Early enteral nutrition in critically-ill patients

Abstract

Critically ill patients have a variety of complex pathologies and are in a multifarious state of catabolism supplanted by external and internal factors. Early enteral nutrition (EEN) is defined as the initiation of enteral feeding within 24-48 hours of hospitalization. Previous studies show the benefits of EEN include supporting the healing process through preservation of the gut mucosa, modulation of the immune response, and suppression of inflammation. However, recent studies suggest the advantages of EEN may not be as robust as previously believed. This review aims to discuss the outcomes of EEN when used in different critical care settings while managing complex disease states such as burns, sepsis, pancreatitis, and upper gastrointestinal bleeding. Evidence indicates that EEN has a positive impact on patient outcomes, hospital costs, length of intensive care unit stay, and preventing complications.

Key Words: Enteral nutrition; Intensive care unit; Adult; Nutrition; Early enteral nutrition; Critically-ill; Parenteral nutrition

Core Tip: Early enteral nutrition (EEN), initiated within 48 hours of intensive care unit admission, demonstrates significant benefits across various critical care settings. This review highlights the role of EEN in reducing mortality, infections, and intensive care unit length of stay among patients with severe burns, sepsis, gastrointestinal bleeds, acute pancreatitis along with patients in critical cardiac, respiratory and neurological disease states. EEN also modulates immune responses, supports gut integrity, and decreases stress-related complications. Although some recent studies question EEN’s efficacy, the overall evidence supports its adoption as a standard care practice for critically ill patients to enhance recovery without substantial adverse effects.

INTRODUCTION

Early enteral nutrition (EEN) is defined as the initiation of enteral feeding within 48 hours of hospital admission[1]. Critically ill patients in intensive care units (ICUs) generally cannot acquire nutrition on their own due to factors such as being heavily sedated, intubated, or too weak to chew. They require supplemental nutrition which is most commonly administered through enteral tube feeds. The earliest concept of enteral feeds extends as far back as 400 B.C when Greek physicians fed patients wine, milk, wheat and broth through the rectum. Max Einhorn, a pioneer of duodenal feeds delivered through a tube, criticized rectal feeding which caused excess irritation and had limited absorption[2]. To date there have been rapid advances in all aspects of enteral nutrition including the delivery systems, types of feeds used with the ability to alter nutritional composition and timing of initiation of feeding. Studies have shown that the desired intake of enteral nutrition was successful in only about 52% of total feeding days of patients in the ICU, with average protein intake at 54% and total energy intake at 66%, showing the need for more intense focus on nutrition[3]. EEN has been studied extensively and found to have many physiologic and economic benefits. The physiologic benefits have been summarized in Table 1. The economic benefits of EEN are attributed to a reduction in the length of ICU stay with swift time to downgrading level of care and decreasing length of hospitalization. This may be due to an overall reduction of complications associated with prolonged illnesses. According to one study, this translates to a decreased average in hospital cost by 14462 dollars per patient[4].

Table 1 A summary of studies exploring the effect of early enteral nutrition in burns patients on a variety of outcomes including intensive care unit length of stay, infection rates and mortality rates.

Ref.	Type of study	Study population	Outcomes
Wasiak et al[20], 2006	Cochrane analysis	-	No difference in all-cause mortality
			No difference in ICU length of stay
			No difference in adverse outcomes
Fuentes Padilla et al[21], 2019	Systematic review	-	No difference in mortality
			No difference in GI complications
Shahi et al [22], 2021	Retrospective review	132 pediatric burns patients	EEN has shorter length of ICU stay
			No difference in GI and infectious complications
Castanon et al[23], 2020	Retrospective RCT	324 geriatric burns patients with TBSA of 31%	EEN associated with lower mortality risk
			EEN had shorter length of ICU stay
Mosier et al[24], 2011	Retrospective cohort analysis	229 burns patients with TBSA of 46%	Early feeding associated with shorter ICU length of stay
			EEN had decreased wound infection rates
Yang et al[25], 2024	Systematic review	1066 severely burned patients	Decreased mortality in EEN
			EEN had less GI and infectious complications
			EEN had shorter length of stay

RCT: Randomized controlled trial; TBSA: Total body surface area; ICU: Intensive care unit; GI: Gastrointestinal; EEN: Early enteral nutrition.

Figure 1 summarizes the physiological benefits of EEN[5-9]. The opinions of the scientific community towards EEN have generally been positive based on studies demonstrating improved outcomes and its role in promoting early recovery in the critically ill. However, more recent studies have challenged these ideas by finding a lack of impact of EEN on patient outcomes and suggesting EEN may even harm the patient[10,11]. One of the most recent studies to be published is the NEED trial, a large multi-center study which did not find any reduction in mortality with earlier initiation of enteral nutrition[12]. The aim of this review article is to summarize the existing literature regarding the use of EEN in various critical care settings and elucidate the effects of EEN on critically ill patients.

Figure 1 Summary of the physiological benefits of early enteral nutrition. EEN: Early enteral nutrition; GALT: Gut-associated lymphoid tissue; IgA: Immunoglobulin A; CRP: C-reactive protein.

