Introduction

The COVID-19 pandemic has led to unprecedented challenges in patient care. This is especially true in those patients with COVID -19 who develop critical illness. While COVID-19 is primarily a respiratory disease, those with severe illness can develop fatal multi-system organ failure. Patients with advanced age and underlying co-morbid medical conditions such as obesity, hypertension, diabetes, chronic lung disease and cardiovascular disease are at higher risk for critical illness and the development of severe acute respiratory distress requiring intensive care unit (ICU) level of care. These patients are subsequently at increased risk for malnutrition given their metabolic state, associated co-morbid conditions, frailty, and decreased oral intake [1••, 2, 3••]. There exist challenges in providing adequate nutrition to the critically ill COVID-19 patient including the use of non-invasive ventilation, prone positioning, need for vasopressor medications, and need for ECMO support. Studies have shown that up to 65% of COVID-19 positive patients admitted to the ICU are malnourished [1••, 4,5,6].

Nutrition societies such as the American Society for Parenteral and Enteral Nutrition (ASPEN) and the European Society for Clinical Nutrition and Metabolism (ESPEN) and critical care societies such as the Society of Critical Care Medicine (SCCM) have published expert statements and guidelines for nutritional management of patients with COVID-19. The purpose of this review is to provide an overview of the current literature, recommendations, and practice guidelines on the nutritional management of and implications associated with COVID-19 infection.

The Gastrointestinal Tract

The gastrointestinal tract (GI) is vital to the health of the human. It allows for water and nutrient absorption while acting as a barrier between the luminal environment and the body. The intestinal barrier consists of a physical barrier which is predominately cellular (epithelial cell layer, vascular endothelium, mucus) and chemical barrier (digestive secretions, immune molecules). Permeability is maintained by tight junctions that regulate the absorption of water and molecules [7]. The intestinal microbiota is a collection of organisms, predominately bacterial species in humans, that live within the intestinal lumen. These organisms contribute to the health of the human by exerting local (nutrient metabolism & uptake, motility, barrier function, and prevention of colonization of pathogenic organisms) and distant (metabolism, immune response) influences based on the composition of the microbiota [8]. The GI tract contains the largest density of lymphoid tissue aggregated into mesenteric lymph node (MLN) and gut-associated lymphoid tissues (GALT), which produces immune cells to maintain barrier integrity and protective immunity [9].

During times of critical illness, there is impairment of the intestinal barrier as well as the composition of the microbiota. Circulatory shock results in three key pathologic changes: increased mucosal permeability, shifting of the symbiotic microbiome to a dysbiotic pathobiome, and development of a proinflammatory environment at the intestinal barrier [2]. In addition, standard practices of organ support (antibiotics, vasopressors, proton pump inhibitors, etc.) in the ICU, directly influence the shift towards a pathobiome [8].

Gastrointestinal manifestations are reported in 2% to 49% of patients with COVID-19. The cellular receptor of COVID-19 is located throughout the GI tract, with the largest abundance in the ileum. Uptake of COVID-19 at the enterocytes result in disruption of mucosal barrier integrity and development of a proinflammatory environment, as well as a reduction in the diversity of the intestinal microbiome, shifting from beneficial commensal bacteria to opportunistic pathogenic species [10]. It has been proposed that the proinflammatory environment expends beyond the GI tract, resulting in host immune system dysfunction and promoting acute respiratory distress syndrome [11].

Nutrition Assessment

With the growing evidence of GI symptoms associated with critical illness, including COVID-19 infection, and the interrelatedness of the gut and nutrition, early nutrition risk screening and assessment is imperative to determine appropriate nutrition interventions.

Guidelines suggest implementation of a nutrition risk screening tool to identify high risk patients requiring nutrition interventions [1••]. Early evaluation (within 48 h of admission) is required to identify pre-existing malnutrition and those at high risk of developing malnutrition [12]. There are multiple validated tools that can be utilized to determine the level of nutritional risk, such as Nutrition Risk Screening 2002 (NRS-2002), Malnutrition Screening Tool (MST) or Malnutrition Universal Screening Tool (MUST), and The Nutrition Risk in Critically ill (NUTRIC) [3••, 13]. Nutrition assessment should be conducted regularly by a nutrition professional to preserve nutrition status and prevent or treat malnutrition to reduce complications and improve clinical outcomes [3••].

