Clinical trial NCT02841241
Conditions: Septic Shock
Keywords: esmolol adrenergic storm septic shock
Sponsor: Intermountain Health Care, Inc.
Start date: 2016-04-01; Completion date: 2017-03-01
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective, single arm, "roll-in" study of esmolol infusion for patients with septic shock with persistent tachycardia after adequate intravenous volume expansion. The study will evaluate the adequacy and efficiency of study protocols for the anticipated, main ECASSS study, which will have a separate entry in clinicaltrials.gov.

Detailed description:
PRIMARY OBJECTIVE:

To evaluate the adequacy and efficiency of study protocols for the anticipated, randomized, controlled ECASSS study. The primary clinical outcome is organ-failure free days at 28 days, with multiple secondary outcomes, including those relevant to function of and compliance with the study protocols.

Arms: arm 1: Esmolol infusion, started without bolus, with slow upward titration to a maximum infusion rate is protocolized, with a target heart rate of 80-90/min
Interventions: intervention 1: Esmolol
Intervention descriptions: intervention 1: Esmolol infusion

Protocol documents:
Prot_SAP_ICF_000.pdf: 
Cover Page 
Official Title: Esmolol to Control 
Adrenergic Storm in Septic Shock - Roll-in 
NCT Number: NCT02841241
Date of Document: 12/16/2016


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Consent Form
What
Esmolol to Control Adrenergic Storm in Septic Shock (ECASSS) – 
ROLL-IN
Where
Intermountain Medical Center
Who
PI:
Samuel Brown, MD, MS (801) 507-6556 
Co- investigators:
Colin Grissom, MD
Michael Lanspa, MD, MS 
Emily Wilson, MS
Ithan Peltan, MD 
Ellie Hirshberg, MD 
Peter Crossno, MD 
Vivian Lee, MD
Sarah Beesley, MD
Samir Parikh, MD
Sponsor:
Intermountain Medical Center
When
Your participation will last until you are discharged from the hospital.
Why 
This research study will evaluate the adequacy and efficiency of study 
protocols for the main ECASSS study. We are investigating a drug called 
esmolol as a treatment for serious infection (“septic shock”).
How         
While you are receiving infusions of medicines like adrenalin to support 
your blood pressure, we will infuse a medication called esmolol that we 
think will help to control the negative effects of the body’s high stress state 
during serious infection. You will also have some blood drawn and have 
ultrasound pictures of your heart taken. We will monitor to see how long it 
takes for your body to improve from the serious infection.
Intermountain Healthcare IRB
IRB NUMBER: 1050147
IRB APPROVAL DATE: 01/16/2017
IRB EXPIRATION DATE: 12/07/2017


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Why is this study being done?
We are asking you to take part in a research study about a drug called esmolol for use 
in septic shock.
Septic shock is a common condition in which infection interrupts the body’s normal 
system of keeping itself in balance. Septic shock occurs when sepsis, a body-wide 
inflammatory response to infection, leads to dangerously low blood pressure. One 
potential way to treat septic shock is to block part of the body’s beta-adrenergic system, 
which is part of the body’s stress response. Such a blockade improves blood flow to the 
heart, decreases the work that the heart has to do, and helps the heart muscle cells. It 
may also protect blood vessels from harm. Esmolol is a “beta-adrenergic blocker” whose 
effects can be adjusted from minute to minute.
This research study is a pilot study. Its purpose is to help us to assess the feasibility of 
conducting a full, complete research study of esmolol infusion in septic shock. This 
study is being done because there is suggestion that a well-known drug called esmolol 
can significantly improve outcomes for patients with septic shock.
Throughout this research study, your study doctor will be Dr. Samuel Brown. Dr. Brown 
and/or his colleagues will communicate with your primary physicians and nurses to 
coordinate your care.
Why are you asking me to take part in the study?
We are asking you to join because you have been admitted to the ICU with septic 
shock, and we think that you may be a good candidate for this study.
Approximately 10 people will take part in this study at Intermountain Medical Center.
Please read this form and ask any questions that you may have before agreeing to be in 
this research study.
Who can be in this study?
You can be in this study if:

You are 18 years old or older.

You have septic shock.

You are receiving vasopressors through a central venous catheter for more than
60 minutes. Vasopressors are medicines that constrict the blood vessels to 
increase blood pressure.
Intermountain Healthcare IRB
IRB NUMBER: 1050147
IRB APPROVAL DATE: 01/16/2017
IRB EXPIRATION DATE: 12/07/2017


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
You have a heart rate of greater than 90 beats per minutes while receiving 
vasopressors for more than 60 minutes. 

You meet certain other medical criteria.
Who cannot be in the study?
You cannot participate in this study if:

You do not give your informed consent.

You are currently receiving artificial heart support (called “extracorporeal 
membrane oxygenation”).

You are pregnant or nursing

You are on hospice.

You are a prisoner.

You have known or current atrial fibrillation (irregular heartbeats).

You were previously enrolled in this trial.

You have a known allergy to esmolol.

You have pulmonary hypertension (high blood pressure in the lungs).

Your heart is unable to circulate enough blood to supply the organs (called 
“cardiogenic shock”).

You have significant atrioventricular dysfunction (a problem with the electrical 
system of the heart).

You are receiving clonidine, guanfacine, or moxonidine
Do I have to join?
No, you do not have to join. Your decision to take part in this study is completely 
voluntary.
What if I decide not to join?
You can choose not to participate in this study. You will still receive standard medical 
care.
Can I stop being in the study if I change my mind later?
Yes. If you join the study, you can decide to stop at any time.
Intermountain Healthcare IRB
IRB NUMBER: 1050147
IRB APPROVAL DATE: 01/16/2017
IRB EXPIRATION DATE: 12/07/2017


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How do I stop if I do not want to be in the study any longer?
Please tell your study doctor if you are thinking about stopping or if you decide to stop. 
Your study doctor can tell you how to stop safely.
It is important to tell the study doctor if you are thinking about stopping so any risks from 
the study drug can be evaluated by your doctor. Another reason to tell your doctor if you 
are thinking about stopping is to discuss what follow-up care and testing could be 
important to you. Your study doctor can also stop you from taking part in this study any 
time if he or she believes it is in your best interest to stop or if the study is stopped.
You can ask us to stop collecting your information, though we will still be able to use the 
information that we have already collected from you. If you would like for us to stop 
collecting your information, you must inform us in writing. You can give this notice to the 
Principal Investigator or research team in person or mail it to:
Samuel Brown, MD 
Shock Trauma ICU
Intermountain Medical Center 
5121 South Cottonwood Street 
Murray, UT 84107
Once we have received your written request, we will stop collecting your information. 
You will not be able to continue in the study. You will not be able to join the study again 
at a later date.
How long will I be in the study?
You will be in the study until you are discharged from the hospital.
What will happen if I decide to take part?
If you are admitted to the ICU with sepsis and you meet the eligibility criteria, we will first 
ask you to sign this consent form. You will undergo a few assessments before you are 
given esmolol, the study drug.
Baseline Assessment:

You will have a full transthoracic echocardiogram (pictures of your heart will be 
taken with an ultrasound).

Your blood will be drawn through your IV line.
Intermountain Healthcare IRB
IRB NUMBER: 1050147
IRB APPROVAL DATE: 01/16/2017
IRB EXPIRATION DATE: 12/07/2017


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
We will record your vital signs and related medical information from your medical 
record.

We will record your age, sex, and contact information.

Special EKG leads will be attached near the regular EKG leads to allow us to 
measure the strength of your heartbeats with a noninvasive device called the 
“NICOM.”
24-hour Assessment

You will have a full transthoracic echocardiogram.

Your blood will be drawn.

We will record your vital signs and related medical information from your medical 
record.
Esmolol infusion
We will confirm that you do not have “cardiogenic shock”, and you will be evaluated to 
see whether you would benefit from salt water infusions, which is a standard treatment 
for septic shock. Once we have evidence that you won’t benefit from further salt water 
infusions, you will be given esmolol. This is the only treatment which is experimental 
and is not done as regular standard-of-care. Esmolol will be increased gradually 
according to a protocol designed for safety. The esmolol infusion will continue while you 
are on vasopressors.
Daily on-treatment assessments
Your blood will be drawn while you are receiving vasopressor medications. We will see 
whether you have any side effects.
Blood samples
Your blood samples will be sent to Beth Israel Deaconess Medical Center (BIDMC), a 
teaching hospital of Harvard Medical School. BIDMC will perform assays on your blood 
samples. This is a type of testing that will let us evaluate the state of your blood vessels.
Tissue banking
As part of this study, we would like to preserve your leftover blood samples in a tissue 
bank to make possible future research. Your blood samples will be kept by Dr. Samir 
Parikh at BIDMC and will be used to help answer future research questions that may arise. 
Before your blood samples are sent to BIDMC, they will be de-identified. This means your 
Intermountain Healthcare IRB
IRB NUMBER: 1050147
IRB APPROVAL DATE: 01/16/2017
IRB EXPIRATION DATE: 12/07/2017


