Early Metabolic Resuscitation: A Potential Solution to Multi-Organ Dysfunction Syndrome in Septic Shock
Phase: PHASE2
Conditions: Multiple Organ Failure, Septic Shock, Severe Sepsis
Sponsor: M.D. Anderson Cancer Center

 
 
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Early Metabolic Resuscitation: A Potential Solution to Multi-Organ Dysfunction 
Syndrome in Septic Shock 
 
 
 
 
 
 
Protocol Number: 2018-0986 
 
 
Study Chair: 
 
Joseph L. Nates, MD MBA CMQ, MCCM 
Professor, Critical Care Department 
 
 
The University of Texas MD Anderson Cancer Center 
 
 
 
 
 
Source of study funds: 
   
Gift from Inversora Carso.  
 
 
 

 
 
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TABLE OF CONTENTS 
STUDY TEAM ROSTER   
 
 
 
 
 
 
Page 5-8 
SUMMARY TABLE  
 
 
 
 
 
 
 
Page 9-11 
 
MAIN PROTOCOL  
 
1) STUDY OBJECTIVES  
 
 
 
 
 
 
Page 12  
1. Primary objective  
2. Secondary objectives  
 
2) BACKGROUND 
 
 
 
 
 
 
 
Page 13 -19 
1. Definitions 
2. Epidemiology 
3. Pathophysiology 
4. Clinical features 
5. Diagnosis 
6. Treatment 
 
3) STUDY RATIONALE 
 
 
 
 
 
 
Page 20-26 
 
4) STUDY DESIGN 
 
 
 
 
 
 
 
Page 27          
 
5) SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
Page 28-31 
1. Inclusion criteria  
2. Exclusion criteria 
3. Study enrollment procedures 
 
6) STUDY INTERVENTIONS  
 
 
 
 
 
Page 32-37 
1. Description of study group   
2. Description of EMR group 

 
 
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3. Duration of intervention 
4. Adherence assessment 
5. Required interventions 
6. Additional fluids to maintain euvolemia 
7. Weaning procedure for EMR solution 
 
7) STUDY PROCEDURES   
 
 
 
 
 
Page 38-42 
1. Data to be collected prior to intervention  
2. Data to be collected prospectively  
 
8) SAFETY ASSESSMENT   
 
 
 
 
 
Page 43-48 
1. Theoretical and potential adverse events.  
2. Management of adverse events 
3. Adverse events and serious adverse events  
 
9) CRITERIA FOR INTERVENTION DISCONTINUATION  
 
Page 49 
 
10) STATISTICAL CONSIDERATIONS 
 
 
 
 
Page 50-56 
1. Outcomes 
2. Sample Size Justification and Randomization 
3. Interim Analysis  
4. Data Monitoring 
 
5. Data Analyses  
6. Safety monitoring for Patients assigned to (SC + EMR) 
 
11)   DATA COLLECTION AND QUALITY ASSURANCE   
 
Page 57-60 
1. Records to be kept 
2. Redcap summary  
3. Data Management 
4. Quality Assurance  
1. Training 

 
 
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2. Quality Control 
3. Protocol Deviations 
4. Monitoring 
 
12)   PARTICIPANTS` RIGHTS AND CONFIDENTIALITY 
 
Page 61-62 
1. Institutional Review Board (IRB) evaluation. 
2. Informed Consent  
3. Subject Confidentiality  
4. Study Modification/Discontinuation  
 
13) PUBLICATION OF RESEARCH FINDINGS 
 
 
 
Page 63 
 
14) REFERENCES   
 
 
 
 
 
 
 
Page 64-70 
 
15) APPENDIX  
 
 
 
 
 
 
 
Page 71-75 

 
 
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STUDY TEAM ROSTER 
Principal Investigator 
Joseph L. Nates, MD, MBA, CMQ, MCCM  
Professor, Deputy Chair, ICUs Medical Director, Department of Critical Care and 
Respiratory Care 
Division of Anesthesiology, Critical Care and Pain Medicine 
1515 Holcombe Blvd, Unit #112 
The University of Texas M. D. Anderson Cancer Center 
Office (713) 792 5040, Fax (713) 745 1869 
jlnates@mdanderson.org 
 
Collaborators 
Kristen J Price, MD, FCCP 
Professor, Chair Department of Critical Care & Respiratory Care 
Division of Anesthesiology, Critical Care and Pain Medicine 
1515 Holcombe Blvd. Unit 0112 
The University of Texas MD Anderson Cancer Center 
kjprice@mdanderson.org 
 
John W. Crommett MD 
Associate Professor, Department of Critical Care and Respiratory Care 
Medical Director, Medical Emergency Rapid Intervention Team (MERIT), Division of 
Anesthesiology, Critical Care and Pain Medicine 
1515 Holcombe Blvd, Unit #112  
The University of Texas M. D. Anderson Cancer Center 
jwcrommett@mdanderson.org 
 
Carmen E. Gonzalez, MD, MSQHS, FACP, FACMQ 
Professor, Department of Emergency Medicine 
Division of Internal Medicine T. Boone Pickens Academic Tower (FCT13.5050)  

 
 
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1515 Holcombe Blvd. Unit 1468, Houston, TX 77030  
The University of Texas MD Anderson Cancer Center 
cegonzalez@mdanderson.org 
 
Cristina Gutiérrez MD  
Assistant Professor, Department of Critical Care and Respiratory Care 
Division of Anesthesiology, Critical Care and Pain Medicine 
1515 Holcombe Blvd, Unit #112 
The University of Texas M. D. Anderson Cancer Center 
cgutierrez4@mdanderson.org 
 
Olakunle Idowu MD 
Assistant Professor, Department of Anesthesiology & Perioperative Medicine 
Division of Anesthesiology, Critical Care and Pain Medicine 
1515 Holcombe Blvd, Unit 0409 
The University of Texas M. D. Anderson Cancer Center 
oidowu@mdanderson.org 
 
Ariel D Szvalb, MD, FACP 
Assistant Professor, Department of Infectious Diseases 
Division of Internal Medicine 
1515 Holcombe Blvd, Unit 1460 
The University of Texas MD Anderson Cancer Center 
adszvalb@mdanderson.org 
 
Donna M Calabrese, MD 
Assistant Professor, Department of Critical Care 
Division of Anesthesiology and Critical Care and Pain Medicine 
1515 Holcombe Blvd, Unit 0112 
The University of Texas MD Anderson Cancer Center, Houston, TX 

 
 
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dcalabre@mdanderson.org 
 
Nicolas Palaskas MD 
Assistant Professor, Department of Cardiology 
Division of Internal Medicine 
1515 Holcombe Blvd. Unit 1451 
The University of Texas MD Anderson Cancer Center, Houston, TX 
NLPalaskas@mdanderson.org 
 
Karen Chen, MD 
Professor, Associate Medical Director ICUs, Department of Critical Care and 
Respiratory Care 
Division of Anesthesiology and Critical Care and Pain Medicine 
1515 Holcombe Blvd. Unit 0112 
The University of Texas MD Anderson Cancer Center, Houston, TX 
kachen@mdanderson.org 
 
Joshua S. Botdorf, DO 
Assistant Professor, Department of Critical Care and Respiratory Care 
Division of Anesthesiology, Critical Care and Pain Medicine 
1515 Holcombe Blvd. Unit 0112.  
The University of Texas MD Anderson Cancer Center 
jsbotdorf@mdanderson.org 
 
Dereddi R Reddy, MD, FACP, FCCP 
Assistant Professor, Department of Critical Care and Respiratory Care 
Division of Anesthesiology, Critical Care and Pain Medicine 
1515 Holcombe Blvd. Unit 0112. 
The University of Texas MD Anderson Cancer Center 
drreddy@mdanderson.org  

 
 
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Nisha Rathi, MD 
Associate Professor, Department of Critical Care and Respiratory Care  
Division of Anesthesiology, Critical Care and Pain Medicine 
1515 Holcombe Blvd. Unit 0112. 
The University of Texas MD Anderson Cancer Center  
nrathi@mdanderson.org 
 
Sajid Haque, MD 
Associate Professor, Department of Critical Care and Respiratory Care  
Division of Anesthesiology, Critical Care and Pain Medicine 
1515 Holcombe Blvd. Unit 0112. 
The University of Texas MD Anderson Cancer Center  
shaque@mdanderson.org 
 
Imrana Malik, MD 
Clinical Associate Professor, Department of Critical Care  
Division of Anesthesiology, Critical Care and Pain Medicine 
1515 Holcombe Blvd. Unit 0112. 
The University of Texas MD Anderson Cancer Center  
imalik@mdanderson.org 
Robert C Wegner, MD 
Assistant Professor, Department of Critical Care and Respiratory Care 
Division of Anesthesiology, Critical Care and Pain Medicine 
1515 Holcombe Blvd. Unit 0112. 
The University of Texas MD Anderson Cancer Center  
rwegner@mdanderson.org 
 
Maria S Gaeta, MD 
Assistant Professor, Department of Emergency Medicine 

 
 
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Division of Internal Medicine 
T. Boone Pickens Academic Tower 
1400 Pressler St. 
The University of Texas MD Anderson Cancer Center  
sgaeta@mdanderson.org 
 
Consuelo Fernandez 
Assistant Manager, Pharmacy Inpatient 
Anderson Central (Y1.5329) 
1515 Holcombe Blvd 
The University of Texas MD Anderson Cancer Center 
cvfernan@mdanderson.org  
 
Study Coordinators 
John Cuenca MD 
Research Assistant II 
1515 Holcombe Blvd, Unit #112 
Department of Critical Care, Division of Anesthesiology and Critical Care, 
The University of Texas M. D. Anderson Cancer Center 
JACuenca@mdanderson.org 
 
Alba Juliana Heatter MD 
Research Assistant II 
1515 Holcombe Blvd, Unit #112 
Department of Critical Care, Division of Anesthesiology and Critical Care, 
The University of Texas M. D. Anderson Cancer Center 
AJHeatter@mdanderson.org 
 
Peyton Martin  
Research Assistant I 

 
 
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1515 Holcombe Blvd, Unit #112 
Department of Critical Care, Division of Anesthesiology and Critical Care, 
The University of Texas M. D. Anderson Cancer Center 
PRMartin1@mdanderson.org 
 
Maria Paula Reyes Ramirez MD 
Research Assistant II  
1515 Holcombe Blvd, Unit #112 
Department of Critical Care, Division of Anesthesiology and Critical Care, 
The University of Texas M. D. Anderson Cancer Center 
Mpreyes1@mdanderson.org 
 
Data coordinator  
Rose Jean Erfe  
Coordinator of Clinical Studies, 
Department of Critical Care, Division of Anesthesiology and Critical Care, 
The University of Texas M. D. Anderson Cancer Center 
rderfe@mdanderson.org 
 
Pharmacological assistance  
Jacob Hall, PharmD, BCNSP,  
Clinical Pharmacist Specialist, Pharmacy Clinical Programs, 
1515 Holcombe Blvd, Unit# 0377 
John Mendelsohn Faculty Center, FC6.3014 
Pharmacy Clinical Programs, The University of Texas M. D. Anderson Cancer Center 
Office (713) 792 4714 
Jhall1@mdanderson.org 
 
Clinical Nutrition assistance  
Kendall F. Stelwagen BS, MS 

 
 
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Clinical Nutrition Specialist, Clinical Nutrition 
1515 Holcombe Blvd, Unit #0322 
Department of Critical Care, Division of Anesthesiology and Critical Care, 
The University of Texas M. D. Anderson Cancer Center 
kfstelwagen@mdanderson.org 
 
Amira Gerges BS, MS 
Clinical Nutrition Specialist, Clinical Nutrition 
1515 Holcombe Blvd, Unit #0322 
Department of Critical Care, Division of Anesthesiology and Critical Care, 
The University of Texas M. D. Anderson Cancer Center 
kfstelwagen@mdanderson.org 
 
Statistical collaborator  
Mike Hernandez  
Senior Statistical Analyst, Biostatistics 
The University of Texas M. D. Anderson Cancer Center 
T. Boone Pickens Academic Tower (FCT4.5005) 
1515 Holcombe Blvd 
mhernandez@mdanderson.org 

 
 
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SUMMARY TABLE 
 
Title 
Early Metabolic Resuscitation: A Potential Solution to 
Multi-Organ Dysfunction Syndrome in Septic Shock 
Question 
Is Early Metabolic Resuscitation the Solution to Multi-
Organ Dysfunction Syndrome in Patients Diagnosed 
with Septic Shock? 
 
