Study of Early Enteral Dextrose in Sepsis
Phase: NA
Conditions: Sepsis
Sponsor: University of Pittsburgh

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Unique Protocol ID:  
PRO17010532  
 
Brief Title:  
Study of Early Enteral Dextrose in Sepsis (SEEDS) 
   
Official Title:  
Study of Early Enteral Dextrose in Sepsis   
 
Secondary IDs:  
5K23GM122069   [U.S. NIH Grant/Contract Award 
Number]  
 
 
 
NCT03454087  
 

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Study of Early Enteral Dextrose in Sepsis (SEEDS):  
A Randomized-Controlled Clinical Trial 
 
 
 
Principal Investigator: 
Faraaz Ali Shah, MD 
Assistant Professor of Medicine 
University of Pittsburgh School of Medicine 
Division of Pulmonary, Allergy, and Critical Care Medicine 
UPMC Montefiore NW 628 
3459 Fifth Avenue 
Pittsburgh, PA 15213 
 
Sub-Investigator: 
Bryan McVerry, MD 
Associate Professor of Medicine  
University of Pittsburgh School of Medicine 
Division of Pulmonary, Allergy, and Critical Care Medicine 
UPMC Montefiore NW 628 
3459 Fifth Avenue 
Pittsburgh, PA 15213 
 
 
 
 
 
 

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Table of Contents 
 
1. Synopsis................................................................................................................................ 4 
2. Glossary................................................................................................................................ 5 
3. Hypothesis and Objectives 
 
3.1 Hypothesis.................................................................................................. 6 
 
3.2 Primary Objective........................................................................................ 
6 
 
3.3 Secondary Objectives.................................................................................. 
6 
4. Background and Significance 
 
4.1 Background 
4.1.1 The clinical background of sepsis................................................. 
6 
 
 
4.1.2 Hyperglycemia and inflammation in sepsis.................................... 
6 
 
 
4.1.3 Nutritional support in sepsis.......................................................... 
7 
 
 
4.1.4 Enteral glucose as an anti-inflammatory  
         intervention in sepsis..................................................................... 
8 
 
 
4.1.5 Activation of the incretin hormone axis in sepsis........................... 
9 
 
 
4.1.6 Host-microbiome interactions as a therapeutic  
         target in sepsis............................................................................... 9 
 
4.2 Significance 
4.2.1 The significance of an interventional trial of early  
          enteral dextrose............................................................................. 10 
5. Research Design and Methods 
 
5.1 General Characteristics 
 
 
5.1.1 Inclusion criteria............................................................................. 11 
 
 
5.1.2 Exclusion criteria............................................................................ 11 
 
5.2 Recruitment and Screening Procedures 
 
 
5.2.1 Initial screening (pre-consent)......................................................... 12 
 
 
5.2.2 Pre-entry screening and consent..................................................... 12 
 
 
5.2.3 Baseline evaluation and randomization........................................... 
12 
 
 
5.2.4 Blinding...........................................................................................13 
 
5.3 Study Treatment 
 
 
5.3.1 Treatment arms............................................................................... 13 
 
 
5.3.2 Study drug...................................................................................... 13 
 
 
5.3.3 Study duration................................................................................ 14 
 
 
5.3.4 Study product formulation and storage........................................... 
14 
 
 
5.3.5 Pharmacy role................................................................................. 14 
 
5.4 Study Exams and Procedures 
 
 
5.4.1 Initial screening (pre-consent)......................................................... 14 
 
 
5.4.2 Pre-entry evaluation and consent.................................................... 14 
 
 
5.4.3 Baseline testing and randomization................................................. 14 
 
 
5.4.4 Study period................................................................................. 14 
 
 
5.4.5 Mid-intervention assessment……..................................................... 14 
5.4.6 Intervention conclusion……............................................................ 
15 
 
 
 
5.4.7 Day 7 testing and procedures.......................................................... 15 
 
 
5.4.8 Day 30 testing and procedures........................................................ 15 
6.0 Experimental procedures 
 
6.1 Screening...................................................................................................... 16 
 
6.2 Clinical assessment....................................................................................... 16 

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6.3 Study procedures 
 
 
6.3.1 Capillary blood glucose measurement............................................. 
16 
 
 
6.3.2 Research blood draws..................................................................... 16 
 
 
6.3.3 Microbiome sampling...................................................................... 16 
7.0 Clinical Management Issues 
 
7.1 Definition of adverse events.......................................................................... 17 
 
7.2 Reporting severe adverse events.................................................................... 18 
 
7.3 Monitoring for adverse events………................................................................ 18 
 
7.4 Indications for study discontinuation.............................................................. 18 
 
7.5 Protocol adherence……………………………………………………………………………………..……… 18 
 
7.6 Clinical nutrition management…..................................................................... 18 
7.7 Data Safety and Monitoring Plan (DSMP)........................................................ 
19 
 
 
7.7.1 Required education in the protection of human  
         research participants....................................................................... 19 
8.0 Data Management and Tracking................................................................................. 20 
9.0 Data Collection and Statistical Consideration 
 
9.1 Sample size and power calculation................................................................. 20 
 
9.2 Proposed statistical analysis.......................................................................... 20 
10.0 Costs and Payments 
 
10.1 Research study payments............................................................................ 21 
11.0 Appendix 
 
11.1 Sepsis-Related Organ Dysfunction Score.................................................... 
22 
 
11.2 Estimation of PaO2/FiO2 from SpO2/FiO2…………………………………..………………... 
23 
 
11.3 Expected adverse events from sepsis…..………………………………………………………... 
24 
12.0 Literature Cited.................................................................................................... 
25 
13.0 Protocol Amendment Log ........................................................................................ 30 
 
 
 
 
 

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1.0 SYNOPSIS 
 
Design 
The study is a prospective randomized double-blinded placebo-
controlled clinical trial to test the effects of early enteral dextrose as a 
therapeutic agent in critically ill patients with sepsis. Primary outcomes 
are differences in circulating plasma levels of the pro-inflammatory 
cytokine IL-6 to be tested 24 hours after randomization. Secondary 
outcomes include differences in circulating incretin hormone levels, 
differences in other pro-inflammatory cytokines including IL-1β and 
TNF-α, changes in intestinal microbial composition and function after 
intervention, glycemic control and variability as assessed by capillary 
blood glucose measurements and exogenous insulin dosing during the 
intervention period, and clinical outcomes including intensive care unit 
(ICU) and hospital stay and in-hospital mortality.  
Duration 
Study participants will be randomized within 48 hours of meeting 
sepsis criteria, undergo a 24 hour intervention and data collection 
period, and will be followed for clinical outcomes. 
Sample Size 
72 participants (36 patients in each arm) 
Population 
Men and women older than 18 years of age with evidence of sepsis 
admitted to the intensive care unit with an existing enteral feeding 
tube (or with imminent plans to place one).   
Regimen 
Participants will be randomized to either receive early low level enteral 
infusion of dextrose (intervention) or enteral free water (placebo 
control).  
 