EARLY FEEDING IN SEVERE BURNS

Severe burn injury is defined as a burn affecting over 40% of a person’s total body surface area (TBSA). These injuries push the body into an accelerated hypercatabolic state which may last for several months and is a hallmark of thermal injury. A study conducted by Hart et al[13] found that patients’ net protein balance and lean mass were in a catabolic state up to 9 months post-burn injury. The stress response in severe burns was described as an initial ebb phase followed by a flow phase. In the ebb phase, there is an attenuation of perfusion to the tissues that lasts 2-3 days. The flow phase follows and is the period with the highest risk of fatality in patients[14]. Studies show that the body releases a storm of inflammatory cytokines and free radicals in response to severe burns. The body also experiences an adrenergic surge that is primarily driven by catecholamines such as cortisol and glucocorticoids. These are the primary drivers of muscle breakdown and catabolism[15]. Despite an increase in insulin production there is a concomitant hepatic resistance to the hormone along with peripheral resistance in muscles to glucose uptake. When coupled with the elevated stress hormones this leads to impaired glucose metabolism and potentially to stress-induced diabetes. Severe burns induce profound cardiovascular dysfunction, manifesting as reduced cardiac output and myocardial depression due to inflammatory cytokines and fluid shifts, leading to a hyperdynamic circulatory state. These acute effects can precipitate long-term cardiac complications, including heart failure and arrhythmias[16]. Several studies conducted in the last century demonstrate that EEN has a profound effect on the recovery of burns patients through various mechanisms. An early notable study conducted by Mochizuki et al[17] on guinea pigs which were subjected to 30% TBSA burns, and measured urinary vanillyl mandelic acid excretion, plasma cortisol, and glucagon, found that immediate post-burn feeding can help mitigate the hypermetabolic state generated by the body. The International Society for Burns Injury practice guidelines recommend that enteral feeds be initiated as soon as possible, provided there are no contraindications affecting delivery of the feeds to the gut such as short bowel syndrome, gastrointestinal (GI) fistulas, or bowel obstruction[18]. The nutritional requirement in burn patients depends on many variables such as age, TBSA covered by burns and gender. This calorie requirement is divided among carbohydrates, fats, and protein, and is supplemented with amino acids and vitamins. There are many formulas that have been generated after calculating the metabolic utilization in burns patients[19]. In the 21^st century, a pinnacle systematic review by Wasiak et al conducted by Cochrane analysis evaluated three randomized controlled trials (RCTs) which used early enteral feeds exclusively in burn patients and compared this to delayed feeds. A variety of factors were assessed including all-cause mortality, length of hospital stays, infection frequency, and adverse events, along with secondary factors including inflammatory markers and weight[20]. They found there was no difference in all-cause mortality between the groups with a relative risk (RR) of 0.74 (P = 0.59). They also noted there was no difference in overall length of stay in the ICU (P = 0.81). Additionally, there was no difference in the number of antibiotic days between EEN and delayed enteral nutrition. Finally, the study found no difference in the number of adverse outcomes [diarrhea, aspiration or need for total parenteral nutrition (TPN)]. However, this analysis included a very small number of studies and there was a paucity of data available[20]. A more recent systematic review conducted by Fuentes Padilla et al[21] analyzed 7 RCTs and found there was unclear evidence supporting EEN over delayed nutrition. In comparing early vs delayed nutrition, there was no difference in mortality risk (RR = 1.00; 1 study, 38 participants; very low-quality evidence). They also did not identify a notable difference in GI complications (RR = 0.84; 59 participants; very low-quality evidence). They also identified one study with low quality of evidence that revealed a longer length of stay in EEN (median of 15 days) compared to a delayed enteral group (median of 12 days)[21]. Shahi et al[22] evaluated EEN in 132 pediatric burns patients and found an improvement in outcomes via a retrospective study. The study found the EEN group had a shorter length of ICU stay vs the delayed nutrition group. Patients in the EEN group also had less underfeeding compared to the delayed group. However, there was no statistical difference in GI complications, infectious complications, and total length of hospital stay[22]. Castanon et al[23] compared the timing of enteral nutrition in geriatric burns patients and a total of 324 patients were studied with a mean TBSA of 31%. Patients receiving EEN were found to have a lower risk of mortality (15.6 vs 26.1% P = 0.044). They were also found to have a shorter length of ICU stay (13 days vs 17 days P = 0.042). These findings allowed them to conclude that EEN improved outcomes[23]. Mosier et al[24] analyzed a cohort of 229 burns patients with a TBSA of 46% ± 18%. Patients fed early did have a shorter ICU length of stay (40.7 vs 52.5 days, P = 0.03) and decreased wound infection rates (54.5% vs 80%, P = 0.01). Their findings remained the same even after adjusting for factors such as age[24]. A larger more recent study was conducted by Yang et al which analyzed 1066 severely burned patients. They found more promising results favoring EEN. They found a reduction of mortality in patients receiving EEN [odds ratio (OR) = 0.39, P = 0.004]. They also found a decrease in the incidence of GI complications (OR = 0.18, P < 0.00001). EEN reduced the length of hospital stay with a mean decrease of -12.08 days (P < 0.00001). They also showed a decrease in the occurrence of sepsis/infection (OR = 0.40, P = 0.0005)[25]. These studies provide evidence that the use of EEN in patients with severe burn injury promotes better outcomes. These benefits are a result of many physiological factors that interplay with the complex metabolic state of burns patients. These benefits are summarized in Table 1.