During initial onset of the COVID-19 pandemic, there was a call for the preservation of PPE standards by the CDC, which relied on coordinated care and remote arrangements to obtain the information required for nutrition screening and assessment [1••, 14•].

Timing of Nutrition Support

Nutrition delivery during COVID-19 infection is generally consistent with the current established standards and guidelines for critically ill patients [15•, 16]. Enteral nutrition (EN) is the preferred modality of nutrition delivery as it supports the functional and structural integrity of the GI tract and maintains the GALT [16]. Disease severity and pre COVID-19 nutritional status determines the modality of delivery as well as the prescribed therapy. Patients with COVID-19 requiring minimal pulmonary support should be allowed volitional intake with the addition of oral nutrition supplements if unable to meet nutritional requirements. If nutrition goals are unable to be met with oral diet alone, if unable to provide oral intake for 3 days or more, if unable to meet 50–65% of nutritional goals within the first 5 days, or if consuming less than 50% during the first week, EN is recommended [1••, 3••].

For critically ill patients, early initiation of EN within 24–36 h, within 48 h of ICU admission, or within 12 h of intubation is recommended [1••, 14•]. Enteral nutrition support should be delivered via a nasogastric or orogastric feeding tube given the ease of placement. A post pyloric feeding tube may be considered in patients with a history of aspiration or in patients at increases risk given certain modalities of non-invasive pulmonary support.

Early trophic feeds can be considered once a patient is resuscitated unless there is a need for increasing vasoactive agent support or with the presence of observed intolerance to EN (RR4) such as abdominal distention, ileus, or vomiting [1••, 17]. Early EN has been shown to improve mortality and reduce infections when compared to delaying or withholding EN [14•, 18, 19]. Furthermore, those started on EN greater than 36 h of admission have been shown to have longer hospital length of stays and number of intubated days [20]. Low-dose, trophic feeds of 10–20 ml/h are favorable over full dose feeds with the goal of advancing to 15–20 kcals per adjusted body weight (ABW) during the first week [15•]. Multiple randomized control trials have shown equivalent mortality outcomes in patients who are given trophic feeds compared to full feeds. [21, 22]. Rapid advancement to full strength EN is cautioned following the NUTRIREA-2 trail. The study showed that early EN advanced to calorie/protein goal on the first day of therapy in critically ill patients requiring vasopressor support was associated with non-occlusive mesenteric ischemia and colonic pseudo-obstruction. [23]. Additionally, patients who are malnourished with high nutritional risk are at increased risk for refeeding syndrome when given higher calorie/protein intake during the acute phase of critical illness. Therefore, a stepwise approach towards the advancement of EN to calorie/protein goal is recommended in the acute phase of critical illness [21].

If unable to reach nutrition goals via EN within the first week, parenteral nutrition (PN) is recommended [3••]. For patients who are low to moderate risk, it is not recommended to supplement PN within the first week of admission to the ICU. ICU patients who underwent supplementation with PN after day seven of EN nutrition support were noted to have a lower incidence of infection, shorter duration of mechanical ventilation and renal replacement therapy, and an earlier discharge from the ICU and the hospital [24]. Early PN is recommended when EN is contraindicated and a patient is at high nutrition risk, malnourished, or has an expected prolonged ICU stay [2]. Initiation of PN may be delayed for 5–7 days for patients considered low nutrition risk [19]. Compared to providing no nutrition support, patients with pre-existing malnutrition have improved mortality with early use of PN [17]. If patients are unable to tolerate EN within first week, PN can be considered on an individualized basis. PN should not be started until all strategies to maximize EN tolerance have been attempted [3••].