Protocol Number 
2018-0986 
Study Size (# of 
patients) 
The sample size will include 112 patients (56 patients 
randomly assigned to each study group). 
 
Study Design 
This is a prospective, single center, un-blinded, 
randomized controlled trial. Patients will be stratified by 
type of malignancy, and blocking will be used to ensure 
balance between study groups. Patients will be 
randomized to either Early Metabolic Resuscitation with 
Standard of Care (SC + EMR) or Standard of Care 
alone (SC).  The randomization will be conducted 
through CORe. 
 
Primary Objective 
The primary objective of this study is to assess the 
efficacy of administering Early Metabolic Resuscitation 
with Standard of Care (SC + EMR) in patients 
diagnosed with septic shock for reducing 28-day 
mortality versus using the Standard of Care alone (SC).  
 
Secondary 
Objective  
1. To assess whether Early Metabolic Resuscitation with 
standard of care (SC + EMR) is an effective strategy to 
reduce ICU mortality, hospital mortality, and 90-day 
mortality relative to SC. ICU mortality is defined as 
mortality at ICU discharge.  
 
2. To compare the time to death from any cause 
between patients administered SC + EMR versus SC 
after being diagnosed with septic shock.   
 
3. To assess whether SC + EMR is an effective strategy 
to reduce complications of septic shock such as: i) acute 
kidney injury, ii) dialysis requirements, iii) need for 
cardiovascular support or days on vasopressors, iv) 
need for invasive ventilation, days on ventilator support, 
v) duration of ICU stay, and vi) duration of hospital stay 
versus SC. 

 
 
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4. To describe the presence of any adverse effects 
between the two study groups (SC + EMR group vs SC 
group); thus, characterizing their safety. 
 
Inclusion Criteria 
1. Adult patients aged 18 years old or older 
 
2. Admitted to the adult medical intensive care unit 
(MICU) 
 
3. Diagnosis of Septic Shock within 12 hours of ICU 
admission, unless the patient is already admitted 
to the ICU, defined as meeting criteria for sepsis 
in addition to the following:  
a. Vasopressor therapy needed to elevate 
MAP ≥65 mmHg. 
o 
 Lactate > 1 mmol/L (9 mg/dL) and/or Base 
excess 
<-2 
after 
adequate 
fluid 
resuscitation 
 
4. Sequential Organ Failure Assessment (SOFA) 
score meeting the following requirements 
a. Cardiovascular SOFA ≥ 2   
b. Total SOFA score ≤12  
 
5. Patients meeting the above and not able to 
tolerate enteral nutrition above 70% of their 
estimated daily caloric need 
 
Study Details 
 
Primary Endpoint 
The primary endpoint is 28-day mortality, defined during 
the time from the day SC+EMR or SC was first 
administered until a patient dies or is followed through 
28 days (whichever comes first). 
Sample Size 
Justification 
The rate of 28 day mortality from septic shock at the UT 
MD Anderson Cancer Center was 70% in 2017. With the 
objective of decreasing this rate to 40%, a sample size 
of 112 patients (56 per group) provides 90% power to 
detect a 30% absolute reduction in the rate of 28-day  
mortality using a two-sided chi-square test at the 0.05 
significance level. We plan to use stratified 
randomization in a 1:1 fashion to assign patients into 
two groups, and a fixed block size consisting of 4 

 
 
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patients will be used.  The randomization will be 
conducted in CORe. 
Brief Analysis Plan 
Descriptive statistics including the mean, standard 
deviation, median, and range will be used to summarize 
continuous variables. Frequency counts and 
percentages will be used to summarize categorical 
variables. Categorical variables, including 28-day 
mortality, will be compared between intervention groups 
using a chi-square test, or Fisher’s exact tests if more 
appropriate. Continuous variables will be compared 
between intervention groups using an independent 
samples t-test, or Wilcoxon rank-sum test if more 
appropriate. 
 
Logistic regression will be used to assess relationships 
between patient characteristics and binary study 
outcomes of interest. Continuous variables, including 
the time on cardiovascular support and time on 
ventilator, will be compared using t-tests or Wilcoxon 
rank-sum tests. 
 
Time to event analyses will be conducted using Cox 
proportional hazards regression.  For 28-day mortality, 
living patients will be censored at the end of 28 day 
follow-up after the treatment was given. For overall 
survival, patients will be followed until time of death or 
date of last follow-up (maximum 6 months).  Kaplan-
Meier plots will be used to visually compare time to 
death from any cause between intervention arms 
followed by a log-rank test to compare survival 
distributions.   
 
 
 
 
 
 
 
 
 
 

 
 
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1.0      STUDY OBJECTIVES 
 
1.1 Primary Objective: 
To assess the efficacy of administering Early Metabolic Resuscitation with Standard of 
Care (SC + EMR) in patients diagnosed with septic shock for reducing 28-day mortality 
versus using the Standard of Care alone (SC). Twenty-eight day mortality is defined 
during the time from the day SC+EMR or SC was first administered until a patient dies 
or is followed through 28 days (whichever comes first). 
 
1.2 Secondary Objectives: 
 
1. To assess whether Early Metabolic Resuscitation with standard of care (SC + EMR) 
is an effective strategy to reduce ICU mortality, hospital mortality, and 90-day mortality 
of septic shock patients relative to SC. ICU mortality is defined as mortality at ICU 
discharge relative to SC. 
 
2. To compare the time to death from any cause between patients administered SC + 
EMR versus SC after being diagnosed with septic shock.   
 
3. To assess whether SC + EMR is an effective strategy to reduce complications of 
septic shock such as: i) acute kidney injury, ii) dialysis requirements, iii) need for 
cardiovascular support or days on vasopressors, iv) need for invasive ventilation, days 
on ventilator support, v) duration of ICU stay, and vi) duration of hospital stay versus 
SC. 
 
4. To describe the presence of any adverse effects between the two study groups (SC + 
EMR group vs SC group); thus, characterizing their safety. 
 
 
 

 
 
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2.0 
BACKGROUND 
 
2.1 Definitions  
Sepsis is defined as a life-threatening condition, which is triggered by an exaggerated 
and unregulated response of the body to an infection. Septic shock consists of the state 
of sepsis where, in addition to the unregulated response, cellular, metabolic, and 
circulatory alterations lead to a marked increase in mortality(1). Previously the spectrum 
of the disease was divided into sepsis, severe sepsis and septic shock, where severe 
sepsis was defined as acute organ dysfunction secondary to documented or suspected 
infection(2). However, in the third international consensus for sepsis and septic shock 
(Sepsis -3) it was determined that the term severe sepsis was redundant and therefore it 
was decided only to use the diagnoses of sepsis and septic shock(1). Even so, today 
most retrospective epidemiological studies continue to use the term severe sepsis in their 
analysis, but this is expected to change over time. 
 
2.2 Epidemiology  
Worldwide, 19 million cases of sepsis are calculated each year, however, it is presumed 
that this value may be even higher due to under reporting, which is considered high in 
low- and middle-income countries (3,4). According to the report of the Center for Disease 
Control and Prevention (CDC) of 2017, sepsis annually affects 1.5 million individuals in 
the United States, of whom 250,000 die (5), which includes it among the top 10 causes 
of death in the US. This generates annual costs of over 24 billion dollars(6); which makes 
this condition a public health priority. 
 
In a recent study not yet published performed by Nates et al. in 2017, a sample of 305 
patients (154 with hematologic malignancies and 108 with solid tumors) with the diagnosis 
of septic shock hospitalized in the ICU of The University of Texas MD Anderson Cancer 
Center were assessed. It was found that the 28 day mortality was 70%. These values 
shed light on the emergent requirement of seeking treatment alternatives that may 
improve outcomes in these patients.  

 
 
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2.3 Pathophysiology  
The normal response of the host to an infection is a complex process in which a 
microorganism is localized and controlled, while injured tissue repair processes are 
undergoing. When the inflammatory response is activated, proinflammatory mediators 
(tumor necrosis factor-alpha (TNFa), IL-1, IL-2, IL-6, among others) chemokines such as 
ICAM-1 and VCAM-1, and nitric oxide (NO) are released. The proinflammatory cytokines 
generate the activation and recruitment of cells of the immune system. Also the 
production of anti-inflammatory mediators such as IL-10 and IL-8 modulate the response 
and lead to homeostasis (8). Sepsis results when the response becomes generalized and 
uncontrolled, affecting normal tissue distant from the original site of infection. The 
mechanisms that lead to the unregulated response are not well known, however several 
studies have shown how the components of the causative organism may be involved in 
the way in which the immune system is stimulated (endotoxins, peptidoglycans, muramil 
dipeptidase and lipoteichoic acid, among others) (9,10). Likewise, studies have pointed 
out the possibility that there is a genetic susceptibility for the development of more severe 
responses, and worse outcomes (11). 
 
The release of proinflammatory cytokines causes fever, hypotension, leukocytosis and 
the induction of other cytokines. In addition, there is an activation of the coagulation 
cascade and fibrinolysis. TNFa plays a key role in the disease and some studies have 
shown a significant increase in patients with septic shock (12). Nitric oxide is a biological 
molecule produced by a large number of cells. It is involved in several pathological 
processes and has been described as having both beneficial and harmful effects at the 
cellular and vascular level (13). At the cellular level NO generates nuclear damage, 
alterations of proteins and phospholipid membranes, and the inhibition of cellular 
respiration in several cell types. At the same time, it has been shown that NO can also 
reduce free oxygen radicals, generating a decrease in cell damage. Therefore its total 
inhibition as a therapeutic measure does not seem to be an adequate intervention and in 
fact it has been proven in clinical studies that the use of inhibitors of nitric oxide synthase 
(NOS) can increase mortality(14). 