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sample will be coded so that your name is not on the sample. BIDMC will not receive any 
information that could be used to identify you. Your samples will be given a number, and 
the identification code linking your name to the number will be kept by Dr. Brown. If you 
want to you have your blood sample withdrawn from the sample repository later, please 
contact Dr. Brown at (801) 507-6556.
Tissue or blood sample obtained from you in this research may help in the development 
of a commercial product by BIDMC or its research partners. There are no plans to provide 
financial compensation to you should this occur.
You do not have to participate in the tissue bank to be in the main part of this study. No 
matter what you decide to do, your decision will not affect your medical care.
You can tell us your choice by initialing one of the choices below:
__ Yes, 
my sample(s) may be saved for future research
(initial)
___ No, 
my sample(s) must be destroyed at the end of this research project.
(initial)
Hospital discharge assessment
When you are discharged from the hospital, we will determine how many days you have 
not had shock (out of 14 days), and we will record your discharge destination.
What are the risks to me if I join the study?
The known risks and side effects are listed below. Your study doctor and other study 
personnel will watch carefully for any side effects, but the doctors do not know in 
advance all the side effects that can happen. Some side effects are mild and others 
can be very serious. Some side effects go away when you stop taking the 
investigational drug but in some cases, side effects can be serious, long lasting or 
may never go away.
Important: You should talk to your study doctor about any side effects that you notice 
while you are taking part in the study.
Risks associated with esmolol include:
Cardiogenic shock (if this develops, esmolol will be stopped)
Excessively slow heart rate or low blood pressure (if this develops, esmolol will be 
Intermountain Healthcare IRB
IRB NUMBER: 1050147
IRB APPROVAL DATE: 01/16/2017
IRB EXPIRATION DATE: 12/07/2017


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stopped)
Common side effects of esmolol:
Slightly lower blood pressure (esmolol will normally be continued, as this is easily 
treated)
Infrequent side effects of esmolol include:
Anxiety, Drowsiness, Nausea, Vomiting, Headache, Nervousness, Redness of the 
face and neck
Rare, but serious side effects of esmolol:
Hypersensitivity (allergic) reaction. This is extremely rare. Patients with known 
hypersensitivity to esmolol are excluded from the study. Should you have a 
hypersensitivity reaction, esmolol infusion will be stopped and you will be treated.
Risks and side effects related to the study procedures:
Echocardiogram: This test is non-invasive. There are no risks from this procedure. 
NICOM: This is a monitoring system device which is also non-invasive. There are no 
risks from this procedure.
Blood tests: Only small volumes of blood will be obtained; the risks are minimal, if any.
Risks related to pregnancy
You cannot participate in this study if you are pregnant. You should not breastfeed a 
baby while in this study.
Are there any benefits to me if I take part in the study?
If esmolol treatment works, we anticipate a direct benefit to patients receiving esmolol 
infusion, including improved chances of survival and freedom from shock.
Will I be updated about new information or developments?
As the study progresses, the study doctor will talk to you about any new information or 
developments that may increase your risk. At that time, you can decide whether to 
continue with the study or not.
What happens if I am injured because I was in the study?
If you become injured while taking part in this study, Intermountain Healthcare can 
provide medical treatment. We will bill you or your insurance company in the usual way. 
Because this is a research study, some insurance plans may not pay for your treatment. 
If you believe you have been injured as a result of being in this study, please call the 
Principal Investigator right away. You may also call the Office of Research at 1-800- 
Intermountain Healthcare IRB
IRB NUMBER: 1050147
IRB APPROVAL DATE: 01/16/2017
IRB EXPIRATION DATE: 12/07/2017


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321-2107.
Who do I ask if I have questions about the study or my rights?
If you have questions about the study, please call the principal investigator, Dr. Samuel 
Brown, at (801) 507-6556.
If you have questions regarding your rights as a research subject or if problems arise 
which you do not feel you can discuss with the Investigator, please contact 
Intermountain’s Office of Research at 1-800-321-2107.
What are the costs of taking part in the study?
You will not incur any costs related with your participation in this research study. Any 
procedures that will be performed as your normal standard of care will be billed to you 
or your insurance company in the usual manner.
Will I be paid if I participate in the study?
You will not be paid for being in this research study.
If I take part in this study, what health information about me will you use?
This is the health information from your medical records that will be used in the study:

Name

Address

Telephone

Medical history and results of clinical testing and monitoring and evaluation

Results from tests and procedures to be performed in this study
This health information will come from the information that you give to the researchers 
and from your medical records at the hospitals and clinics where you’ve been treated.
The researchers may need to share your information with others; however, this 
information will not identify you. Information that could identify you will be replaced with 
a code that will be used instead. The others working on this study who may receive that 
information are:

Researchers at University of Chicago and Beth Israel Deaconess Medical 
Center
Important: You need to know that laws protect your health information when it is held by 
hospitals and healthcare providers. But if your health information goes to someone else, 
your health information may not be protected by those laws.
Intermountain Healthcare IRB
IRB NUMBER: 1050147
IRB APPROVAL DATE: 01/16/2017
IRB EXPIRATION DATE: 12/07/2017


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Your health information may be viewed for the following purposes, and laws protect the 
confidentiality of your health information when used by these groups for these purposes:

Intermountain’s IRB (Institutional Review Board) to oversee the safety and 
ethics of the study

Intermountain employees to do their job (such as give treatment, for billing 
matters or to make sure the research is done correctly).

The Food and Drug Administration and others to comply with law.
If you decide to take part in this study and sign this form, you permit researchers to use 
your health information for this study. If you want to take part in this study, please sign 
this form. If you don’t want to participate, please don’t sign this form.
You can always ask to see your medical information at any time; however, you will not 
be able to see your health information that is used in this study until the study is 
finished.
Your agreement—which is called an authorization—to use your health information as 
part of this study continues without ending.
Intermountain Healthcare IRB
IRB NUMBER: 1050147
IRB APPROVAL DATE: 01/16/2017
IRB EXPIRATION DATE: 12/07/2017


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CONSENT
I have read and I understand this consent document. I have had the opportunity to ask 
questions. I understand that my participation is voluntary and that I am free to withdraw 
at any time, without giving any reason, without my medical care or legal rights being 
affected. I understand that sections of any of my medical notes may be looked at by 
responsible individuals from Intermountain Healthcare or from regulatory authorities 
where it is relevant to my taking part in research. I give permission for these individuals 
to have access to my records. I will be given a signed copy of the consent and 
authorization form to keep.
I agree to participate in this research study and I authorize you to use and to 
disclose health information about me for this study, as you have explained in this 
document.
Participant’s Name (Print)
Participant’s Signature
Date & Time
Name of Person Obtaining Authorization and Consent
Signature of Person Obtaining Authorization and Consent
Date & Time
Intermountain Healthcare IRB
IRB NUMBER: 1050147
IRB APPROVAL DATE: 01/16/2017
IRB EXPIRATION DATE: 12/07/2017


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SURROGATE CONSENT
If the participant is unable to give consent and authorization, consent and authorization is 
given by the following authorized personal representative of the individual.
Therefore, I agree to consent to the treatment of Patient (Name:
) 
and I meet the following conditions of surrogate consent:
    Health Care Agent (as named in an Advance Health Care Directive)
    Legal Guardian
OR
If no health care agent or legal guardian has been appointed, a Surrogate Health Care 
Decision Maker is utilized. The health care decision maker must be over 18 years of age; 
must have health care decision making capacity; must be reasonably available; and has 
not been disqualified by the patient. The health care decision maker can be in 
descending order of priority and authority:
Check applicable:
    Spouse; unless divorced, legally separated or found by a court to have 
acted in a manner that should preclude having a priority position.
    a child.
    a parent.
    a sibling.
    a grandparent.
    a grandchild.
    other; if a family member listed above is not available, this person 
should exhibit special care and concern for the patient and be familiar 
with the patient’s personal values.
State relationship to patient:  
Name of Authorized Personal Representative
Signature of Authorized Personal Representative
Date & Time
Name of Person Obtaining Authorization and Consent
Signature of Person Obtaining Authorization and Consent
Date & Time
Intermountain Healthcare IRB
IRB NUMBER: 1050147
IRB APPROVAL DATE: 01/16/2017
IRB EXPIRATION DATE: 12/07/2017


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INFORMED CONSENT 
TO CONTINUE TO
PARTICIPATE IN RESEARCH
and 
AUTHORIZATION TO USE & DISCLOSE 
PROTECTED HEALTH INFORMATION
My legal representative previously gave consent for me to be in this research 
study. This is because I was unable to make my own decision because I was ill.
My condition has now improved. I have read & understand the information on this 
consent form. All of my questions about the study have been answered to my 
satisfaction. I freely agree to continue to participate in this research study.
I authorize you to use & disclose health information about me for this study, as 
you have explained in this document.
Participant’s Name (Print)
Participant’s Signature
Date & Time
Name of Person Obtaining Authorization and Consent
Signature of Person Obtaining Authorization and Consent
Date & Time
Intermountain Healthcare IRB
IRB NUMBER: 1050147
IRB APPROVAL DATE: 01/16/2017
IRB EXPIRATION DATE: 12/07/2017


Esmolol to Control Adrenergic Storm in Septic Shock (ECASSS) – ROLL-IN 
Acronym: ECASSS-ROLL-IN
Version: 5
Investigators:
Samuel M. Brown, MD MS
Colin K. Grissom, MD
Michael J. Lanspa, MD MS
Emily Wilson, MS
Ithan Peltan, MD
Ellie Hirshberg, MD
Peter Crossno, MD 
Vivian Lee, MD
Sarah Beesley, MD
Samir Parikh, MD


Table of Contents
1.0
Abbreviations and Definitions.................................................................................3
2.0
Study Summary.............................................................................................................4
2.5
Inclusion criteria ....................................................................................................................4
2.6
Exclusion criteria...................................................................................................................5
3.0
STUDY DESCRIPTION ................................................................................................6
3.1 Background.................................................................................................................................6
3.2
Study Design...........................................................................................................................9
4.0
Study population and enrollment .........................................................................10
5.0 
Study Procedures.....................................................................................................13
6.0
Data Collection and Safety Monitoring .............................................................15
7.0
Statistical plan.............................................................................................................16
8.0
Risk Assessment .......................................................................................................16
9.0
Human Subjects .........................................................................................................18
REFERENCES............................................................................................................................22