 

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2.0 GLOSSARY 
 
Cytokine: a cell-signaling protein released by immune cells in response to infection or injury 
 
Enteral Nutrition: feeding or nutrients that are provided directly into the stomach or intestines 
 
Glucagon-like peptide 1 (GLP-1): an incretin hormone released in the distal intestines and colon  
 
Glucose-dependent insulinotropic peptide (GIP): an incretin hormone released in the proximal small 
intestine  
 
Interleukin-1 beta (IL-1β): a pro-inflammatory cytokine involved in the pathogenesis of sepsis 
 
Interleukin-6 (IL-6): a pro-inflammatory cytokine involved in the pathogenesis of sepsis 
 
Incretin: an intestine-derived hormone released in response to enteral nutrients with a primary function 
of potentiating insulin release from the pancreas 
 
Microbiome: the community of micro-organisms including all bacteria, viruses, and fungi that reside 
within animals and humans 
 
Parenteral Nutrition: feeding or nutrients that is provided intravenously  
 
Sepsis: a syndrome characterized by a pro-inflammatory response to infection 
 
Tumor Necrosis Factor alpha (TNF-α): a pro-inflammatory cytokine involved in the pathogenesis of 
sepsis 
 
 

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3.0 HYPOTHESIS AND OBJECTIVES 
3.1 Hypothesis  
• 
Early enteral dextrose decreases inflammation, increases incretin hormones, prevents 
hyperglycemia, and preserves a healthy gut microbiome in critically ill septic patients  
3.2 Primary objective   
• 
To test the effects of early enteral dextrose on inflammation in critically ill septic patients as 
measured by the pro-inflammatory cytokine interleukin-6 (IL-6) 
3.3 Secondary objectives 
• 
To determine the effect of early enteral dextrose on glucose metabolism in critically ill septic 
patients 
• 
To determine the effects of early enteral dextrose on the gut microbiome in critically ill septic 
patients. 
• 
To determine the effects of early enteral dextrose on clinical outcomes in septic patients.  
 
4.0 BACKGROUND AND SIGNIFICANCE 
 
4.1 Background 
 
4.1.1 The clinical problem of sepsis 
 Sepsis, a complex syndrome characterized by an overwhelming inflammatory response to 
infection, affects over 1 million Americans annually and is associated with substantial health care costs, 
in-hospital mortality or 20-30%, and significant long-term functional and neurocognitive deficits in 
survivors.1-4 Exaggerated pro-inflammatory responses early in the course of sepsis have been associated 
with increased organ dysfunction and lower survival.5  
 
Despite advances in our understanding of sepsis pathophysiology including inflammatory 
responses, endothelial dysfunction, and coagulation abnormalities, no specific therapies targeting the 
underlying mechanisms of sepsis have been successfully developed (ex- anti-IL-1 therapy, activated 
protein C).6,7 Instead, the therapies that have demonstrated the greatest benefit in survival from sepsis 
have been the early use of broad spectrum antibiotics and resuscitative intravenous fluids. Sepsis 
management guidelines focus primarily on reducing delay to these life-saving therapies and providing 
additional supportive therapies including vasoactive medications and mechanical ventilation as necessary 
since late implementation is associated with worse outcomes.8-10  
  
4.1.2 Hyperglycemia and inflammation in sepsis 
Approximately 40% of patients in the intensive care unit develop hyperglycemia, and, of those, 
one third do not have pre-existing diabetes.11 The development of hyperglycemia in previously non-
diabetic patients with sepsis (referred to as stress hyperglycemia) is associated with increased organ 
dysfunction and mortality.12-16 Stress hyperglycemia shares many characteristics with diabetes mellitus 
type 2: disrupted glucose homeostasis, impaired insulin sensitivity, inflammation, and counter-regulatory 
hormone imbalance. Once hyperglycemia develops, it further increases production of pro-inflammatory 
cytokines, suppresses neutrophil activity, and increases leukocyte adhesion and migration.20-22 While 

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initial clinical trials in critically ill patients demonstrated mortality benefits with tight glycemic control 
using intravenous insulin,17 subsequent trials have failed to replicate the same benefits with the use of 
insulin alone.18,19 Better understanding of the mechanisms contributing to hyperglycemia during sepsis 
and newer strategies to prevent its development, as proposed in our study, rather than respond once 
hyperglycemia has occurred are needed to improve patient outcomes. 
 
4.1.3 Nutritional support in sepsis 
The provision of nutrition is a cornerstone of supportive therapy in critically-ill patients, yet 
uncertainty remains regarding the optimal timing, dose, and route of administration.23-25 Sepsis represents 
a catabolic stress state and patients are frequently unable to consume any calories of their own volition 
due to their clinical condition and associated care. Nutritional support in the intensive care unit can be 
provided to septic patients by either the parenteral or enteral route. Recent clinical trials have highlighted 
potential harm with the early initiation of parenteral nutrition in critically ill patients, and, as such, current 
guidelines favor the provision of nutrition support via enteral route. The optimal timing and dose of 
enteral nutritional support during sepsis remains uncertain.26,27  Current guidelines state28: 
 
• 
 “nutrition support therapy in the form of early enteral nutrition should be initiated within 24–
48 hours in the critically ill patient” (Quality of Evidence: Very Low) 
• 
 “in the setting of hemodynamic compromise or instability, EN should be withheld until the 
patient is fully resuscitated and/or stable. Initiation/re-initiation of EN may be considered with 
caution in patients undergoing withdrawal of vasopressor support.” (Expert consensus) 
 
Nutrition is provided to septic patients with the goals of preserving lean body mass, preventing 
malnutrition, and facilitating recovery. Providing nutrition via enteral route is also believed to maintain 
the integrity of intestinal epithelium, prevent bacterial translocation, and even potentially modulate 
inflammatory responses.28-31 Importantly the benefits of enteral nutrition are noted at low (so-called 
“trophic”) levels of support.32 As described in this proposed protocol, the benefits of low-level enteral 
support in the acute phase of sepsis may include activation of endogenous endocrine pathways to 
regulate glucose metabolism, modulation of the acute systemic inflammatory response, and preservation 
of the healthy intestinal microbiome. However, clinical evidence for the dose and timing of enteral 
nutrition is limited and guidelines are based largely on studies of low quality or expert consensus. 
Although current guidelines recommend early nutrition, within the first 24 to 48 hours in critically ill 
patients, clinical studies specifically in septic patients are lacking and the effects of early nutrition therapy 
on mechanistic pathways underlying illness and recovery remain unknown.  
Despite the guideline recommendations for early initiation of enteral nutrition, clinical 
observations from the Acute Lung Injury Registry at UPMC Presbyterian Hospital show more than half of 
septic patients receive no enteral nutrition within the first 48 hours perhaps due the expert consensus 
recommendation to avoid enteral nutrition during periods of hemodynamic compromise. The SCCM 
guidelines base this recommendation in part on the theoretical risk of bowel ischemia, but this is a rare 
clinical condition that occurs in less than 1% of patients receiving enteral nutrition.33 Furthermore, a 
retrospective propensity score based analysis of critically ill patients demonstrated that patients with 
hemodynamic instability requiring vasopressors not only tolerated enteral support but had a reduction in 
mortality compared to similar patients who did not receive enteral support.34 The potential benefit of 
enteral nutrition in this retrospective study of critically ill patients highlights the need for further 
prospective clinical trials to better characterize the effects of early enteral support with a focus on 
understanding underlying physiology and mechanisms of disease. 
 

