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. Author manuscript; available in PMC: 2021 Mar 1.
Published in final edited form as: JPEN J Parenter Enteral Nutr. 2019 May 30;44(3):541–547. doi: 10.1002/jpen.1608

Rationale for and Design of the Study of Early Enteral Dextrose in Sepsis (SEEDS): A Pilot Placebo-Controlled Randomized Clinical Trial

Faraaz Ali Shah 1,2, Georgios D Kitsios 1,3, Yingze Zhang 1, Alison Morris 1,3, Sachin Yende 2,4, David T Huang 4,5, Christopher P O’Donnell 1, Bryan J McVerry 1,3
PMCID: PMC6884652  NIHMSID: NIHMS1029517  PMID: 31148210

Abstract

Background:

Sepsis is characterized by life-threatening organ dysfunction caused by a dysregulated host response to infection and affects over a million Americans annually. Loss of glycemic control in sepsis is associated with increased morbidity and mortality, and novel approaches are needed to promote euglycemia and improve outcomes in sepsis. Recent studies from our laboratory demonstrate that early low-level enteral dextrose infusion in septic mice attenuates the systemic inflammatory response and improves glycemic control by inducing intestine-derived incretin hormone secretion.

Aim:

The aim of the Study of Early Enteral Dextrose in Sepsis (SEEDS) is to test the effect of a 24-hour enteral dextrose infusion in critically-ill septic patients as a therapeutic agent to decrease systemic inflammation and promote euglycemia.

Methods:

SEEDS is a single-center, double-blind, randomized, controlled trial that will enroll 60 septic patients admitted to the intensive care units at the UPMC Health System in Pittsburgh. Participants will be randomized 1:1 to receive enteral dextrose (n=30) or water (placebo, n=30) infusion for 24 hours. The primary outcome is the circulating interleukin-6 (IL-6) level measured after the 24-hour infusion compared between dextrose and placebo groups. Secondary outcomes include post-infusion circulating insulin, incretin, and other pro-inflammatory cytokine levels, as well as incidence of hyperglycemia and hypoglycemia during the infusion period.

Discussion:

This trial will characterize the effects of early enteral dextrose on endogenous endocrine pathways and the systemic inflammatory response in sepsis. The results of this trial will inform future larger interventional studies of early enteral nutrients in critically-ill patients with sepsis.

Keywords: enteral nutrients, dextrose, sepsis, inflammation, incretin, microbiome

CLINICAL RELEVANCY STATEMENT

The Study of Early Enteral Dextrose in Sepsis (SEEDS) is a single-center double-blind placebo-controlled randomized clinical trial testing the effects of an early low-level enteral dextrose infusion on systemic inflammation in critically-ill patients with sepsis (NCT03454087). Secondary and exploratory analyses will examine the effects of early enteral dextrose on incretin release, glycemic control, and microbiome composition.

BACKGROUND

Incretin hormones are released from the intestine in response to enteral nutrients and promote insulin secretion from pancreatic beta cells in a glucose-dependent manner.1,2 Targeted interventions that potentiate incretin secretion (for example, incretin analogues or inhibitors of the dipeptidyl peptidase-IV protease) improve glycemic control in diabetic patients while minimizing the risk of hypoglycemia.3 In addition to promoting insulin release, incretin-based therapies improve insulin sensitivity in peripheral tissues, decrease systemic inflammation, and lower the risk of cardiovascular death.4,5 Due to beneficial extra-pancreatic effects, novel applications of incretin-based therapies are under investigation for several disorders including non-alcoholic liver disease and neurodegenerative disorders.6,7