EARLY FEEDING IN SEPSIS

Sepsis is classically defined as a condition in which there is life-threatening organ dysfunction as a result of dysregulated host response to infection. When there is an infection in the body, pathogen-associated molecular patterns commence an initial immune response. Pathogen-associated molecular patterns are recognized by the body’s receptors and lead to the release of several pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-1, IL-6 and IL-17. In sepsis, this response becomes massive, causing a cytokine storm. This has been attributed to the imbalance between T helper 17 (Th-17) and regulatory T (Treg) cells, which serve to secrete inflammatory and anti-inflammatory cytokines, respectively[26]. The excessive inflammation results in severe endothelial dysfunction with subsequent hypoperfusion. There is also activation of the coagulation cascade resulting in disseminated intravascular coagulation producing further hypoperfusion and ischemia. In addition, mitochondrial dysfunction aggravates tissue injury by decreasing energy perfusion. All these factors contribute to organ dysfunction that is a hallmark of sepsis. The systemic hypoperfusion can manifest as a sequela of any injury. The global health burden of sepsis is extensive, with an incidence of nearly 58 out of every 100000 admitted to the ICU. Of this, nearly 42% of patients expire in the hospital, indicating the severity of the disease and need to manage these patients in a rapid and aggressive way[27]. In 2016, the Surviving Sepsis Campaign by the Society of Critical Care Medicine recommended the initiation of EEN with feeds beginning as soon as possible[28]. The current guidelines for their 2021 Surviving Sepsis campaign recommends enteral feeds be initiated within 72 hours of the diagnosis of sepsis[29]. Despite the lack of strong evidence to support the recommendations, EEN is encouraged as there are no detrimental effects to patients. Liu et al[30] analyzed data on 63 patients admitted to the ICU for sepsis of which 35 received EEN within 48 hours of admission to the ICU while 28 received delayed enteral nutrition (DEN). They found that 28-day mortality in the EEN group was 37.14% vs 42.86% for the DEN group. However, this was not statistically significant (P = 0.261). They did find a statistically significant decrease in length of ICU stay in the EEN vs the delayed group (12.89 vs 15.89 days; P < 0.05). The study also identified the unique finding of a decrease in Th-17 cells, which secrete IL-17, a major cytokine causing excessive inflammation in sepsis in the EEN group. Treg cells are involved in modulating inflammation and it was found that the EEN group had a slight decrease in these cells with better control of inflammation as compared to the delayed nutrition group[30]. Another study was conducted by Sun et al[31] on 53 septic patients admitted to the ICU, of which 26 received EEN (within 24-48 hours of admission) and delayed nutrition (after day 4 of admission). They did not find any difference in the 28-day mortality between the EEN and delayed nutrition group (P = 0.728). Similar to Liu et al[30], they found a significant decrease in the length of ICU stay in the EEN group (8.31 ± 4.26 vs 11.22 ± 5.43; P = 0.035). Patients in the EEN group had a significantly lower Th-17 cell percentage on the 7^th day of admission compared to that in the delayed group (P = 0.002). However, they did not identify a significant difference in Treg cells[31]. Patel et al[32] conducted a study on patients with septic shock admitted to the ICU on pressor support. In the EEN group (15 patients), feeding was initiated within 24 hours, provided up to 600 kcal/day while on vasopressors and advanced after vasopressor discontinuation. In the delayed group (16 patients), enteral feeding was delayed until vasopressors were stopped for at least 3 hours, then started and gradually advanced. Physicians could opt to start EN after 48 hours but were encouraged to wait until vasopressors were no longer needed. While this study was carried out to show the feasibility of initiating feeds on pressor support, they did have some notable findings. The EEN group had 25 ICU-free days as compared with the delayed group (P = 0.014). The EEN group had 27 ventilator-free days, compared with 14 in the delayed group (P = 0.009)[32]. Jiang et al[33] performed a secondary analysis of an acute GI grade study for patients with sepsis. The study included 163 patients, who were divided into the EEN group (85 patients) with enteral nutrition within 24 hours and the delayed group (78 patients) with enteral nutrition after 24 hours. They found that the patients in the EEN group had lower 28-day (28.2% vs 43.6%, P = 0.041) and 60-day mortality rates (36.5% vs 52.6%, P = 0.039) than those in the delayed group. However, contrary to previous studies, they found the length of ICU stay in the EEN group was longer than in the delayed group (11 vs 10 days; P = 0.022)[33]. From these studies, it can be assumed that EEN provides beneficial outcomes and offers no significant harm as compared to delayed nutrition in patients with sepsis. Therefore, initiation of early feeds in critically ill septic patients is recommended.

EARLY FEEDING IN UPPER GI BLEEDING

Upper GI bleeding (UGIB) is a very common medical emergency with an extremely high incidence of severe complications and high risk of mortality if not managed properly. Nearly 117 out of every 100000 ICU patients developed an UGIB, with inpatient costs nearing 7125 dollars on average per UGIB[34]. The mortality rate of UGIB is staggering, reaching nearly 10% in patients hospitalized for UGIB and as high as 26% in patients who are hospitalized for other causes[35]. UGIBs in the ICU usually manifest in two ways. The first involves patients who are on mechanical ventilation. These patients may develop UGIB due to stress-induced gastropathy. Multiple small ulcers or erosions form in the fundus of the stomach causing mild blood loss. They are painless and asymptomatic. The second scenario involves a patient with a severe UGIB that is moved to the ICU after undergoing endoscopy. There are a variety of causes, including Mallory-Weiss tears, peptic ulcers, gastritis, or variceal bleeds. The blood loss in these patients is often high enough to cause symptomatic hypotension, hypovolemia and shock.