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4.1.4 Enteral glucose as an anti-
inflammatory 
intervention 
in 
sepsis 
Simple carbohydrates, such 
as dextrose, are readily digested 
and absorbed in the intestinal tract.  
Recent data from our lab suggest 
that low level enteral dextrose 
provision 
(~10% 
daily 
caloric 
requirements) early in the course of 
sepsis attenuates the systemic 
inflammatory 
response 
and 
improves glucose disposal in mice. 
In 
our 
first 
set 
of 
experiments, we used intravascular 
endotoxin (LPS), a component of 
the cell wall of gram negative bacteria, administered to 10 week old C57BL/6J male mice to test the effects 
of intravenous (IV, parenteral) and intragastric (enteral) dextrose in the acute phase of sepsis.  
Infusion of a low level of IV dextrose in endotoxemic mice significantly impaired glucose tolerance 
compared to either IV dextrose or LPS alone. Enteral dextrose infusion at an equivalent level of support, 
however, increased insulin secretion and preserved glucose disposal in endotoxemic mice. Furthermore, 
infusion of early enteral dextrose in endotoxemic mice was associated with improvement in mean arterial 
blood pressure and attenuated the systemic inflammatory response, evidenced by reduced levels of the 
pro-inflammatory cytokine IL-6 by 35-50% (Figure 1) compared to endotoxemic mice receiving saline 
infusion or intravenous (IV) dextrose.  Similar trends were noted for the pro-inflammatory cytokines IL-1β 
and TNF-α. Thus, early enteral dextrose infusion in endotoxemic mice had beneficial effects on the 
systemic inflammatory response as well as glucose metabolism. 
In 
a 
second 
set 
of 
experiments, we examined the 
effects of IV and enteral dextrose in 
a pneumonia model of sepsis. Mice 
were 
infected 
with 
Klebsiella 
pneumoniae and 24 hours after 
septic insult were randomized to 
receive (1) IV dextrose, (2) enteral 
dextrose, or (3) enteral saline. 
Infusion of IV dextrose in septic 
mice 
was 
associated 
with 
hyperglycemia 
and 
decreased 
survival. Mice receiving IV dextrose 
exhibited 100% mortality at 36 hr 
whereas 25% of septic mice 
receiving enteral saline survived to 
72 hours. In contrast, infusion of 
enteral dextrose increased survival 
to ~70% at 72 hours (Figure 2). Mice 
receiving enteral dextrose also 
Figure 1: Enteral dextrose infusion in mice exposed to endotoxin (LPS) 
decreases circulating levels of pro-inflammatory cytokines such as IL-6 
0
2 4
4 8
7 2
0
2 0
4 0
6 0
8 0
1 0 0
H o u rs
P e rc e n t s u rv iv a l
IV  D e xtro se
E n te ra l S a lin e
E n te ra l D e x tro s e
Catheterization + 
Inoculation
Infusion 
started
Figure 2: Enteral dextrose improved survival at 72 hours in a Klebsiella 
pneumoniae septic mouse model. In contrast, intravenous dextrose infusion in 
this pneumonia model markedly worsened survival.  

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demonstrated improved systemic inflammation, blood pressure, and glucose control compared to mice 
receiving enteral saline.  
Taken together, our data suggest that early enteral dextrose administration at low levels of caloric 
support attenuates systemic cytokine release, improves glucose tolerance, improves hemodynamics, and 
prevents mortality in the acute phase of sepsis in mice. Consequently, early enteral glucose provision 
could constitute a method to regulate the inflammatory response and metabolic function in patients with 
sepsis. However, this approach has not yet been explored in humans. 
 
4.1.5 Activation of the incretin hormone axis in sepsis 
Improvements in glucose homeostasis with provision of enteral dextrose in our model appear to 
be mediated through the incretin hormone pathway. The incretin hormones glucose-dependent 
insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted by intestinal cells in 
response to enteral administration of carbohydrates, proteins, and lipids, and improve glucose disposal 
by increasing insulin secretion and sensitivity and suppressing glucagon activity.35,36 Relevant to our study, 
incretin hormones also demonstrate immunomodulatory effects in addition to effects on glycemic control. 
In animal studies, incretin hormones decrease systemic inflammation and cytokine release in chronic 
inflammatory models.37-42 Incretin hormone receptors are present on macrophages in both mice and 
humans43,44 and thus increased incretin release may have direct effects modulating acute inflammation in 
sepsis. Therapies targeting increased incretin activity, including incretin analogues and inhibitors of the 
dipeptidyl peptidase IV (DPP IV) protease, are FDA approved and widely used for the treatment of type 2 
diabetes,36,45,46 and clinical trials have studied the effect of GLP-1 analogues in critically ill patients.47,48  
Our data suggest that activation of incretin hormone pathways plays a vital role in mediating the 
beneficial effects of enteral dextrose in endotoxemic mice.49,50 Infusion of low-level continuous enteral 
dextrose in our model increases circulating levels of the incretin hormone GIP. When incretin signaling is 
blocked with pharmacologic agents, the beneficial effects of enteral dextrose on glucose tolerance, insulin 
secretion, and inflammation are lost. Blocking GIP, which is released more proximally in the intestine, 
appears to be more detrimental than blocking GLP-1 in our model. Further supporting the therapeutic 
potential of incretin hormones, exogenous infusions of GLP-1 and GIP were able to rescue glucose 
tolerance, improve insulin release, and decrease inflammation in endotoxemic mice receiving intravenous 
dextrose, the group of mice that had previously demonstrated the worst glucose tolerance. Thus, 
targeting the endogenous incretin hormone pathway in septic patients with the use of enteral dextrose 
infusion may provide a novel means of maintaining euglycemia and modulating the systemic inflammatory 
response while preventing the hypoglycemia that is often associated with exogenous insulin 
administration. 
 
4.1.6 Host-microbiome interactions as a therapeutic target in sepsis 
Recent research has highlighted the importance of understanding the complex interactions 
between the critically ill host and the endogenous micro-organisms in the human intestinal tract in the 
development and evolution of sepsis.51,52 The advent of culture-independent techniques for the study of 
microbes with next-generation sequencing has revealed that humans harbor in their gastrointestinal 
tracts up to ~ 4 trillion bacteria, which collectively with viruses and fungi are referred to as the human 
microbiome.53 In healthy individuals, the gastrointestinal microbiome plays important commensal 
homeostatic roles, including nutrient metabolism, hormone and vitamin biosynthesis, immune response 
modulation, preservation of mucosal integrity and colonization resistance against invasive pathogens.54 
Dysbiosis or disruption of a “healthy” gut microbiome is associated with a loss of commensal microbiota 
resulting in increased susceptibility to pathogens and dysregulated immune responses.55  

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The gut microbiome in sepsis is severely disturbed by effects of the pathophysiologic processes 
of sepsis (e.g. gut hypoperfusion, endogenous catecholamines, systemic hyperglycemia etc.) but also from 
critical care interventions, including systemic antibiotics, gastric acid suppression, and nutrition delivery 
interruptions.51,52 The dysbiotic gut microbiome is now considered a central orchestrator in sepsis (gut-
origin sepsis), both in triggering pathogen invasion (microbial translocation) and in mediating distal end-
organ damage by inflammatory mediators (gut-lymph hypothesis).56,57 Interactions at the interface 
between the intestinal mucosal layer and the indigenous microbiome result in barrier integrity failure on 
the epithelial side, and in pathogen expansion on the micro-organism end that dominate their respective 
microbial communities.58 Restoration of a healthy gut microbiome through early enteral nutrition is 
emerging as an appealing therapeutic goal in sepsis,51,52 but the effects of different types of enteral 
nutrition on the gut microbiome have not been well-defined. Given that commensal microbiota depend 
on host nutrition for their survival,59 early enteral dextrose in septic patients may assist may promote 
maintenance of a healthy gut microbiome in sepsis.  
At the same time, dextrose administered in the stomach or duodenum is expected to be 
completely absorbed in the jejunum, and thus, we do not anticipate that our experimental arm 
intervention will have measurable effects in the colonic microbiota. However, little is known about the 
composition and evolution of gastric/proximal intestinal microbiome in sepsis, and gastric acid 
suppression and dysmotility from sedatives are well known to promote bacterial growth in critically-ill 
patients.51 Given that the stomach forms a reservoir for bacterial aspiration in the upper and lower airways 
of critically-ill patients with downstream infectious complications, we will comprehensively examine the 
microbiome profiles of different parts of the upper aerodigestive tract (oral swabs, tracheal aspirates and 
gastric aspirates) to assess for a potential impact of enteral dextrose on host microbial communities. We 
will also examine stool samples or rectal swabs as proxies for the assessment of the colonic microbiome 
to examine its relatedness to the aerodigestive tract microbiota and possible impact of our intervention.  
 
