Evaluating the Effect of Chronic Antihypertensive Therapy on Vasopressor Dosing in Septic Shock
Conditions: Septic Shock
Sponsor: Rush University Medical Center

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Evaluating the effect of chronic antihypertensive therapy on vasopressor 
dosing in septic shock 
 
 
1. PURPOSE OF THE STUDY AND BACKGROUND 
 
1.1. Hypothesis 
 
• 
Chronic β-blocker or Angiotensin-Converting Enzyme (ACE)-inhibitor use is associated with 
decreased cumulative doses of vasopressors administered in the first 48 hours of septic shock 
 
1.2. Purpose of the study 
 
• 
The primary objective is to determine the effect of chronic β-blocker or ACE-inhibitor on 
cumulative vasopressor dosing in the first 48 hours of septic shock.    
 
• 
The secondary objectives of this study  
o To determine the effect of chronic β-blocker or ACE-inhibitor on cumulative vasopressor 
dosing in the first 6, 12, and 24 hours of septic shock.    
o To determine the effects of chronic β-blocker or ACE-inhibitor  on:  
▪ 
Adequate fluid resuscitation 
▪ 
Cumulative inotrope use (48 hours) 
▪ 
Cumulative hydrocortisone use at 6, 12, 24, and 48 hours 
o To determine cumulative vasopressor dose of patients on chronic calcium channel 
blocker or other antihypertensives (clonidine, hydralazine, angiotensin-receptor-blocker 
(ARB)) 
 
1.3. Background 
 
Literature suggests that extended periods of tachycardia, in patients with shock, are associated 
with increased mortality.1-4 Interventional trials have suggested that increased doses of 
catecholamines are associated with the increased mortality and the administration of esmolol 
infusions may improve survival in patients with shock requiring vasopressor agents. 1  
 
What remains unknown is the effect of home exposure to antihypertensive therapies, 
specifically beta-blockers and ACE-inhibitor. This study will evaluate the effects of home 
antihypertensive therapy with beta-blockers and ACE-inhibitor on vasopressor dose 
administered within the first 48 hours of septic shock.   
 
2. STUDY DESIGN 
 
2.1. Overview 
 
This will be a retrospective four-cohort study.  The four cohorts will be septic shock patients 
that were: 1) not on either a chronic β-blocker or ACE-Inhibitor, 2) on chronic β-blocker, 3) on 
chronic ACE-Inhibitor, and 4) on both chronic β-blocker and ACE-inhibitor 
 
2.2. Rationale for Study Design 
 
This study design was chosen since the primary objective is to compare cumulative vasopressor 

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doses.  Many patients that present with septic shock have multiple comorbidities necessitating 
chronic therapy with either β-blocker, ACE-Inhibitor, or both.  Because little is known about 
the effects of chronic antihypertensives on vasopressor dosing and the severity of septic shock, 
a retrospective study was chosen.  
 
2.3. Rationale for Dosage 
 
Rationale for dosage is not applicable to this study because we will only be collecting pre-
existing medical data with no prospective interventions and dosing is routine care. 
 
 
3. CHARACTERISTICS OF THE RESEARCH POPULATION 
 
3.1. Subject Characteristics 
 
Number of Subjects:  
 
It is estimated that approximately 200 patients will be included for this study.  The 
individual number for each group will vary based on screening. 
 
Gender and Age of Subjects:  
 
No restrictions apply to gender of the study subjects.  Only adult, non-pregnant patients 
will be included, defined as 18 years of age or older. 
 
a) Racial and Ethnic Origin:  
 
No restrictions apply to race or ethnic origin of the study subjects. 
 
3.2. Inclusion and Exclusion Criteria  
  
a) Inclusion Criteria:  
 
• 
Adult patients 18 years of age or older 
• 
Diagnosis of septic shock requiring vasopressor therapy (norepinephrine, 
epinephrine, phenylephrine, dopamine, or vasopressin) 
• 
Admitted to the medical intensive care unit (MICU) at Rush University Medical 
Center (RUMC) 
• 
Time frame: 01/01/2012 to 08/1/2016 
 
b) Exclusion Criteria:  
 
• 
Pregnant patients 
• 
Transfer from outside hospital on vasopressors 
• 
Admitted in cardiopulmonary arrest 
• 
Prior arrest within 24 hours of admission to RUMC 
 
4. SUBJECT IDENTIFICATION, RECRUITMENT AND CONSENT 
 
4.1. Method Of Subject Identification And Recruitment 

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The study will be retrospective, and collected data will be a result of routine care.  Adult 
patients 18 years of age or older with septic shock who received treatment with a vasopressor 
will be assessed for inclusion.  Patients will be excluded if they are pregnant, transferred from 
outside hospital on vasopressor, admitted in cardiopulmonary arrest, prior arrest within 24 
hours of admission to RUMC or if they required neuromuscular blockade.   
 