Sepsis is a syndrome characterized by a dysregulated immune response to an infectious insult8, with exaggerated pro-inflammatory response early in sepsis being associated with increased organ dysfunction and lower survival.9,10 Disruption of glycemic control in sepsis is detrimental as the development of either hyperglycemia or hypoglycemia is associated with adverse outcomes.11–13 Given that incretin hormones promote glucose control with a reduced risk of hypoglycemia, they represent an attractive therapeutic target in sepsis. A recent systematic review in critically-ill and peri-operative populations demonstrated improved glycemic control and reduced need for exogenous insulin with use of incretin-based therapies.14 In preclinical septic models, acute administration of incretin-based therapies attenuates inflammation and improves survival.15,16 Furthermore, our laboratory recently demonstrated that provision of early low-level enteral dextrose infusions stimulates endogenous incretin hormones in endotoxemic mice resulting in increased insulin secretion, improved glycemic control, and decreased cytokine release.17 The Study of Early Enteral Dextrose in Sepsis (SEEDS) will test the hypothesis that an early low-level enteral dextrose infusion initiated in acutely septic patients will attenuate the systemic inflammatory response as evidenced by decreased circulating interleukin (IL)-6 (Figure 1). SEEDS will also characterize the effects of early enteral dextrose on insulin and incretin secretion, on glycemic control, and on other pro-inflammatory cytokines in secondary analyses.

Figure 1.

Figure 1

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Conceptual Model of the Effects of Early Enteral Dextrose on Incretin Release and Systemic Inflammation in Critically-Ill Septic Patients. GIP, Glucose-Dependent Insulinotropic Peptide; GLP-1, Glucagon-Like Peptide-1; GLP-2, Glucagon-Like Peptide-2; IL-6, Interleukin-6.

As an exploratory analysis, the SEEDS trial will examine the effects of enteral dextrose on the composition of the host microbiome. Disruption of a “healthy” gut microbiome in critical illness is associated with a loss of commensal microbiota resulting in increased susceptibility to pathogens and dysregulated immune responses.18,19 As the effects of early enteral nutrients in the setting of sepsis are unclear, the SEEDS trial will examine the effects of early enteral dextrose on microbiome composition in concert with effects on incretin hormone release and inflammation.

METHODS

Trial Design

SEEDS is a single-center randomized double-blind placebo-controlled trial testing the effect of an early enteral infusion of dextrose in critically-ill patients with sepsis. The trial protocol was approved by the Institutional Review Board (IRB) at the University of Pittsburgh (PRO17010532). The trial protocol is designed to be compliant with both the Consolidated Standards of Reporting Trials (CONSORT) and the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 statements.20,21

Participants

Screening

Screening evaluations to determine eligibility will be conducted daily by study investigators and clinical research coordinators in the Multidisciplinary Acute Care Research Organization (MACRO) at the University of Pittsburgh based on chart review of new patients being admitted to an intensive care unit (ICU) in the UPMC Health System in Pittsburgh. Initial screen for inclusion and exclusion will rely on review of admitting diagnoses consistent with sepsis or septic shock 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, presence or absence of a nasogastric or orogastric tube, and use of invasive mechanical ventilation. For individuals meeting eligibility criteria, the potential participant or his or her legally authorized representative will be contacted by a member of the treating intensive care unit team and offered the opportunity to participate in a clinical trial. If that agreement is obtained, a member of the research team will introduce the study to the subject or legally authorized representative and will review other inclusion and exclusion criteria to finalize eligibility.

Inclusion Criteria:

We plan to enroll patients 18 years of age or older admitted to an ICU at the UPMC Health System within 48 hours of meeting criteria for sepsis as defined by a confirmed or suspected infection and an increase from baseline in a modified Sepsis-Related Organ Failure (SOFA) score of greater than or equal to 2 points [modified to exclude the criteria for bilirubin and neurologic status as liver function tests and Glasgow Coma Scale (GCS) are not uniformly obtained for septic patients at the UPMC Health System]. When baseline SOFA scores for an organ system are unknown, we will assume the score is 0, consistent with current sepsis definitions.8 We plan to enroll only participants with available enteral access defined by (1) an existing nasogastric or orogastric tube, (2) an existing percutaneous endoscopic gastrostomy (PEG) tube, or (3) imminent plans to place a nasogastric or orogastric tube.