Nutrition Targets

Caloric and protein dose recommendations vary based on timing of initiation, body habitus/weight, and patients’ clinical condition and co-morbidities. It is recommended to utilize indirect calorimetry to quantify patients’ energy requirements when feasible [1, 3]. Alternatively, predictive equations or weight-based formulas can be utilized when indirect calorimetry is not feasible [3••]. While predictive equations may be inaccurate due to over and under-estimating requirements [3••, 25], there is validation for the use of the Penn State Equation as a more efficient alternative to indirect calorimetry [25, 26]. Weight-based equations that have been recommended for use include: 25–30 kcals/kg/day per ASPEN/SCCM guidelines or 20–25 kcals/kg/day per ESPEN guidelines [16, 27]. For obese individuals, recommended caloric goals are 11–14 kcals/kg ABW-day for Body Mass Index (BMI) 30–50 kg/m2 and 22–25 kcals/kg ideal body weight (IBW) per day for BMI > 50 kg/m2 [2]. For individuals requiring Extracorporeal Membrane Oxygenation (ECMO) support, energy needs may be increased up to 30 kcals/kg/day [13, 28].

During the first week of critical illness, initial caloric goal should aim for 15–20 kcals/kg ABW-day, which should equate to about 70–80% of estimated energy requirements [2, 14•]. Following the early phase of acute illness, advancing to isocaloric nutrition is recommended [3••]. The recommended protein dose goal for individuals with critical illness is 1.2–2 g/kg ABW-day [1••, 2, 3••, 14•]. For obese individuals with BMI > 30 kg/m2, the recommended protein goal is 2–2.5 g/kg IBW-day [2]. For individuals on continuous renal replacement therapy, protein goals are 2–2.5 g/kg ABW-day [16]. Nutrition prescriptions should aim to provide 1.5 g/kg/day of protein, which was shown to achieve nitrogen equilibrium [29]. For individuals requiring ECMO support, protein needs may be increased to 1.5–2 g/kg/day [13, 28]. Special considerations when monitoring feeding regimens include accounting for non-nutrition calories from propofol and dextrose to prevent over- or under-feeding [1••]. Table 1 describes the recommended weight-based nutrition targets in further detail.

Table 1 Key points
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Monitoring Tolerance, Troubleshooting, Adjustments

About half of COVID-19 patients admitted to the ICU experience hypomotility-related complications that manifests as abdominal pain, nausea, vomiting, diarrhea, or abdominal distention [29]. The COVID-19 pathogen targets receptor cells in the respiratory tract and GI tract (specifically ileum and colon) [30, 31]. Within the digestive tract, the pathogen is believed to alter normal intestinal flora. Common GI symptoms include anorexia, nausea, vomiting, diarrhea, and abdominal pain [2, 32]. The development of GI symptoms has been noted to be associated with disease severity [16] (Table 2).

Table 2 Recommended weight-based nutrition targets in COVID-19
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Recommendations for GI-related interventions are as follows:

  • Addition of prokinetic agents (intravenous erythromycin or metoclopramide or combination) during episodes of nausea, vomiting, or ileus to encourage gut motility [15•, 33]

  • Post pyloric feeding, but do not concentrate formula with delayed gastric emptying

  • Reducing feeding rate or volume, or adjust to concentrated formula to alleviate distention or improve absorption during episodes of abdominal distention [15•, 33]

  • Semi-elemental feeding regimen for better absorption or ensuring a continuous feeding regimen during episodes of non-medical induced diarrhea [16, 19, 27].

Although there are conflicting practices with the use of gastric residual volume (GRV) to evaluate gastric emptying, risk of aspiration, and cut-off volumes for holding EN, it is not recommended to check GRV as it has not been found to be reliable or useful [1••, 23]. It is recommended to monitor for regular bowel movements and passage of flatus [14•].

Prone positioning is not considered a contraindication for EN despite hypothetical GI intolerance given flat body positioning and likely use of high dose sedative and paralytic agents [34]. Prone positioning does not appear to increase EN intolerance or GI complications with most patients demonstrating tolerance to gastric feeds [14•, 33, 35]. During prone positioning, it is recommended to mitigate potential risk factors as feasible and maintain head of bed elevation in reverse Trendelenburg position (greater or equal to 10–25 degrees) while feeding to decrease the risk of aspiration, and to hold feeds for 1 h when shifting positions [14•, 15•, 33, 36]. Early hypocaloric EN prescription should started and advanced as tolerated [1••, 15•, 35].

