Enteral nutrition in septic shock: A pathophysiologic conundrum

Abbreviations ASPEN American Society for Enteral and Parenteral Nutrition EBF epithelial barrier function EN enteral nutrition ESPEN European Society for Parenteral and Enteral Nutrition GI gastrointestinal ICU intensive care unit IL-1β interleukin 1β IL-6 interleukin 6 NE norepinephrine NOBN nonocclusive bowel necrosis PN parenteral nutrition RCT randomized controlled trial SCCM Society of Critical Care Medicine SSC Surviving Sepsis Campaign TJ tight junction TNF-α tumor necrosis factor-alpha INTRODUCTION

Septic shock causes >5 million deaths worldwide and is defined as a subset of sepsis in which underlying microcirculatory and cellular abnormalities emanating from an inflammatory and immune response to an infectious pathogen are profound enough to substantially increase mortality.1 Clinically, septic shock manifests as hypotension requiring vasopressor support and lactic acidosis.1 Early recognition followed by prompt initiation of antimicrobial provision, fluid resuscitation, and supportive care measures remains the cornerstone of management. Short of these interventions, few therapies exist for septic shock.2

Respiratory failure necessitating mechanical ventilation is common in septic shock, which necessitates artificial nutrition support, a key component of supportive care. Meta-analyses of randomized controlled trials (RCTs) comparing early (within 24–48 h) enteral nutrition (EN) with standard of care (ie, no or delayed EN) in mixed populations of critically ill patients have shown early EN is associated with fewer infectious complications and reduced mortality.3 Thus, early EN is recommended by multiple nutrition societies for the general critically ill patient unable to maintain volitional intake.3-5

However, the overall role, timing, and dose of EN in septic shock remain less clear. On the one hand, septic shock represents a form of hemodynamic instability, and introducing luminal nutrients into a gut at risk for hypoperfusion increases the risk of gut-related complications, including the most grave consequence of nonocclusive bowel necrosis (NOBN).6 On the other hand, mortality from septic shock exceeds 50%, and death is often preceded and caused by multiple organ dysfunction syndrome, which derives, in part, from impaired gut epithelial barrier function (EBF), which EN has been shown to preserve.7-10 Hence, clinicians struggle with the decision to start EN in the early acute phase of critical illness when patients are in shock.

This narrative review will (1) describe the pathophysiologic conundrum septic shock poses for EN initiation, (2) outline guideline-based recommendations for EN in septic shock, (3) identify the role of parenteral nutrition (PN) in septic shock, and (4) identify postguideline studies evaluating the role, timing, dose, and titration of EN in septic shock.

WHAT IS THE PATHOPHYSIOLOGIC CONUNDRUM OF INITIATING EN IN SEPTIC SHOCK?

Septic shock is a form of vasodilatory shock with dysregulated and heightened inflammation and immune responses that contribute to gut dysfunction. A brief review of the pathophysiology of vasodilatory shock and associated gut dysfunction will shed light on the conundrum faced by clinicians regarding EN initiation.

Septic shock causes widespread vasodilation, which reduces systemic oxygen delivery via reduced relative effective circulatory volume and leads to widespread cellular and tissue hypoxia.11 Early in septic shock, blood flows away from the nonessential splanchnic circulation toward vital organs like the brain and heart. In small-intestinal villi, arterial blood flows towards the villus tip (apex).7 Venous blood flows toward the base. In circulatory shock, in which blood oxygen levels are lower than in homeostasis, the villus tip is the last portion to receive oxygen, rendering it susceptible to ischemia and sloughing, which impairs EBF. A vicious cycle is created when systemic inflammation, often observed in sepsis and septic shock, increase inflammation-inducing cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β). These cytokines impair EBF via multiple mechanisms, including mucosal thinning, epithelial cell apoptosis, and reduced gene expression of tight junction (TJ) proteins.7, 12, 13 In a review of 15 studies, Vermette et al concluded urinary concentration of TJ Zona occludens proteins and claudins stratified by sepsis severity, with higher urinary concentrations suggesting greater severity of disease and gastrointestinal (GI) injury.14 In turn, impaired EBF activates gut-derived proinflammatory responses, worsening systemic inflammation.