4.2 Significance 
 
4.2.1 The significance of an interventional trial of early enteral dextrose 
Current clinical guidelines suggest the early initiation of enteral tube feed formulations within the 
first 24-48 hours of intensive care unit admission, but evidence is lacking on the physiologic and 
mechanistic effects of these interventions in the acute phase of sepsis. Results from our animal models 
suggest that early administration of enteral dextrose at low levels has potential benefits on the systemic 
inflammatory response and on glucose metabolism while also providing some caloric support. With this 
study, we propose an interventional trial to test the effects of early enteral dextrose on inflammation and 
glycemic control in septic patients. Our study utilizes a low-cost intervention during the most acute phase 
of illness, a time when most patients are not receiving any support by the enteral route. Our study will 
provide important information on the effects of early enteral nutrients on inflammatory and endocrine 
pathways as well as on the gut microbiome. Our study has important implications for clinical care. Results 
consistent with our animal models that demonstrate enteral dextrose improves inflammation and 
glycemic control in septic patients would support a larger interventional trial testing the effect of very 
early enteral nutrition, similar to early antibiotics or resuscitative fluids, in septic patients. Thus, the 
results of this clinical trial will be vital in informing future studies of the effects of enteral nutrients in 
critically ill patients. 
 

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5.0 RESEARCH DESIGN AND METHODS 
 
This study is a single-center, prospective, double-blinded, randomized placebo-controlled clinical 
trial to determine the therapeutic effects of early enteral dextrose in critically ill patients admitted with 
sepsis. This trial will have an interventional arm in which participants receive a low level enteral dextrose 
infusion and a placebo control arm in which participants will receive an enteral free water infusion. The 
primary outcome of this study is the extent of systemic inflammation as determined by circulating levels 
of the pro-inflammatory cytokines IL-6 measured at the end of the intervention. Secondary outcomes 
include measures of glycemic control by capillary blood glucose; measures of insulin, C-peptide, and the 
incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1); 
measures of other pro-inflammatory cytokines including IL-1β and TNF-α; determination of the 
composition and function of the aerodigestive tract and colonic microbiome; and clinical measures 
(including incidence of emesis, ICU length of stay, hospital length of stay, mortality).  
5.1 General characteristics 
 
We will include patients 18 years or older diagnosed with sepsis at the time of admission to an 
intensive care unit (ICU) at UPMC Presbyterian, UPMC Montefiore, UPMC Shadyside, or UPMC 
McKeesport hospitals. Etiology of sepsis can include any organ system (e.g. pneumonia, urinary tract 
infection, severe soft tissue infection, etc.) as long as the type of infection does not preclude use of the 
gastrointestinal tract for nutrition and medication administration (e.g. peritonitis).  
5.1.1 Inclusion criteria 
1. Adults aged 18 years and older admitted to an ICU at UPMC Presbyterian, UPMC 
Montefiore, UPMC Shadyside, or UPMC McKeesport. 
2. New presentation of sepsis characterized by a confirmed or suspected infection, with an 
acute increase from baseline in a modified Sepsis-Related Organ Failure Assessment 
(SOFA) score of greater than or equal to 2 points (Appendix 11.1). If baseline values are 
unknown, baseline SOFA score of 0 will be assumed. 
3. Available enteral access defined by: (1) an existing nasogastric or orogastric tube, (2) 
plans to place a nasogastric or orogastric tube, or (3) an existing percutaneous 
endoscopic gastrostomy (PEG) tube.  
4. Less than 48 hours since meeting criteria for sepsis. 
5. Expected to stay at least 24 hours in the ICU.  
 
5.1.2 Exclusion Criteria  
1. Pre-existing continuous enteral tube feed use prior to study entry. 
2. Diabetic ketoacidosis or diabetic hyperosmolar hyperglycemic syndrome. 
3. Previously enrolled in this study within the same hospital admission.  
4. ICU physician request to exclude patient based on clinical assessment or 
contraindication to enteral feeding. 
5.2 Recruitment and screening procedures 
This is a single center RCT with recruitment to be performed in the ICUs of UPMC Presbyterian, 
UPMC Montefiore, UPMC Shadyside, and UPMC McKeesport hospitals.  

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5.2.1 Initial screening (pre-consent):   
The principal investigators will introduce the study to ICU physicians in the In-Service Session 
before the start of the study and in ongoing staff meetings, grand rounds, and in any other ICU meetings. 
The study procedures, eligibility criteria, and study window will be explained. With this knowledge, the 
clinicians in the ICU will be able to assist in identifying potential subjects and communicate this to the 
study team for possible enrollment. 
Screening evaluations to determine eligibility will be conducted daily by the study team based on 
chart review of documentation for new patients being admitted to the ICU with a diagnosis of 
sepsis/septic shock. Initial assessment will rely on review of admitting diagnoses as recorded by treating 
physicians, admitting medical documentation, and lab and imaging results to assess possible sources of 
infection, presence or absence of organ dysfunction, and use of invasive mechanical ventilation. Initial 
screen for inclusion/exclusion will based on chart review. For those individuals meeting criteria for 
enrollment, the subject or his/her legally authorized representative (LAR) will be contacted by a member 
of the clinical ICU team and offered the opportunity to participate in the clinical trial. This will avoid “cold 
calling” coercion that could occur if direct contact by research team members was the initial method of 
assessing willingness to enroll. If that agreement is obtained, a member of the research team will 
preliminarily introduce the study to the subject or LAR. At that time, a member of the study team will 
review other inclusion and exclusion criteria with the LAR to assess eligibility.   
 
5.2.2 Consenting process:  
The PI or a designated physician co-investigator will follow-up the preliminary discussion to 
answer any additional questions and obtain written authorization and consent for participation from 
subjects or their LAR. The investigator or a co-investigator will discuss the nature of the research study 
and study procedures with the participant or LAR inclusive of the risks and potential benefits of study 
participation. In cases where the LAR is not present in the hospital, the study will be discussed over the 
telephone. If the LAR agrees, the consent form (ICF) will be e-mailed or faxed to the number provided by 
the LAR. No research activities can start before the signed document is received from the LAR. The PI or 
any physician investigator who discussed the study by phone must sign, date, and time the consent form 
when it is received (date/time of receipt, not the date of discussion).  
Pennsylvania law defines no specific surrogate decision maker for health care. However, if consent 
is obtained from a surrogate decision maker, the basis for establishing his/her identity should be one of 
the following: Durable Power of Attorney for Health Care, next of kin, or following lines of sanguinity in 
order of relationship (i.e., court appointed guardian, spouse, natural or adoptive parent, adult child, adult 
sibling, any other available adult relative related through blood or marriage known and documented to 
have made decisions for the subject in prior health care settings). 
Rights as a research subject will be explained and ample time for the participant or LAR to review 
the consent document prior to obtaining written signature of informed consent will be given. After this 
detailed discussion of the study and conclusion of any questions, the study investigator and/or co-
investigator will obtain informed consent with documentation of the consenting process, prior to 
beginning any research activities. All participants and LARs will be informed of their right to withdraw the 
patients from study participation at any time. Additionally, enrolled patients will have the right to 
withdraw from the study once decision-making capacity is regained if the patients recover quickly from 
their acute illness (e.g. with early liberation from the ventilator while the patient is still in the study).  
After consent, the pre-entry procedures include those listed in Section 5.4.2. Pre-entry 
evaluations must be completed within 12 hours prior to study entry.  
 
5.2.3 Baseline evaluation and randomization:  

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If pre-entry evaluation is acceptable, the participant will be enrolled in the study and undergo 
baseline testing included in Section 5.4.3. At that point, the participants will be randomized to 
interventional and placebo control arms. Enrollment into interventional and placebo arms will be 
stratified at one level by the presence or absence of pre-existing self-reported diabetes mellitus utilizing 
separate randomization tables. The University of Pittsburgh Medical Center Investigational Drug Service 
(UPMC-IDS) will be responsible for randomization, blinding, and providing the study infusion at the 
bedside to the clinical team.  
 