Exclusion Criteria:

We will exclude patients who: (1) are already receiving enteral tube feeds prior to the start of the intervention infusion because pre-existing enteral nutrients will confound our results; (2) present with diabetic ketoacidosis or diabetic hyperosmolar hyperglycemic syndrome as the tight control of caloric intake that is required will be challenging in a blinded study testing enteral dextrose; (3) are expected to survive less than 24 hours (the duration of the infusion); and (4) patients who are unable to tolerate enteral infusions based on the clinical assessment of the treating provider.

Interventions

At study entry, participants will be randomized 1:1 to receive either an enteral dextrose or enteral water infusion (Figure 2). For patients randomized to the intervention arm, 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 a rate of 10 mL per hour for 24 hours (total: 120 grams of dextrose in 240 mL, similar to the amount of calories delivered by carbohydrates in an equivalent volume of standard tube formulations at UPMC Health Systems). For patients randomized to the placebo control arm, water will be infused at a rate of 10 mL per hour to control for the potential effects of volume on the secretion of incretin hormones from enteroendocrine cells.

Figure 2.

Figure 2

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Schedule of Procedures for the Study of Early Enteral Dextrose in Sepsis.

Study procedures:

Baseline Characteristics:

Study investigators will collect the following pre-randomization baseline variables for each participant from the electronic medical record in a deidentified manner: age, gender, race, body mass index, presence or absence of diabetes mellitus (determined by self-report and/or by review of electronic medical record for inpatient and outpatient diagnoses and any available hemoglobin A1c levels), SOFA score, complete blood count, basic metabolic panel, and lactate.

Capillary blood glucose management.

Blood glucose will be monitored by capillary blood measurement (Precision Xceed Pro, Abbott Diabetes Care Ltd.) during the 24-hour intervention period no less frequently than every six hours starting at the time of the start of infusion in both intervention and placebo arms. More frequent glycemic monitoring may be utilized as part of the care dictated by the treating ICU team. Corrective insulin use, if any, will be at the discretion of the treating clinical team and not study investigators.

Research blood draws.

Blood will be drawn for plasma and serum collection at two time points (prior to the start of the investigational infusion and at the end of the infusion period) for measurement of proinflammatory cytokine and endocrine hormone levels (insulin, C-peptide, glucagon, hemoglobin A1c [pre-infusion only], and incretins).

Microbiome sampling.

Noninvasive samples that capture microbial communities across the aerodigestive tract, including oral swabs, tracheal aspirates, gastric aspirates, and stool (or rectal swabs), will be collected for determination of microbiome composition at the following time points: (1) after randomization and prior to the start of infusion, (2) at the end of the 24-hour infusion period, and (3) seven days after the start of infusion if the patient remains within the ICU.

Clinical nutrition management – common to both arms.

The clinical intensive care unit team will be encouraged by study investigators to avoid the use of dextrose-containing intravenous infusions or enteral tube feed formulations during the 24-hour intervention period. Study infusions will be held for nausea or vomiting, for increased gastric residuals, or for any diagnostic testing at the discretion of the clinical team. 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 will be at the discretion of the treating ICU team.

Outcomes

Primary:

The primary outcome will be circulating levels of the pro-inflammatory cytokine IL-6 measured at the end of the 24-hour infusion compared between the intervention and placebo groups. We chose IL-6 as the primary outcome because of its correlation with mortality and disease severity in sepsis22–24 and its importance in the dysregulated glucose metabolism noted in diabetes mellitus25,26, as well as findings from our preclinical studies that suggested that changes in incretin hormones induce changes in IL-6.17

Secondary:

Pre-specified secondary outcomes include: (1) differences between groups in glycemic control during the 24-hour intervention period as determined by regular capillary blood glucose measurements; (2) differences in insulin, C-peptide, glucagon, and the incretins glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-1 levels at the completion of the infusion; (3) differences in other pro-inflammatory cytokines (e.g.- interleukin (IL)-1β and tumor necrosis factor (TNF)-α); (4) change in pro-inflammatory cytokines compared to pre-infusion values, and (5) differences in patient-centered clinical outcomes including incidence of emesis, intensive care unit and hospital length of stay, and in-hospital mortality measured up to 30 days after the start of investigational infusion.