Figure 2 shows the types of GI bleeds based on location. The etiology of UGIB helps guide the initiation of enteral feeds. In stress-induced gastropathy, EEN is initiated and may even help prevent further bleeding. In massive UGIBs, feeds are often held to prevent the risk of rebleeding. This delay in initiation of feeds stems from the idea that intragastric pH is critical to controlling bleeds as clot formation over ulcers requires optimal pH[36]. Pepsin is one of the main proteolytic enzymes that causes breakdown of these stabilizing clots and is inactivated at a pH > 4.5. Feeding causes an increase in secretion of gastric acid leading to a decrease in pH, activating pepsin and causing further bleeds. However, it was found that there was a minimal effect of enteral nutrition on gastric pH[36]. With the introduction of acid suppressive agents (proton pump inhibitors and H2-antagonists), it was found that enteral feeds do not lead to change in gastric pH[37]. This implies that the initiation of EEN soon after endoscopy is not harmful and may even be beneficial. A study conducted by Lo et al[38] in 2015 on 70 cirrhotic patients with acute variceal bleeding managed with band ligation compared patients who received EEN (4 hours post-banding) and delayed nutrition (48 hours post-banding). They found there was no statistically significant difference in the rates of rebleeding between early enteral feeds vs late enteral feeds. They also found a statistically significant reduced length of hospital stay in the EEN group (6.0 ± 2.4 days) vs the delayed feeding group (7.5 ± 3.1 days) (P < 0.05)[38]. These findings were similar to that found by Goda et al[39], who divided 90 cirrhotic patients with acute variceal bleeds into an EEN group and a delayed group. The study found no significant difference in rebleeding of banded varices when starting EEN. Sidhu et al[40] conducted a more intense study in which 101 cirrhotic patients received enteral feeds 1 hour post-banding. Their findings supported existing studies and revealed that there was no statistically significant difference in rebleeding in the two groups. The studies also found there was no difference in 1 month mortality rates [3 (5.76%) vs 4 (8.16%); P = 0.75] and early infections were less in the EEN group vs the delayed group[40]. Jatin et al[41] supported these findings in 2023 with a study including 80 cirrhotic patients who underwent banding. They found a difference in rebleeding rates, with 2.5% in the early feeding group vs 5% in the late feeding group; however, there was no statistical difference. There were no differences in infection rates as well, demonstrating a lack of variation between early and late enteral feeding[41]. The findings in the study by Gong et al[42] contrasted these views. The study was designed to include 209 patients who bled from peptic ulcers and had endoscopic hemostasis. Enteral nutrition was started within 24 hours in the early feeding group and 48 hours in the delayed group. They found that recurrent bleeding rates were higher in the early feeding group; however, they did not reach statistical significance. They also identified a decrease in mortality rates from 5.9% in the early feeding group vs 14.1% in the late feeding group[42]. These studies show that EEN is non-inferior to delayed nutrition in UGIBs and may even offer benefits such as improved mortality outcomes and decreased infection rates. The findings suggest initiating EEN in UGIB with caution.

Figure 2  Types of gastrointestinal bleeds based on location.