5.2.4 Blinding:  
The UPMC-IDS will dispense investigational infusions that conceal infusion contents with an 
opaque cover, thus the treating ICU clinicians, nursing staff, and study investigators will be blinded to 
group allocation. Group allocation will remain concealed until blinding is broken after final data analysis 
is completed.  
 
5.3 Study treatment 
 
5.3.1 Treatment arms 
At study entry, the participant will be randomized into an interventional arm that will receive an 
enteral dextrose infusion or a control arm that will receive enteral free water placebo.  
 
1a: Enteral dextrose infusion: A standard solution of 50% Dextrose (0.85 kcal/mL) will be initiated 
within 48 hours of meeting sepsis criteria and will be infused at 10 mL per hour for 24 hours. For 
a participant that would have an expected daily caloric requirement of 2000 kcal per day, enteral 
dextrose infusion would deliver approximately 20% of the daily caloric need. As a reference, the 
enteral tube formulation Jevity 1.2 provides 1.2 kcal/mL and is often infused at 10 mL per hour 
upon initiation of enteral tube feeding. Thus the volume and level of delivered calories in the 
study group will be similar to the amount delivered in low level enteral tube feed formulations. 
 
1b. Placebo control: Patients in the placebo control arm will receive enteral free water at a rate 
of 10 mL per hour following randomization to control for the effects of an enteral infusion. 
Although these participants will not receive any enteral calories, a retrospective review of 
critically ill patients admitted to the Acute Lung Injury Registry at the University of Pittsburgh with 
a patient population similar to the patients we will enroll to this study revealed that (1) less than 
10% of patients receive any enteral infusions in the first 48 hours of ICU admission, (2) greater 
than 50% of calories are delivered in intravenous infusions rather than the enteral route, and (3) 
total level of caloric support in the absence of enteral feeding is approximately 10-15% of daily 
caloric needs.  
 
5.3.2 Study drug 
 
Dextrose infusion: 50% Dextrose solution will be infused via an oro/nasogastric tube by ICU 
nursing personnel per standard practices. The solution will be prepared and provided by the IDS 
and will be infused at a rate of 10 mL per hour for 24hr through a standard enteral nutrition pump. 
No additional water flushing will be necessary. Interruption/discontinuation of the infusion will 
be at the discretion of the treating physicians. Symptoms/signs of intolerance including vomiting 
or aspiration will be considered an adverse event. Gastric residuals will not be checked monitored 
in this study as they are not required per current critical care guidelines.28  

Page | 15                                                                              Protocol Version 3.1    01/24/2019 
    
 
 
5.3.3 Study duration 
Study treatment will be administered for a total of 24 hrs. Subsequent decisions for type/rate of 
enteral nutrition following the 24hrs will be at the discretion of the medical ICU team.  
 
5.3.4 Study product formulation and storage  
50% Dextrose solution and free water solution will be stored at room temperature in a dry place  
 
5.3.5 Pharmacy role 
The UPMC-IDS will be responsible for (1) preparation of 50% Dextrose and free water solutions, 
(2) randomization of participants into intervention and placebo groups, and (3) distribution of 
intervention solutions such that clinical team and investigators are blinded to group allocation.  
 
5.4 Study exams and procedures 
 
Study exams are described below and in Table 5.1.  
 
5.4.1 Initial screening (pre-consent) 
• 
Review of admission documentation in ICU and assessment of eligibility.  
 
5.4.2 Pre-entry evaluation and consent 
• 
Clinical assessment 
• 
Medical history 
• 
Informed consent 
 
5.4.3 Baseline testing and randomization 
• 
Baseline clinical variable recording 
• 
Pre-intervention capillary blood glucose measurement 
• 
Initial research blood draw (up to 4 hours prior to the start of infusion) 
• 
Aerodigestive tract samples for microbiome analyses (up to 4 hours prior to the start of infusion): 
o Oral swab 
o Tracheal aspirate (if the patient is on mechanical ventilation) 
o Gastric aspirate  
• 
Colonic tract samples for microbiome analyses (up to 4 hours prior to the start of infusion) 
o Rectal swab 
o Stool sample (if available) 
 
5.4.4 Study period 
• 
Initiation of study interventions as per protocol for 24 hrs  
• 
Hemodynamic monitoring per ICU protocol 
• 
Capillary blood glucose approximately every 6 hours 
 
5.4.5 Mid-intervention assessment 
• 
Clinical assessment by study team member to monitor status and tolerance to infusion to be 
performed 12 hours after the start of infusion +/- 4 hours 

Page | 16                                                                              Protocol Version 3.1    01/24/2019 
    
 
 
5.4.6 Intervention conclusion – End of infusion period 
• 
Second research blood draw (up to 2 hours prior to the end of infusion or ½ hour after) 
• 
Repeat aerodigestive tract samples for microbiome analyses (+/- 2 hours to the end of infusion): 
o Oral swab 
o Tracheal aspirate (if the patient is on mechanical ventilation) 
o Gastric aspirate  
• 
Repeat colonic tract samples for microbiome analyses (+/- 2 hours to the end of infusion) 
o Rectal swab 
o Stool sample (if available) 
 
5.4.7 Day 7 testing and procedures 
• 
Review of electronic medical record for length of stay and in hospital mortality 
• 
For patients still within the hospital, repeat aerodigestive and colonic tract samples for 
microbiome analyses (+/- 1 day) 
o Oral swab 
o Tracheal aspirate (if the patient is on mechanical ventilation) 
o Gastric aspirate (if a gastric/enteric tube remains in place) 
o Rectal swab 
o Stool sample (if available) 
 
5.4.8 Day 30 testing and procedures 
• 
Review of electronic medical record for clinical variables including length of stay and in hospital 
mortality 
 
 
Table 5-1. Schedule of Procedures  
 
 
Pre-
Entry 
Screen 
Baseline 
Study 
Period 
12 
hrs 
24 
hrs 
Day 7 
Day 30 
Documentation of 
Sepsis 
X 
 
 
 
 
 
 
 
Medical Review for 
Inclusion/Exclusion 
X 
X 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
Baseline Characteristic 
Measurement 
 
X 
X 
 
 
 
 
 
Clinical Assessment 
 
 
X 
 
X 
X 
 
 
Blood Glucose 
Measurement 
 
 
X 
X 
 
 
 
 
Research Infusion 
 
 
 
X 
 
 
 
 
Research Blood Draw 
 
 
X 
 
 
X 
 
 
Microbiome sampling 
 
 
X 
 
 
X 
X 
 
Review of Electronic 
Medical Record 
 
 
X 
 
 
X 
X 
X 

Page | 17                                                                              Protocol Version 3.1    01/24/2019 
    
 
 
6.0 EXPERIMENTAL PROCEDURES 
 
6.1 Screening 
 
The screening form will be completed by study personnel. Diagnosis of sepsis will be based on 
review of medical chart by criteria in 5.1.1.  
 
6.2 Clinical assessment 
 
A clinical assessment will be performed at enrollment by a study physician and subsequently by study 
personnel at designated time points, to include review of clinical diagnoses, physical exam findings, 
microbiological, clinical, and physiological and laboratory information.  
 
6.3 Study procedures 
 
6.3.1 Capillary blood glucose measurement 
Blood glucose will be monitored by capillary blood measurement for the 24 hour intervention 
period no less frequently than every six hours starting at the time of randomization in both usual care and 
intervention arms. Capillary blood glucose measurements in the ICU are obtained by fingerstick utilizing 
less than 10 microliters of blood and do not require an additional blood draw. Current sepsis guidelines 
recommend preventing hyperglycemia as part of best care practices but variability remains in glycemic 
monitoring among critically ill patients.10 We will ensure blood glucose is checked routinely at least every 
6 hours in patients enrolled in our study. If capillary blood glucoses are already ordered as part of the 
medical care in the ICU, these glucose checks will be utilized for study purposes. More frequent glycemic 
monitoring may be utilized as part of the care dictated by the medical ICU team and will not disqualify 
patient from the study. 
 