Esmolol to Control Adrenergic Storm in Septic Shock (ECASSS) – ROLL-IN
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Abbreviations and Definitions
APACHE II = Acute Physiology and Chronic Health Evaluation, version 2
BIDMC = Beth Israel Deaconess Medical Center
CVP = Central venous pressureECMO = Extracorporeal Membrane Oxygenation
ER = Emergency Room
GVEC = Graded Volume Expansion Challenge
ICU = Intensive Care Unit
IMC = Intermountain Medical Center
ITT = Intention to Treat
LAR = Legally Authorized Representative
OFFD = Organ-Failure-Free Days at 28 days
P/F = PaO2/FiO2 ratio
SAE = Serious Adverse Event
ScvO2 = Central venous oxygen saturation
SMC = Safety Monitoring Committee
SOFA = Sequential Organ Failure Assessment score
SUSAR = Serious and Unexpected Suspected Adverse Reaction
Definitions
Adverse Event: Any untoward medical occurrence associated with the use of a drug or 
study procedure, whether or not considered drug related. (cf. 21 CFR 312.32(a))
Adverse reaction: An adverse reaction means any adverse event caused by a drug. 
Adverse reactions are a subset of all suspected adverse reactions where there is a 
reason to conclude that the drug caused the event.
Intention to Treat (ITT): All eligible and consented patients who undergo esmolol 
infusion will be included in the ITT cohort for the purposes of analyzing the primary and 
secondary study outcomes.
Legally Authorized Representative: An individual, judicial, or other body authorized 
under applicable law to consent on behalf of a prospective patient to the patient's 
participation in the clinical study. 
Life-threatening adverse event or life-threatening suspected adverse reaction: An 
adverse event or suspected adverse reaction is considered "life-threatening" if, in the 
view of the investigator, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. (cf. 21 CFR 312.32(a))
Organ-failure-free days: As of day 28, the number of calendar days on which the 
patient receives none of (a) vasopressor therapy, (b) mechanical ventilation, or (c) renal 
replacement therapy. If the patients dies on or before day 28, they have -1 organ-failure-
free days.
Serious adverse event (SAE) or serious suspected adverse reaction or serious 
unexpected suspected adverse event (SUSAR). An adverse event or suspected 
adverse reaction is considered "serious" if, in the view of the investigator, it results in any 
of the following outcomes: Death, a life-threatening adverse event, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect. Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and may 


Esmolol to Control Adrenergic Storm in Septic Shock (ECASSS) – ROLL-IN
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require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (cf. 21 CFR 312.32(a))
Study Day: The first day of esmolol infusion is study day zero. The next day is study day 
one, and so on etc. 
Study Drug: Esmolol infusion for septic shock patients with persistent tachycardia after 
adequate volume expansion.
Study hospital: Defined as the hospital where the patient is enrolled. 
Study withdrawal: Defined as permanent withdrawal from the study before the 
completion of study activities. This does not include those subjects who have completed 
the esmolol infusion. If a patient or surrogate requests to withdraw from the study, 
investigators should seek explicit permission to continue data collection for relevant 
outcomes. 
Suspected adverse reaction: any adverse event for which there is a reasonable 
possibility that the drug caused the adverse event. Reasonable possibility means that 
there is evidence to suggest a causal relationship between the drug and the adverse 
event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than an adverse reaction, as per 21 CFR 312.32(a).
Unexpected adverse event or unexpected suspected adverse reaction. An adverse 
event or suspected adverse reaction is considered "unexpected" if it is not listed in the 
investigator brochure (or package insert) or is not listed at the specificity or severity that 
has been observed. "Unexpected," as used in this definition, also refers to adverse 
events or suspected adverse reactions that are mentioned in the investigator brochure or 
package insert as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring 
with the particular drug under investigation. (cf. 21 CFR 312.32(a))


Esmolol to Control Adrenergic Storm in Septic Shock (ECASSS) – ROLL-IN
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2.0
Study Summary
2.1
Title: Esmolol to Control Adrenergic Storm in Septic Shock (ECASSS) – ROLL-
IN 
2.2
Objective: To evaluate the adequacy and efficiency of study protocols for the 
main ECASSS study.
2.4
Study design: Prospective, single arm, feasibility (“roll-in”) study of esmolol 
infusion in septic shock.
1.
Inclusions. We will include patients admitted to the ICU for sepsis who are within 
48 hours of septic shock and ICU admission and are simultaneously tachycardic 
(heart rate >90/min) and on vasopressors for > 60 min. Patients must meet 
criteria at the time of enrollment.
2.
Final safety check. After enrollment and before esmolol infusion, ScvO2, 
transthoracic echocardiogram, evaluation of fluid responsiveness, and review of 
telemetry/EKGs will occur to assure that no exclusion criteria are present.
a.
If no exclusion criteria are present, patients will start esmolol infusion
b.
If patient is still fluid responsive but otherwise has no exclusions, fluid will 
be administered by explicit protocol until no longer fluid responsive, and 
then the patient will receive esmolol infusion. If tachycardia has resolved 
as a result of volume expansion, esmolol infusion will not occur until 
tachycardia and vasopressor administration co-occur. After esmolol 
infusion, volume expansion will be managed as part of the esmolol 
titration protocol.
c.
Patients who fail the final safety check will NOT start esmolol infusion but 
will be followed for non-interventional aims (e.g., serial TTEs, vascular 
biomarkers) to understand better the natural history of cardiogenic shock 
superimposed on septic shock.
3.
Esmolol infusion 
a.
Esmolol infusion, started without bolus, with slow upward titration to a 
maximum infusion rate is protocolized (see protocol in Appendix 1), with a 
target heart rate of 80-90/min.
b.
Esmolol infusion will be stopped in the event that cardiogenic shock, 
excessive bradycardia, grade 2 or grade 3 heart block, or hypotension,or 
bronchospasm occur, as per protocol.
4.
Other care
a.
ICU patients are managed according to current Surviving Sepsis 
campaign guidelines as per usual practice.
b.
Vasopressor infusion titrations according to protocol are recommended, 
while clinicians retain the ability to titrate as they feel clinically indicated. 
Norepinephrine should be the primary vasopressor; at 0.25 mcg/kg/min of 
norepinephrine, a second vasopressor agent (preferentially, vasopressin 
0.03 units/min or epinephrine) may be added; at 0.5 mcg/kg/min, stress-
dose steroids (hydrocortisone 150-200 mg IV daily or equivalent, in 
divided doses) may be added.


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2.5
Inclusion criteria
1.
Age ≥ 18 years 
2.
Within 48 hours of admission to the ICU and septic shock (sepsis present at time 
of admission)
a.
Septic shock defined by consensus criteria as
i.
At least two SIRS criteria 
ii.
Suspected or documented infection
iii.
Receiving vasopressors to treat hypotension after at least 20 
ml/kg intravenous crystalloid volume expansion 
3.
Receiving vasopressors through a central venous catheter for more than 60 
minutes.
4.
Arterial catheter in place or expected to be placed imminently.
5.
Heart rate > 90/min while receiving vasopressors for more than 60 minutes.
6.
Adequately volume expanded, as manifest by any of the following, performed as 
part of routine clinical care (i.e., no study procedures will be performed before 
signed consent). If none of these measures are clinically available, the 
clinical attending must confirm that volume expansion is adequate. (After 
enrollment, a final safety check will confirm the adequacy of volume expansion.)
a.
Central venous pressure (CVP) > 15 mm Hg.
b.
Negative Passive-Leg Raise (PLR) maneuver (<10% increase in cardiac 
output after PLR).
c.
No cardiac output response (<10% increase) after rapid infusion (<5 min) 
of 250 ml of IV crystalloid (i.e., a graded volume expansion challenge 
[GVEC]).
d.
For patients who happen to be breathing passively on a positive pressure 
mechanical ventilator delivering at least 8 ml/kg tidal volumes and in 
normal sinus rhythm, stroke volume variability <10% (such patients are 
acknowledged to be uncommon; the protocol does not recommend or 
require the induction of passive breathing).
2.6
Exclusion criteria
1.
Lack of informed consent.
2.
Currently receiving ECMO.
3.
Known pregnancy or nursing.
4.
Patient is a prisoner.
5.
Patient on hospice (or equivalent comfort care approach) at or before the time of 
enrollment.
6.
Known or current atrial fibrillation.
7.
Previously enrolled in the trial.
8.
Known allergy to esmolol or vehicle (see Appendix 2 for BREVIBLOC vehicle 
ingredients).
9.
Receipt of nodal blocking agents (see Appendix 3 for list of such agents) within 
three half lives 
10. Hemoglobin < 7 gm/dl.
11. Cardiac arrest within 24 hours.
12. Pulmonary hypertension (moderate or severe), from documented history of prior 
right heart catheterization or current evidence on TTE of any of the following

mPAP ≥ 35mmHg


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
SPAP ≥ 60mmHg
13. Cardiovascular collapse, as manifested by inability to achieve a MAP of 65 
mmHg with vasopressor therapy.
14. Cardiogenic shock, as defined by any of the following

Cardiac index ≤ 2 L/min/m2

Ejection fraction ≤ 25%

ScvO2 ≤ 60% 

Current infusion of any dose of dobutamine, milrinone, or dopamine

Current infusion of epinephrine for clinically diagnosed cardiogenic shock
15. Significant atrioventricular dysfunction

Sick sinus syndrome

PR interval > 200 msec

Current evidence or prior history of Grade 2 or Grade 3 heart block

Pacemaker or plans to place a pacemaker
16. Pheochromocytoma or status asthmaticus
17. Receiving clonidine, guanfacine, or moxonidine
18. Hemoglobin < 7 gm/dl
19. Cardiovascular collapse (failure to achieve MAP of 65mmHg)
20. Cardiac arrest within 24 hours
21. Worse than moderate aortic stenosis

Known aortic stenosis, with any of (1) mean gradient ≥ 40 mmHg OR (2) 
maximum gradient ≥ 60mmHg OR (3) aortic valve area ≤ 1.0cm2 OR (4) 
aortic valve area index ≤ 0.85cm2/m2 body surface area.
22. Worse than mild mitral stenosis

Known mitral stenosis, with any of (1) valve area ≤ 1.5 cm2 OR mean 
gradient ≥ 5 mmHg.
2.7
Sample size: The study will enroll up to 10 patients at 1 center.
2.8
Non-clinical outcomes for ROLL-IN:
1.
Proportion of eligible patients consented
2.
Proportion of compliance with final safety check
a.
Protocol compliance is considered adequate where compliance is 100% 
for the safety check.
3.
Proportion of protocol compliance
a.
For the esmolol titration protocol, each hour (the closest value of heart 
rate to the hour) during the esmolol infusion will be determined to be “in 
range” or “out of range,” with 3bpm margin for compliance (i.e., heart rate 
77 to 93bpm). The initiation and cessation of esmolol will also be included 
as a timepoint for evaluation of compliance. Protocol compliance is 
considered adequate where overall compliance on hourly checks is 
>80%.
b.
For STOP events, protocol compliance is considered adequate at 100%.
i.
30min moving average of cardiac index below threshold
ii.
30min moving average of norepinephrine infusion rate above 
threshold
iii.
Clinician determines that shock has substantially worsened on 
esmolol.