 
 
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In the early septic phase, cellular metabolism is upregulated with systemic inflammation 
which leads the organism to enter into a hypermetabolic state (15). This is mainly caused 
by the requirement of supra physiological energy to deal with  fever, amplified protein 
synthesis, tachycardia and tachypnea(16). It is estimated that basal energy requirements 
for a septic patient could reach up to 10,000 calories per day (17).  This critical need for 
supplemental nutrients may not be met since it occurs under critical illness 
(thermodynamically closed system in which metabolic substrates are not administered to 
the patient) (16). This hypermetabolism also produces a large amount of toxic cellular by-
products, such as hydrogen peroxide (H2O2), which under normal conditions, is well 
degraded by the enzyme glutathione peroxidase. In critically Ill patients, glutathione is 
commonly depleted and there is a significant increase in H2O2, cellular toxicity occurs, 
and a greater decrease in glutathione stores can be observed (18,19).  In fact, low levels 
of glutathione have been indirectly related to increased mortality even after the subject 
survived the infectious insult(20). 
 
After the above-mentioned process has been established, inflammatory products, such 
as nitric oxide and the reactive nitrogen species, can cause mitochondrial dysfunction 
due to the inhibition of the electron transport chain by direct blocking of respiratory 
enzymatic complexes, causing oxidative stress damage, and promoting mitochondrial 
DNA breakdown. All of these processes lead to a decrease in mitochondrial function in 
terms of the use and production of ATP, which triggers cytotoxicity and hypometabolism 
in the late phase of the disease. This has been described as a hibernation-like state where 
the organs reduce their metabolism in an attempt to survive the inflammation caused by 
sepsis (21). 
The clinical relevance of mitochondrial dysfunction in septic shock has been studied 
extensively. In a study of 28 septic shock patients who underwent a skeletal muscle 
biopsy at 24 hours after ICU admission, the ATP concentrations in the muscle (a marker 
of mitochondrial oxidative phosphorylation) were significantly lower in the 12 patients who 
died compared to the 16 who survived. Additionally, there was an association between 
overproduction of NO, decrease of antioxidants and the severity of the clinical outcome 

 
 
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(22). This led to the conclusion that the cellular lesions were due to dysoxia, which is the 
inability to use the oxygen even under the presence of adequate concentrations. This is 
also known as oxygen limited energy depletion. Strikingly, in studies of patients who died 
from septic shock, both electron microscopy and immunohistochemical markers revealed 
that cell death was rare in septic patients with cardiac and renal dysfunction. The degree 
of cell injury or death was not related to the severity of the organ dysfunction. It was then 
considered that the presence of morphological changes in the mitochondria would explain 
the energetic crisis that results in organ dysfunction in the absence of cell death (23). This 
reinforces the theory that this hibernation-like response may initially start as a mechanism 
of cell survival, but ultimately ends in multi-organ dysfunction and death.  
 
2.4 Clinical features  
Sepsis clinical presentation is variable and depend to a great extent on the initial site of 
the infection, causal agent, colony count, the pattern of organ failure, patient's baseline 
health status, and the interval before initiation of treatment (3). Acute organ dysfunction 
most commonly affects the respiratory and cardiovascular systems; the first, usually 
manifested by tachypnea and acute respiratory distress syndrome and the second by 
hypotension and acute elevation of serum lactate. Hypotension may become refractory 
to volume expansion and may require the use of vasopressors and in addition, myocardial 
dysfunction may also occur (2,3,24). Likewise, the brain and kidneys can be affected; the 
clinical manifestations of central nervous system involvement may manifest with 
alterations in the state of consciousness. Neuroimaging generally shows no focal lesions, 
and the results of electroencephalography are usually consistent with non-focal 
encephalopathy. Polyneuropathy can also be evidenced in these patients(25). Acute 
kidney injury usually presents with a decrease in urinary output and an increase in serum 
creatinine, and these patients may require renal replacement therapies. It is important to 
highlight that acute kidney injury continues to have between 60% and 80% mortality. It is 
also important to note that a MAP <75 mmHg is associated with a higher incidence of 
renal failure(26). Finally, paralytic ileus, hepatic dysfunction, alterations in coagulation 
and glucose control are frequent in patients with sepsis and septic shock (3,27) 

 
 
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2.5 Diagnosis 
Sepsis can be clinically diagnosed with an increase of 2 points in the baseline SOFA 
score of the patient (Table 1) in the context of an infectious process. Septic shock is the 
state of sepsis, where cellular, metabolic and circulatory alterations are also present, 
measured by the elevation of lactate levels above 2 mmol/L and the requirement of 
vasopressors to maintain a mean arterial pressure (MAP) greater than or equal to 65 
mmHg (1). However, severe sepsis can be diagnosed with an increase of lactic acid 
above > 1 mmol/L (28).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Table 1 SOFA score(29)  
SOFA score 
0 
1 
2 
3 
4 
Respiratory 
PaO2/FIO2 
(mmHg) 
 
SaO2/FIO2 
 
 
 
 
 
>400 
<400 
<300 
<200 
<100 
 
221-301 
142-220 
67-141 
<67 
Coagulation 
Platelets 103/mm3 >150 
<150 
<100 
<50 
<20 
Liver 
Bilirubin (mg/dl) 
<1.2 
1.2-1.9 
2.0-5.9 
6.0-11.9 
>12 
Cardiovascular 
Hypotension 
NO 
MAP<70 Dopamine 
<5 or 
Dobutamine 
Dopamine >5 
or 
Norepinephrine 
<=0.1 
Epinephrine 
<=0.1 
Dopamine >15 
or 
Norepinephrine 
>0.1 
Or epinephrine 
>0.1 
Central Nervous 
System 
Glasgow Coma 
Scale 
15 
13-14 
10-12 
6-9 
<6 
Renal 
Creatinine mg/dl 
<1.2 
1.2-1.9 
2.0-3.4 
3.5-4.9 
>5 
 
Urinary Output 
ml/d 
<500 
<200 
*SOFA= Sequential Organ Failure Assessment.  

 
 
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2.6 Treatment  
Different therapies have been studied to improve the treatment of sepsis and septic 
shock. There is no clear evidence that these can change the course of the disease, 
therefore the current treatment recommendations are based mainly on antibiotic and life 
support management(30). Due to the implications of the disease, it is necessary to 
develop new therapeutic interventions, which should be based on the pathophysiology of 
the disease and on the metabolic and cellular effects that lead to multi-organ failure.  
 
The metabolic approach previously described by different authors is, in our opinion, the 
next step that should be considered in the management of the patient in septic shock. 
While this may bring therapeutic benefits and additionally reduce the economic burden of 
the disease, further investigation is required.  
 
 
 
 
 
 
 
 
 
 

 
 
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3.0     STUDY RATIONALE 
Increasing ATP production before mitochondrial respiration slows down may prevent 
multi-organ dysfunction in sepsis(21,31). We hypothesize that providing large doses of 
glucose, protein, and essential metabolic cofactors early in the management of patients 
with sepsis can prevent this hibernation-like state (31). 
 
The theory substantiating early metabolic resuscitation (EMR) is provided by a number of 
preliminary studies. In sepsis, there is known to be near universal dysfunction in 
mitochondria resulting in inefficient utilization of energy. This happens because the 
biochemical pathways of oxidative phosphorylation are inhibited in cells of septic patients 
(21,31,32). Complex I of the electron transport chain exists in both red blood cells and 
muscle tissue and the inhibition of the transport chain results in inefficient utilization of 
energy stores(32), which are often already deficient in critically ill patients(31,33,34). 
 
Supporting our hypothesis regarding EMR involves the use of GIK (Glucose, Insulin and 
Potassium) therapy.  This therapy has been studied extensively in the cardiac population, 
and has been of particular interest in cardiac surgery reviving stunned myocardium, 
although evidence remains limited.  The theory is similar to the use of amino acids 
whereby substrates replenish the Krebs cycle (via anaplerosis). The recent IMMEDIATE 
trial in acute myocardial infarction patients showed no difference in 30 day mortality, but 
a reduction in hospital mortality and incidence of cardiac arrest(35).   
 
Several case reports in septic shock patients have supported the use of GIK infusions, 
particularly in patients with low output shock where insulin-glucose infusions have led to 
improved hemodynamic parameters in cases unresponsive to inotropes (36–38).  There 
remains a lack of well-designed large RCTs to support this intervention, although in a 
controlled environment such as an ICU, this does not represent a significant risk. In our 
protocol, we will be using some of the principles of GIK therapy to improve perfusion and 
oxygen metabolism to prevent organ dysfunction.  This will be achieved through the use 

 
 
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of early infusion of glucose  and a solution of free amino acids with additional essential 
metabolic cofactors and insulin. 
 
Further evidence to support our hypothesis draws upon research done at Cambridge 
University.  Nitric oxide (NO) and reactive nitrogen species inhibit mitochondrial 
complexes responsible for the production of ATP (39). Sepsis is a clinical situation where 
overproduction of reactive nitrogen species has been implicated in its pathophysiology 
(21).  In this situation, glucose becomes critical to cell survival via glycolytic production of 
ATP at a time when mitochondrial production of ATP has been inhibited(39). Patients with 
septic shock demonstrated a strong association between decreased mitochondrial 
function, specifically loss of ATP synthase activity in peripheral blood mononuclear cells, 
and increased mortality (50, 51). 
 
Differences with Total Parenteral Nutrition 
To avoid any confusion, we must address the distinct nature of our approach from that of 
early total parenteral nutrition (TPN) in the ICU, given that this last intervention has 
caused great controversies(41).  The EMR described in this protocol might be considered 
on a superficial level to be similar to early parenteral nutrition, given that both interventions 
share most of their components.   Early metabolic resuscitation is distinct from early TPN 
for several reasons: 
 
• Firstly, the acuity in time of EMR is much greater. This is an intervention that has 
to be started as soon as possible after the patient presents the first signs of septic 
shock and is considered to be in a hypermetabolic state. This contrasts to early 
TPN, which is often administered only within the first 48 hours and has the 
objective of supplying nutritional requirements (42).  
• Secondly, the nutrients within EMR are specifically intended to best support 
cellular respiration in sepsis. For example, glucose is considered to be an essential 
substrate as in the absence of glucose, moderate levels of NO are known to cause 
necrosis simply by respiratory inhibition. Adequate levels of glucose are known to 

 
 
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prevent necrosis in vitro (39). Typical TPN solutions do not provide large quantities 
of glucose.  
• Thirdly, in the EMR protocol, we are not using lipids, which are a common 
component of TPN. The rationale of the exclusion of this component is due to the 
fact that studies have shown an increase in lung injury due to the administration of 
lipids. In the initial phase of septic shock, it is well known that tissues become 
hypoxic, preventing adequate beta-oxidation of fatty acids. We consider that the 
inclusion of lipids may cause more risk than benefit in the early phase of septic 
shock.  
• The use of carbohydrates in hypoxic states is based on the Pasteur Effect which 
states that the consumption of carbohydrates is inversely proportional to the 
availability of oxygen. 
• Glucose provides a P/O ratio (number of molecules of ATP synthesized by each 
pair of electrons travelling down the electron transport chain) of 3, as opposed to 
a P/O ratio of 2 provided by lipids.  
 