Exploratory:

Pre-specified exploratory outcomes include changes in the community structure of the aerodigestive microbiome comparing enteral dextrose and placebo groups based on 16S ribosomal RNA sequencing.

Sample size determination:

Based on prior published estimates of circulating cytokines in critically-ill septic patients at 24 hours (mean IL-6 ± standard error: 627 ± 13 pg/mL)27, we estimate that recruitment of seven patients in each arm will provide 90% power to detect a 15% difference (94 pg/mL or higher) between groups in IL-6 levels with an alpha error of 0.05. In this study, we plan to enroll 30 patients in each arm to minimize the risk of unbalanced baseline characteristics.28 Of note, in our septic mouse model, early initiation of enteral dextrose reduced levels of IL-6 by ~40%.17

Randomization

Participants will be randomized by the Investigational Drug Service (IDS) at UPMC Health System in 1:1 fashion to receive either dextrose or placebo infusion by a computer-generated sequence. Randomization will be stratified by the presence or absence of pre-existing diabetes mellitus as determined by patient interview or by review of the electronic medical record. Block size will be unknown to treating physicians and investigators. Investigational infusions will be dispensed by the IDS and utilized in a concealed manner, thereby blinding study participants, intensive care unit providers, nursing staff, and study investigators to group allocation. Investigators will remain blinded to group allocation until completion of the final data analysis.

Statistical methods

Primary statistical analysis will compare levels of the pro-inflammatory cytokine IL-6 measured after the 24-hour infusion between intervention and placebo groups in an intention-to-treat analysis with a two-sided alpha of 0.05.

Secondary analyses will include determination of differences in other pro-inflammatory cytokines and circulating incretin hormone levels, incidence of hypoglycemia and hyperglycemia during the 24-hour intervention period, and clinical outcomes including ICU and hospital length of stay, as well as in-hospital mortality measured at 30 days after the start of the infusion. Standard analytic methods will be applied. Continuous variables will be compared by t-test or Mann-Whitney U test as appropriate. Dichotomous variables will be compared by chi-squared analysis or Fisher’s exact test. Analyses comparing changes from baseline values will be performed as an analysis of covariance with post-infusion values as the outcome and covariate adjustment for pre-infusion values. Results for secondary outcomes will be presented with 95% confidence intervals and will be adjusted for multiple comparisons.

For exploratory analyses with microbiome samples and derived 16S rRNA gene sequences, ecological analyses of alpha diversity (richness-Shannon and evenness-Dominance), beta diversity (Bray-Curtis dissimilarity index) and taxonomic compositions of samples will be performed before and after the 24-hour infusion. Non-parametric statistical comparisons of alpha and beta-diversity metrics will be performed between baseline and follow-up microbiome samples for each body site (at 24 hours and 7 days post-infusion) and ordination methods for visualization of taxonomic differences will be utilized.

Data safety monitoring plan:

A local Data Safety and Monitoring Board (DSMB) comprised of individuals who do not include study investigators and are free from financial and academic conflicts has been assembled for study monitoring. 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, and will issue recommendations as appropriate to the continuation, modification, or termination of the study. Any reportable serious adverse events (defined as fatal, immediately life-threatening, or permanently disabling) that are unexpected and are suspected to be related to study interventions will be disclosed within 24 hours to the IRB and the DSMB. No interim analysis is planned for this pilot study.

Publication of results:

Trial results will be disseminated in accordance with the Recommendations for Conduct, Reporting, Editing, and Publication of Scholarly Work by the International Committee of Medical Journal Editors (ICMJE) and will be reported as per the Consolidated Standards of Reporting Trials (CONSORT) statement guidelines.20

DISCUSSION

The Study of Early Enteral Dextrose in Sepsis (SEEDS) is designed to test the effects of enteral dextrose as a therapeutic strategy to decrease systemic inflammation and promote euglycemia. This study is a bench-to-bedside translation of preclinical findings in murine models of sepsis demonstrating that early low-level enteral dextrose attenuates the pro-inflammatory cytokine response and improves glycemic control.17