As the severity of a patient’s pulmonary disease worsens, circulatory shock may develop. Blood is shunted towards the vital organs (brain/heart) from the non-vital organs (GI tract). Blood pressure augmentation with vasopressors results in further reduction in mesenteric blood flow. Based on expert consensus, the 2016 ASPEN/SCCM guidelines recommended EN be held for hemodynamically unstable patients until the patient is resuscitated or stabilized. Nonocclusive mesentery ischemia (NOMI) resulting in bowel ischemia is the most feared complication of EN therapy in the setting of hypo perfused bowel. Multiple randomized control trials have demonstrated EN tolerance in shock states, with an incidence of NOMI (0.3–2%) [17]. The highest rate of NOMI was with EN seen in the NUTRIREA-2 study where calorie/protein goal delivery was achieved on day one [23].

Supplements, Vitamins, Minerals

Associations have been reported between adverse clinical outcomes and deficient intakes of the micronutrient’s vitamin A, vitamin E, vitamin B6, vitamin B12, zinc, and selenium with vital infections [37]. It has been suggested to consider supplementation with vitamin A, vitamin D, vitamin B, vitamin C, omega-3 fatty acids, selenium, zinc, and iron for patients with COVID-19 infection [38, 39]. However, there is no current established evidence to support routine micronutrient supplementation use that may prevent or improve clinical outcomes with COVID-19 [3••]. Some research has suggested maintaining the daily allowance intake for vitamins and minerals for the malnourished patient at risk for or with COVID-19 [5]. Overall, there has been conflicting recommendations and observations for vitamin and mineral supplementation for COVID-19 infection [2, 40]. While low serum zinc levels have been found to be prevalent among critically ill patients with COVID-19 at the time of ICU admission, empiric replacement is not recommended due to the risk of toxicity and interfere with copper metabolism with prolonged periods of supplementation [41,42,43]. Considerations should be made for thiamine and folic acid supplementation for patients at risk for refeeding syndrome [40].

Refeeding Syndrome and Nutrition Lab Utilization

Serum laboratory measurements should be regularly evaluated and adjustments to medical nutrition therapy should be made as indicated. This is especially true considering studies have shown that up to 65% of COVID-19 positive patients admitted to the ICU are malnourished [1••, 4,5,6]. One prospective cohort study of critically ill patients with COVID-19, found that 82% were at risk of refeeding syndrome [44]. Refeeding syndrome is a range of metabolic and electrolyte abnormalities resulting from the reintroduction or increased volume of calories after prolonged period of low or absent caloric intake. Calorie sources can vary from oral diet, EN, PN, or IV dextrose solution. Refeeding syndrome can manifest over a spectrum of severity and laboratory findings include a reduction in electrolytes (phosphorus, potassium, magnesium) or thamin deficiency. This usually develops hours to days following nutritional therapy [45].

Some of the suggestions and recommendation for laboratory monitoring parameters include checking electrolytes daily during the first week of nutritional therapy (every 12 h for those at risk for refeeding syndrome), then 1–2 times per week. Glucose should be monitored every 4 h for the first two days of nutritional therapy and every 48 h for stable patients. Elevated blood glucose levels may occur as part of metabolic stress, as well as secondary to the use of steroids or dextrose infusions [40]. Rental function should be monitored at least 3 times/week, liver function tests 2 times/week, and triglycerides 2 times/week or every 72 h if the patient is receiving propofol. Lactate and blood gas in the critically ill should be monitored daily when starting nutritional therapy to monitor for tissue hypoperfusion. Albumin and CRP should be checked on admission and every 20 days [46].