Patients will be reviewed from 01/01/2012 to 08/1/2016.  A list of MICU patients will be 
generated by the corresponding ICD-9 and ICD-10 codes for septic shock.  Patients will be 
stratified into 4 groups:  1) not on either a chronic β-blocker or ACE-Inhibitor, 2) on chronic β-
blocker, 3) on chronic ACE-Inhibitor, and 4) on both chronic β-blocker and ACE-inhibitor.   
 
4.2.    Process of Consent 
 
This study is a retrospective study and therefore it is not feasible to obtain consent.  Direct 
patient involvement is not needed in the study and information will only be gathered from pre-
existing data in the patients’ medical record.  All data will be de-identified to limit the chance 
of exposure of protected health information (PHI). 
 
5. METHODS AND STUDY PROCEDURES 
 
5.1. Efficacy & Safety Assessments  
 
The electronic medical record system (EPIC) will be used to collect data, including: patient age, 
gender, weight, height, BMI, race, past medical history (hypertension, diabetes, heart failure, 
afib/flutter, arrhythmia, history of myocardial infarction, history of CVA, CAD, CKD, 
dyslipidemia, asthma, COPD, cancer), Charlson Comorbidity Index, hospital length of stay, 
medical intensive care unit (MICU) length of stay.  Prior to admission medications include:  
beta-blockers, ACE-inhibitors, amlodipine, diltiazem, ARBs, hydralazine, clonidine, hctz, loop 
diruetics, amiodarone, other antiarrhythmics.  Vasopressor types and cumulative doses 
including:  norepinephrine, epinephrine, phenylephrine, dopamine, and vasopressin.  
Epinephrine, phenylephrine, and dopamine will be converted to norepinephrine equivalents in 
concordance with other literature: 100 mcg dopamine equivalent to 1 mcg norepinephrine, 1 
mcg epinephrine equivalent to 1 mcg norepinephrine, and 2.2 mcg phenylephrine equivalent to 
1 mcg norepinephrine.5,6  Concomitant medications including:  hydrocortisone, inotrope use, 
crystalloid type and amount, colloid use, albumin use, timing of antibiotics, and sedation choice 
if given.  Clinical information collected include:  Peak lactate, MAP, mechanical ventilation, in 
hospital mortality, 28 and 90 day mortality if available.  SOFA score will be calculated as a 
measure of disease severity.   
 
Study Timeline: 
 
Date 
Activity 
September 2016 
Rush University Medical Center IRB approval 
October - November 2016 
Data collection 
December 2016 
Data analysis 
January 2017 
Study presentation and manuscript preparation 
 
5.2. Costs to the Subject 
 
There will be no costs to the subjects as this is an evaluation of pre-existing medical data. 

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5.3. Payment for Participation 
 
Subjects will not receive compensation for their participation in this study. 
 
 
6. CONCOMITANT AND DISALLOWED MEDICATIONS 
 
Concomitant and disallowed medications are not applicable to this study design. 
 
7. SUBJECT WITHDRAWALS 
 
Given the design of this study, subject withdrawal will not be an issue encountered. 
 
8. STUDY DRUG/DEVICE/BIOLOGIC ADMINISTRATION/ASSIGNMENT 
 
This study does not involve the implementation of a study drug, device, or biologic. 
 
9. SAFETY AND REPORTABLE EVENTS 
 
Given the design of this study we will not be prospectively collecting adverse events that 
require reporting. 
 
10. RISK/BENEFIT ASSESSMENT 
 
10.1. Potential Risks 
 
There are minimal risks to the study subjects.  The only potential risk is invasion of privacy 
since medical records will be accessed.  All data will be de-identified to limit the chance of 
exposure of PHI. 
 
10.2. Protection Against Risks 
 
It will be the responsibility of the primary investigator (PI) for data collection and storage in a 
safe, secure area and password protected computer when identifying eligible patients.  Research 
Electronic Data Capture (REDCap) will be used for data collection and storage. Patient 
confidentiality will be maintained by recording only de-identified data onto the data collection 
form.  Although the data collected and stored in REDCap will be exported for analysis, the 
exported data will contain no unique, patient-identifying information. 
 
10.3. Potential Benefits to Subjects 
 
There are no potential benefits to patients in this study 
 
10.4. Alternatives to Participation 
 
There are no alternatives to participation available for study subjects given the design of the 
study 
 
11. CONFIDENTIALIATY OF DATA AND INFORMATION STORAGE  

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It will be the responsibility of the primary investigator (PI) for data collection and storage in a 
safe, secure area and password protected computer when identifying eligible patients.  Research 
Electronic Data Capture (REDCap) will be used for data collection and storage. Patient 
confidentiality will be maintained by recording only de-identified data onto the data collection 
form.  Although the data collected and stored in REDCap will be exported for analysis, the 
exported data will contain no unique, patient-identifying information. 
 