The conundrum faced by clinicians is as follows: introducing luminal nutrients into a (hypoperfused) gut of a patient with septic shock may increase enterocyte workload without sufficient oxygen delivery to meet the demand needed for adenosine triphosphate–dependent absorption, which can produce cellular ischemia and increase the risk of gut-related complications. NOBN, which carries a mortality in excess of 80%, is the most serious gut-related complication.15 In addition, when luminal nutrients are introduced into a hypoperfused gut, blood may be redistributed into the splanchnic circulation, a phenomenon known as splanchnic “steal.” Increased gut blood flow may be at the expense of systemic perfusion, which is already compromised in circulatory shock, and may clinically manifest as increased cellular hypoxia, lactate production, and increasing vasopressor dose.

On the other hand, septic shock represents a critical illness–defining condition in which patients are propelled into the early acute phase of critical illness, which is punctuated by unbridled catabolism and proteolysis (which contribute to energy debt and acquired sarcopenia, respectively) and heightened inflammation (which contributes to gut epithelial barrier dysfunction and gut dysbiosis). Epithelial barrier dysfunction and dysbiosis serve to generate gut-derived inflammation. In the early acute phase of critical illness, EN has been shown to preserve EBF via multiple animal model–derived mechanisms, including (1) increased Paneth cell function, (2) goblet cell secretion of defensins, (3) increased TJ protein production, (4) enterocyte proliferation, and (5) reversing gut dysbiosis.12, 16

Human data evaluating the impact of EN on EBF are limited to non–critically ill patients. Buchman et al showed commencing EN after a period of deprivation in eight healthy human volunteers restored small-bowel mucosal thickness and villus height, resolved intestinal edema, and reduced intestinal permeability.17 Ralls et al found bowel that received enteral nutrients had significantly greater EBF, as measured by transepithelial resistance and immunofluorescence staining, compared with unfed bowel. There are limited human data on the impact of EN in septic shock. In an ancillary study of the NUTRIREA-2 trial (discussed in detail below), in which more than two-thirds of patients had septic shock, Piton et al aimed to determine the effect of enterally and parenterally delivered nutrition on gut mucosa by measuring plasma citrulline, a marker of enterocyte mass and function.18 Patients randomized to early (full-dose) EN, as compared with PN, had significantly higher plasma citrulline concentration on intensive care unit (ICU) day 3 (median 18.7 [13.4–29.2] vs 15.3 [9.8–21.2]) micromoles/L, which suggests early EN is associated with greater preservation of EBF.19

WHAT DO GUIDELINES RECOMMEND FOR EN IN SEPTIC SHOCK?

The Surviving Sepsis Campaign (SSC) International Guidelines for managing patients with sepsis and septic shock and major nutrition society guidelines provide recommendations for nutrition support in sepsis and septic shock. In 2008, the SSC International Guideline did not provide recommendations for nutrition support.20 In the 2012 SCC guideline, a section outlining recommendations for initiating oral nutrition and EN was introduced, and by the 2017 SCC guideline, additional RCT-level data allowed for recommendations on the modality, timing, and dose of nutrition in sepsis and septic shock.2, 21 Despite evolution of the SSC guidelines, low- and moderate-quality evidence inform (weak) recommendations for early EN in mechanically ventilated patients with sepsis and septic shock.2

Among nutrition society guidelines, the 2016 American Society for Enteral and Parenteral Nutrition (ASPEN) and Society of Critical Care Medicine (SCCM) and the 2019 European Society for Parenteral and Enteral Nutrition (ESPEN) critical care nutrition guidelines provide disparate recommendations for EN in septic shock. The ASPEN/SCCM guideline recommends, based on expert consensus, to withhold EN during hemodynamic instability and until the patient is adequately resuscitated and to cautiously consider EN initiation in patients undergoing withdrawal of vasopressor support.3 The 2019 ESPEN guideline states, “In patients with septic shock receiving vasopressors or inotropes, no evidence-based answer can be proposed as no interventional studies have been reported to date.”5

WHY NOT SIMPLY USE PN IN CIRCULATORY SHOCK?