EARLY FEEDS IN CRITICALLY ILL CARDIAC PATIENTS

Patients in the cardiothoracic ICU (CTICU) include those who have undergone complex cardiac and/or thoracic surgeries, such as coronary artery bypass grafting, valve replacement, and heart or lung transplant. These patients often present with significant comorbidities and require intensive postoperative monitoring and management. Additionally, the CTICU manages patients with severe cardiothoracic conditions, including acute coronary syndromes, heart failure, and cardiogenic shock. These patients often require advanced therapies such as mechanical circulatory support, invasive hemodynamic monitoring, and mechanical ventilation[43]. The complexity of these patients requires scrutiny in every aspect of care and nutrition is a crucial component. There is currently a paucity of data on the timing of initiating EEN in the CTICU setting. More recent studies have suggested that EEN in the CTICU can provide benefits such as improving short-term outcomes, reducing post-operative infection rates, enhancing nutritional status, and thus contributing to overall better clinical outcomes in this critically ill patient population. Zheng et al[44] conducted a retrospective cohort study in 2024 on 1846 patients with cardiogenic shock. 1398 patients received EEN and 448 received delayed enteral nutrition. After 1:1 propensity matching and adjusting for confounders, patients with EEN had better 30-, 90- and 180-day survival outcomes [hazard ratio (HR) = 0.803, P = 0.045; HR = 0.729, P = 0.001; and HR = 0.778, P = 0.008, respectively]. Patients who had DEN also had longer length of hospitalization (17 days vs 12 days; P < 0.001)[44]. A retrospective study published in 2023 by Shen et al[45] aimed to look at the short-term outcomes and survival in patients who received EEN in the CTICU. The study included 720 patients with a CTICU stay of 4 days or greater. The study population was further divided into patients that received EEN and patients that received DEN. EEN resulted in a median CTICU and hospital length of stay 3 days shorter compared with the delayed DEN group (P = 0.026 and P < 0.001, respectively). They also found that EEN reduced the incidence of respiratory infections by 8.8% (P = 0.017) and blood infections by 3.5% (P = 0.048). EEN was also found to have better glycemic control with decreased insulin requirements during the first 7 days of ICU stay (P = 0.036). There was however, no significant difference in long-term survival at 28 days and 1 year follow-up[45]. A prospective randomized controlled pilot study published in 2017 by Efremov et al[46] found that EEN using a calorie-dense and protein rich formula improved nutritional status using surrogate nutritional markers. This was a small-scale study conducted on 40 mechanically ventilated, post-cardiac surgery patients who received either standard isocaloric EEN or calorie-dense, protein-rich EEN. The study found that EEN with the calorie-dense formula provided significantly more energy and protein enterally on the 2^nd, (P < 0.0001), 5^th (P = 0.036), and 7^th days (P = 0.024) post-surgery. Patients receiving the calorie-dense formula were also found to have lower requirements for parenteral nutrition. The study analyzed surrogate nutritional markers in these patients, finding significant differences in prealbumin concentration on post-operative day 14 (P = 0.04) and transferrin levels were found to be significantly higher in the calorie-dense group on post-operative days 3 (P = 0.037), 5 (P = 0.011), and 7 (P = 0.018). However, there was no significant difference in C-reactive protein between these groups. Although these markers are indicative of improved nutritional status and recovery, the study did not directly assess morbidity and mortality in this specific patient population[46]. With the recent increased utilization of mechanical-circulatory support, extracorporeal membrane oxygenation (ECMO) has become more widely applied in CTICU patients with cardiopulmonary failure. Patients receiving ECMO often require high-dose vasopressor therapy, accompanied by paralytic and sedative medications. Current literature regarding EEN in this patient population is limited; however, more recent studies have supported the initiation of EEN in ECMO patients. A single center retrospective review conducted between May 2012 to July 2021 by Lu et al[47], concluded that EEN was safe and well-tolerated by patients receiving ECMO for greater than 24 hours. The study included 65 patients, 42 of which received venovenous-ECMO and 23 whom received venoarterial-ECMO. There was a longer length of ICU and hospital stay in the EEN group vs the DEN group (P < 0.001); however, patients in the EEN group were found to have a higher success rate weaning off ECMO, compared with the DEN group (P = 0.006). Patients in the EEN group had a significantly reduced mortality rate (P < 0.001). There was also a significant difference in EN intolerance between the EEN group (36.1%) and the DEN group (82.8%), with abdominal distension and elevated gastric residual volumes being more common in patients receiving DEN[47]. Overall, there is limited research regarding the specific application of EEN in the CTICU. With careful consideration of clinical status, current research supports the initiation of EEN in this critically ill population. A summary of these findings are shown in Table 2.

Table 2 Summary of studies on the effects of early enteral nutrition in patients with cardiothoracic disorders including those in the intensive care unit.

Ref.	Type of study	Study population	Outcomes
Zheng et al[44], 2025	Retrospective cohort study	1846 patients with cardiogenic shock	EEN was associated with improved survival outcomes and decreased length of hospitalization
Shen et al[45], 2024	Retrospective RCT	720 patients with 4 days or greater CTICU stay	EEN was associated with shorter length of hospital and ICU stay and reduced incidence of respiratory and blood infections
			Better glycemic control and reduced insulin needs
			No significant difference found in long-term survival
Efremov et al[46], 2017	Prospective RCT	40 mechanically ventilated, post-cardiac surgery patients who received either standard isocaloric EEN or calorie-dense, protein-rich EEN	EEN led to reduced requirements for parenteral nutrition
Lu et al[47], 2023	Retrospective review	65 patients, 42 of which received VV-ECMO and 23 whom received VA-ECMO	EEN safe and well-tolerated by patient’s receiving ECMO for more than 24 hours
			EEN associated with higher success rates of weaning off ECMO and reduced mortality
			Delayed EN group to had significantly higher feeding intolerance as compared with the EEN group

RCT: Randomized controlled trial; EEN: Early enteral nutrition; ICU: Intensive care unit; CTICU: Cardiothoracic intensive care unit; ECMO: Extracorporeal membrane oxygenation; VV-ECMO: Venovenous-extracorporeal membrane oxygenation; VA-ECMO: Venoarterial-extracorporeal membrane oxygenation.

EEN IN PANCREATITIS

In the United States, the incidence of acute pancreatitis has been reported to range from 5 cases to 30 cases per 100000 person-years, with evidence suggesting an increasing trend in recent years[47-53]. Specifically, the American College of Gastroenterology notes that the incidence of acute pancreatitis has been increasing by 2%-5% per year. Globally, the age-standardized mortality rate decreased from 1.7 per 100000 in 1990 to 1.4 per 100000 in 2019. Acute pancreatitis has a high mortality due to severe infectious complications, often leading to sepsis and multiple organ failure. The mainstays of therapy for acute pancreatitis include fluid resuscitation, pain management, and nutritional support. Patients are often initially kept nil per oral to allow the pancreas to recover, although studies and guidelines now support the initiation of EEN depending on the patient’s tolerance.