12. RESEARCH INFORMATION IN MEDICAL RECORDS 
 
No research information will be included in the patient’s medical record. 
 
13. DATA ANALYSIS AND MONITORING 
 
13.1. Sample Size Determination 
 
There are limited data for proper evaluation of a sample size.  However, there was a smaller 
presented study that had a dramatic decrease in norepinephrine dose in patients on a β-blockers 
or ACE-inhibitors prior to admission for patients in circulatory shock of any kind.7 Using these 
data, estimated 48h cumulative mean dose for norepinephrine patients not on anti-hypertensives 
will be 50 mg (SD = 10) and estimated 48h cumulative mean dose for norepinephrine for beta 
blocker, ACE-Inhibitor, and beta-blocker + ACE-Inhibitor groups will be 25 mg (SD = 10).  
Using a 4-way fixed effects ANOVA power calculation with estimated effect size from 
previous study (f = 1.08) the total sample size would be 16  
 
 
F tests - ANOVA: Fixed effects, omnibus, one-way 
 
Analysis: A priori: Compute required sample size  
 
Input:Effect size f 
= 1.0825318 
 
α err prob 
= 0.05 
 
Power (1-β err prob) 
= 0.95 
 
Number of groups 
= 4 
 
Output:Noncentrality parameter λ= 23.4375020 
 
Critical F 
= 3.2388715 
 
Numerator df 
= 3 
 
Denominator df 
= 16 
 
Total sample size 
= 20 
Actual power 
=   0.9609969 
 
However, the current proposed study is specifically looking at septic shock and the anticipated 
effect is unknown.  Therefore, using a 4-way fixed effects ANOVA power calculation with a 
medium effect (f = 0.25) has a total sample size of 180 patients. 
 
 
F tests - ANOVA: Fixed effects, omnibus, one-way 
 
Analysis: A priori: Compute required sample size  
 
Input:Effect size f 
= 0.25 
 
α err prob 
= 0.05 
 
Power (1-β err prob) 
= 0.80 
 
Number of groups 
= 4 
 
Output:Noncentrality parameter λ= 11.2500000 
 
Critical F 
= 2.6559389 
 
Numerator df 
= 3 

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Denominator df 
= 176 
 
Total sample size 
= 180 
 
Actual power 
= 0.8039869 
 
A list of ICU patients will be generated by the corresponding ICD-9 and ICD-10 codes for 
septic shock during the inclusion time frame, randomized and screened until reaching the 
minimum power and equal groups (n = 200, 50 patients in each group) 
 
13.2. Planned Statistical Analysis 
 
All data will be reported using descriptive statistics with mean (SD) used to describe normally 
distributed data and median (interquartile range [IQR]) used for non-normal data or data with a 
significant number of outliers.  Distribution of data and assessment of normality will be 
analyzed.  Chi-squared, Fisher’s Exact and Student’s t-test as appropriate will be used to assess 
differences among the study cohorts.  A 4-way fixed effects ANOVA will be utilized for the 
primary outcome, cumulative vasopressor dose at 48 hours.  Post hoc pairwise comparisons 
will be completed between groups using Bonferroni’s, Turkey, or Hochberg’s GT2 depending 
on final group size and variance.  Statistical support for data evaluation will be sought out if 
necessary. 
 
REFERENCES 
 
1. Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical 
outcomes in patients with septic shock: A randomized clinical trial. JAMA. 2013;310(16):1683-1691. 
 
2. Sander O, Welters ID, Foex P, Sear JW. Impact of prolonged elevated heart rate on incidence of major cardiac 
events in critically ill patients with a high risk of cardiac complications. Crit Care Med. 2005;33(1):81-8; discussion 
241-2. 
 
3. Schmittinger CA, Torgersen C, Luckner G, Schroder DC, Lorenz I, Dunser MW. Adverse cardiac events during 
catecholamine vasopressor therapy: A prospective observational study. Intensive Care Med. 2012;38(6):950-958. 
 
4. Parker MM, Shelhamer JH, Natanson C, Alling DW, Parrillo JE. Serial cardiovascular variables in survivors and 
nonsurvivors of human septic shock: Heart rate as an early predictor of prognosis. Crit Care Med. 1987;15(10):923-
929. 
 
5. Lamontagne F, Meade MO, Hebert PC, et al. Higher versus lower blood pressure targets for vasopressor therapy 
in shock: A multicentre pilot randomized controlled trial. Intensive Care Med. 2016;42(4):542-550. 
 
6. Brown SM, Lanspa MJ, Jones JP, et al. Survival after shock requiring high-dose vasopressor therapy. Chest. 
2013;143(3):664-671. 
 
7. Sokol S, Lat I, Bauer S, et al. Impact of prior antihypertensive therapy on outcomes for patients with circulatory 
shock. Critical Care Medicine. 2015;43(12 Supplement 1):266-277.