key: cord-0905244-4ob2gkmr
authors: Shah, Faraaz Ali; Kitsios, Georgios D.; Yende, Sachin; Dunlap, Daniel G.; Scholl, Denise; Chuan, Byron; Al-Yousif, Nameer; Zhang, Yingze; Nouraie, Seyed Mehdi; Morris, Alison; Huang, David T.; O’Donnell, Christopher P.; McVerry, Bryan J.
title: A Pilot Double-Blind Placebo-Controlled Randomized Clinical Trial to Investigate the Effects of Early Enteral Nutrients in Sepsis
date: 2021-10-08
journal: Crit Care Explor
DOI: 10.1097/cce.0000000000000550
sha: 3907937746bf19f152f2b4352a516846ea96ce0c
doc_id: 905244
cord_uid: 4ob2gkmr

Preclinical studies from our laboratory demonstrated therapeutic effects of enteral dextrose administration in the acute phase of sepsis, mediated by the intestine-derived incretin hormone glucose-dependent insulinotropic peptide. The current study investigated the effects of an early enteral dextrose infusion on systemic inflammation and glucose metabolism in critically ill septic patients. DESIGN: Single-center, double-blind, placebo-controlled randomized pilot clinical trial (NCT03454087). SETTING: Tertiary-care medical center in Pittsburgh, PA. PATIENTS: Critically ill adult patients within 48 hours of sepsis diagnosis and with established enteral access. INTERVENTIONS: Participants were randomized 1:1 to receive a continuous water (placebo) or enteral dextrose infusion (50% dextrose; 0.5 g/mL) at 10 mL per hour for 24 hours. MEASUREMENTS AND MAIN RESULTS: We randomized 58 participants between June 2018 and January 2020 (placebo: n = 29, dextrose: n = 29). Protocol adherence was high with similar duration of study infusion in the placebo (median duration, 24 hr [interquartile range, 20.9–24 hr]) and dextrose (23.9 hr [23–24 hr]) groups (p = 0.59). The primary outcome of circulating interleukin-6 at end-infusion did not differ between the dextrose (median, 32 pg/mL [19–79 pg/mL]) and placebo groups (24 pg/mL [9–59 pg/mL]; p = 0.13) with similar results in other measures of the systemic host immune response. Enteral dextrose increased circulating glucose-dependent insulinotropic peptide (76% increase; 95% CI [35–119]; p < 0.01) and insulin (53% [17–88]; p < 0.01) compared with placebo consistent with preclinical studies, but also increased blood glucose during the 24-hour infusion period (153 mg/dL [119–223] vs 116 mg/dL [91–140]; p < 0.01). Occurrence of emesis, ICU and hospital length of stay, and 30-day mortality did not differ between the placebo and enteral dextrose groups. CONCLUSIONS: Early infusion of low-level enteral dextrose in critically ill septic patients increased circulating levels of insulin and the incretin hormone glucose-dependent insulinotropic peptide without decreasing systemic inflammation.

C urrent guidelines recommend initiation of early enteral nutrition for critically ill patients, but the mechanisms through which early enteral nutrition may improve outcomes in these patients remain unclear (1, 2) . Proposed beneficial effects of enteral nutrition include preservation of mucosal integrity of the intestinal tract, prevention of bacterial translocation, and reduction in critical illness-induced catabolism (3, 4) , but the effects of enteral nutrition on metabolic and inflammatory pathways specifically in septic populations are not well established. A potential mechanism by which enteral nutrition may improve outcomes is through its effects on incretins (5, 6) . The intestine-derived incretin hormones glucosedependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are released in response to enteral nutrients and increase insulin release in a glucose-dependent manner, thereby preventing hyperglycemia with a theoretical lower risk of hypoglycemia compared with exogenous insulin (7, 8) . Incretins also exert pleiotropic anti-inflammatory effects and, in preclinical sepsis studies, incretin analogs attenuate systemic inflammation, decrease organ injury, and improve survival (6, (9) (10) (11) . Exogenous incretin analogs have been tested in critically ill patients in trials of glycemic control but have not translated into clinical practice (12, 13) . Promotion of the incretin axis by enteral nutrients in sepsis may exert similar therapeutic effects.