As mentioned before, timing is crucial. Studies in animal models suggest that 
mitochondrial respiration may be initially increased and eventually declines after a 
prolonged (>12-16 hours) septic insult(43). Of note, these animal models are typically 
performed in rodents (specifically rats) in whom, according to P Hochachka, their 
biological time must be multiplied by a factor of 5 if we are to translate it into human 
biological time. The crux of the metabolic intervention lies in the timing of the initiation, 
which should occur only during the hypermetabolic phase marked by the typical clinical 
and hemodynamic findings (tachypnea, hyperthermia, tachycardia, increased cardiac 
Index). 
 
This goes along with the novel concept that patients suffering from septic shock (Ken 
Mattox) should be treated under the light of Chaos Theory.  The basic concept of Chaos 
Theory, as stated by James Gleick, refers to the “sensitive dependence on the initial 
conditions”, meaning that as time goes by, the introduction of any additional variable into 

 
 
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a complex system (i.e. biological system), may have exponential results. Once septic 
shock is established, we are on a clock. We hypothesize that multi-organ dysfunction is 
caused by bioenergetic failure. The law of mass action states that “the rate of reaction is 
directly proportional to the concentration of the participating molecules”. The crux of the 
matter may lie in the timely delivery of critical mass (energy), before mitochondrial 
respiration slows down, with the ultimate goal of achieving cellular homeostasis. 
 
The following components are pivotal for the EMR intervention. 
 
 Free Amino Acids – Anaplerosis  
During sepsis and cardiac ischemia, it has been shown that mitochondria are not as 
readily able to create ATP through oxidative phosphorylation and beta-oxidation and as 
such, must rely on other substrates(32,44).  This can be achieved through anaplerosis via 
carboxylation of pyruvate and with the replenishment of the tricyclic acid cycle (Krebs 
cycle), accessed through the induction of intermediary metabolites provided by glucose 
and free amino acids(44).  This is the rationale for the inclusion of free amino acids 
infusion as part of the protocol.  The shift of metabolism to primary utilization of protein is 
well documented in the critically ill patient population(45).  In fact, the amount of protein 
metabolized by a septic patient is limited only by the rate at which it can be liberated from 
the skeletal muscle(45).  This argument supports a protocol in which we provide early 
calories and high amounts of free amino acids to the septic shock patient to support 
underlying organ function before catastrophic metabolic failure occurs. 
 
Insulin 
Insulin has many potential actions which may be beneficial in sepsis.  
1. Insulin may benefit patients by facilitating glucose transportation into certain 
tissues such as striated muscle and adipose tissue.  
2. Insulin also replenishes the depleted tricyclic acid cycle by anaplerosis. 

 
 
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3. Insulin suppresses the production of macrophage inhibitory factor (MIF), TNF-
alpha, IL-1, IL-6, and free radicals, enhances endothelial NO generation, and 
enhances the production of anti-inflammatory cytokines IL-4, and IL-10(46).  
4. Insulin increases metabolic rate, in turn increasing turnover of ATP, with this being 
the most important goal of intermediary metabolism.  
5.  Insulin has an indirect inotropic effect on the heart due to its metabolic effects 
(46,47).   
6. Insulin decreases fatty acid levels. Furthermore, fatty acids are less efficiently 
oxidized when compared to glucose(47).  
7. Insulin stimulates the pentose phosphate pathway, pivotal to nucleotide 
regulation, synthesis of glutathione, and availability of cytochrome p450, amongst 
others.  
 
Thiamine 
With regard to the vitamins included in the intervention proposed, thiamine is an essential 
vitamin for aerobic metabolism, acting as a key juncture for the Krebs cycle as well as in 
the pentose-phosphate pathway. Thiamine is a cofactor for pyruvate dehydrogenase, 
which converts pyruvate into acetyl co-enzyme A for use in the Krebs cycle.  Deficiency 
of thiamine leads to lactate generation and a relative deficiency may exist in the context 
of the hypermetabolic state of sepsis.  A small study has demonstrated that the 
administration of thiamine leads to decreased lactate levels in those who were thiamine 
deficient – a surprisingly high level of 35% of septic patients within the study (47). In 
addition, thiamine also exerts action via alpha-ketoglutarate (one of two factors regulating 
substrate oxidation, with the other being the electron transfer chain).  Thiamine has a 
positive effect on the pentose phosphate pathway via transketolase, which feeds F-6P 
and G3P back to the glycolytic pathway. The pentose phosphate pathway plays a part in 
the regulation of thyroid, adrenal, liver, erythrocyte, leukocyte, and adipose tissue 
intermediary metabolism, as well as in the synthesis of nucleotides (NAD, and NADP vital 
for catabolic and biosynthetic pathways respectively) and the synthesis of glutathione and 

 
 
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P-450.  Thiamine may therefore help to resolve derangements in thyroid and adrenal 
function that are often implicated in sepsis pathophysiology(21). 
 
Studies have shown a decrease in requirement of renal replacement therapy in patients 
with septic shock that received thiamine (p=0.04) (48). In another RCT in which thiamine 
was used as a metabolic resuscitator in patients with septic shock, it was noted that in 
those patients with a baseline deficiency, the administration of thiamine  was associated 
with a significantly lower lactate level at 24 hours (p=0.03) and a decrease in mortality 
over time (p=0.047)(49). 
 
Ascorbic Acid (Vitamin C) 
Vitamin C is a potent antioxidant that directly scavenges oxygen free radicals, restore 
cellular antioxidants, and is an essential cofactor for iron and copper containing 
enzymes(50). Patients with sepsis may have low Vitamin C levels, which can only be 
corrected with intravenous Vitamin C. In a recent pharmacokinetic study, it was described 
that 2 g/d dose was associated with normal plasma concentrations, and that 10 g/d dose 
was associated with supranormal plasma concentrations, increased oxalate excretion, 
and metabolic alkalosis (51). In a before-and-after study, there was a statistically 
significant mortality decrease after the administration of a combination of vitamin C (6g 
day), thiamine and hydrocortisone, from 40.4% to 8.5%(52), although these were striking 
results, the study had several limitations and has caused criticism with regard to the 
Hawthorne effect. However, this important observation needs further randomized studies. 
Our EMR protocol does not include corticosteroids, since the most recent large RCT 
performed did not show any improvement with the use of this medication in septic shock 
patients(53).  
 
Other vitamins,  
Finally, it is worth noting that there are several vitamins and minerals included which 
would be excessive to individually explain in detail. These vitamins and minerals are 
essential factors in normal human metabolism. By providing these nutrients, septic shock 

 
 
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patients may more efficiently utilize the substrates provided, increasing their metabolic 
rate to overcome the septic insult. 
 
The imminent need to identify novel therapies, improve survival, and decrease the 
economic burden generated by the patients suffering from septic shock is a top priority. 
If our therapeutic approach proves to be effective in demonstrating a significant reduction 
in mortality, the clinical and social impact could be highly relevant.  A decrease in mortality 
and incidence of multi-organ dysfunction syndrome has the potential to reduce the 
disability associated with septic shock.   
 
The rationale of selecting 28-day mortality as the primary endpoint of the study is that in 
our population the ICU length of stay and Hospital length of stay have wide variability 
(ICU LOS = Mean 9.45days  ± 13.06 min: 0 days  max: 104 days, and Hospital LOS = 
Mean 26.4 days ± SD 26.4 min:1 day, max: 242 days). This variability increases the risk 
of biases at the moment of the analysis, therefore selecting a more objective point in time 
will allow us to perform a better analysis. Additionally the Food and Drug Administration 
and other licensing authorities consider the 28-day timeframe better for assessing drug 
efficacy, this because shorter periods may not be sufficient to determine the effect of the 
treatment and longer time spans may make difficult to differentiate causes of 
mortality(54). This last point is particularly important in our oncologic population where 
the comorbidities and prognosis may reduce long term survival.  
 
 
 
 
 
 
 
 
 

 
 
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4.0 
STUDY DESIGN 
 
This is a prospective, single center, un-blinded, randomized controlled trial. Patients will 
be stratified by type of malignancy, and blocking will be used to ensure balance between 
study groups. Patients will be randomized to either Early Metabolic Resuscitation with 
Standard of Care (SC + EMR) or Standard of Care alone (SC).   
Patients will be recruited from the Intensive Care Unit at The University of Texas MD 
Anderson Cancer Center with the intention of assessing the impact of (SC + EMR) on 
mortality: i) 28-day ii) during hospitalization,  iii) in the ICU, and iv) at 90 days along with 
other known complications of septic shock relative to SC. 
 
 

 
 
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5.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
5.1 Inclusion Criteria 
 
• Adult patients aged 18 years old or older 
• Admitted to the adult medical intensive care unit (MICU) 
• Diagnosis of Septic Shock within 12 hours of ICU admission , unless the patient is 
already admitted to the ICU,  defined as meeting criteria for sepsis in addition to 
the following: 
o Vasopressor therapy needed to elevate MAP ≥65 mmg Hg.  
o Lactate > 1 mmol/L (9 mg/dL) and/or Base excess <-2 after adequate fluid 
resuscitation. 
• Sequential Organ Failure Assessment (SOFA) score meeting the following 
requirements 
o Cardiovascular SOFA ≥ 2   
o Total SOFA score ≤12  
• Patients meeting the mentioned inclusion criteria and not able to tolerate enteral 
nutrition above 70% of their estimated daily caloric need 
            
5.2 Exclusion Criteria 
 
• Do Not Resuscitate (DNR), 
• Comfort Care and end-of-life patients  
• Patients with SOFA score greater than 12 
• Pregnant women 
• Jehovah witnesses that do not accept albumin.  
• Active bleeding (e.g., gastrointestinal bleeding) 
• Acute neurological syndromes (e.g., stroke, hemorrhage, etc)  
• End-stage Renal Disease (ESRD) 
• Transaminitis  

 
 
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• Renal replacement therapy 
• Chronic Liver Disease 
o Childs-Pugh Class C or 
o Diagnosis of Cirrhosis 
• Heart rate less than 50 bpm,  
• Respiratory rate less than 8 rpm, 
• Temperature less than 95`F or 35`C 
• Tumor Lysis Syndrome 
• Myasthenia gravis 
• Sulfite Allergy:  amino acids administration are contraindicated.  It is more common 
in steroid dependent asthmatics.  (Please note that this is NOT sulfa allergy and is 
NOT contraindicated patients with sulfa allergy). Sulfites are present in dried fruits, 
beer, wines, sausages, jams, maple syrup, and many other food products. 
• Serum sodium concentration < 130 mEq/L or >150 mEq/L (Note: Once serum 
sodium levels are ≥ 130 or ≤ 150 mEq/L within 12 hours after meeting inclusion 
criteria, the patient can then be considered for the study. This is only a temporary 
restriction. 
• Serum Creatinine level: SCr ≥ 3 mg/dL(Note: Once serum creatinine levels are ≤ 
2.5 mg/dL within 12 hours after meeting inclusion criteria, the patient can then be 
considered for the study. This is only a temporary restriction). 
• Urine output < 400 cc/24hrs(Note: Once urine output levels are ≥ 400 cc within 12 
hours after meeting inclusion criteria, the patient can then be considered for the 
study. This is only a temporary restriction). 
• Hyperkalemia K > 5.5 mEq/L (Note: Once potassium levels are ≤ 5.5 mEq/L within 
12 hours after meeting inclusion criteria, the patient can then be considered for the 
study. This is only a temporary restriction). 
• Hyperglycemia: Glucose > 250 mg/dL (Note: Once glucose is below 250 mg/dL 
within 12 hours after meeting inclusion criteria, the patient can then be considered 
for the study. This is only a temporary restriction.) 