The SEEDS trial is novel in its focus on endogenous stimulation of incretin hormones in sepsis. Incretin-based therapies have revolutionized the care of patients with diabetes mellitus4,29,30, and preclinical studies demonstrate anti-inflammatory effects of incretins and suggest benefits in septic animal models.16,31–34 Early clinical trials of exogenous incretin administration to critically ill patients have demonstrated beneficial effects on glycemic control 35,36, and in this trial we extend those observations to test whether endogenous incretin stimulation can be targeted through provision of enteral dextrose. We hypothesize that increasing circulating incretins using enteral dextrose will decrease systemic inflammation. We will specifically enroll septic patients during a time frame in which enteral nutrition is often deferred due to concerns about need for resuscitation but may improve hemodynamic stability. Furthermore, SEEDS will provide information on the effects of enteral dextrose on microbial community structure in septic patients. The change in the host microbiome in response to early enteral nutrition in critical illness is an area of ongoing research37, and prior studies in healthy individuals have demonstrated that the intestinal microbiome shifts within days in response to dietary changes.38 Given that commensal microbiota rely mainly on availability of enteral nutrients for their survival, critical illness places them in an acute starvation state when the host is not enterally fed.19 In such starvation states, pathogenic bacteria can sense the depletion of carbohydrates in the gastrointestinal tract and proliferate, increase their virulence, and even change the microenvironment to their benefit.39,40 We hypothesize that low-level enteral dextrose may prevent disruption of commensal microbiota by providing an exogenous energy supply and may reduce virulence of enteral pathogens.41 Thus, SEEDS will provide new insights on the modulation of inflammatory pathways, incretins, and microbiome composition in response to enteral nutrients specifically in septic patients.

Finally, we chose to focus on only enteral dextrose as opposed to other nutrients in our clinical trial to directly translate findings from our preclinical studies.17 Lipids and amino acids also stimulate incretin release from enteroendocrine cells but have not been characterized in settings of critical illness and may be a focus of future studies.1 Of note, some studies have suggested that increased protein delivery in the first week of critical illness may be associated with decreased likelihood of ICU discharge and higher mortality in critically ill patients42–44, and utilizing dextrose alone may obviate potential risks with early amino acids. We considered including a third arm in SEEDS that would receive either usual care or tube feeds, but were resource limited in this initial pilot study. However, the lack of a third arm will not limit our ability to understand the mechanisms of inflammation and incretin release as proposed in this clinical trial. We also plan to obtain blood samples at additional time points in future studies to better characterize the longitudinal course of systemic inflammation in response to early enteral dextrose. While the primary outcome of this study is focused on the acute effects of dextrose infusion on inflammation, the results from secondary outcomes including incidence of dysglycemia, ICU and hospital length of stay, and in-hospital mortality will be informative for the design of future larger interventional studies in critically-ill septic patients.

Conclusions

In this study, we propose an interventional trial to test the therapeutic effects of early enteral dextrose on inflammation and glycemic control in septic patients admitted to the intensive care unit. Our study utilizes a low-cost intervention during the most acute phase of illness and will provide important information on the effects of early enteral dextrose on inflammatory and endocrine pathways in septic patients.

Acknowledgements:

We acknowledge Denise Scholl, Mary Stefanick, and the staff of the Multidisciplinary Acute Care Research Organization (MACRO) at the University of Pittsburgh for their work in protocol development, regulatory assistance, screening, and recruitment for this clinical trial. We thank Kathryn Nauman for her assistance with the figures for this manuscript. Most importantly, we thank the patients and their family members for their participation in SEEDS with the hope that the information learned will help improve the care delivered to future patients.

Funding: This trial is funded by grants from the National Institutes of Health: K23 GM122069 (FS), K23 HL139987 (GDK), P01 HL114453 (CPO, BJM). Statistical support was provided by the Clinical and Translational Science Institute at the University of Pittsburgh through the National Institutes of Health Grant UL1-TR-000005.

Footnotes

Clinical Trial Registration: This trial is registered on ClinicalTrials.gov under identifier NCT03454087 as of March 5, 2018 with the full trial protocol (version 3.1 on January 24, 2019).

Trial Status: Enrolling.

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