In prior preclinical studies, we demonstrated that low-level enteral dextrose infusion in mice exposed to endotoxin improved glucose disposal, increased insulin release, decreased insulin resistance, and decreased systemic inflammation dependent on endogenous increases in the incretin hormone GIP (14) . Similarly, enteral dextrose promoted euglycemia and improved survival in a murine model of Klebsiella pneumoniae (15) . We conducted the Study of Early Enteral Dextrose in Sepsis (SEEDS) to translate our preclinical findings to the bedside and test the effects of an early low-level enteral dextrose infusion in critically ill septic patients. We hypothesized that enteral dextrose would increase incretin hormones, promote euglycemia, and decrease systemic inflammation compared with a placebo control.

SEEDS was a pilot single-center randomized placebo-controlled clinical trial testing an early enteral dextrose infusion in critically ill patients with sepsis (ClinicalTrials.gov registration number NCT03454087). Details of the design and rationale have been previously published (16) . The trial protocol was approved by the University of Pittsburgh Institutional Review Board (PRO17010532, STUDY19080314) and funding was provided by the National Institutes of Health (K23GM122069). SEEDS was coordinated through the Multidisciplinary Acute Care Research Organization at the University of Pittsburgh in accordance with the Declaration of Helsinki. An independent data safety and monitoring board met prior to trial launch and every 6 months thereafter to monitor for complications and provide recommendations for continuing, modifying, or stopping the trial. Investigators remained blinded to group assignment for participants until completion of data analysis in October 2020. The authors are accountable for data accuracy and completeness and for trial fidelity to the protocol. All data are reported in concordance with Consolidated Standards of Reporting Trials guidelines (17) .

SEEDS enrolled adult participants 18 years old or older presenting with sepsis in an ICU at an academic tertiary-care medical center in Pittsburgh, PA (UPMC Presbyterian Hospital). Participants were enrolled within the first 48 hours of meeting sepsis criteria defined as a confirmed or suspected infection with an increase from baseline of two or greater in the Sequential Organ Failure Assessment (SOFA) score in accordance with Sepsis-3 guidelines (18) . A modified SOFA score was used for screening purposes that excluded the bilirubin and neurologic criteria since liver function tests and Glasgow Coma Scale are not uniformly obtained for septic patients at our institution. We included patients with established enteral access defined by the presence of a nasogastric or orogastric tube, imminent plans to place a nasogastric or orogastric tube, or an existing percutaneous gastrostomy tube. We excluded patients who had already started enteral nutrition, were receiving treatment for diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome at the time of screening, or were deemed unable to tolerate enteral infusions by the treating team. Written informed consent was obtained directly from participants or from legally authorized representatives.

Participants in SEEDS were randomized 1:1 into intervention and placebo arms. We stratified enrollment the presence or absence of self-reported diabetes mellitus, using separate randomization tables generated by the UPMC Investigational Drug Service. We had considered enrolling only nondiabetic patients in SEEDS to more directly test our preclinical findings since diabetic patients can demonstrate both attenuated increases in incretins in response to enteral nutrients as well as decreased insulin secretion in response to GIP (19) (20) (21) but chose to prioritize recruitment of a sample representative of the population of critically ill septic patients treated at our institution. Investigational infusions were dispensed with an opaque cover to conceal contents. Participants and bedside clinicians remained blinded to group allocation throughout the study.

All participants underwent a preinfusion research blood draw no more than 2 hours prior to the start of investigational infusion. Subsequently, participants received an investigational infusion of either 50% dextrose (intervention) or free water (placebo) at 10 mL per hour for 24 hours via an existing enteral access tube using a standard infusion pump. The carbohydrate content provided from enteral dextrose over 24 hours (~400 kcal) was similar to that in most enteral tube feed formulations at trophic levels (~10-20 cc/ hr) and was consistent with the level of caloric support provided in our preclinical studies (~10-40%) (14, 15) . Capillary blood glucose was monitored every 6 hours with more frequent monitoring by the clinical team permitted if indicated. Corrective insulin use, if any, was at the discretion of the clinical team. Investigational infusions were paused as needed for clinical care. Gastric residuals were not monitored as part of the study, and any decision to interrupt or discontinue investigational infusion was made by treating clinicians. Initiation of enteral nutrition by the clinical team during the infusion period prompted cessation of investigational infusion. Administration of medications during the infusion period that could influence glucose metabolism (e.g., propofol and IV dextrose) or systemic inflammation (e.g., glucocorticoids) was recorded (22, 23) . Notably, although IV dextrose does not directly stimulate incretin release, the magnitude of incretin release could be influenced by circulating blood glucose levels (8, 24) . A second research blood draw was performed 24 hours after the start of infusion. After completing the infusion period, further nutrition support was at the discretion of treating ICU clinicians. Review of electronic medical records continued for 30 days following the start of infusion for clinical outcomes.