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c.
For VOLUME EXPANSION events, protocol compliance is considered 
adequate at 90%. 
4.
Amount of research coordinator time spent on different tasks
2.8.1
Anticipated primary clinical outcome for main trial (this will also be 
recorded for ROLLIN): Organ-failure-free days at 28 days. An organ-failure-free day is 
defined as a calendar day on which the patient receives none of (a) vasopressor 
therapy, (b) mechanical ventilation, or (c) renal replacement therapy.
2.8.2
Anticipated secondary clinical outcomes for main trial (these will also be 
recorded for ROLLIN):
1.
All-cause hospital mortality
2.
All-cause 28-day and 90-day mortality
a.
Mortality will be ascertained through telephone followup for patients who 
were discharged alive before 90 days.
3.
Peak serum high-sensitivity troponin
a.
Troponin will be measured on day 0 and day 1.
4.
LV global longitudinal strain at 24 hours
5.
Time to transition to quiescent vascular phenotype, as defined by serum Angpt-2 
level < 1ng/ml.
6.
ICU-free days to day 28
a.
Patients who die before 28 days will be assigned -1 ICU-free days, using 
a methodology similar to that used for organ-failure-free days.
7.
Cardiogenic shock/requirement for inotropes through day 14. This is a binary 
variable and is met when any of the following is present
a.
Dobutamine or milrinone infusion at any dose, lasting > 60min
b.
CI ≤ 2 L/min/m2 lasting > 30 min on NICOM
c.
ScvO2 ≤ 60% on any measurement
8.
Development of second or third degree heart block.
3.0
STUDY DESCRIPTION
3.1 Background
3.1.1 Septic shock is a significant clinical and scientific problem
Septic shock, a common syndrome in which infection leads to potentially fatal disruption 
of organismal homeostasis, accounts for 10% of all ICU admissions and 30% of all ICU 
mortality. Approximately 200,000 patients die annually in the USA from septic shock. 
Septic shock is a state of extreme biological stress associated with rapidly evolving 
hemodynamic, physiologic and metabolic dysfunction, as the host attempts to 
reestablish homeostasis in the face of severe infection.1,2 Progressive cardiovascular 
dysfunction is often the penultimate step before death from septic shock.3
3.1.2 Sympathetic nervous system over-stimulation impairs cardiovascular 
function in septic shock
While immune activation and autonomic nervous system stimulation are crucial to the 
adaptive host response to infection, in the right setting (high pathogen virulence or 
infectious load, genetics of the host, non-genetic susceptibility, duration of time without 
anti-infective therapy) these adaptive responses become pathogenic. Sympathetic over-


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stimulation can drive a positive feedback loop of cardiovascular and other organ 
dysfunction, the “multiple organ dysfunction syndrome” (MODS), which is the signature 
of septic shock. The hemodynamic changes of septic shock result from dynamic 
interactions between cardiovascular system homeostasis, the host immune response, 
and therapeutic interventions such as catecholamine infusions and intravascular volume 
expansion.1 Ironically, although endogenous catecholamines—which engage the widely 
distributed α- and -adrenergic receptors—are increased ~20-fold in septic shock, 
administration of exogenous catecholamines is a cornerstone of current management.4 
The adrenergic over-stimulation in septic shock is of central interest because (1) 
cardiovascular dysfunction is central to the MODS that precedes death, (2) the usual 
treatment paradigm for septic shock involves further adrenergic stimulation, (3) there are 
safe, effective, and selective adrenergic antagonists that may be beneficial in treatment 
of septic shock, and (4) there are now non-invasive methods to assess cardiovascular 
responses to septic shock and its treatment. An integrative approach to the interplay 
between the sympathetic nervous system and cardiovascular dysfunction in sepsis may 
be crucial to improving outcomes after septic shock. This harmful interplay affects both 
elements of the cardiovascular system: the heart and the blood vessels.
3.1.3 Adrenergic over-stimulation harms the heart
The hyper-adrenergic state, in combination with excess cytokine production, results in a 
spectrum of myocardial injury often grouped under the general category of septic 
cardiomyopathy. Septic cardiomyopathy is remarkably common, despite a historical 
belief that sepsis was primarily or exclusively a hyperdynamic state.5,6 Abnormalities of 
systolic1 and diastolic7,8 function are independent risk factors for death from septic 
shock.3 Autopsy studies of septic shock demonstrate extensive myocyte injury, 
contraction band necrosis, and interstitial edema in 90-100% of patients.9,10 The 
catecholamine therapy used to treat septic shock may, paradoxically, worsen septic 
cardiomyopathy. Indeed, the extent of myocardial necrosis has been shown to correlate 
with dose and duration of catecholamine therapy.9 Recent observational studies show 
that catecholamine inotrope use is associated with an increased 90-day mortality in 
septic shock after adjusting for disease severity and propensity to receive catecholamine 
inotropes.6 Catecholamine over-stimulation can incite a parallel syndrome called “tako 
tsubo” or “catecholamine” cardiomyopathy in non-septic individuals. Tako tsubo 
cardiomyopathy shares functional, pathological, and clinical features with septic 
cardiomyopathy, and is also associated with increased mortality.11 Though distinct from 
septic cardiomyopathy, tako tsubo cardiomyopathy provides independent evidence of 
catecholamine cardiotoxicity. 
3.1.4 Adrenergic over-stimulation harms the vasculature
The cellular basis for inflammation-induced vascular permeability is well described.12-15 
Junctions between adjacent endothelial cells rapidly disassemble in response to 
inflammatory triggers, resulting in vascular leakage. Vascular leakage not only 
contributes to shock, and lung injury, but inflamed endothelium posts an array of cell 
surface molecules that promote leukocyte adhesion and thus end organ damage.12-14,16 
Observational studies suggest that sympathetic over-stimulation is linked to endothelial 
cell damage.17-19 Given (A) the vasculature’s emerging importance in septic shock 
outcomes, (B) the paucity of knowledge regarding catecholamine action on the 
endothelium, and (C) multiple reports that even non-septic states of adrenergic excess 
induce vascular inflammation and injury,20-23 there is a pressing need to understand how 
-blockade may ameliorate the pro-leakage, pro-inflammatory vascular phenotype of 
septic shock.


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3.1.5 The heart and blood vessels represent an integrated system
The primary expression and determinant of mortality in septic shock is the integrated 
host cardiac and vascular response to infection and inflammation. Inflammatory cytokine 
release is associated with myocardial depression, endothelial barrier dysfunction, and 
vascular hyporeactivity. Together, these responses lead to the classic “distributive” 
physiology of septic shock, compounded by increasingly recognized myocardial 
dysfunction. The cardiovascular system is controlled by an ancient neural-endocrine 
system that regulates the integrated function of heart and vessels. Via this baroreflex 
system, the autonomic nervous system regulates systemic perfusion by adjusting 
vascular tone, compliance, cardiac contractility, and heart rate. While traditionally heart 
and vasculature are consider separately, in reality they are an integrated system. 
Microvascular dysfunction within the heart results in myocardial edema, whereas 
extracardiac microvascular dysfunction contributes to MODS. Thus microvascular 
dysfunction affects both intracardiac and extracardiac vessels, contributing to septic 
cardiomyopathy and MODS, playing a crucial role in the pathological positive feedback 
loops that characterize septic shock. Furthermore, cardiac dysfunction contributes to 
downstream endothelial dysfunction. 
Heart rate variability, a non-invasive measure of the baroreflex measured from changes 
in the inter-beat interval, allows for the inspection of integrated cardiovascular function. 
Heart rate variability provides unique insights into severity of illness in primary cardiac 
disease,24-26 acute trauma27 and sepsis.28,29 In healthy states, heart rate exhibits 
nonlinear patterns of complexity, including fractal self-similarity across time scales.30,31 A 
technique called detrended fluctuation analysis, which quantifies the variability in inter-
beat intervals over different time scales, allows the assessment of whether fractal 
complexity is preserved or disrupted. Fractal complexity was strongly associated with 
early outcomes in septic patients in research conducted by this research team32 and was 
associated with sepsis in neonates, a population for which heart rate variability has been 
extensively evaluated.33
3.1.6. -adrenergic blockade may be therapeutic in septic shock
Norepinephrine, the primary adrenergic agonist maintaining vasomotor tone in septic 
shock, commonly increases heart rate and myocardial contractility, but excessive 
stimulation results in cell death followed by fibrosis and pathological remodeling, effects 
predominantly mediated via β-adrenergic receptors. Excess catecholamines also have a 
direct cardiotoxic effect through oxidative damage on the myocardial membrane.34 -
blockers have long demonstrated utility in non-septic myocardial dysfunction through 
mechanisms, including (a) inhibition of direct cardiotoxic effects of catecholamines, (b) 
improvement in myocardial function by reducing heart rate and oxygen demand, (c) 
attenuation of neurohormonal vasoconstriction and apoptotic mechanisms, and (d) 
protection of the microvasculature.35
While advocacy for -blockade in sepsis has recently risen, little is understood about in 
vivo mechanisms of effect during the adrenergic storm of sepsis.36-39 A pilot randomized, 
unblinded trial of esmolol infusion in tachycardic patients with septic shock suggested 
that this 1-blocker was associated with significantly decreased mortality, higher stroke 
volume, lower arterial lactate, and lower norepinephrine dosage.40,41 Unfortunately, the 
control-group hospital mortality was 81%, far higher than predicted by current severity 
scores, thus limiting generalizability. That trial also failed to provide important 
mechanistic insights. Nonetheless, the positive overall result from the Italian phase 2 trial 
identifies both the safety of esmolol infusions in septic shock patients with tachycardia 