6.3.2 Research blood draws 
Blood will be drawn for plasma and serum at two time points (a) at the time of randomization and 
(b) after the completion of the intervention period. Approximately 10 mL of blood will be drawn each time 
either by venipuncture or by drawing blood from existing indwelling catheters (central venous lines or 
arterial lines) by the patient’s bedside nurse. Blood will be drawn into several tubes including serum, EDTA, 
and BD P800 collection tubes.  
 
6.3.3 Microbiome sampling 
Aerodigestive and colonic tract samples will be collected as follows at baseline, at the end of the 
infusion period, and at day 7:  
 
Oral swabs: A swab will be gently rubbed on the tongue dorsum, the hard palate, the buccal 
mucosa, and the gingiva. Specimens will be secured in a sterile tube and stored in a locked freezer 
until bacterial nucleic acid extraction procedures. The procedure will be performed twice in order 
to obtain samples for both bacterial DNA and RNA extractions.  
 

Page | 18                                                                              Protocol Version 3.1    01/24/2019 
    
 
Tracheal aspirates: Five to 10 ml of tracheal aspirates will be collected using a sterile catheter 
during endotracheal tube suctioning if the patient remains on mechanical ventilation for the study 
period. Samples are collected according to standardized protocols by trained respiratory 
therapists. Such samples are typically collected as part of routine clinical care, but are usually 
discarded. Samples will be transported immediately in wet ice. Sample aliquots are stored at -
80oC in a locked freezer until bacterial nucleic extraction procedures. 
 
Gastric aspirates: Ten to 20 ml of gastric aspirates will be collected through the existing feeding 
tube. A first sample of gastric aspirate will be collected prior to initiation of experimental 
infusions. If no gastric aspirate obtained, then instillation of approximately 20 mL of water 
through the feeding tube will be performed for suctioning an adequate amount of gastric aspirate, 
which will be placed in a sterile specimen cup and then stored at -80oC in a locked freezer until 
bacterial nucleic acid extraction procedures. At 24 hr, we will obtain a gastric aspirate of 10-20 
mL, again stored in similar fashion. At day 7, we will obtain a similar specimen if a feeding tube is 
still in place and the patient remains in the ICU.  
 
Stool samples: If stool is available, a portion of the sample will be taken and stored in a sterile 
specimen cup, as above.  
 
Rectal swabs: A swab will be gently advanced through the anal sphincter in the anal vault and 
gently rubbed on the rectal mucosa. Specimens will be secured in a sterile tube and stored at -
80oC in a locked freezer until bacterial nucleic acid extraction procedures. The procedure will be 
performed twice in order to obtain samples for both bacterial DNA and RNA extractions. 
 
7.0 CLINICAL MANAGEMENT ISSUES 
 
7.1 Definition of adverse events 
An adverse event will be defined as any unintended and unfavorable symptom or outcome during 
the 24 hour intervention period.  
 
7.1.1 Vomiting 
Vomiting in study and use of anti-emetic agents in participants will be recorded and incidence will 
be compared in intervention and placebo groups. In the event of emesis, enteral study infusion will be 
temporarily discontinued and will be restarted per ICU management guidelines for enteral infusions. 
Gastric residuals will not be monitored in this study. 
 
7.1.2 Diabetic ketoacidosis and hyperglycemia hyperosmolar syndrome (HHS) 
The development of either diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome during 
the intervention period of this study will prompt cessation of enteral infusion to allow for the strict control 
of caloric delivery required in the treatment of these syndromes.  
 
7.1.3 Ischemic bowel 
 
Ischemic bowel is a rare and potentially serious complication associated with enteral feeding 
occurring in less than 1% of patients.33 Ischemic bowel presents with intolerance to enteral feedings 
manifested by emesis, abdominal pain, or bloating and is characterized by ischemia or necrosis of the 
intestinal tissue thought to be related to diversion of blood flow to intestinal blood vessels in response to 

Page | 19                                                                              Protocol Version 3.1    01/24/2019 
    
 
enteral nutrients during periods of hypotension and shock. By utilizing only dextrose this risk is expected 
to be minimal. 
 
7.2 Reportable severe adverse events 
 
Critically ill septic patients represent a population in whom life-threatening multi-organ 
dysfunction and a high rate of untoward medical events are commonly seen routinely during their clinical 
course as part of their presenting medical condition. In an effort to document only clinically-relevant 
untoward medical events that have a greater likelihood of being study related, study endpoints (including 
level of glycemic control, incidence of emesis, incidence of hypotension) and certain pre-specified 
expected events for critically ill septic patients (see Appendix 11.3) will not be reported as serious adverse 
events if they occur during the 24-hour intervention period. Reportable serious adverse events (defined 
as fatal or immediately life-threatening or those that are permanently disabling) that are unexpected and 
are suspected to be related to study interventions will be disclosed within 24 hours to the IRB.   
 
7.3 Monitoring for adverse events 
Participants will be assessed for adverse events by both the study investigators and by the treating 
ICU team during 24 hours of study intervention. Record of adverse events in the usual care and 
intervention arms will be made available to the DSMB. 
 
7.4 Indications for study discontinuation 
 
 
The following indications will be criteria for study discontinuation: 
• 
Request by participant. 
• 
Serious adverse event related to intervention. 
• 
Medical need to hold further enteral infusions including impending intra-abdominal surgery. 
• 
Clinical evaluation by either the investigator or ICU physician that continuation of the intervention 
would be unsafe including blood glucose greater than 500 mg/dL, severe ileus, or development 
of severe abdominal pain or emesis related to study intervention. 
• 
Discretion of the investigator. 
• 
Decision by data safety and monitoring board to discontinue enrollment. 
 
7.5 Protocol adherence 
Participants in both the placebo and intervention group will be assessed to determine the (1) the 
number of interruptions in enteral study infusion and (2) total amount of time that enteral study infusion 
was successfully administered during the 24 hour intervention period.  
 
7.6 Clinical nutrition management 
The clinical ICU team will be encouraged by study investigators to avoid the use of dextrose-
containing intravenous infusions and enteral tube feed formulations during the 24 hour intervention 
period. Study infusions will not be given concomitantly with enteral tube feeds. If enteral tube feeds are 
started during the intervention period, the study infusion will be stopped and the total time the study 
infusion was delivered will be recorded. Research specimens will still be collected for these participants. 
After the 24 hour intervention period, further nutrition support (if any) will be at the discretion of the 
clinical ICU team. 

Page | 20                                                                              Protocol Version 3.1    01/24/2019 
    
 
7.7 Data Safety and Monitoring Plan (DSMP) 
The data safety and monitoring plan for this research study will be conducted by a local Data 
Safety and Monitoring Board (DSMB) that will be created to review this study. The individuals to be chosen 
for the DSMB will be free from financial and academic conflicts, will not include study investigators, and 
will have the expertise required to understand and identify any issues that would arise with the conduct 
of a clinical trial in critically ill patients. 
The DSMB will meet every six months to review: (1) trial performance with a focus on recruitment, 
(2) protocol adherence, (3) completeness of data management, and (4) trial safety. 
 