Special Populations

Obesity and COVID-19

The World Health Organization defines overweight and obesity as “abnormal or excessive fat accumulation that presents a risk to health,” with a body mass index (BMI) over 25 kg/m2 considered overweight and over 30 mg/m2 considered obese [47]. Worldwide, 1.9 billion adults were overweight and 650 million were obese in 2016 [47]. The 2017 global burden of disease estimates that over 4 million people dying each year are a result of being overweight or obese [48]. Obesity and the associated metabolic syndrome have been shown to increase the risk for severe disease and decreased survival in COVID-19 [49,50,51,52]. Obese individuals are at risk for the development of a double burden of overnutrition and malnutrition due to fat accumulation and loss of skeletal muscle mass [53]. Additionally, micronutrient deficiencies worsen the burden of malnutrition affecting metabolism and immune function [54, 55].

ASPEN/SCCM have published recommendations for nutritional support of critically ill patients with obesity [16]. Hypocaloric, high-protein nutrition may be used to mobilize adipose stores, preserve lean body mass, and lower the metabolic risks of overfeeding. The goal of EN should not be greater than 65–70% of energy requirement as measured by indirect calorimetry. If IC not available, the suggested weight-based recommendations include: 11–14 kcal/kg ABW per day for BMI 30–50 kg/m2 and 22–25 kcal/kg IBW per day for those with BMI > 50 kg/m2. Protein goal recommendations are 2.0 g/kg IBW for BMI 30–40 kg/m2 and up to 2.5 g/kg IBW for BMI ≥ 40 kg/m2 [16]. It is important to monitor labs for hyperlipidemia, hyperglycemia, hypercapnia, fluid overload, and liver fat accumulation in this patient population.

With no comprehensive studies specifically focused on the management of nutrition in obese individuals with COVID-19, ESPEN has published a set of clinical practice guidelines for nutritional management of COVID-19 patients with obesity based on best available knowledge and clinical experience [49]. Figure 1 summarizes the ESPEN clinical practice guideline recommendations.

Fig. 1
figure 1

Summarization of ESPEN expert statements and practical guidance on nutritional management of individuals with obesity and COVID-19. Barazzoni et al. [49]

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Extracorporeal Membrane Oxygenation (ECMO) and COVID-19

For critically ill patients with COVID-19, the severity of respiratory failure may prompt the need for ECMO to support oxygenating and ventilation. Patients on ECMO have prolonged hospitalization and significant inflammation contributing to the risk for malnutrition, which is associated with worse outcomes. Some of the challenges associated with ECMO support that have been documented include delayed gastric emptying and higher risk for enteric ischemia [14•]. Observational literature has shown that patients on ECMO tolerate gastric EN safely [2, 56, 57]. A study by Obhe et al., found that compared to delayed EN, early EN within 2 days of initiating ECMO had a decrease in 28-day mortality, and there were no incidences of enteric ischemia [58]. In a second study by Park et al., there was a decrease in 90-day mortality with increased EN energy and protein delivery [59]. While the literature is sparce with regards to nutrition in COVID patients requiring ECMO support, extrapolation of the existing literature on critically ill patient’s requiring ECMO suggests that early EN is safe and tolerated [57]. The recommendation for nutritional therapy during ECMO includes early initiation of EN at trophic dose with slow advancement over the first week of critical illness [2]. As discussed previously, recommendations for nutritional doses include energy needs increase to 30 kcals/kg and protein need increase to 1.5–2 g/kg per day [28].

Conclusion

There are significant unprecedented challenges with regards to the care of patients with critical illness secondary to COVID-19 infection. One such challenge is that of nutritional assessment, prevention, and treatment of malnutrition in this patient population. While nutrition societies such as ASPEN and ESPEN and critical care societies such as SCCM have published expert statements and guidelines for nutritional management of patients with COVID-19, much of the existing literature has been extrapolated from that of nutritional support therapy recommendation for generalized critically ill patient. Studies have demonstrated that early EN is safe and well-tolerated in critically ill patients with COVID-19 given they have no contraindications to EN. Recommendations for dosing of energy and protein requirements, including for obese individuals and those requiring ECMO support, follow the basic principles of critical care nutrition support for critically ill patients. The data and literature in the field of nutrition, and nutrition support therapy in COVID-19 infection is continuously evolving.