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and suggests an urgent need to conduct a more definitive and mechanistically 
sophisticated clinical trial.
3.1.6.1. -adrenergic blockade has direct cardiac effects
In the heart, -blockade improves coronary perfusion, decreases myocardial work, and 
directly reduces cardiomyocyte dysfunction, especially via selective 1-blockade. The 
net effects can be monitored via measurement of left ventricular (LV) strain,42-46 a 
technique our group has repeatedly validated as a more sensitive and specific marker of 
cardiac dysfunction in septic patients. Additionally 1-blockade may improve myocardial 
performance (especially through providing more time for ejection and relaxation, as 
measured by the tissue Myocardial Performance Index). -blockade has long been 
considered an option for improving autonomic nervous system homeostasis and 
restoration of heart rate variability: after myocardial infarction -blocker improves 
parasympathetic tone.47 
3.1.6.2. -adrenergic blockade has effects on the microvasculature
To prevent unopposed vascular leakage and inflammation, the endothelium possesses 
natural braking mechanisms. The Tie2 pathway appears to be a central actor in the 
braking response. Tie2 is a receptor expressed predominantly by endothelial cells, 
where it maintains vascular barrier function.48,49 Normally, Tie2 is tonically activated by 
Angiopoietin-1 (Angpt-1), a protein ligand secreted from nearby vascular smooth muscle 
cells. As our group and others have shown, activated Tie2 both maintains barrier 
function and defends the barrier against virtually all known triggers of permeability—
indeed, in the context of experimental sepsis, Tie2 activation by Angpt-1 improves organ 
function and survival.50-57 During inflammatory states, the function of Tie2 is antagonized 
by a ligand secreted from the endothelium itself called Angpt-2. Angpt-2 unseats Angpt-1 
from the receptor, deactivates signaling through Tie2, and as a result, potentiates 
inflammation and vascular leakage. Circulating Angiopoietin levels predict vascular injury 
and adverse outcomes in sepsis and other critical illness,58 while therapeutic inhibition of 
Angpt-2 rescues vascular leak and mortality in experimental sepsis.59-61 In sum, Tie2 
appears to be a major toggle for the endothelium to switch between barrier protection 
and vascular leakage.53-57
Several lines of evidence suggest that -blockade may improve endothelial function, 
especially via Tie2. A pilot study of infantile hemangioma suggested a potent regressive 
effect of -blockade on these benign endothelial tumors;62 a follow-up controlled trial 
demonstrated ~15-fold improvement with -blockade.63 Crucially, these inherited 
hemangiomatous disorders arise from mutations in TIE2.64,65 Specific to sepsis, an 
uncontrolled study in humans40 and a randomized trial in rats66 suggested that esmolol 
infusion significantly improved endothelial function and in turn, overall survival.
3.2
Study Design
Prospective, single arm, feasibility (“ROLL-IN”) study of esmolol infusion in septic shock.
3.3
Objective
To assess the adequacy of subject identification and enrollment procedures. To assess 
the adequacy and efficiency of study protocols. To evaluate the estimates of coordinator 
burden for screening and enrollment.
3.5.1
Non-clinical outcomes for ROLL-IN:


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1.
Proportion of eligible patients consented
2.
Proportion of protocol compliance
3.
Amount of research coordinator time spent on different tasks
3.5.2
Anticipated primary clinical outcome for main trial: Organ-failure-free days at 
28 days. Defined as the number of calendar days on which the patient receives none of 
(a) vasopressor therapy, (b) mechanical ventilation, or (c) renal replacement therapy. 
(Patients who die before 28 days will be assigned -1 organ-failure-free days in order to 
avoid making death equivalent to prolonged organ dysfunction.) For example, a patient 
who died on day 12 would have -1 organ-failure-free days, while a patient who resolved 
all organ dysfunction on day 9 but died on day 30 would be categorized as having 19 
organ-failure-free days.
3.5.3
Anticipated secondary outcomes for main trial
1.
All-cause hospital mortality
2.
All-cause 28-day and 90-day mortality
a.
Mortality will be ascertained through telephone followup for patients who 
were discharged alive before 90 days.
3.
Peak serum high-sensitivity troponin
a.
Troponin will be measured on day 0 and day 1.
4.
24-hour LV strain, as assessed by echocardiography
5.
Days to transition to a quiescent vascular phenotype.
6.
ICU-free days to day 28
a.
Patients who die before 28 days will be assigned -1 ICU-free days, using 
a methodology similar to that used for organ-failure-free days.
7.
Cardiogenic shock/requirement for inotropes through day 14. This is a binary 
variable and is met when any of the following is met
a.
Dobutamine or milrinone infusion at any dose, lasting > 60 min
b.
CI ≤ 2 L/min/m2 lasting > 30 min on NICOM
c.
ScvO2 ≤ 60% on any measurement
3.6.2
Anticipated prespecified subgroups
1.
Patients with abnormal LV strain on the initial echocardiogram (>-18%)
2.
Patients with an abnormal tMPI (> 0.39) on the initial echocardiogram
3.
Patients receiving an epinephrine infusion at the time of enrollment
4.
Patients with a non-quiescent vascular phenotype at the time of enrollment
5.
Patients over the age of 65 years
4.0
Study population and enrollment
The study will enroll 10 patients at one clinical center. Patients will be recruited from the 
ICUs of Intermountain Medical Center. The objective is to screen every newly admitted 
patient with septic shock to determine eligibility.
4.1
Screening


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Appropriate subjects will be identified through review of the ER census and Intensive 
Care Unit (ICU) log several times a day, or by automated computer alerting, where 
available. Patients who are admitted from the ER of an outside hospital will be 
considered; patients transferred from an inpatient ward/ICU at an outside hospital will 
not be considered. Patients who are transferred to the ICU from a hospital ward of the 
study hospital will be considered if (a) sepsis was present at the time of admission to the 
hospital ward from the study hospital ER, and (b) the total time on the hospital ward was 
less than 24 hours. Permission to approach patients and/or their families will be 
requested from the clinical team caring for the patient. All patients meeting inclusion 
criteria will be entered into a screening log. Intermountain Medical Center has dedicated 
study physicians and coordinators who are certified and trained in human subjects 
protection and understand the study protocol. These individuals will oversee and/or 
perform screening and enrollment activities.
4.2
Inclusion Criteria
Subjects will be considered eligible for the study when they are older than 18 
years of age, admitted to an ICU with septic shock, and for at least an hour, they are 
receiving vasopressors through a central venous catheter and have a heart rate > 
90/min. Subjects must meet the heart rate and vasopressor criteria at the time of 
enrollment.
Inclusion Criterion
Justification/Description
Age ≥ 18 years
Children are physiologically distinct from adults
Septic shock
Meets consensus criteria:
a.
≥2 SIRS criteria
b.
Suspected or confirmed infection
c.
Receiving vasopressor infusion to treat 
hypotension after at least 20ml/kg intravenous 
crystalloid volume expansion
Adequately volume expanded
Designed to include only non-compensatory 
tachycardia, that which persists after adequate volume 
expansion. Being no longer fluid responsive requires 
any one of
a.
CVP > 15 mmHg
b.
Negative Passive Leg Raise (PLR) maneuver (< 
10% increase in cardiac output during PLR)
c.
Stroke volume increase < 10% in response to 
rapid (< 5 min) infusion of at least 250 ml 
crystalloid solution
d.
In patients being passively mechanically 
ventilated, stroke volume variability (measured by 
a valid method, including NICOM) < 10%
Receiving vasopressor infusion via 
central venous catheter
At least 60 min of any infusion rate of norepinephrine, 
epinephrine, vasopressin, or phenylephrine
Current or imminent placement of 
arterial catheter
Allows continuous measurement of blood pressures 
during esmolol infusion and is standard in the study 
ICU.
Tachycardia (>90/min)
Heart rate must remain > 90/min for at least one hour, 
while the patient is receiving vasopressors
4.3
Exclusion Criteria