The primary outcome was circulating levels of interleukin-6 (IL-6) measured 24 hours after the start of infusion. Prespecified secondary outcomes included: 1) glycemic control during the infusion period including occurrence of hypoglycemia (defined by any blood glucose less than 70 mg/dL) and hyperglycemia (any blood glucose greater than 180 mg/dL), 2) circulating endocrine hormone levels (insulin, C-peptide, GIP, and GLP-1), 3) other measures of the host immune response (interleukin-1 receptor antagonist [IL1ra], tumor necrosis factor receptor 1 [Tnfr1], suppressor of tumorigenicity 2 [ST2], procalcitonin, and pentraxin-3), 4) occurrence of emesis during the infusion period, and 5) clinical outcomes including hospital and ICU length of stay and inhospital mortality measured at 30 days after the start of infusion. Cutoff for hyperglycemia was selected based on the Surviving Sepsis guidelines (25) as well as local thresholds for the use of corrective insulin at our institution. Since cutoffs to define hyperglycemia have varied widely in critical care studies (26) (27) (28) (29) , in post hoc analyses, a range of cutoffs were tested. Both insulin and C-peptide levels were tested as the former may be influenced by exogenous insulin administered during clinical care. Measures of the host immune response were chosen based on previous studies supporting associations of the selected pathways with hyperglycemia (28, (30) (31) (32) (33) .

At each time point, 10-mL blood was collected by bedside nursing staff into serum, EDTA, and P800 tubes (BD Biosciences, Catalog Number 366420, San Jose, CA), the latter containing a proprietary cocktail of protease inhibitors to improve accuracy in the measurement of incretin hormones (34) . Samples were processed within 60 minutes of collection. Samples were centrifuged for 10 minutes at 800 × g at either room temperature (EDTA tubes) or at 4° (P800 tubes). All samples were aliquoted and stored at -80°C until final analysis. A custom Luminex panel was used to measure IL-6, Tnfr1, ST2, pentraxin-3, and procalcitonin in EDTA plasma samples (Fisher-Scientific, Waltham, MA). A Meso Scale Discovery U-plex panel was used to measure insulin, C-peptide, GIP, GLP-1, and IL-1ra in P800 plasma samples (Meso Scale Discovery, Rockland, MD). Biomarker analysis were performed www.ccejournal.org

October 2021 • Volume 3 • Number 10 using a Bio-Plex 100 Analyzer (Bio-Rad, Hercules, CA) according to the manufacturers' instructions.

In primary statistical analyses, we assessed IL-6 measured 24 hours after starting investigational infusion compared between the intervention and placebo groups in an intention-to-treat analysis by the Wilcoxon rank-sum test. Based on published estimates of circulating cytokines in critically ill mechanically ventilated patients (35), we estimated seven patients per arm would provide 90% power to detect a 15% difference between the groups in IL-6 levels with an alpha error of 0.05. We planned to enroll 30 participants in each arm to decrease the risk of unbalanced covariates between the groups (36) . In secondary analyses, we compared continuous variables measured during the infusion period and at the 24-hour time point by Wilcoxon rank-sum test and compared dichotomous variables with Fisher exact test. We assessed changes in endocrine hormones and in measures of the host response from baseline values by analysis of covariance (ANCOVA) with postinfusion values as the outcome and covariate adjustment for preinfusion values. We chose the ANCOVA approach to understand changes in continuous variables based on literature suggesting its superiority over comparisons of the absolute differences in randomized controlled trials (37, 38) . CIs for ANCOVA estimates were generated from bootstrapped analyses utilizing 500 iterations. Results for secondary analyses involving biomarkers were adjusted for multiple comparisons by the method of Simes (39) . Post hoc analyses explored differences between the groups in biomarkers stratified by diabetic status. Ventilatorfree days were calculated at 30 days from the start of investigational infusion with a value of 0 assigned to participants who died before 30 days consistent with prior studies (40) . Survival was visualized with Kaplan-Meier curves and analyzed by log-rank test.