Furthermore, monthly meetings for the monitoring of individual case review will be conducted by 
the Principal Investigators and research team with review of the following items: recruitment, enrollment, 
retention, all adverse events, unanticipated problems, withdrawals and any breaches of confidentiality. A 
regular review of accrued data will be done to ensure data integrity and validity and to ensure that there 
is no change in the risk to benefit ratio of the study. Any serious or unexpected adverse events, 
unexpected problems that involve risk to the participants or others, or breaches of confidentiality will be 
reported to the Institute Review Board (IRB) in compliance with IRB Policies and Procedures. Reporting to 
the NIH will be the responsibility of the Principal Investigator and the research team. 
All Serious Adverse Event reporting to the IRB will occur within 24 hours of notification to the 
Principal Investigator and or research team for appropriate action and file reporting in accordance with 
the IRB’s stated policy for reporting adverse events. If an unexpected adverse event occurs, the 
investigators will re-assess the risk/benefit ratio of the study and submit any modifications deemed 
necessary to the IRB for approval. At the time of the IRB renewal the PI will submit in writing the 
information about the frequency of the monitoring, the dates that the monthly meetings took place, any 
external factors or relevant information that might have an impact on the safety or ethics of the study, 
and final recommendations related to the continuation, changing, or termination of the study.  
 
 7.7.1 Required education in the protection of human research participants 
Most participants are expected to have cognitive impairment at some time during the study given that 
study population was specifically selected to be high risk for delirium and long-term cognitive impairment 
due to sepsis. This vulnerable population cannot be substituted since these forms of cognitive impairment 
are the focus of our investigation. 
All participants who are enrolled when cognitively impaired will be given the opportunity to consent to 
further participation (or to withdraw) once they regain decision making capacity. Both participants and 
their authorized representatives can choose to withdraw the participant from the study at any time.   
All principal and co-investigators listed on Institutional Review Board-approved protocols at University of 
Pittsburgh are required to participate in a course entitled “The Education and Certification Program in 
Research & Practice Fundamentals (RPF)”. This web-based tutorial is a requirement of the IRB for protocol 
submission.  
The University of Pittsburgh requires registration of all principal and co-investigators on the Pitt 
CITI Access Portal. The Collaborative Institutional Training Initiative (CITI) is an organization whose goal is 
to develop and distribute high quality, peer reviewed educational resources for the research investigators. 
CITI training programs have become the de facto standard to meet Responsible Conduct of Research (RCR) 
and Human Subjects Research training requirements at most institutions in the United States. 
Certifications in Responsible Conduct of Research and Human Subjects Research (either biomedical or 
social/behavioral) are required for individuals conducting research projects involving human subjects. 
Further information on training required at the University of Pittsburgh may be found at the following 
website: http://www.rcco.pitt.edu/ResearchTrainingRequirements.htm. 
 

Page | 21                                                                              Protocol Version 3.1    01/24/2019 
    
 
8.0 DATA MANAGEMENT AND TRACKING  
 
Data collected during this randomized clinical trial will be stored on an electronic database on the 
password-protected UPMC network. Any printed documents containing relevant data from the clinical 
trial will be stored in a locked cabinet in the office of Dr. Shah in UPMC Montefiore Hospital. Dr. Shah will 
be responsible for monitoring the security and confidentiality of the database and associated protected 
health information including participant name, date of birth, and medical record number on a monthly 
basis. Quality control for the database will be performed with range checks and inspection of any outlier 
values by Dr. Shah or Dr. McVerry. 
The electronic medical record of participants will be accessed to obtain patient demographics, 
hemodynamic parameters, and laboratory and imaging results relevant to determining the severity of 
illness. The only individuals who will access identifiable medical record information are those who already 
have (or will have been given) access to the identifiable medical records, granted by the privacy office, by 
means of their job responsibilities. Dr. Shah and Dr. McVerry have legitimate access to these medical 
records as part of their clinical responsibilities.  
 
9.0 DATA COLLECTION AND STATISTICAL CONSIDERATIONS  
 
9.1 Sample size and power calculation 
 
Prior published estimates of cytokine levels in septic patients at 24 hours,61 suggest that 
recruitment of 7 patients in each group will provide 90% power to detect a 15% difference in IL-6 with an 
alpha error of 0.05 (Table 9.1). However, we will need to consider the risk of unbalanced baseline 
characteristics in our sample and allow for dropouts as well. Therefore, 36 patients will be enrolled in each 
group, which will provide greater than 90% power to detect 15% difference in IL-6.62 In our septic mouse 
model, early initiation of enteral dextrose reduced levels of IL-6 by a much larger amount (~40%) than we 
are currently powering our clinical trial. 
 
 
 
 
 
 
 
 
 
 
 
 
9.2 Proposed statistical analysis 
 
Primary statistical analysis comparing levels of pro-inflammatory cytokines will be determined by t-test 
(or non-parametric test if indicated) by intention-to-treat analysis. Differences in secondary continuous 
outcome variables between intervention and control groups will be determined by t-test or non-
parametric test as appropriate. Differences in dichotomous secondary outcomes (development of 
Table 9.1: Per Group Estimates for Detecting 
Differences in Circulating Cytokines 
Difference 
Power 
IL-6 
15% 
80% 
6 
15% 
90% 
7 
20% 
80% 
4 
20% 
90% 
5 

Page | 22                                                                              Protocol Version 3.1    01/24/2019 
    
 
hyperglycemia, in-hospital mortality, etc.) will be determined by chi-squared analysis or Fisher’s exact test 
as appropriate.  
 
10.0 COSTS AND PAYMENTS  
 
10.1 Research study payments 
 
No research payment will be provided to participants or health care proxys in this study. When principal 
investigators are unavailable, study co-investigators will aide in screening, consenting, and enrolling 
participants and will be compensated $20 for research activities. Principal investigators will not be 
reimbursed for research activities. 
 
 
 
 

Page | 23                                                                              Protocol Version 3.1    01/24/2019 
    
 
11.0 APPENDIX 
 
11.1 Modified Sepsis-Related Organ Failure Assessment (SOFA) score 
Adapted from Singer et al,62 modified to exclude assessments of liver function 
 
 
Score 
Organ System 
0 
1 
2 
3 
4 
Respiratory  
PaO2/FiO2  
Greater than or equal 
to 400 
Less than 400 but 
greater than or equal 
to 300 
Less than 300 but 
greater than or equal 
to 200 
Less than 200 but 
greater than 100, with 
respiratory support 
Less than 100, with 
respiratory support 
Coagulation 
Platelet count 
Greater than or equal 
to 150,0000 
Less than 150,000 but 
greater than or equal 
to 100,000 
Less than 100,000 but 
greater than or equal 
to 50,000 
Less than 50,000 but 
greater than or equal 
to 20,000 
Less than 20,000 
Cardiovascular 
Blood pressure 
Mean arterial pressure 
greater than or equal 
to 70 mmHg 
Mean arterial pressure 
less than 70 mmHg but 
not requiring 
vasopressor therapy 
Requiring vasopressor 
therapy with dopamine 
less than 5 μg/kg/min 
for at least 1 hour or 
dobutamine at any 
dose 
Requiring vasopressor 
therapy with either 
dopamine 5.1-15 
μg/kg/min or 
epinephrine less than 
or equal to 0.1 
μg/kg/min or 
norepinephrine 0.1 
μg/kg/min for at least 1 
hour 
Requiring vasopressor 
therapy with either 
dopamine greater than 
15 μg/kg/min or 
epinephrine greater 
than 0.1 μg/kg/min or 
norepinephrine 0.1 
μg/kg/min for at least 1 
hour 
Central nervous system 
Glasgow Coma Scale 
15 
13-14 
10-12 
6-9 
Less than 6 
Renal 
Creatinine (mg/dL) 
Less than 1.2 
1.2-1.9 
2.0-3.4 
3.5-4.9 
Greater than or equal 
to 5 
Urine output (mL/day) 
 
 
 
Less than 500 but 
greater than or equal 
to 200 
Less than 200 
 
Note: If the PaO2 is unavailable, this trial will allow for the substitution with the oxygen saturation 
(SpO2) for calculation of the SOFA score as per the table in Appendix 11.2. 
 