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Exclusions are designed to protect patient safety and maximize scientific integrity. They 
primarily relate to individuals who may not tolerate -blockade. Coenrollment in other 
interventional studies will not be allowed.
4.3.1
List of Exclusions and Reason for Exclusions
Exclusion Criterion
Justification/Description
Cardiogenic shock 
Safety consideration: -blockade may worsen 
preexisting cardiogenic shock. Cardiogenic shock 
defined as any one of
a.
Cardiac Index ≤ 2 L/min/m2 
b.
ScvO2 ≤ 60% 
c.
Ejection Fraction ≤ 25%
d.
Current infusion of any dose of dobutamine, 
milrinone, or dopamine
e.
Current infusion of epinephrine to treat clinically 
diagnosed cardiogenic shock.
Preexisting heart block
Safety consideration: -blockade may worsen heart 
block.
Defined as any of the following 
a.
Sick sinus syndrome
b.
PR interval > 200 msec
c.
Any current evidence or history of Grade 2 or 
Grade 3 heart block
d.
Pacemaker or plans to place a pacemaker
Atrial fibrillation at time of enrollment
Substantial noise associated with exposure, 
hemodynamic measurements, and outcomes; may 
require independent heart rate control or cardioversion.
Current nodal blockers or anti-arrhythmic 
agents
Safety consideration: risk of excess nodal blockade. 
Increased experimental noise.
Receipt of any of the following within 3 half lives (see 
full list in Appendix)
a.
Non-dihydropyridine calcium channel blockers 
b.
Digitalis
c.
Anti-arrhythmics (e.g., amiodarone, dronedarone, 
mexiletine)
d.
Beta blockers
Receiving clonidine, guanfacine, or moxonidine
Safety issue
Moderate or severe pulmonary hypertension
Possible safety consideration; risk of hemodynamic 
deterioration.
Defined as a documented history of prior right heart 
catheterization or current evidence on TTE of any of 
the following.
a.
mPAP ≥ 35 mmHg
b.
SPAP ≥ 60 mmHg
Allergy to esmolol or vehicle
Rare, but required for patient safety.
Admitted for hospice or comfort care
Incomplete and biased data on both exposure and 
outcome.
Inability to obtain consent within 48 hours of 
ICU admission
This study does not qualify for waiver of consent
Active pregnancy or nursing
Physiology of pregnant patients distinct; potential risks 
to fetus unknown; drug levels in breast milk.
Prisoners
Septic shock is not specific to prisoners, so ethical 
concerns emphasize the protection of autonomy.
Previously enrolled in this trial
Violation of the independence assumption.
Pheochromocytoma or status asthmaticus
Safety issue associated with beta blockade
Hemoglobin < 7 gm/dl
Exclude anemia as cause of tachycardia; avoid risk of 
impaired oxygen delivery related to anemia 
Cardiovascular collapse
Safety consideration; failure to achieve 65mmHg MAP 
with vasopressors.


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Cardiac arrest within 24 hours
Safety consideration
Worse than moderate aortic stenosis
Known aortic stenosis, with any of (1) mean gradient ≥ 
40 mmHg OR (2) maximum gradient ≥ 60mmHg OR (3) 
aortic valve area ≤ 1.0cm2 OR (4) aortic valve area 
index ≤ 0.85cm2/m2 body surface area. This is a 
hypothetical safety consideration.
Worse than mild mitral stenosis
Known mitral stenosis, with any of (1) valve area ≤ 1.5 
cm2 OR mean gradient ≥ 5 mmHg. This is a 
hypothetical safety consideration.
4.4 
Enrollment Time Window
Patients must be enrolled within 48 hours of ICU admission and septic shock and 
must still meet inclusion criteria at the time of enrollment.
4.5
Women and Minorities
Every effort will be made to assure adequate representation of women and 
minorities. The study inclusion and exclusion criteria (other than the pregnancy 
exclusion) do not differentially exclude women or minorities.
5.0 Study Procedures
5.1
Common Management Strategies 
5.1.1
Study Startup Procedures
Potential candidates will be screened according to the algorithm outlined in FIGURE 1. A 
study investigator will review, with the research coordinator, all study inclusions and 
exclusions before consent and enrollment.


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Figure 1


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5.1.1.1 Review for final exclusions
A study investigator will review, with the research coordinator, all study inclusions and 
exclusions before consent and enrollment. After enrollment, according to the protocol 
depicted in FIGURE 2, study personnel will confirm that cardiogenic shock is absent and 
adequate volume expansion has occurred. These evaluations are performed after 
consent because they involve study procedures, which cannot be required of subjects 
who have not consented. If cardiogenic shock is documented at this point, a subject will 
be followed for outcomes and biomarkers but esmolol will not be infused. After the final 
safety check has been completed and the patient is confirmed eligible for study drug 
infusion, study drug infusion should be started as soon as possible and within 3 hours of 
passing the final safety check.
5.1.1.2 Evaluation for cardiogenic shock
If cardiogenic shock is documented at this point, a subject will be followed for outcomes 
and biomarkers but esmolol will not be administered. This step involves evaluation of LV 
ejection fraction, measurement of ScvO2, and direct measurement of cardiac index using 
the NICOM bioreactance device.
5.1.1.3 Review of fluid responsiveness/adequacy of volume expansion
After the lack of cardiogenic shock has been confirmed and still before esmolol infusion, 
subjects will be evaluated for fluid responsiveness. Once the subject has been 
determined to no longer be fluid responsive, applying the tests outlined in section 4.2, 
esmolol will be infused. If, in the investigator’s best judgment, one of those markers of 
fluid responsiveness is providing a false negative result, s/he may require additional 
volume expansion, in consultation with the treating team, before initiation of esmolol 
infusion.
Figure 2
5.1.2 Ventilator management
ARDS Network low-stretch ventilation (as is the standard at IMC) will be used for all 
mechanically ventilated patients, given the proportion of patients with septic shock who 
have ARDS and evolving data suggesting that patients at risk for ARDS merit low-stretch 
ventilation. Ventilator weaning will be performed as per institutional protocol. Weaning 
will not wait until esmolol infusion has ceased.
5.1.3 Baseline Assessment


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In addition to the evaluation for inclusion and exclusion criteria, the following parameters 
will be obtained on all subjects. Unless otherwise specified, measurements will be those 
closest in time to enrollment.

Full TTE, including strain measurements

Serum for troponin

Plasma for vascular biomarkers (e.g., angiopoietin)

Heart rate variability

Vasoactive medications (e.g., agent, infusion rate)

Vital signs

Ventilator settings (e.g., PEEP, PF or SF ratio, tidal volume, plateau pressure)

Admission APACHE II/IV score and components

SOFA scores and constituents

Age

Sex

Race/ethnicity

Contact information
5.1.4
24-hour assessment, including early protocol

Full TTE, including for strain

Serum for vascular biomarkers, including Troponin

Heart rate variability

Vasoactive medications (e.g., agent, infusion rate)

SOFA scores and constituents

APACHE II/IV score and constituents

Vital signs

Ventilator settings (e.g., PEEP, PF or SF ratio, tidal volume, plateau pressure)
5.1.5
On-treatment assessments

Incidence of protocol violations

Incidence of adverse reactions

SOFA scores and constituents

APACHE II/IV score and constituents
5.1.6
Hospital discharge assessment

Organ-failure-free days at 28 days

Vital status at hospital discharge

Discharge destination (home, home with services, SNF, rehab, LTACH)
5.1.7
Management of blood samples

Troponin will be tested in the Intermountain clinical laboratory

Vascular biomarkers will be tested in Dr. Parikh’s laboratory at BIDMC. Locally at 
IMC, they will be centrifuged and stored at -80C before transportation on dry ice.
5.2
Esmolol infusion
The esmolol infusion will be managed as per the protocol in APPENDIX 1. 
Esmolol will be stopped and cannot be restarted without explicit investigator approval for 
STOP events. Further needs for volume expansion will be assessed on the basis of 
VOLUME EXPANSION events. If the patient is taken to the operating room, esmolol 


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infusion will be stopped when the patient leaves the ICU for the OR and will only be 
resumed after reevaluation of cardiac index and adequacy of volume expansion, given 
the possibility of changes in volume status and degree of shock during surgery.
6.0
Data Collection and Safety Monitoring
6.1
Data Collection and Data Quality Monitoring
Research coordinators and/or investigators will collect data and record them on paper or 
electronic CRFs. Data will be analyzed internally. Data quality will be reviewed using 
front-end range and logic checks at the time of data entry and back-end monitoring of 
data. Patient records and case report forms will be examined on a random spot check 
basis to evaluate the accuracy of the data entered into the database and monitor for 
protocol compliance.
6.2
Safety Monitoring
The safety of this feasibility “roll-in” study will be monitored by a three-member safety 
monitoring committee (SMC). The SMC will have full access to all study data (including a 
narrative account of each patient’s course) and will review for any major adverse events 
at 3 patients enrolled and at 6 patients enrolled. While septic shock is a high-mortality 
condition at baseline, every death during esmolol infusion will be reported (including 
narrative account and full study data) within 24 hours to the chair of the SMC by the 
study PI. Further details of safety monitoring and reporting are given at Appendix 4.
7.0
Statistical plan
7.1
Statistical Analysis
The primary comparison is between treatment assignment and organ-failure-free days at 
28 days. Secondary analyses are the evaluation of adequacy of screening, enrollment, 
and study protocols.
7.2
Sample size
This “roll-in” feasibility study will allow us to confirm the adequacy of compliance with 
management protocols, and the time intensity of study enrollment and CRF completion. 
These roll-in data will be used to allow rapid initiation of a much larger multi-center trial 
once funding is secured.
7.3
Additional data
Investigators at the University of Chicago are performing a parallel study under similar 
protocol, overseen by the University of Chicago IRB and monitored by their own Safety 
Monitoring Committee. Data from the University of Chicago study will be shared with 
investigators at IMC to allow analysis of the experience at the two centers. All data 
transfers will be over-seen by applicable IRB approvals, consent documents, and data 
use/data sharing agreements and will not occur without appropriate agreements and 