 
 
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• Hypophosphatemia: Serum Phosphorous < 1.5 mg/dL (Note: Once phosphorus is 
above 1.5 mg/dL within 12 hours after meeting inclusion criteria, the patient can 
then be considered for the study. This is only a temporary restriction.) 
• Hyperphosphatemia: Serum Phosphorous >  6.5 md/dL(Note: Once phosphorus 
is below  6.5 mg/dL within 12 hours after meeting inclusion criteria, the patient can 
then be considered for the study. This is only a temporary restriction.) 
• Patient with a history of metabolic abnormality in any one of the following amino 
acids: Alanine, Arginine, Cysteine hydrochloride, Glycine, Histidine, Isoleucine, 
Leucine, Lysine acetate, Methionine, Phenylalanine, Phosphoric acid, Proline, 
Serine, Threonine, Tryptophan, and Valine 
Any other condition in which the ICU clinical team feels the patient should not be 
a candidate for the protocol.  
 
5.3 Study Enrollment Procedures 
 
A. Upon admission to the Emergency room or MICU, patients diagnosed with septic 
shock will be referred by the ICU attending to the designated study personnel who 
will then screen the patient for inclusion and exclusion criteria. The Basic Metabolic 
Panel (BMP) and patient medical chart history will be reviewed. If patient meets 
inclusion criteria (and no exclusion criteria) the patient’s primary attending will be 
contacted for permission to enroll patient into the study.  If the attending physician 
agrees, the patient (or if patient unable to consent, the patient’s Legal 
Representative Power of Attorney or Next of Kin) will be approached. 
 
B. A discussion will be held with the next of kin and/or patient as appropriate to 
discuss the study procedures, possible adverse effects and research rationale.  
Informed consent will be mandatory and we will provide ample time to answer any 
questions or concerns about the protocol. A fully informed consent will be recorded 
in writing as per local guidance. It will be made clear to the participant and relatives 
that they are under no obligation to participate in the study and are free to withdraw 

 
 
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at any time, without giving a reason.  Please see appendix for consenting material. 
If there is a possibility of pregnancy (defined as women <60 who have not been 
postmenopausal for at least one year or have not had a hysterectomy) then a 
serum or urine B-HCG test will be taken (with consent) prior to enrollment into the 
study.  Refusal of pregnancy test will be considered grounds for exclusion. 
The research coordinator will track all the potential candidates (patients meeting 
inclusion criteria) not included in the study in parallel due to logistical limitations 
(e.g. lack of research staff on weekends).  
C. Screening will be within 12 hours of patient being admitted to the ICU.  Recruitment 
and initiation of study solution (where applicable) must occur both within twelve 
hours of the recorded onset of septic shock and admission to the MICU. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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6.0 STUDY INTERVENTIONS 
 
6.1 Description of study groups 
 
There will be two arms or groups in this study 
1. 
(Standard of Care: SC) - follow institutional ICU management algorithm for 
septic shock  
2. 
(Early metabolic resuscitation with Standard of Care: SC + EMR) -  
infusion of EMR solution with Standard of Care 
 
 
6.2 Description of EMR protocol group 
 
The combined EMR solution will be infused at a set rate (<12hours or > 12 hours) as the 
main metabolic resuscitation strategy. Additional volume may be required to achieve 
euvolemia. This will be in the form of either albumin (if serum albumin < 3 as mentioned 
below) or crystalloids depending on the clinical situation and the serum sodium content.  
The early metabolic support components include the following: 
 
Table 2 show the components of the EMR solutions per liter

 
 
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Table 2. EMR Solution  
EMR  SOLUTION WILL BE PREPARED IN A BAG WITH THE FOLLOWING 
COMPONENTS 
EMR I  (with potassium) 
EMR II * (without potassium) 
Dextrose 50% with Potassium Phosphate 
30 mmol 
Dextrose 50% with Sodium Phosphate  
30 mmol 
Sodium Acetate 75 mEq 
Sodium Acetate  55 mEq 
Sodium Chloride 75 mEq 
Sodium Chloride 55  mEq 
Thiamine 500 mg 
Thiamine 500 mg 
Folic Acid 1 mg 
Folic Acid 1 mg 
Zinc Sulfate 5 mg 
Zinc Sulfate 5 mg 
Selenium 60 mcg 
Selenium 60 mcg 
Copper 1.2 mg 
Copper 1.2 mg 
Chromium 12 mcg 
Chromium 12 mcg 
Magnesium Sulfate 16 mEq 
Magnesium Sulfate 16 mEq 
Multivitamin for Injection 10 ml 
Multivitamin for Injection 10 ml 

 
 
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*If the level of K is > 5.0mmol/L the patient will receive EMR II. Any conditions, which the 
K+ trend is rising, clinicians could opt to switch EMR solution to prevent hyperkalemia.  
This solution does not contains potassium phosphate, but contains sodium phosphate. 
Sodium content is consequently adjusted to have a compatible concentration 
 
 
 
 
 
 
Insulin 25 units (actrapid) 
Insulin 25 units (actrapid) 
SPECIFICATIONS OF THE TREATMENT AND ADJUVANTS  
A. EMR solutions: will be infused at 0.5 ml/kg/h by CVC. If serum glucose is 
greater than 180mg/dL-250mg/dL, EMR solution will be infused at 0.25 ml/kg/h. 
Prior to starting EMR infusion, a bolus of 500mg IV of thiamine should be 
administered to all patients on SC+EMR arm of treatment. 
 
B. Clinisol 15% AA. Infusion rate (IV) will be 0.25 ml/kg/hr for the first 12 hours, then 
0.5 ml/kg/h for the remainder of the intervention – this must be infused via a 
dedicated Central Venous Catheter.  
 
C. If serum albumin is lower than 3 g/dL, then use Albumin 25% 100ml IV Q 8 hours 
until serum albumin level ≥ 3 g/dL – this can be infused peripherally or centrally.  
Once albumin >3g/dL this can be stopped, but should resume whenever albumin 
falls <3g/dL  
 
D. Vitamin C 1g q 8h IV (100 ml per gram of Vitamin C)  

 
 
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Total amount of administered fluids on day one.  
 
EMR I or II formula during first 12 hours: EMR 0.5 ml/kg/h + Clinisol 0.25 ml/kg/h + 
Vitamin C 100 ml q8. EMR + Clinisol: 0.75 ml/kg/h in a 70 kg individual will be 630 mL/12 
hr + (100 ml VitC x 1 times).  
TOTAL= 730 mL within the first 12h of treatment 
 
EMR I or II formula after 12 hours:  EMR 0.5 ml/kg/h + Clinisol 0.5 ml/kg/h + Vitamin 
C 100ml q8. EMR + Clinisol = 1ml/kg/h in a 70 kg individual will be 840 mL/12hr + (100ml 
VitC x 3 times) 
TOTAL = 1.98 L/24h  
 
For SC+ EMR Arm – Serum targets: 
a. Target serum Albumin > 3 g/dl 
b. Target serum Magnesium of  3mg/dl 
 
Sodium management  
a. <130 meq/L use Sodium Chloride 0.90% and call the PI 
b. 130-134 meq/L use Plasmalyte 
c. 135-140 meq/L Ringer’s Lactate  
d.  >140 meq/L use Sodium Chloride 0.45% 
 
6.3 Duration of intervention 
The above infusions will be started and continued for seven days unless the patient dies 
or is discharged from the ICU.  Infusions have to be continuously maintained and not 
stopped for any routine investigations.  If the patient is tolerating enteral tube feeds at 
≥70% of goal for a full 24 hours as determined by the ICU dietician, the intervention will 
be stopped (established weaning process to avoid precipitation of hypoglycemia). 
 
 

 
 
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6.4 Adherence Assessment 
Adherence will be defined as continuous infusion of study solutions 90% of the time from 
onset of study until cessation.  This will be assessed via the electronic patient record, 
which will record infusion stop/start times.  
 
Patients who have requested to be withdrawn from the study or achieve Comfort Care 
status during ICU stay will be removed from the study.  Those who die or begin renal 
replacement will be followed up but the interventions will be stopped.   
 
6.5 Required interventions 
 
If the patient does not have a central venous access or arterial line, then this patient 
cannot be included in the study. All patients treated for septic shock must have central 
venous and arterial access as standard of care. All participants must have both a central 
venous catheter and arterial line inserted.  As this represents standard of care in septic 
shock, this is likely to be universal and will not be an impediment to enroll patients.  
  
6.6 Additional fluids to maintain euvolemia 
Additional fluids following sodium algorithm may be required in order to achieve 
euvolemia. This should be according to the attending physician’s clinical judgement after 
assessment of the overall hemodynamic parameters and resuscitation status, including 
pressure (macrocirculation), flow (microcirculation), and function (metabolism). If function 
is compromised (e.g., rising creatinine, decrease in urine output, rising liver function tests) 
consider optimizing the coronary and systemic pressure gradient. 
 
 
 
 
 
 

 
 
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Figure 1. Sodium and Albumin to maintain euvolemia  
 
 
6.7 Weaning procedure for EMR solution  
To wean EMR, decrease rate of both solutions, EMR I or II and Clinisol to half the 
current rate for 4 hours, and then discontinue. Check serum glucose within 30 minutes 
of discontinuation of EMR. Further decisions regarding management of IVF, amino acid 
infusions or parental nutrition will be at the discretion of the ICU team or the primary 
team.  
 