Based on the discussion thus far, if there is risk for harm and a lack of robust data to inform guideline recommendations for EN in septic shock, why not simply use early exclusive PN, which may thwart gut-related complications and provide energy to reduce energy debt and protein to optimize nitrogen balance? Historically, PN in critically ill patients has been associated with more infectious and metabolic complications, as compared with EN, and ASPEN/SCCM and ESPEN critical care nutrition guidelines continue to recommend early EN over PN in critically ill patients.3, 5 However, evolving critical care practices have led to improved central venous catheter care and enhanced glycemic control. Two large contemporary multicenter pragmatic trials (CALORIES and NUTRIREA-2) have compared early PN with EN in critically ill patients.22, 23 Relevant to feeding in shock, the NUTRIREA-2 trial asked, “In mechanically ventilated critically ill patients in circulatory shock (receiving vasopressor), does intervention with early PN, as compared to early EN, improve all-cause 28-day mortality?” The study was powered for a 28-day all-cause mortality benefit with early PN. Under concealed allocation and in a 1:1 manner, NUTRIREA-2 randomized 1202 patients (two-thirds in septic shock) to early EN and 1208 to early PN and found no difference in 28-day all-cause mortality between early EN and PN (37% in EN vs 35% PN, P = .33).23 However, the early EN group, as compared with PN, had more vomiting (34% vs 24%, P < .0001), diarrhea (36% vs 33%, P = .009), bowel ischemia (2% vs <1%, P = .007), and colonic pseudo-obstruction (1% vs <1%, P = .04).23 More GI complications in the early EN group may be the result of introducing full-dose early EN (17.8 kcal/kg/day) into critically ill patients with predominant septic shock on an average norepinephrine (NE) dose >0.50 mcg/kg/min. NUTRIREA-2 patients were randomized to early full-dose EN; however, clinical trials evaluating the impact of lower doses of EN on EBF are lacking.

Although there is not a consensus definition of high dose, a patient receiving an NE dose >0.5 mcg/kg/min is often considered to be in refractory shock.24 Thus, adverse GI events in patients who received early EN may be related to providing full-dose EN in patients with refractory shock. More data are needed to compare EN doses in hemodynamically unstable patients. Overall, the results of NUTRIREA-2 and recent meta-analyses comparing early EN with PN demonstrate early PN may be a safe option when early EN will not or cannot be provided.

WHAT IS THE CLINICAL EVIDENCE FOR INITIATING EN IN SEPTIC SHOCK?

Evidence for early EN in septic shock must first demonstrate safety, tolerance, and clinical efficacy. A recent review of all published human observational and RCT-level data that provided EN in circulatory shock found the gravest consequence, NOBN, occurred at a rate of 0.3%.15 Among the observational studies, no cases of NOBN were reported in the three evaluating EN in septic shock,25-27 septic shock patients tolerated up to 70% goal energy,25 patients tolerated EN up to an NE dose of 0.14 mcg/kg/min,27 and early EN (compared with no or late EN) was associated with improved outcomes such as duration of mechanical ventilation.26

Other observational studies, not exclusively in septic shock patients, noted safety, tolerance, and associated improved clinical outcomes with EN in circulatory shock.28-33 In a large observational study evaluating outcomes of mechanically ventilated patients with circulatory shock receiving early vs late EN, Ohbe et al found bowel ischemia occurred in 21 of 8606 (0.2%) patients who received early EN and 50 of 17,216 (0.3%) patients who received late EN.34 Approximately one-third of patients had septic shock. Early EN, as compared with late EN, was associated with lower 28-day mortality in patients on low- (<0.1 mcg/kg/min) and medium-dose (0.1–0.3 mcg/kg/min) NE.34

Five prospective observational studies have evaluated the influence of EN on gut blood flow in adult patients with circulatory shock.15 Of these, three studies were conducted in patients with septic shock.15 Two findings are worth noting. First, all studies reported improved splanchnic blood flow and hepato-splanchnic energy balance. Second, 0 (of 269) patients developed NOBN. One retrospective study evaluating the change in vasopressor dose after EN initiation in patients with septic shock did not find a significant difference in the change in NE dose in patients receiving trophic or full-dose EN.35

Since 2011, seven RCTs with at least one EN arm have enrolled patients with circulatory shock.22, 23, 36-40 Two of seven trials (REDOX and NUTRIREA-2) had circulatory shock as an inclusion criteria, and nonocclusive mesenteric ischemia occurred in 0.3% and 2% in those receivingEN, respectively.23, 38, 41 More recently, a single-center pilot RCT evaluated the feasibility of delivering early EN in mechanically ventilated patients with septic shock.41 Thirty-one patients were randomized under concealed allocation to early trophic EN or no EN. The study was deemed feasible with >90% protocol compliance. As compared with "no EN," the early trophic EN group had less vomiting over the first 7 days (20% vs 56%, P = .038), more ventilator-free days (27 vs 14 days, P = .009), and more ICU-free days (25 vs 12 days, P = .014).41

For now, barring contraindications to EN (eg, bowel obstruction, gut-derived sepsis awaiting source control), initiating low-dose (eg, trophic) EN may be reasonable in adequately resuscitated patients with septic shock, although larger RCT-level data are needed to inform the efficacy of this strategy and explore mechanisms for the postulated gut benefits of early EN in septic shock.