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approvals in place. Data privacy and confidentiality for the University of Chicago data will 
comply with relevant regulations and safeguards.
8.0
Risk Assessment
8.1
Potential Risks
There are potential risks (as well as benefits) to study subjects. Selective 1-blockade in 
septic shock has reasonable pilot data in favor of its safety; our observations about 
improved survival with relative bradycardia also suggest that interventions to induce 
relative bradycardia will be safe. The primary concerns about risk related to 1-blockade 
in septic shock (based on theoretical considerations) are of decreased cardiac output, 
which is why we will titrate esmolol without bolus doses, starting at very low doses, and 
we will exclude patients with preexisting or intercurrent cardiogenic shock. After enrollment 
and before esmolol infusion, we will perform a final verification that cardiogenic shock is 
not present (using the NICOM™ measurements and initial research echocardiogram). 
Patients with preexisting conduction system disease may also be at risk for heart block or 
excessive bradycardia, so they are excluded from this study as well (this will also be 
verified before esmolol infusion, from the EKG monitors at the patient’s bedside). 
We have chosen esmolol because it is 1-selective (thereby decreasing the 
hypothetical risk of pulmonary effects possible with non-selective -blockade), because it 
is available as a continuous infusion (thereby limiting the risk of bolus-associated adverse 
effects) and because it has a very short half-life (allowing essentially immediate cessation 
of effect when the infusion is stopped). The theoretical side effects of esmolol infusion 
would all reverse within minutes of discontinuation of esmolol, and explicit rules will dictate 
discontinuation of esmolol infusion.
8.1.1
Alternative treatments
While some individual clinicians have advocated use of intravenous metoprolol, another 
1-blocker, the longer duration of action and the lack of availability as a continuous 
infusion led us not to recommend metoprolol for this trial. There is no evidence-based 
alternative treatment currently available for the adrenergic over-stimulation associated 
with septic shock. Since participation in this study is voluntary, all patients who choose not 
to enroll will receive the treatment consistent with the highest standard of care established 
at their institutions. 
8.2
Risk abatement strategies
8.2.1
Cardiogenic shock. As indicated above, patients with preexisting cardiogenic 
shock are excluded from enrollment, and after enrollment a formal evaluation to exclude 
cardiogenic shock will be performed before esmolol infusion. The esmolol titration 
protocol incorporates continuous monitoring of cardiac output using the non-invasive 
NICOM™ device, and in the rare situation that cardiogenic shock should ensue, esmolol 
titration will be discontinued and appropriate supportive measures will be instituted. Our 
use of a no-bolus, slow upward titration protocol for the esmolol infusion is specifically 
designed to avoid this potential complication.
8.2.2
Excessive bradycardia and/or hypotension. As indicated above, patients with 
preexisting conduction system disease are excluded from enrollment, and a formal 
evaluation to exclude conduction system disease will be performed before esmolol 
infusion. In the event that hypotension or excessive bradycardia should ensue during 
esmolol infusion, esmolol will be discontinued and appropriate supportive measures will 


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be instituted. Our use of a no-bolus, slow upward titration protocol for the esmolol infusion 
is specifically designed to avoid this potential complication.
8.2.3
Hypersensitivity reaction. This is extremely rare. Patients with known 
hypersensitivity to esmolol or vehicle are excluded from the study. Should this occur, 
esmolol infusion will be stopped and appropriate treatment measures will be instituted. 
The short half-life of esmolol avoids concerns about treatment of anaphylaxis in patients 
on -blockers, should anaphylaxis occur.
8.3 
Protection against loss of privacy/breach of confidentiality
In order to protect a potential subject’s privacy, study staff will only approach potential 
subjects (or LARs) in a private setting. Once consented, we will take multiple steps to 
protect the study subject from breach of confidentiality. The list linking the subject’s 
name and medical record number will be kept behind the hospital firewall in a password-
protected file. This file is only accessible through the hospital server to those individuals 
given password approval to access the file. Furthermore, the electronic database 
(REDCap) will be coded with a unique study identifier rather than with individually 
identifiable PHI (other than certain dates of service, as indicated above). The paper copy 
of CRFs will be stored in a locked cabinet at Intermountain Medical Center. The plasma 
sent to BIDMC for vascular biomarker assays will be managed according to standard 
practice for research samples, under an appropriately executed material transfer 
agreement.
8.4
Potential benefits
If esmolol proves efficacious, we anticipate a direct benefit to patients receiving esmolol 
infusion, specifically improvements in organ-failure-free days and/or survival.
8.5
Risks vs. benefits
We have specifically designed the study intervention and esmolol titration protocol to 
minimize to the maximal extent possible the risks associated with this study. Based on 
our preliminary data and an Italian pilot study, we believe that the risk-to-benefit ratio for 
individual patients is favorable.
9.0
Human Subjects
Each study participant or a legally authorized representative (LAR) must sign and date 
an informed consent form. Institutional review board (IRB) approval is required before 
any subject is entered into the study.
9.1 Selection of Subjects 
Federal regulations at 45 CFR 46(a)(3) require equity/distributive justice in human 
subjects research. The participating ICUs will be screened to determine whether any 
patient meets inclusion and not exclusion criteria, drawing on routine clinical data. No 
protocol-specific tests nor procedures will be performed as part of the screening 
process. Potential subjects will not be approached until the clinical team has granted oral 
permission to approach the patient and/or LAR for informed consent. Study exclusion 


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criteria neither unjustly exclude classes of individuals from participation in the research 
nor unjustly include classes of individuals for participation in the research. The 
recruitment of subjects are therefore equitable/just.
9.2 Justification for Including Vulnerable Subjects 
The present research aims to investigate the safety and efficacy of a specific treatment 
for patients with critical illness. Due to the nature of critical illness, the majority of these 
patients will have impaired decision-making capabilities. This study cannot be conducted 
if limited to enrolling only those subjects with retained decisional capacity. Hence, 
subjects recruited for this trial are not being unfairly burdened with involvement in this 
research simply because they are easily available.
9.3 Informed Consent 
Federal regulations at 45 CFR 46.111(a)(5) require informed consent to participate in 
research. As ECASSS will enroll critically ill, intubated patients, the large majority of 
initial consents will be from the subject’s LAR, and thus the remainder of this section will 
focus on LARs. The investigator is responsible for ensuring that the LAR understands 
the risks and benefits of participating in the study, and answering any questions the LAR 
may have throughout the study and sharing any new information in a timely manner that 
may be relevant to the LAR’s willingness to continue the subject’s participation in the 
trial. The consenter will make every effort to minimize coercion, including not allowing a 
Study Investigator to participate in obtaining consent when s/he is currently providing 
clinical care to the subject. All study participants or their LARs will be informed of the 
objectives of the study and the potential risks. The informed consent document will be 
used to explain the risks and benefits of study participation to the LAR in simple terms 
before the subject is entered into the study, and to document that the LAR is satisfied 
with his or her understanding of the risks and benefits of participating in the study and 
desires to participate in the study. The Study Investigator is responsible for ensuring that 
informed consent is obtained from each subject or LAR. This includes obtaining the 
appropriate signatures and dates on the informed consent document prior to the 
performance of any protocol procedures and prior to the administration of study agent. 
9.4 Continuing Consent 
For subjects for whom consent was initially obtained from a LAR, but who subsequently 
regain decisional capacity while in hospital, investigators will seek formal reconsent for 
continuing participation, inclusive of continuance of data acquisition. The initial consent 
form signed by the LAR will reflect that such consent will be attempted and will be 
updated when such “reconsent” is obtained.
9.5 Withdrawal of Consent 
Patients may withdraw or be withdrawn (by the LAR) from the trial at any time without 
prejudice. Data recorded up to the point of withdrawal will be included in the trial 
analysis, unless consent to use their data has also been withdrawn. If a patient or LAR 
requests termination of the trial drug during the treatment period, the drug will be 
stopped but the patient will continue to be followed up as part of the trial. If a patient or 
LAR withdraws consent during trial treatment, the trial drug will be stopped but 
permission will be sought to access medical records for data related to the trial. If a 


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patient or LAR wishes to withdraw from the trial after completion of trial treatment, 
permission to access medical records for trial data will be sought.
9.6 Identification of LARs
Many of the patients approached for participation in this research protocol will be 
decisionally impaired due to their critical illness. Hence, most patients will not be able to 
provide informed consent. Accordingly, informed consent will be sought from the 
participants legally authorized representative (LAR), as defined at 45 CFR 46 102 (c). In 
this study, LARs will be identified as stipulated by relevant regulations and statutes as 
required by IRBs, as per the standards defined for clinical decision making, as is the 
standard practice in human subjects research.
9.7 Confidentiality 
Federal regulations at 45 CFR 46 111 (a) (7) requires when appropriate, adequate 
provisions to protect the privacy of subjects and to maintain the confidentiality of data. 
To maintain confidentiality, all case report forms and reports will be identified only by a 
coded number. The coded number will be generated by a computer, and only the study 
team will have access to the codes. All records will be kept in a locked, password 
protected computer. All computer entry and networking programs will be done with 
coded numbers only. All paper case report forms will be maintained inside a locked 
office.
10 Adverse Events
Patient safety is central to this study protocol. Each investigator is responsible for the 
safety of the study participants under his/her care. Investigators will determine daily 
whether any adverse events occurred during the period from enrollment through 24 
hours after the completion of the esmolol infusion.
10.1 The following adverse events will be collected in the adverse event case report 
forms: 

Serious adverse events 

Nonserious adverse events that are considered by the investigator to be related 
to study drug or study procedures or of uncertain relationship (Appendix 4) 

Adverse events that lead to permanent discontinuation of the study drug infusion. 
STOP events, as outlined in the titration protocol, are reportedly separately, 
recognizing that STOP events often will be related to the underlying septic shock 
rather than being drug- or protocol-related, as determined by their persistence for 
more than 20min after discontinuation of esmolol (at which points the effects of 
esmolol will have resolved). STOP events that require the permanent 
discontinuation of study drug infusion will be reported as adverse events.
A clinical trial adverse event is any untoward medical event associated with the use of a 
drug or study procedure in humans, whether or not it is considered related to a drug or 
study procedure. 
After randomization, adverse events related to protocol procedures or occurring 
after the patient receives the first dose of study drug must be evaluated by the study 
investigator. If the adverse event is judged to be reportable, the investigator will report to 