From June 2018 to February 2020, 1,054 patients were screened for eligibility of which 186 met eligibility criteria (eFig. 1, Online Supplement, http://links.lww. com/CCX/A814). Of these, a total of 58 of a target 60 patients were successfully enrolled and underwent randomization; one patient had clinical decompensation with rapid increases in vasopressor requirements prior to the start of investigational infusion and was not included in the analyses of biomarkers but was included in analyses of clinical outcomes. The SEEDS trial ended in March 2020 before completion of target enrollment secondary to shutdown of research operations during the coronavirus disease 2019 pandemic. Of the 58 randomized participants, median age was 60.9 years (interquartile range, 50.4-70.7), 32 were male (55%), and 50 were White (86%). Twenty-five participants (43%) had preexisting diabetes, and median admission modified SOFA score (excluding the neurologic and liver components) was 7 (6-9). Pneumonia was the most common infection (74%). Baseline characteristics were similar between the groups ( Table 1) .

Median duration of investigational infusion was 24 hours (20.9-24 hr) in the placebo group and 23.9 hours (23-24 hr) in the enteral dextrose group (p = 0.59). In terms of concomitant medications that could affect inflammation or glucose metabolism, we found similar use of propofol, glucocorticoids, and exogenous IV dextrose (used only as carriers for IV medications in enrolled patients) between the groups (Supplementary Table 1 , http://links.lww.com/CCX/A814). Two patients in each group had infusions stopped due to emesis (p > 0.99). One patient in the enteral dextrose group was switched from investigational infusion to enteral tube feeds when an insulin drip was started for euglycemic ketoacidosis. No patients developed mesenteric ischemia.

The primary outcome of circulating IL-6 measured 24 hours after the start of infusion did not differ between placebo (median, 24 pg/mL [interquartile range, 9-59 pg/mL]) and enteral dextrose (32 pg/mL ) groups (p = 0.240). In secondary analyses, IL-1ra, Tnfr1, ST2, and procalcitonin were also similar between the groups (Supplementary Table  2 , http://links.lww.com/CCX/A814). Pentraxin-3 measured at the end of infusion was increased in the enteral dextrose group (4,825 pg/mL [2,065-9,895 pg/mL]) compared with placebo and results were consistent in both nondiabetic and diabetic participants (Fig. 2) . p = 0.001) during the infusion period were similarly increased in the enteral dextrose group; however, amount of corrective insulin administered did not differ between the groups (p = 0.132). A trend toward increased occurrence of hyperglycemia (defined by any blood glucose above 180 mg/dL during the infusion period) was observed in the enteral dextrose group (55.2% vs 32.1%; p = 0.068), with consistent results at other cutoff thresholds that reached statistical significance in post hoc analyses. Two patients in the placebo group (7.1%) developed hypoglycemia compared with one patient in the enteral dextrose group (3.5%; p = 0.487). At the 24-hr time point, participants in the enteral dextrose group had higher circulating GIP (1,396 pg/mL [764-1,973] vs 581 [267-838]; p = 0.004) and higher insulin levels (158 [86-215]; p = 0.036) compared with the placebo group. GLP-1 and C-peptide at the 24-hour time point did not differ significantly between the groups (Supplementary Table  5 , http://links.lww.com/CCX/A814). After adjustment for preinfusion values, enteral dextrose significantly increased GIP, insulin, and C-peptide levels compared with placebo (Fig. 3) . Post hoc analyses suggested consistent effects of enteral dextrose on increasing GIP regardless of diabetic status but also potential blunting of increases in insulin and c-peptide in diabetic participants (Supplementary Table 5 

All randomized participants (n = 58) were included in intention-to-treat analyses of clinical outcomes regardless of receipt of investigational infusion. Ventilatorfree days, ICU length of stay, and hospital length of stay did not significantly differ between the placebo and enteral dextrose groups (Supplementary Table 7 , http://links.lww.com/CCX/A814). At 30 days after the start of infusion, seven participants each had died in placebo (24.1%) and enteral dextrose (24.1%) arms with no significant differences in survival (p = 0.98; eFig. 2, http://links.lww. com/CCX/A814).

