
 
 
Antihypertensive group:   ACE   /   ARB   /   other 
 
 
Antihypertensive medication: ____________________
Duration of therapy: ________________ 
 
 
Preoperative creatinine: ___________ 
Diabetes: No  /  NIDDM  /  IDDM
 
 
 
Peripheral vascular disease:  Y  /  N 
 
 
DVT prophylaxis:  SCD  /  SQ heparin  /  SQ enoxaparin  /  other _______________ 
 
 
 
STUDY ID: ______________________ 


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