WHAT IS THE CLINICAL EVIDENCE FOR TITRATING EN DOSE IN SEPTIC SHOCK?

The 2016 ASPEN/SCCM guideline indicated getting the general critical care patient at high nutrition risk to goal energy within 48 h, whereas the more recent 2019 ESPEN guideline suggests restricted (eg, hypocaloric) feeding during the acute phase of critical illness with increase to 80%–100% by ICU day 3. Unfortunately, it is unclear when patients transition between the early and late acute phases and chronic phase of critical illness. Phasing critical illness based simply on duration of ICU stay may lead to, for example, missed opportunities to optimize nutrition when patients transition out of the acute phase or inadvertent and rapid increase in EN rate during the acute phase of critical illness, which may be detrimental to those at risk of enteral feeding intolerance, refeeding syndrome, and uncontrolled hyperglycemia. For those at risk of complications from rapid titration of EN, the best evidence for restricting energy intake with slow titration during the first week of critical illness comes from a multicenter RCT from Australia and New Zealand. Doig et al randomized critically ill patients with refeeding syndrome, defined by a serum phosphate level of <0.65 mmol/L within 72 h of starting nutrition, to protocolized energy restriction or standard of care. Nutrition dose titration in the restricted-energy group was guided by serum phosphate levels. The standard-of-care group had four times the hourly energy target as the restricted-energy group over the first 48 h. More patients were alive at day 60 in the protocolized restricted-energy group, as compared with the standard-of-care group (78% vs 91%, P = .002). Seventeen of 331 (5%) randomized patients had sepsis at baseline, which limits generalizability of study findings in patients with sepsis and septic shock.

There is no direct evidence on how to adjust EN rate in patients with septic shock. Three multicenter RCTs (EDEN, PERMIT, and TARGET) that included patients with septic shock compared lower with higher EN doses during the first week of critical illness and found no difference between the two strategies, which suggests that maintaining restricted-energy EN during the first week of critical illness may be reasonable; however, until further data are available to guide which patient phenotype benefits from faster up-titration (without acquiring aforementioned complications), a tailored approach to EN titration, based on clinical parameters (eg, defervesce, reduced vasopressor dose) to determine when patients transition between the phases of critical illness, may be reasonable.

CONCLUSIONS

Septic shock characterizes the early acute phase of critical illness, which is typified by hyperinflammation with gut dysfunction and dysbiosis. Even though major critical care nutrition guidelines agree on early EN for the general critical care patient unable to maintain volitional oral intake, the role and optimal timing and dose of EN in septic shock are less clear. Fear of serious complications, such as NOBN, may prevent clinicians from initiating EN in patients with septic shock; however, the lack of EN may be detrimental for the EBF. Despite more GI complications observed in the NUTRIREA-2 study, which may have been a consequence of early full-dose EN in refractory shock, pooled data from observational studies and contemporary RCTs that evaluated EN in circulatory shock suggest NOBN is rare, at a rate of 0.3%. Furthermore, EN has been tolerated and associated with improved outcomes across multiple observational studies. A single-center pilot RCT found trophic dose EN was safe and tolerated and generated signals for clinical benefit. Until further data are available, starting low-dose (trophic) EN in critically ill patients with septic shock (during the acute phase of critical illness) may be reasonable, to reap the EBF-preserving effect of EN. Unfortunately, when patients transition between the early and late acute and then chronic phases of critical illness remains unclear, and until further data are available, EN titration based on weighing risk factors for complications against the benefits of greater nutrition dose is reasonable.

CONFLICT OF INTEREST

None declared.

AUTHOR CONTRIBUTIONS

Jayshil J. Patel contributed to conception/design of the research; Jayshil J. Patel, Anuj Shukla, and Daren K. Heyland contributed to acquisition, analysis, or interpretation of the data; Jayshil J. Patel drafted the manuscript; Jayshil J. Patel, Anuj Shukla, and Daren K. Heyland critically revised the manuscript; and Jayshil J. Patel, Anuj Shukla, and Daren K. Heyland agree to be fully accountable for ensuring the integrity and accuracy of the work. All authors read and approved the final manuscript.

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