The potential role of incretins and incretin-based therapies has recently been highlighted as a priority research goal for studies of nutrition and metabolism in critically ill patients (5) . Prior randomized controlled trials have tested exogenous incretin-based therapies in critically ill patients with results suggesting reduced hyperglycemia; however, the prior trials used continuous IV infusions of incretins at supraphysiologic levels, which may be impractical in clinical practice (12, 13, 41) . In this pilot randomized clinical trial, we investigated whether delivery of enteral nutrients could promote endogenous incretin release in septic patients with similar therapeutic benefits. We demonstrated that an early low-level enteral dextrose infusion increased circulating levels of the incretin GIP as well as insulin and c-peptide but did not decrease circulating IL-6 or hyperglycemia compared with a placebo control. The findings from SEEDS contrast the preclinical studies from our laboratory that informed the trial (14, 15) , where infusion of enteral dextrose in septic mice increased GIP and endogenous insulin, resulting in euglycemia rather than the trend toward hyperglycemia observed in SEEDS. Despite the increase in GIP, enteral dextrose did not reduce circulating IL-6 in contrast to findings in the preclinical models. Notably, the variability in IL-6 observed in SEEDS was higher than the published estimates that informed our sample size calculations; thus, larger studies may be needed to definitively rule out differences. Clinical outcomes did not differ between intervention and placebo groups in SEEDS, but the study was underpowered in this regard as the focus of this pilot trial was the characterization of the physiologic response to enteral nutrients.

The challenges of translating findings from preclinical sepsis studies to clinical trials are well documented (42, 43) . In preclinical studies, animals are exposed to identical insults with identical biospecimen collection to improve rigor and reproducibility of results. In contrast, in clinical trials, inciting insults vary, and timing from sepsis onset is never certain. Variability in age, demographics, comorbidities, and in the host response may all contribute to differential responses to a therapeutic intervention (44) . Most relevant to SEEDS are the differences in response to enteral dextrose by diabetic status, whereby diabetic patients demonstrated a blunted endogenous insulin response despite increases in GIP. Incretin resistance, in particular to GIP, has been well documented in diabetic and obese patients (19, 20) , and GLP-1 (which was not increased by enteral dextrose) may be required for beneficial effects of incretins in septic patients. Full enteral nutrition (which includes lipids, amino acids, and complex carbohydrates) might promote GLP-1 but was not tested in SEEDS given limited safety data on its use in septic shock prior to study launch. Since then, a single-center pilot trial of 49 patients with septic shock demonstrated the safety of trophic enteral feeds compared with no nutrition with reductions in ICU length of stay (45) . The potential contributions of GLP-1 to the therapeutic effects of enteral nutrition (if any) remain unknown. Additionally, although several pilot trials have tested the effects of exogenous GLP-1 infusion or GLP-1 analogs in mixed populations of critically ill patients and demonstrated reductions in hyperglycemia (6, 12, 13, (46) (47) (48) , no large multicenter trial of incretin-based therapy has as yet been completed though conduct of such a trial has been encouraged in a recent research statement (5) . Importantly, our pilot study has several strengths including the use of a placebo control, maintenance of blinding and allocation, good protocol adherence, and successful randomization with minimal imbalances between the groups despite the small sample size. Few critical care studies have used a randomized clinical trial framework to understand how biomarker profiles change in response to nutritional strategies (49, 50) , and studies of nutrition specifically in septic populations are rare (51) .

In this pilot trial, we demonstrated the feasibility of pairing an enteral intervention with specimen collection to understand changes in molecular pathways in response to nutrition in a translational bench to bedside study. We propose that future studies in critically ill septic patients similarly incorporate biomarker collection to understand mechanistic changes in response to nutritional support, to better characterize why patients differ in response to nutrition, and to inform strategies to better individualize care.

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We thank coinvestigators Ali Al-Khafaji, Arun Rajaratnam, Nauman Farooq We also thank the ICU nurses at UPMC Presbyterian Hospital for their generous support of the SEEDS trial and the care for their patients. Most importantly, we thank the patients and families that participated in SEEDS with the goal of advancing scientific knowledge.