Figure 3A shows major causes of acute pancreatitis. EEN in acute pancreatitis has been shown to reduce infectious complications, including both pancreatic and systemic infections. A metanalysis conducted in 2013 by Li et al[49], found that enteral nutrition initiated within 48 hours of admission for acute pancreatitis was correlated with a significant reduction in infection. Specifically, there was a significant reduction in catheter-related septic complications [OR = 0.26; 95% confidence interval (CI): 0.11-0.58, P < 0.05] and in pancreatic infection (OR = 0.49; 95%CI: 0.31-0.78, P < 0.05). This study also found a significant reduction in the length of hospitalization (mean difference: -2.18; 95%CI: -3.48 to -0.87; P < 0.05), and in mortality (OR = 0.31; 95%CI: 0.14-0.71, P < 0.05)[49]. A systematic review and meta-analysis published in 2018 by Song et al[50] showed similar findings. This analysis aimed to evaluate the efficacy and safety of initiating enteral nutrition within 48 hours of admission in patients with severe acute pancreatitis. The study used data from 10 RCTs and compared EEN to DEN or TPN. Results showed a significant reduction in the rate of multiple organ failure in the EEN group as compared with the DEN or TPN group (RR = 0.58, 95%CI: 0.43-0.77, P = 0.0002). EEN was associated with reduced rates of systemic infections (RR = 0.75, 95%CI: 0.61-0.93, P = 0.009) and local septic complications (RR = 0.42, 95%CI: 0.26-0.69, P = 0.0005), when compared with DEN or TPN[50]. Another large-scale systematic review and meta-analysis published in 2024 by Liang et al[51], aimed to look at the effects of early vs delayed enteral feeding in patients with severe acute pancreatitis. They found that hospital length of stay was significantly lower in the EEN group than the DEN group (mean difference: -2.35, 95%CI: -2.89 to -1.80; P < 0.0001). The cost of hospitalization was significantly less in the EEN group, with results suggesting an average savings of 50% as compared with the DEN group. This study also looked at feeding intolerance and mortality as secondary outcomes, with no significant difference found between the groups[51]. These findings are summarized in Table 3.

Figure 3 Main etiology and types of acute pancreatitis. A: Major causes of acute pancreatitis; B: Types of pancreatitis divided based on severity.

Table 3 A summary of studies on the effects of early enteral nutrition on pancreatitis and its outcomes.

Ref.	Type of study	Study population	Outcomes
Li et al[49], 2013	Meta-analysis	11 studies involving 775 patients with acute pancreatitis	EEN associated with significant reduction in both pancreatic and systemic infections
			EEN associated with reduction in hospital length of stay
Song et al[50], 2018	Systematic review and meta-analysis	10 randomized controlled trials comparing EEN to late EN or TPN	Significant reduction in the rate of multiple organ failure, along with reduced rates of systemic infections and local septic complications in the EEN group
Liang et al[51], 2024	Systematic review and meta-analysis	20 trials including 2168 patients with acute pancreatitis	Reduced hospital length of stay and lower cost of hospitalization in the EEN group

EEN: Early enteral nutrition; EN: Enteral nutrition; TPN: Total parenteral nutrition.

Figure 3B shows the types of pancreatitis divided based on severity. The American Gastroenterological Association (AGA) agrees that EEN reduced the risk of infected peripancreatic necrosis and multi-organ failure. AGA guidelines support the initiation of enteral nutrition to decrease the risk of infected necrosis. The association also recommends trialing oral nutrition immediately in patients without nausea and vomiting, and the absence of severe ileus or GI obstruction. The AGA recommends initiating tube feeding via nasogastric/nasoduodenal tube to be initiated as soon as possible and recommends against initiation of TPN in these patients. Risks of EEN include feeding intolerance and aspiration risk. Studies have shown that some patients may experience feeding intolerance, often manifesting as nausea, vomiting, or abdominal pain. The risk of aspiration, specifically seen with nasogastric feeding, can often be mitigated through upright positioning of the patient[52,53].

EARLY NUTRITION IN RESPIRATORY ILLNESS

Respiratory conditions such as acute respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD) exacerbation are major causes of ICU admissions as these patients frequently require mechanical ventilation. COPD is characterized by persistent airflow limitation due to chronic alveolar damage. COPD is irreversible and carries a high risk of progressing into acute respiratory failure. The prevalence of COPD was nearly 10.6% worldwide in 2020[54]. An acute exacerbation of COPD is a clinical state characterized by sustained cough, increased sputum production and/or dyspnea. On average a patient with COPD experiences 2 episodes of acute exacerbation per year and nearly 10% of those require hospitalization[55]. A previous study published in 2005 estimated that nearly 90% of the COPD patients admitted to the ICU required intubation and mechanical ventilation. Hospital mortality was as high as 24.5%, with a 5-year mortality rate of nearly 70%[56]. The idea that malnutrition in patients with COPD predisposes them to severe infections has been suggested and this population is thought to have more severe COPD. This is due to mismatch between increased demand and decreased supply of nutrients. Chronic hypoxemia can damage the gastric mucosa creating alterations in the GI flora, leading to inadequate absorption of nutrients. Due to parenchymal damage, the alveoli lose elasticity, requiring an increased work of breathing to maintain oxygen saturation[57]. Malnourishment leads to a decrease in the quality and quantity of lung tissue, contributing to the vicious cycle of aggravating COPD. There is also weakness of the body’s respiratory musculature secondary to malnutrition, leading to increased work of respiration and increasing metabolic demand[58]. Furthermore, malnutrition can cause immunological dysfunction and can predispose patients to infections[59]. Thus, overall management of nutrition in patients with COPD is of significant interest.