 
 
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7.0 STUDY PROCEDURES 
 
7.1 Data to be collected prior to start of intervention 
 
1. Patient demographics at time of ICU admission (age, gender, weight, 
height, BMI, race, ethnicity, date of birth) 
 
2. Past medical and surgical history as recorded in the latest admission on 
the electronic patient record (EPR) 
 
3. Date and reason for hospital admission, and source of admission. 
 
4. Date, time and reason for ICU admission including any concomitant 
problems 
 
5. Date and time of septic shock onset (start time defined by criteria for 
septic shock, vital information that should be carefully determined, since 
“Timely delivery of EMR before Mitochondrial Respiration slows down” is 
the crux of the study) 
 
6. Suspected source of sepsis 
 
7. Presence or absence of oncologic disease, state and diagnosis of 
metastatic disease at time of ICU admission if known 
 
8. Nutritional status based on the assessment by the dietitian in the ICU 
(this may be recorded after onset of intervention if not available initially) 
including any history of weight loss or signs of malnutrition 
 
9. Patient vital signs and hemodynamic status 

 
 
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10. Supplementary oxygen and NIV/intubation status 
 
11. Baseline CBC, blood chemistry panel, coagulation screen and ABG 
(baseline defined as within 12 hours of randomization for venous tests 
and 4 hours for ABG – if these have not been done we will send additional 
baseline investigations) 
 
12. Any relevant microbiology results (blood, urine cultures, wound cultures, 
serum microbiological tests) and pertinent imaging results (radiology 
reports only – images not to be recorded) 
 
13. Admission Sequential Organ Failure Assessment (SOFA) score 
 
14. Pregnancy status - women of child bearing potential (defined as women 
<60 who have not been postmenopausal for at least one year or have 
not had a hysterectomy) will have either a serum or urine B-HCG test to 
exclude pregnancy.  A positive pregnancy test is grounds for exclusion 
from the study.  This will have already been undertaken as a part of 
screening if the above criteria are met. 
 
7.2 
Data to be collected prospectively 
 
Vital signs including blood pressure, heart rate, respiratory rate, pulse oximetry, co-
oximetry will be measured, as well as cardiac assessment by 2D echocardiogram. The 
following information will be collected prospectively if available. The order sets describe 
the timing and frequency of the lab draws. If clinical condition indicates, blood tests may 
occur more frequently at discretion of primary team.  Additional tests may not necessarily 
be recorded.  The below order sets indicate minimum frequency. Day 0 is day of 
recruitment. 

 
 
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Daily SOFA scores - will be generated automatically by the electronic health record if this 
option exists in the institution or manually with table 1 once daily.  
 
Laboratory Data:  
 
1. Complete Blood Count and Coagulation profile 
a. First 24hrs after start of intervention: every 8 hours ± 120 minutes 
b. After 24hrs of intervention: every 12 hours ± 120 minutes 
 
2. Cultures (as ordered by primary team – we will not specify culture   requirements 
though at least one set of blood cultures should be taken as required by sepsis 
management algorithm) 
 
3. Liver function tests and lipase 
a. First 24hrs after start of intervention: every 12 hours ± 120 minutes 
b. After 24hrs of intervention: every 24 hours ± 120 minutes 
 
4. Serum cholesterol (to be collected once daily only days 1, 3, 5) 
 
5. Thyroid test: Thyroid function tests (to be collected once daily only days 1, 3, 5) 
 
6. Blood chemistry panel 
a. Includes: Albumin, BUN, Ca2+, Na+, K+, Cl-, CO2, Creatinine, Glucose, 
Phosphorus, and Gama-Glutamyl transpeptidase 
b. First 24-hrs after start of intervention: every 4 hours ± 120 minutes (Will 
require VAMP System or similar blood sparing device to avoid wasting 
blood) 
c. After 24-hrs of intervention: every 8 hours ± 120 minutes 
 
7. Arterial blood gas and venous blood gas (via central venous catheter) 

 
 
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a. First 24hrs after start of intervention: every 4 hours ± 120 minutes 
b. After 24hrs of intervention: every 8 hours ± 120 minutes 
 
8. Lactic acid 
a. First 24-hrs after start of intervention: every 4 hours ± 120 minutes 
b. After 24-hrs of intervention: every 8 hours ± 120 minutes 
 
9. Serum Cortisol once daily (morning) 
 
10. Uric acid once daily (morning) 
 
11. Inflammatory markers (ESR, Procalcitonin) to be collected once daily.  
 
12. Creatinine phosphokinase (to be collected once daily only on day 1, 3, 5) 
 
Outcome data: 
1. Length of stay (LOS) 
a. Time from hospital admission to admission to the ICU (Length of stay 
before admission to the ICU) 
b. Length of the stay in the ICU 
c. Length of hospital stay  
2. Mortality 
a. Hospital mortality 
b. ICU mortality 
c. 28 day mortality 
d. 90 day mortality  
 
3. Ventilator days – ventilator free days,  duration of intubation (days)  
4. Any newly documented hospital acquired infection(s) 
5. Any acute kidney injury as defined by acute kidney injury network criteria: 
a. An acute (within 48h) rise in serum creatinine of 0.3g/dl or more 

 
 
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b. A percentage increase of serum creatinine of 50% or more 
c. Documented oliguria <0.5 ml/kg/hr for >6 hours 
d. Need for dialysis 
e. Dialysis free days 
6. Inotropic free days and duration of inotropic support (hours or days) 
7. Vital signs and any hemodynamic monitoring (cardiac index, CVP, ScvO2) 
implemented will be recorded – there is no specific requirement for hemodynamic 
monitoring beyond arterial-line recorded MAP/BP/HR. 
8. All patients will be followed up for up to 90 days.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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8.0 SAFETY ASSESSMENTS 
 
8.1 Theoretical and potential adverse events 
 
The study intervention is assessing an infusion containing products, which are normal 
components of the diet and are not toxic in themselves. Although this trial is expected to 
be very safe there are four main etiologies by which harm may occur in any of the groups: 
 
 
1. 
Fluid overload 
2. 
Electrolyte disturbances  
3. 
Hyper/hypoglycemia 
4. 
Hypersensitivity reactions 
 
Such events are frequent in an ICU, and medical personnel are well trained and 
experienced to deal with these situations.  This, combined with the very close monitoring 
provided by ICU means that a serious adverse reaction is thought to be exceedingly 
unlikely.  All of the described scenarios already have ICU management protocols. 
 
As the study is unblinded, attending physicians and care team members will be aware of 
the contents of the solutions being infused.  Thus, if the study team is not available to 
advise, the care team should be able to make a decision based on clinical factors and 
may use their discretion to discontinue the intervention where necessary.

 
 
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8.2 Management of anticipated adverse events 
 
1. Fluid overload 
 
This is considered to be very unlikely as sepsis and particularly septic shock are 
conditions where aggressive fluid resuscitation is recommended (30).  The amount of fluid 
administered daily is considered to be relatively conservative.  Furthermore, patients 
requiring renal replacement therapy will be excluded for further intervention, so harm from 
this intervention is highly unlikely. 
 
There is no consensus or standard definition of fluid overload. We ask physicians to 
discontinue other fluids in preference to the EMR investigation fluids when possible. If 
there is severe fluid overload whereby the primary team finds it necessary to discontinue 
the fluid, then the patient will be withdrawn.  It is not considered acceptable to slow the 
rate of the study solution – if this is felt to be essential, then the study solutions will be 
weaned and fluid management left to the care of the primary team. 
 
2. Electrolyte abnormalities 
 
a. Hyperkalemia (see appendix) 
i. Once potassium reaches ≥5 mmol/L EMR solution I (with potassium) 
has to be substituted with EMR solution II (without potassium) – EMR 
II has to continue despite hyperkalemia.  EMR I has to replace EMR 
II once potassium levels reach ≤4 mmol/L 
ii. Potassium levels over ≥5.5mmol/L have to be treated with standard 
ICU protocol.  If EMR I is infused this has to be recorded as an 
adverse event and EMR I must be immediately replaced with EMR II 
 
b. Hypokalemia (K ≤3)  (see appendix)  

 
 
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The ICU patients typically demonstrate low serum potassium level 
between 3 and 3.5, which are typically treated using the standard 
ICU electrolyte replacement protocol. Only serum potassium level of 
≤ 3 will be reported as an adverse event.   
c. Hypernatremia (Na >150)  
i. Discuss with study team – this may be criteria for cessation of 
intervention. Record as adverse event.  If study team not immediately 
available (i.e. weekends, nights) wean infusion at discretion of 
attending responsible. 
  Caution with glucose once EMR is stopped – glucose 
management algorithm must continue to be followed. 
 
d. Hyponatremia (Na <130)   
i. Additional sodium replacement (or diuresis) at discretion of primary 
team 
ii. If SIADH suspected and for fluid restriction – intervention has to be 
weaned.  Caution with glucose once EMR is stopped(weaned) – 
glucose management algorithm must continue to be followed. 
 
e. Severe Hypermagnesemia (Mg >4 mg/dl) 
i. Study intervention is to be stopped.  Record as adverse event.  
Manage as per ICU protocol 
 
f. Hypomagnesemia (Mg <1.5mg/dl) 
i. Replace as per ICU guidelines – N.B. target magnesium is ≥3mg/dl 
in intervention group 
 
g. Aluminum toxicity 
i. Aluminum toxicity is seen in neonates; however, this population is 
excluded in our study.  

 
 
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ii. Patients in renal failure are at risk of bio-accumulating aluminum 
when solutions contain >50 micrograms/L. In this study, patients with 
renal failure are excluded and free amino acids only contains <25 
micrograms/L.  
iii. Currently, to measure blood aluminum levels is not standard of care 
in a) patients not at risk of bio-cumulating the metal, b) patients 
receiving solutions that contain aluminum below 50 micrograms/L.  
iv. Aluminum toxicity is not an expected adverse event in this study 
patient population.  
 
h. Hypophosphatemia (PO4 <1mg/dl) 
i. Additional replacement as per standard ICU guidelines 
 
i. Hyperphosphatemia (PO4  >6.5mg/dL) 
i. Check renal function and calcium. Discuss with principal investigator. 
Hyperphosphatemia is not usually symptomatic and does not usually 
cause direct toxicity. The product of calcium x phosphate should be 
less 
or 
equal 
to 
60. 
Record 
as 
adverse 
event                      
 
3. Hyper/hypoglycemia (see appendix)  
 
For the very likely event of hyper/hypoglycemia in the EMR group we have 
developed an algorithm, which is a slight modification of standard ICU glucose 
management protocols and itself refers to ICU sliding scale insulin protocols.  As 
glucose management is anticipated as a potential issue, monitoring of glucose is 
to occur at least hourly in the treatment arm.  Please see appendix for detailed 
information on glucose management.  Target glucose is 140-180mg/dl. 

 
 
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4. Allergic reactions (related to study components or suspected relation) 
 
• Urticarial reaction 
o Begin antihistamine. Record as possible adverse event. Monitor 
patient – if EMR components suspected as the causative AND 
worsening reaction consider stopping solution and replace with 
D50 IV solution and exclude the patient from the protocol. At the 
same time treat the patient until reaction resolves. (Frequent 
glucose monitoring once solution discontinued). Contact principal 
investigator and follow hypersensitivity institutional protocol. 
 