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the SMC his/her assessment of the potential relatedness of each adverse event to study 
drug or study procedure. Investigators will assess if there is a reasonable possibility that 
the study drug or procedure caused the event, based on the criteria outlined in Appendix 
4. Investigators will also consider whether the event is unanticipated or unexplained 
given the patient’s clinical course, previous medical conditions, and concomitant 
therapies. 
10.2 SERIOUS ADVERSE EVENTS 
Serious adverse event collection begins after the patient or LAR has signed informed 
consent and has received study drug or undergone study procedures. If a patient 
experiences a serious adverse event after consent, but prior to receiving study drug, the 
event will NOT be collected unless the investigator feels the event may have been 
caused by a study procedure. 
Investigators must alert the chair of the SMC of any serious and study drug or study 
procedure related adverse event within 24 hours of investigator awareness of the 
event. Alerts issued via telephone are to be immediately followed with official notification 
on the adverse event case report form. See Appendix 4 for reporting timelines for 
serious, unexpected, study related events (SAEs) and serious, unexpected suspected 
adverse reactions (SUSARs).
As per federal definitions (primarily in 21 CFR 312.32(a)), a serious adverse event is 
any adverse event that results in one of the following outcomes: 

Death

A life-threatening event, one that places the subject at immediate risk of death 
(this does not include an event that, had it been more serious, would have placed 
the subject at immediate risk of death)

Prolonged inpatient hospitalization or rehospitalization 

Persistent or significant disability/incapacity, indicating a substantial disruption of 
a person's ability to conduct normal life functions (i.e., the adverse event resulted 
in a significant, persistent or permanent change, impairment, damage or 
disruption in the patient's body function/structure, physical activities and/or quality 
of life). 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious adverse events when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
Given the short-acting nature of esmolol and the limited duration of the study 
infusion, surveillance for adverse events will extend through 24 hours after completion of 
the esmolol infusion. Serious adverse events will be collected during and for 24 hours 
after the esmolol infusion, regardless of the investigator's opinion of causation. 
Thereafter, serious adverse events are not required to be reported unless the 
investigator feels the events were related to study drug or a protocol procedure.


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APPENDIX 1
ECASSS ROLL-IN Study Drug Titration protocol
Fundamental rules for study drug titration:
The target heart rate is 85 bpm. Start study drug infusion at 20 mcg/kg/min, without 
bolus, if HR ≥ 100 bpm. If HR >90 bpm and <100 bpm, start study drug infusion at 10 
mcg/kg/min, without bolus. Increase by 20 mcg/kg/min every 20 minutes as long as HR 
> 90 bpm, to a maximum dose of 100 mcg/kg/min. If HR < 80 bpm and > 70 bpm, 
decrease infusion rate by 10 mcg/kg/min; if HR ≤ 70 bpm and > 60 bpm, decrease 
infusion rate by 20 mcg/kg/min. Stop study drug infusion whenever a STOP EVENT 
occurs. Study drug infusion is completed 3 hours after vasopressor infusions have 
stopped. The up-titrations can be smaller than stipulated if the clinician and/or 
investigator feels that a small up-titration is indicated. Up-titrations should not occur 
during a REASSESS VOLUME STATUS event.
Study drug should be preferentially infused centrally; where no port is available, study 
drug should not be infused into a small peripheral vein or via butterfly catheter.
STOP EVENTS: 
1.
If HR is ever ≤ 60 bpm, immediately stop infusion for 20 minutes, then restart at 
half the previous infusion rate, rounded to nearest 10 mcg/kg/min. Do not resume 
infusion until HR > 70 bpm.
2.
If vasopressor dose increases by 0.2 mcg/kg/min norepinephrine (or equivalent) 
AND doubles within 60 min despite adequate volume expansion, STOP the study 
drug infusion. Alternatively, if the treating clinician believes that the shock is 
worsening significantly, STOP the study drug infusion. Do not resume without 
explicit approval of study physician.
3.
If cardiogenic shock develops (ScvO2 ≤ 60% OR LV Ejection Fraction ≤ 25% OR 
Cardiac Index ≤ 2.0 L/min/m2), STOP the study drug infusion. Do not resume 
without explicit approval of study physician.
4.
If clinically apparent bronchospasm develops, STOP the study drug infusion. Do 
not resume.
5.
If Grade 2 or Grade 3 heart block develops, immediately STOP the study drug 
infusion. Do not resume.
REASSESS VOLUME STATUS EVENTS:
When markers of potential preload deficit occur (urine output < 0.5 ml/kg/hr OR 
vasopressor dosage increase), immediately EVALUATE FOR VOLUME 
RESPONSIVENESS. A vasopressor dosage increase is defined as at least 0.05 
mcg/kg/min absolute AND 20% relative increase in the norepinephrine (or equivalent) 
infusion.
Titrate vasopressors as per local practice to maintain MAP ≥ 65mmHg. Norepinephrine 
is the preferred primary vasopressor.


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APPENDIX 2: Constituents of the esmolol (BREVIBLOC) vehicle
Sodium Chloride, USP
Water for Injection, USP
Sodium Acetate Trihydrate, USP
Glacial Acetic Acid, USP
Sodium Hydroxide
Hydrochloric Acid


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APPENDIX 3: List of nodal blocking agents
Acebutolol
Amiodarone
Atenolol
Betaxolol
Bisoprolol
Bretylium
Carvedilol
Digoxin/digitalis
Diltiazem
Disopyramide
Dofetilide
Dronedarone
Esmolol
Flecainide
Labetalol
Metoprolol
Nadolol
Nebivolol
Penbutolol
Pindolol
Procainamide
Propafenone
Propranolol
Quinidine sulfate
Sotalol
Timolol
Verapamil


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APPENDIX 4.
As noted in section 10.2, investigators will report all adverse events that are 
serious and study drug or study procedure related to the chair of the SMC within 24 
hours. The SMC and the PI will then notify the IRB. 
The PI, in consultation with the chair of the SMC, will determine if a SAE has a 
reasonable possibility of having been caused by the study drug or procedure, as outlined 
in 21 CFR 312.32(a)(1). The PI, in consultation with the SMC chair, will also determine 
whether the event is unexpected. An adverse is considered “unexpected” if it is not listed 
in the investigator brochure or the study protocol (21 CFR 312.32(a)). For this study, the 
esmolol (Brevibloc®) package insert serves as the investigator brochure. If a 
determination is made that a serious adverse event has a reasonable possibility of 
having been caused by the drug, it will be classified as a suspected adverse reaction. If 
the suspected adverse reaction is unexpected, it will be classified as a serious 
unexpected suspected adverse reaction (SUSAR). 
The PI will report all unexpected and study related deaths, SAEs, and SUSARs 
to the SMC and IRB within 7 days after report of the event. A written report will be sent 
to the SMC and IRB within 15 calendar days. The SMC will also review all adverse 
events and clinical outcomes during scheduled interim analyses.
A4.1. UNANTICIPATED PROBLEMS (UP) 
Investigators must also report Unanticipated Problems, regardless of severity, 
associated with the study drug or study procedures within 24 hours. An unanticipated 
problem is defined as follows: any incident, experience, or outcome that meets all of the 
following criteria: 

Unexpected, in terms of nature, severity, or frequency, given the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and the 
characteristics of the subject population being studied; 

Related or possibly related to participation in the research, in this guidance 
document, possibly related means there is a reasonable possibility that the 
incident, experience, or outcome may have been caused by the procedures 
involved in the research; 

Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
A4.2. DETERMINING RELATIONSHIP OF ADVERSE EVENTS TO STUDY DRUG OR 
PROCEDURES 
Investigators will grade the strength of the relationship of an adverse event to esmolol or 
study procedures as follows: 
• Definitely Related: The event follows: (a) a reasonable, temporal sequence from 
study drug or a study procedure; and (b) cannot be explained by the known 
characteristics of the patient’s clinical state or other therapies; and (c) evaluation 
of the patient’s clinical state indicates to the investigator that the experience is 
definitely related to study procedures. 
• Probably or Possibly Related: The event should be assessed following the 
same criteria for “Definitely Related”. If in the investigator’s opinion at least one 
or more of the criteria are not present, then “probably” or “possibly” associated 
should be selected. 


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• Probably Not Related: The event occurred while the patient was receiving 
esmolol or undergoing study procedures but can reasonably be explained by the 
known characteristics of the patient’s clinical state or other therapies. 
• Definitely Not Related: The event is definitely produced by the patient’s clinical 
state or by other therapies administered to the patient. 
• Uncertain Relationship: The event does not meet any of the criteria previously 
outlined. 
Certain serious adverse events will not require adjudication; they will always be 
understood to be drug-related.
•
Third-degree heart block while receiving esmolol infusion.
A4.3. CLINICAL OUTCOMES THAT MAY BE EXEMPT FROM ADVERSE EVENT 
REPORTING 
Study-specific clinical outcomes of septic shock, as outlined in Sections 2.8 and 3.5 
(Primary and Secondary Outcomes) and Section 5.1 (Assessments) are exempt from 
adverse event reporting unless the investigator deems the event to be related to the 
administration of study drug or the conduct of study procedures (or of uncertain 
relationship). The following are examples of events that will be considered study-specific 
clinical outcomes 
•
Death not related to the study drug or procedures. 
•
Cardiovascular events: changes in doses of vasoactive drugs or VOLUME 
EXPANSION events. 
•
Organ dysfunction events: changes in the SOFA score and its constituents.
•
Cardiogenic shock that does not resolve 20 minutes after cessation of esmolol
A4.4. DECISION TREE FOR REPORTING ADVERSE EVENTS
Adapted from Ranieri VM, Thompson BT, Barie PS et al. Drotrecogin alfa (activated) in 
adults with septic shock. N Engl J Med. 2012 May 31;366 (22):2055-64. Epub 2012 May 
22. PubMed PMID: 22616830 with permission of Dr. Thompson.


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