The vicious cycle of malnutrition in COPD is shown in Figure 4. There is a paucity of data regarding EEN in COPD patients admitted to the ICU. Mansouri et al[60] conducted a study in 129 patients with COPD who needed mechanical ventilation. They provided EEN to 66 patients and delayed nutrition to 63 patients. Those in the EEN group (15.85 ± 11.91 days) had a statistically significant reduced length of stay vs the delayed group (22.17 ± 13.87 days). However, no statistically significant difference was noted in 60-day mortality, between the two groups. No significant difference was noted in detrimental outcomes, including ventilator-associated pneumonias, arrhythmias, GI bleeds and renal dysfunction among the two groups. Interestingly, the rate of pleural effusions, was greater in the DEN group (63.5% vs 43.9%, P = 0.02)[60]. ARDS is a clinical syndrome consisting of diffuse inflammation of the lung along with edema leading to acute respiratory failure and is a frequent cause of ICU admissions. The condition is a result of excessive activation of the host’s immune response, leading to diffuse alveolar damage, with injury to the lung epithelium and endothelial barriers. This provokes an abrupt movement of fluid from the pulmonary vasculature into the alveolar airspaces. This alveolar flooding causes a ventilation-perfusion mismatch, impairs gas exchange resulting in hypoxemia and acute hypoxic respiratory failure characteristic of ARDS. ARDS often develops within 1 week of the inciting event[61]. The prevalence of ARDS in critically ill ICU patients was estimated at nearly 10.4% in 2016. The mortality ranges from 34.9% to 46.1% depending on disease severity[62]. Patients who develop ARDS often need to be intubated, with early intubation demonstrating better outcomes[63]. Patients with ARDS are like other critically ill patients. They are in a catabolic state with increased metabolic demand. They are also in a hyper-inflammatory state causing both local and systemic damage to the body. EEN has been shown to assist both in providing nutrition and attenuating the inflammatory response in lung tissue[64]. As with COPD, there is a paucity of data on the effects of EEN in adult patients with ARDS. We identified a study conducted in the pediatric ICU by Powell et al[65] which included 151 patients aged 2 months to 18 years of which 41 received EEN and 110 received delayed nutrition. Mortality was found to be lower in the EEN group (2.4%) vs the delayed group (30%, P = 0.006). Even after adjusting for age, EEN was shown to have a lower mortality rate. They also identified that EEN group had a shorter length of stay in the ICU (P < 0.001). They then split the cohort into mild, moderate and severe disease and found that EEN had better outcomes in the mild ARDS group[65]. Although there is a lack of sufficient studies on the effect of EEN in critically ill patients suffering from respiratory disease, the existing data point to a benefit in initiating early feeds in this population, especially in patients with mild ARDS and COPD exacerbation. However, further studies exploring the impact of EEN on long-term outcomes among these patients need to be conducted to establish a definitive relationship supporting the use of EEN in this subset of patients.

Figure 4  Vicious cycle of malnutrition in chronic obstructive pulmonary disease.