• Anaphylaxis 
o As mentioned above, if EMR causes an anaphylaxis reaction, 
begin emergency anaphylaxis management as per ICU protocol.  
Record serious adverse event and inform research team 
immediately.  Stop solution and replace by D50 IV solution until a 
decision is made to exclude the patient from the protocol. At the 
same time treat the patient until reaction resolves.  Caution with 
glucose once EMR is stopped – glucose management algorithm 
must continue to be followed.  Contact study lead. 
 
8.3 Adverse Events and Serious Adverse Events 
 
• An adverse event (AE) is generally defined as any unfavorable and 
unintended diagnosis, symptom, sign (including an abnormal laboratory 
finding), syndrome or disease which either occurs during the study, having 
been absent at baseline, or if present at baseline, appears to worsen. 
Adverse events have to be recorded regardless of their relationship to the 
study intervention. 
 

 
 
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• A serious adverse event (SAE) is generally defined as any untoward 
medical occurrence that results in death or that is life threatening, requires 
inpatient hospitalization or prolongation of existing hospitalization, results in 
persistent or significant disability/incapacity, or in a congenital anomaly. 
 
As discussed in 8.1, the study solution is not a novel pharmaceutical product and 
is unlikely to cause any significant adverse event.  Theoretical complications of the 
solution are common problems in critical care units. Vigilance and close 
monitoring, together with high staffing levels in ICU reduce the potential for harm.  
Bearing these facts in mind, there are only  three scenarios, which will be reported 
as serious adverse events in the EMR group: 
 
1) Anaphylaxis (to study components) 
2) Arrhythmia secondary to electrolyte disturbance 
3) Hypoglycemia (<70mg/dL) 
 
These will be monitored for via electronic medical records.  All suspected adverse 
reactions and above adverse events must be reported by unit staff or research 
team to the principle investigator who will provide within 1 week such reports to the 
Institutional Review Board.  We estimate that adverse reactions are not very likely, 
as this study lacks novel pharmaceutical agents. Patient safety has been 
thoroughly considered by the study chairs. 
  
 
Only the adverse events and serious adverse events that happen within the 7 days 
of enrollment will be logged and reported to the IRB.   
 
 
 

 
 
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9.0 
CRITERIA FOR INTERVENTION DISCONTINUATION 
 
These include: 
• 
Patient’s consent withdrawn 
• 
Patient’s discharge from the ICU 
• 
Allergy to any of the components of EMR 
• 
Patient requiring renal replacement therapy 
• 
Patient’s death 
• 
Patient changed to Comfort Care status 
• 
Patients receiving greater than 70% of their nutritional needs via enteral 
nutrition 
• 
Unable to undergo placement of CVC for any technical reasons or withdrawal 
of CVC 
• 
Severe fluid overload or electrolyte abnormality requiring discontinuation (as 
described in Chapter 7) 
• 
Jehovah’s Witness who decides not to accept albumin. 
 
• 
If patient develops a known contraindication, or an unspecified condition where 
the clinician thinks the patient should be taken off the protocol, then there 
should be a discussion and treatment should be weaned according to safety 
protocol. 
 
 
In case of discontinuation, please follow weaning procedure detailed in section 6.7.  
 
 
 
 
 
 
 

 
 
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10.0 STATISTICAL CONSIDERATIONS 
 
10.1 Study Endpoint and Outcomes 
 
The primary objective of this study is to assess the efficacy of administering Early 
Metabolic Resuscitation with Standard of Care (SC + EMR) in patients diagnosed with 
septic shock for reducing 28 day  mortality versus using the Standard of Care alone (SC).  
 
The primary endpoint of the study is 28-day mortality. The rationale for selecting the 28-
day timeframe as the primary endpoint for comparison is that the MDACC ICU length of 
stay and the hospital length of stay in patients diagnosed with septic shock have wide 
variability (ICU LOS = Mean 9.45 ± 13.06 min: 0 max: 104, and Hospital LOS = Mean 
26.4 ± SD 26.4 min:1, max: 242). This variability is incurred from sources that cannot be 
controlled.  For this reason, measures such as 28-day and 90-day mortality provide more 
objectivity and align with outcomes described in the literature. 
 
Secondary outcomes include ICU mortality, hospital mortality, 90-day morality, incidence 
of acute kidney injury (dichotomous variable), time on cardiovascular support (continuous 
variable), time on ventilator (continuous variable) and length of ICU and hospital stays 
(continuous variables).  
 
10.2 Sample Size Justification and Randomization  
 
The rate of 28 day mortality from septic shock at the UT MD Anderson Cancer Center 
was 70% in 2017. With the objective of decreasing this rate to 40%, a sample size of 112 
patients (56 per group) provides 90% power to detect a 30% absolute reduction in the 
rate of 28 day mortality using a two-sided chi-square test at the 0.05 significance level. 
We plan to use stratified randomization in a 1:1 fashion to assign patients into two groups, 
and a fixed block size consisting of 4 patients will be applied for this purpose.  The 
randomization will be conducted in CORe (Figure 2).  

 
 
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Tables 3 displays effect sizes that correspond with conducting a test of equal 
proportions after randomizing 56 patients to each study arm.  The first scenario in Table 
3 is what we have currently provided in the protocol.  Subsequent scenarios in Table 3 
illustrate the change the in the effect size as the Type I error increases.  Table 4 is 
provided to illustrate effect size results if the power is reduced to 80%.  Smaller effect 
sizes are detectable if you increase Type I error or reduce power.   
 
Table 3.  Effect size with varying Type I error with Sample Size and Power controlled at 56 
patients per study arm and 90%, respectively 
 
 
 
Sample Size Per Study 
Group 
Effect Size (percentage point 
change from  𝜋𝜋ො0 = 70%) 
Type I error 
 
 
 
N = 56 
-30% (0.70 vs 0.40) 
0.05 
 
 
 
N = 56 
-27% (0.70 vs 0.43) 
0.10 
 
 
 
N = 56 
-25% (0.70 vs 0.45) 
0.15 
 
 
 
N = 56 
-24% (0.70 vs 0.46) 
0.20 
 
 
 
 
 
 
Estimates provided by (nQuery Advisor v7.0) for the difference between two proportions using a two-
sided chi-square test.  
 
Table 4.  Effect size with varying Type I error with Sample Size and Power controlled at 56 
patients per study arm and 80%, respectively 
 
 
 
Sample Size Per Study 
Group 
Effect Size (percentage point 
change from  𝜋𝜋ො0 = 70%) 
Type I error 
 
 
 
N = 56 
-26% (0.70 vs 0.44) 
0.05 
 
 
 
N = 56 
-23% (0.70 vs 0.47) 
0.10 
 
 
 
N = 56 
-21% (0.70 vs 0.49) 
0.15 
 
 
 
N = 56 
-20% (0.70 vs 0.50) 
0.20 
 
 
 
 
 
 
Estimates provided by (nQuery Advisor v7.0) for the difference between two proportions using a two-
sided chi-square test

 
 
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Figure 2. Sample size and randomization  
 
 
The septic shock patients will be stratified by type of malignancy given that hematologic 
patients may be more morbid than solid tumor patients. SC + EMR: Early Metabolic 
Resuscitation plus Standard of Care SC: Standard of Care. Blue boxes represent the 
group of patients that will receive EMR plus Standard of Care intervention and the pink 
boxes represent the group that will receive Standard of Care alone.

 
 
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10.3 Interim Analysis 
The parameters indicated in the full analysis set comprised of 112 patient for detecting 
an effect size of -30% (.70 vs .40) with a 2-sided test and Type I error of 5% conferring > 
90% power were used to develop interim stopping boundaries based on the method of 
Lan-DeMets with an O’Brien Flemming type spending function. An interim analysis will be 
conducted when the first 56 patients (28 patients randomized per treatment arm) have 
been evaluated for the primary endpoint.  Figure 1 provides the stopping boundaries for 
early termination on a p-value scale for both superiority and futility (East Version 
6.3.1).  At the interim analysis, a p-value < 0.003 or a p-value > 0.864 elicits early stopping 
for superiority or futility, respectively. The PI will make the final determination whether to 
terminate or continue with the trial after evaluating the study results.  Accrual will not be 
suspended while this analysis is being conducted. 
Figure 1. Stopping boundaries (on a P-value scale) for early termination due to superiority 
or futility  
 

 
 
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10.4 Data Monitoring 
 
During the course of the study, safety and data quality monitoring will be performed on 
an ongoing basis by the Research Coordinator and the Principal Investigator. The clinical 
research coordinator will be responsible for collecting and recording all clinical data. This 
includes ensuring that all source documents exist for the data on the case report forms, 
ensuring all fields are completed appropriately, and all corrections are done according to 
Good Clinical Practice (GCP’s). Any inconsistencies/deviations will be documented. The 
P.I. will review the obtained data for each patient on an ongoing basis.  
 
10.5 Data Analyses 
 
Descriptive statistics including the mean, standard deviation, median, and range will be 
used to summarize continuous variables. Frequency counts and percentages will be used 
to summarize categorical variables. Categorical variables, including 28 day mortality, will 
be compared between intervention groups using a chi-square test, or Fisher’s exact tests 
if more appropriate. Continuous variables will be compared between intervention groups 
using an independent samples t-test, or Wilcoxon rank-sum test if more appropriate. 
 
Logistic regression will be used to assess relationships between patient characteristics 
and binary study outcomes of interest. Continuous variables, including the time on 
cardiovascular support and time on ventilator, will be compared using t-tests or Wilcoxon 
rank-sum tests. 
 
Time to event analyses will be conducted using Cox proportional hazards regression.  For 
28-day mortality, living patients will be censored after one month after the treatment was 
given.  For overall survival, patients will be followed until time of death or date of last 
follow-up (maximum 6 months).  Kaplan-Meier plots will be used to visually compare time 
to death from any cause between intervention arms followed by a log-rank test to compare 
survival distributions.  

 
 
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10.6 Safety monitoring for Patients assigned to (SC + EMR) 
 
Patient safety will be monitored group sequentially for the first 50 patients in (SC + EMR) 
group.  The monitoring rule will be applied in cohorts of size 10 during the 7 days of 
treatment.    
 
Patient safety will be monitored to ensure that the rate of select AEs described in Section 
8.2 (which include: severe fluid overload, untreatable electrolyte abnormalities, severe 
hyper/hypoglycemia, allergic reactions) does not exceed 25%. If the AE rate exceeds 
25%, then the novel treatment approach of (SC + EMR) exceeds an acceptable rate and 
the trial will suspend accrual, while at the same time, protecting patients from the burden 
of being exposed to an untoward therapy.  
 
We will employ Bayesian stopping boundaries derived using a beta-binomial distribution. 
We will consider the treatment as acceptable if the AE rate during the first seven days 
post administration of (SC + EMR) is below 25%.  The following prior probability for the 
AE rate will be modeled with a beta distribution (1, 1).  Allowing θT to denote the true rate 
of AEs, the trial will suspend accrual if the Prob(θT > 0.25 | data) > 0.80. Patients will be 
monitored in cohorts of size 10 according to the following stopping boundaries displayed 
in Table 3. 
 