 

Page | 24                                                                              Protocol Version 3.1    01/24/2019 
    
 
11.2 Estimation of PaO2/FiO2 from SpO2/FiO2 
Adapted from Huang et al63 
 
SpO2 
FiO2 
0.3 
0.35 
0.4 
0.45 
0.5 
0.55 
0.6 
0.65 
0.7 
0.75 
0.8 
0.85 
0.9 
0.95 
1 
80% 
141 
127 
111 
98 
89 
81 
74 
68 
63 
59 
55 
52 
49 
47 
44 
81% 
151 
129 
113 
101 
91 
82 
76 
70 
65 
60 
57 
53 
50 
48 
45 
82% 
155 
132 
116 
103 
93 
84 
77 
71 
66 
62 
58 
55 
52 
49 
46 
83% 
158 
136 
119 
106 
95 
86 
79 
73 
68 
63 
59 
56 
53 
50 
47 
84% 
162 
139 
122 
108 
97 
89 
81 
75 
70 
65 
61 
57 
54 
51 
49 
85% 
167 
143 
125 
111 
100 
91 
83 
77 
71 
67 
63 
59 
56 
53 
50 
86% 
171 
147 
129 
114 
103 
94 
86 
79 
73 
69 
64 
61 
57 
54 
51 
87% 
177 
151 
132 
118 
106 
96 
88 
81 
76 
71 
66 
62 
59 
56 
53 
88% 
182 
156 
137 
121 
109 
99 
91 
84 
78 
73 
68 
64 
61 
58 
55 
89% 
189 
162 
141 
126 
113 
103 
94 
87 
81 
75 
71 
67 
63 
60 
57 
90% 
196 
168 
147 
130 
117 
107 
98 
90 
84 
78 
73 
69 
65 
62 
59 
91% 
203 
174 
153 
136 
122 
111 
102 
94 
87 
81 
76 
72 
68 
64 
61 
92% 
213 
182 
159 
142 
128 
116 
106 
98 
91 
85 
80 
75 
71 
67 
64 
93% 
223 
191 
168 
149 
134 
122 
112 
103 
96 
89 
84 
79 
74 
71 
67 
94% 
236 
202 
177 
157 
142 
129 
118 
109 
101 
94 
89 
83 
79 
75 
71 
95% 
252 
216 
189 
168 
151 
138 
126 
116 
108 
101 
95 
89 
84 
80 
76 
96% 
273 
234 
205 
182 
164 
149 
136 
126 
117 
109 
102 
96 
91 
86 
82 
 
 
 

Page | 25                                                                              Protocol Version 3.1    01/24/2019 
    
 
11.3 Expected Adverse Effects of Sepsis 
 
The following events are expected to occur with a reasonable frequency in the typical course of 
a critically ill patient with sepsis: 
 
Constitutional: Fever, malaise, hypothermia, chills, rigors 
 
Cardiovascular: Hypotension, arrhythmias (atrial fibrillation, atrial flutter, ventricular 
fibrillation, ventricular tachycardia), tachycardia, bradycardia, myocardial ischemia, syncope, 
shock  
 
Pulmonary: Acute lung injury, dyspnea, hypoxemia, aspiration, atelectasis, mucus plugging, 
pneumothorax, pleural effusion, pulmonary embolism 
 
Gastrointestinal: Nausea, vomiting, abdominal pain, paralytic ileus, ischemic bowel, gastritis, 
gastrointestinal bleeding, acute liver failure, pancreatitis 
 
Renal: Dysuria, urinary retention, urinary frequency, incontinence, acute kidney injury, acute 
tubular necrosis, oliguria, acute interstitial nephritis, acidosis or alkalosis, hypokalemia or 
hyperkalemia, hyponatremia or hypernatremia 
 
Hematology: Anemia, thrombocytopenia, abnormal coagulation, disseminated intravascular 
coagulation, hematoma, hemorrhage, venous thrombosis, pancytopenia 
 
Neurology: Headache, confusion, delirium, hallucinations, agitation, anxiety, critical illness 
neuropathy 
 
Musculoskeletal: Leg cramps, hemiparesis, quadriparesis, neuromuscular weakness, critical 
illness myopathy 
 
Dermatology: Rash, bruising, cellulitis, Steven-Johnson syndrome, decubitus ulcer 

Page | 26                                                                              Protocol Version 3.1    01/24/2019 
    
 
12.0 LITERATURE CITED 
 
1. 
Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology 
of severe sepsis in the United States: analysis of incidence, outcome, and associated 
costs of care. Critical care medicine. Jul 2001;29(7):1303-1310. 
2. 
Angus DC, van der Poll T. Severe sepsis and septic shock. The New England journal of 
medicine. Nov 21 2013;369(21):2063. 
3. 
Liu V, Escobar GJ, Greene JD, et al. Hospital deaths in patients with sepsis from 2 
independent cohorts. Jama. Jul 02 2014;312(1):90-92. 
4. 
Mayr FB, Yende S, Angus DC. Epidemiology of severe sepsis. Virulence. Jan 01 
2014;5(1):4-11. 
5. 
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. Feb 
1993;103(2):565-575. 
6. 
Opal SM, Fisher CJ, Jr., Dhainaut JF, et al. Confirmatory interleukin-1 receptor antagonist 
trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, 
multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. 
Critical care medicine. Jul 1997;25(7):1115-1124. 
7. 
Ranieri VM, Thompson BT, Barie PS, et al. Drotrecogin alfa (activated) in adults with 
septic shock. The New England journal of medicine. May 31 2012;366(22):2055-2064. 
8. 
Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in 
patients with severe sepsis or septic shock in whom early goal-directed therapy was 
initiated in the emergency department. Critical care medicine. Apr 2010;38(4):1045-
1053. 
9. 
Kumar A, Haery C, Paladugu B, et al. The duration of hypotension before the initiation of 
antibiotic treatment is a critical determinant of survival in a murine model of Escherichia 
coli septic shock: association with serum lactate and inflammatory cytokine levels. The 
Journal of infectious diseases. Jan 15 2006;193(2):251-258. 
10. 
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13.0 PROTOCOL AMENDMENT LOG 
 
• Version 1.0  
o Initial IRB submission: November 22, 2017. 
o Approved by Scientific Reviewer: January 4, 2018. 
o Changes requested by IRB: January 25, 2018. 
 
• Version 2.0 
o Changes in this version 
▪ Mid-Intervention Assessment added in section 5.4.5. 
▪ Indications for Study Discontinuation updated in section 7.4 to include 
clinical evaluation that continuation of the intervention is unsafe due to 
elevated blood sugar, severe ileus, or severe abdominal pain or emesis as 
criteria for discontinuation. 
▪ Required Education in the Protection of Human Research Participants 
updated in section 7.7.1 to reflect that participants are at high risk for 
delirium and cognitive impairment at the time of consent. 
o Protocol updated February 8, 2018 
o Informed Consent forms updated February 18, 2018 
 
• Version 3.0 
o Changes in this version 
▪ Exclusion Criteria (Section 5.1.2) updated to include ICU physician request 
to exclude patient based on contraindication to enteral feeding. 
▪ Study Exam and Procedures (Section 5.4) updated to include time frames 
for sample collection at pre-infusion, 24-hour, and day 7 time points. 
▪ Day 28 Testing and Procedures (Section 5.4.8) changed to Day 30 Testing 
and Procedures. 
▪ Baseline Evaluation and Randomization (Section 5.2.3) updated to reflect 
that enrollment into intervention and placebo arms will be stratified at 
one level by the presence or absence of pre-existing diabetes mellitus.  
▪ Research Payments (Section 10.1) updated to include payment for co-
investigators for screening, consenting, and enrollment activities. 
 
• Version 3.1 
o Changes in this version 
▪ Modified to reflect expansion of recruitment to the ICUs at UPMC 
Shadyside and UPMC McKeesport Hospitals in Section 5.1, Section 5.11, 
and Section 5.2.