EARLY NUTRITION IN NEUROCRITICAL CONDITIONS

Neurocritical care involves management of patients which neurological injuries. Cases managed in the neuro-ICU include stroke, traumatic brain injury (TBI), sub-arachnoid hemorrhage, intracerebral hemorrhage, and spinal cord injury. We further explored the association between nutrition and two major neurological injuries: Stroke and TBI. Stroke is the second leading cause of death and third leading cause of disability across the globe. Stroke is defined as a syndrome of acute and focal neurological deficits as a result of injury to the central nervous system. The injury is a vascular insult, either infarction (85%) or hemorrhage (15%)[66]. Recent estimates have revealed there are nearly 12.2 million cases of stroke per year, giving rise to an economic burden of over 700 billion dollars. Nearly 6.5 million people are estimated to succumb to strokes every year[67]. TBI is an insult to the brain due to an external force. TBI consists of two broad categories, penetrating (where an object passes through the skull) and non-penetrating (brain is moved without being contacted directly). Globally, it is estimated that 69 million patients suffer from TBI. Based on several factors, patients are classified into mild, moderate and severe TBI. Nearly 55.9 million people suffer from mild TBI, which generally does not require admission to the ICU. The remaining 13 million suffer from moderate or severe TBI which usually requires intensive care[68]. As with other critical conditions, stroke and TBI trigger a hypercatabolic state with increased demand. A vast majority of patients with TBI were found to require nearly 200% of their regular nutritional demands following brain trauma[69]. The FOOD trial determined that nutritional status in stroke patients served as an excellent indicator of long-term outcomes[70]. These studies provide evidence that nutrition plays a key role in acute neurologic disease states. Chiang et al[71] conducted a study on 297 patients with severe TBI where 145 patients received EEN, and 152 patients received delayed nutrition. They found a significantly lower mortality in patients who received EEN (26.9%) vs those who received delayed nutrition (92.1%; P < 0.001). They also found that patients had greater improvement of Glasgow Coma Scale scores over 7 ICU days in the EEN group vs the delayed group (P < 0.001). They did not evaluate differences in ICU length of stay[71]. In another larger study involving patients with severe TBI in Japan, Ohbe et al[72] explored the differences in 1100 patients receiving EEN and 1980 patients receiving delayed nutrition. They did not identify significant differences in mortality between the two groups (16% vs 17%, P = -0.86). A decreased length of stay (38 days vs 42 days, P < 0.007) was noted in the EEN cohort[72]. Choi et al[73] conducted a study on neurosurgical patients admitted to the ICU where they analyzed 1353 patients. Of these, 152 patients received EEN, 969 patients received delayed nutrition, and 232 patients received early parental nutrition. ICU mortality was significantly lower in the EEN group (3.3% vs 29%, P < 0.001). A significantly lower 28-day mortality was also noted (5.3% vs 30.4%, P < 0.001)[73]. Wang et al[74] conducted a study in 997 critically ill stroke patients, of which 564 received EEN in 48 hours and 433 received DEN. Their results contrast the findings of other studies, with patients receiving EEN experiencing a higher risk of mortality vs those who received delayed nutrition. They attributed this to possible increased gastric load, leading to aspiration events along with increasing sympathetic hyperactivation in stroke patients secondary to increased intracranial pressure, interfering with GI function[74]. We found that more data exist on the analysis of EEN in patients with TBI than any other neurologic condition. There is insufficient data regarding the effects of EEN in patients with stroke. Considering stroke is among the leading causes of morbidity and mortality in the world, it would be beneficial to explore the effects of EEN on disease outcomes. However, from the existing data, we can conclude that EEN can be advantageous in patients with TBI and other neurocritical conditions but should be used with caution in patients with stroke until more research is available.

EARLY NUTRITION IN SURGICAL PATIENTS

The topic of EEN in surgical patients is beyond the scope of discussion in this article, it would be beneficial to discuss this in a separate article. However, it is important to mention that EEN has been found to have many benefits in post-operative patients. Some of these studies are summarized in Table 4.

Table 4 A summary of studies on a variety of surgical patients and the effects of early enteral nutrition on their recovery and other outcomes.

Ref.	Type of study	Study population	Findings
Shu et al[75], 2016	Meta-analysis	1095 patients with digestive tract surgeries	Decrease in infectious and non-infectious complications in EEN
			No difference in hospital length of stay
Herbert et al[76], 2019	Cochrane systematic review	1437 patients with lower digestive tract surgeries	Shorter length of stay in hospital in EEN
			No difference in post-operative complications
			No difference in mortality
Burcharth et al[77], 2021	Cochrane systematic review	1309 patients with major abdominal surgery	Decrease in mortality in EEN
			No difference in post-operative complications
Chen et al[78], 2023	Retrospective analysis	121 patients with gastrointestinal tumors requiring surgery	Better post-operative nutritional status in EEN
			Faster recovery time in EEN
			Increased risk of adverse effects in EEN

EEN: Early enteral nutrition.

Strengths and limitations

This study explores the wide assortment of literature and studies available regarding EEN, which typically has lesser importance in the mind of clinicians in the management of critically ill patients. We conducted a thorough review of RCTs and meta-analyses in the past few decades, with focus on more recent articles. There exists a paucity of articles that condense this information into a single source of information and focused on some of the most common conditions that are encountered in the ICU. This article can help guide clinicians in the ICU to make decisions on starting EEN in patients based on available evidence and feasibility. This study does have a few limitations. We primarily focused on the adult population and did not focus on pediatric populations independently. There was also emphasis on specific critical conditions, certain articles were found to include a broad inclusion criteria of ICU patients but there was a lack of detail on what the underlying pathology of the patient populations were hence could not be included into this article[75-83].

CONCLUSION

EEN, initiated within 48 hours of ICU admission, consistently improves patient outcomes across various critical care settings. EEN reduces rates of mortality, infection, and length of ICU stay amongst patients with severe burns and acute pancreatitis; shortens ICU stays and modulates inflammation in sepsis; does not increase rebleeding risks in upper GI bleeds while reducing hospital length of stay; and enhances recovery in cardiac critical care patients. Certain conditions may not allow for EEN, including lack of access to the GI tract, hemodynamic instability (e.g., uncontrolled shock, high-dose vasopressors), severe gut dysfunction (e.g., bowel ischemia, obstruction, prolonged ileus, uncontrolled GI bleeding), high-output fistulas, abdominal compartment syndrome, severe vomiting or malabsorption, and end-of-life conditions. However, if these contraindications are not present, the benefits support adoption of EEN as a standard practice to improve patient recovery without significant adverse effects. In addition to this, further studies should be conducted to tailor individualized protocols for initiation of EEN based on multiple factors including but not limited to the underlying pathology, tolerance and overall responsiveness to EEN. There could also be further research into the exact formulation of enteral feeds for specific conditions, including total calories, protein, carbohydrates, fats, essential vitamins, minerals and other additives.