Table 4 illustrates the operating characteristics associated with the Bayesian stopping 
rule.  The probability of stopping accrual early is 61% if the true AE rate is 30%.    
 
 
 
 
 
 
 

 
 
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Table 3.  Stopping Boundaries assuming prior θT ~ beta (1, 1) 
Number of Patients 
Evaluated 
Recommended stopping 
accrual if ≥ AEs are observed  
10 
4-10 
20 
7-20 
30 
10-30 
40 
13-40 
50 
15-50 
 
*stopping boundaries and operating characteristics supplied using 
(https://ibl.mdanderson.org/BTM/) 
 
Table 4:  Operating Characteristics for the Bayesian Sequential Design 
True AE Rate 
Probability of Stopping 
Accrual Early 
Average Sample Size 
0.1 
0.014 
49.5 
0.2 
0.180 
43.7 
0.3 
0.610 
29.9 
0.4 
0.928 
17.7 
0.5 
0.996 
12.3 

 
 
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 11.0  DATA COLLECTION AND QUALITY ASSURANCE 
 
11.1 Records to Be Kept 
 
All patient-reported outcomes, laboratory, and clinical data gathered in this protocol will 
be stored in a password-protected database. A digital data collection form will be used to 
record data relating to outcomes described (to be included in appendix).  All patient 
information will be handled using anonymous identifiers. Linkage to patient identity is only 
possible after accessing a password-protected database. Access to the database is only 
available to individuals directly involved in the study. Information gathered for this study 
will not be reused or disclosed to any other person or entity, or for other research. Once 
the research has been completed, identifiers will be retained for as long as is required by 
law and by institutional regulations, and at that point will be destroyed. 
 
11.2 REDCap Summary 
 
Study data will be collected and managed using REDCap (Research Electronic Data 
Capture) electronic data capture tools hosted at MD Anderson. REDCap (www.project-
redcap.org) is a secure, web-based application with controlled access designed to 
support data capture for research studies, providing: 1) an intuitive interface for validated 
data entry; 2) audit trails for tracking data manipulation and export procedures; 3) 
automated export procedures for seamless downloads to common statistical packages; 
and 4) procedures for importing data from external sources. In the case of multi-center 
studies REDCap uses Data Access Groups (DAGs) to ensure that personnel at each 
institution 
are 
blinded 
to 
the 
data 
from 
other 
institutions. 
REDCap 
(https://redcap.mdanderson.org) is hosted on a secure server by MD Anderson Cancer 
Center's Department of Research Information Systems & Technology Services. REDCap 
has undergone a Governance Risk & Compliance Assessment (May 2014) by MD 
Anderson's Information Security Office and found to be compliant with HIPAA, Texas 
Administrative Codes 202-203, University of Texas Policy 165, federal regulations 
outlined in 21CFR Part 11, and UTMDACC Institutional Policy #ADM0335. 

 
 
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Those having access to the data include the study PI and research team personnel. Users 
are authenticated against MDACC's Active Directory system. External collaborators are 
given access to the database once approved by the PI, with their access expiring in 6 
months but renewable in 6 month increments at the request of the PI. The application is 
accessed through Secure Socket Layer (SSL). All protected health information (PHI) will 
be removed from the data when it is exported from REDCap for analysis. All dates for a 
given patient will be shifted by a randomly generated number between 0 and 364, thus 
preserving the distance between dates. Dates for each patient will be shifted by a different 
randomly generated number. 
Following publication, study data will be archived in REDCap. Since study data may be 
useful for future research studies performed under separate IRB approved protocols, 
study data will be archived indefinitely in REDCap. Since REDCap is a secure electronic 
database with controlled access, and because patient identifiers may be needed to link 
study data to data from other sources under future IRB approved protocols, patient 
identifying information will be retained in the archived database. 
 
11.3 Data Management  
 
The PI will oversee the day-to-day operation of the project along with the Project 
Coordinator.  The PI is responsible for reporting on trial progress to the IRB and he will 
take responsibility for the conduct of the research team, including, in general, optimal 
research ethics, adherence to protocol, and commitment to study completion. Specifically, 
site start-up and maintenance, protocol refinement, assurance of data quality, and trial 
success are the responsibility of both co-applicants and collaborators.   
 
 
 
 
 
 

 
 
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11.4 Quality Assurance 
 
 
11.4.1 Training 
 
Prior to the undertaking of the study, several educational sessions will be provided to ICU 
physicians (faculty and trainees), nurses, and advanced nurse practitioners (where 
present).  These will be provided by the study chair Dr. Joseph Nates or their designees.  
These sessions will focus on training ICU staff with the protocol with particular focus on: 
• New definitions of sepsis and septic shock 
• Rationale and purpose of study 
• The interventions given 
• Possible adverse reactions and how to manage them (particular focus on 
electrolytes & glucose) 
• Criteria for intervention discontinuation 
• Study team composition and contact information 
• Adverse event reporting 
 
11.4.2 Quality Control 
 
Integrity of data is ensured by oversight from MD Anderson’s Data Monitoring and Safety 
Board.  As well as adverse event reporting and annual reports will be provided to the 
DSMB with the help of the trial statisticians in order to ensure integrity of the data.  Along 
with planned recording for protocol deviations, we feel this will ensure the integrity and 
quality of the data recorded 
 
11.4.3 Protocol Deviations 
 
Deviations from protocol, whether or not they may lead to harm or risk of harm, will be 
recorded by investigators and provided to the principle investigator who may share these 

 
 
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with the DSMB.  Protocol deviations, if felt to be significant, will be shared with statisticians 
and included in potential analyses where possible.   
 
11.4.4 Monitoring 
 
Protocol compliance will be assessed by review of records, including inpatient electronic 
records, by the research team during the collection of study outcomes.  All consent 
documents and any other information collected non-electronically will be reviewed by the 
principle investigator.  The MD Anderson Data and Safety Monitoring Board (DSMB) may 
decide to audit the research at any stage and review the progress of the research at the 
frequency they so desire. 

 
 
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12.0 PARTICIPANT RIGHTS AND CONFIDENTIALITY 
 
12.1 Institutional Review Board (IRB) evaluation 
 
This study and any amendments to it are subject to review by the MD Anderson 
Institutional Review Board before the commencement of any research activities.  The MD 
Anderson IRB is registered with the Office for Human Research Protections and is 
compliant with all international, national and local guidelines pertaining to the conduct of 
research using human subjects. 
 
12.2 Informed Consent 
 
A signed IRB approved consent form will be obtained from the subject or, if the subject’s 
lacks decision-making capacity, the subject’s legally authorized representative   will sign 
the consent form on their behalf. The consent form describes the purpose of the study, 
the procedures to be followed, and the risks and benefits of participation.  A copy of the 
consent form will be given to the subject or to the subject’s legally authorized 
representative, and this fact will be documented in the subject’s record. 
 
12.3 Subject Confidentiality 
 
Study confidentiality standards will be followed handling the data.  No patient identifiable 
data will be shared outside of the research team.  All computer entry for data analysis will 
be done using study identification numbers only.  Clinical information will not be released 
without written permission of the subject, except as necessary for monitoring by IRB, the 
FDA, or the OHRP. 

 
 
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12.4 Study Modification/Discontinuation 
 
The study may be modified or discontinued at any time by the IRB, the OHRP, the FDA, 
or other government agencies as part of their duties to ensure that research subjects are 
protected. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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13.0 PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by the policies and procedures 
developed by MD Anderson.  Any publications or presentations must be agreed with the 
co-principle investigators prior to publication. 
 
 
 

 
 
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14.0 REFERENCES 
 
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Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, 
et al. The Third International Consensus Definitions for Sepsis and Septic Shock 
(Sepsis-3). JAMA. 2016 Feb;315(8):801–10.  
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Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, et al. 
Surviving sepsis campaign: International guidelines for management of severe 
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Angus DC, van der Poll T. Severe Sepsis and Septic Shock. N Engl J Med. 2013 
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Adhikari NKJ, Fowler RA, Bhagwanjee S, Rubenfeld GD. Critical care and the 
global burden of critical illness in adults. Lancet (London, England). 2010 
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5.  
Center for Disease Control and Prevention. Sepsis Statistics. 2017.  
6.  
Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ. Two decades 
of mortality trends among patients with severe sepsis: a comparative meta-
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Bone RC. Immunologic dissonance: a continuing evolution in our understanding 
of the systemic inflammatory response syndrome (SIRS) and the multiple organ 
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8.  
Tapper H, Herwald H. Modulation of hemostatic mechanisms in bacterial 
infectious diseases. Blood. 2000 Oct;96(7):2329–37.  
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Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, et al. 
The cardiovascular response of normal humans to the administration of 
endotoxin. N Engl J Med. 1989 Aug;321(5):280–7.  
10.  Frantz S, Ertl G, Bauersachs J. Mechanisms of disease: Toll-like receptors in 
cardiovascular disease. Nat Clin Pract Cardiovasc Med. 2007 Aug;4(8):444–54.  
11.  Pinsky MR, Vincent JL, Deviere J, Alegre M, Kahn RJ, Dupont E. Serum cytokine 
levels in human septic shock. Relation to multiple-system organ failure and 
mortality. Chest. 1993 Feb;103(2):565–75.  

 
 
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12.  Vincent JL, Zhang H, Szabo C, Preiser JC. Effects of nitric oxide in septic shock. 
Am J Respir Crit Care Med. 2000 Jun;161(6):1781–5.  
13.  López A, Lorente JA, Steingrub J, Bakker J, McLuckie A, Willatts S, et al. 
Multiple-center, randomized, placebo-controlled, double-blind study of the nitric 
oxide synthase inhibitor 546C88: Effect on survival in patients with septic shock*. 
Crit Care Med. 2004 Jan;32(1):21–30.  
14.  KC B. Infectious Diseases. In: McPhee SJ, Hammer GD: Pathophysiology of 
Disease. New York: McGraw-Hill,; 2010. 57–83 p.  
15.  Pravda J. Metabolic theory of septic shock. World J Crit Care Med. 2014;3(2):45.  
16.  Borgen L. Total parenteral nutrition in adults. Am J Nurs. 1978 Feb;78(2):224–8.  
17.  Lyons J, Rauh-Pfeiffer A, Ming-Yu Y, Lu XM, Zurakowski D, Curley M, et al. 
Cysteine metabolism and whole blood glutathione synthesis in septic pediatric 
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18.  Biolo G, Antonione R, De Cicco M. Glutathione metabolism in sepsis. Crit Care 
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19.  Karapetsa M, Pitsika M, Goutzourelas N, Stagos D, Tousia Becker A, Zakynthinos 
E. Oxidative status in ICU patients with septic shock. Food Chem Toxicol. 2013 
Nov;61:106–11.  
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15. APPENDIX 
 
 
 
 
 
 
 
 
 
 
 

 
 
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