Nutrition Therapy and Critical Illness

Practical Guidance for the ICU, Post-ICU, and Long-Term Convalescence Phases

Arthur Raymond Hubert van Zanten; Elisabeth De Waele; Paul Edmund Wischmeyer


Crit Care. 2019;23(368) 

In This Article

Nutrition Therapy During ICU Stay

The European Society for Clinical Nutrition and Metabolism (ESPEN) recently published evidence-based guidelines on medical nutrition therapy for critically ill patients.[11] Early enteral nutrition (EEN) is recommended, as it is superior over delayed enteral nutrition (EN) and early parenteral nutrition (PN). There are only few reasons to delay EN (Table 1).

When to start EEN in patients in shock is a matter of debate; however, EN can be commenced after the initial phase of hemodynamic stabilization, and it is not necessary to delay EN until vasopressors have been stopped.[12,13] In the NUTRIREA-II trial among severe circulatory shock patients, an increased risk of splanchnic ischemia and gastrointestinal intolerance was observed induced by "forced" EEN.[14] However, in recent post hoc analysis from NUTRIREA-II, higher levels of citrulline were observed after 3 ICU days (reflecting enterocyte mass) in patients on EEN, suggesting EEN is beneficial for the gut mucosa even in severe circulatory shock patients.[15]

Progressive Administration of Calories

Based on pathophysiological insights from metabolism in the early phase of critical illness, this phase is characterized by inflammation, increased energy expenditure, insulin resistance, and a catabolic response leading to generation of energy from stores such as hepatic glycogen (glucose), fat (free fatty acids), and muscle (amino acids). Feeding ICU patients is essentially different compared with feeding the healthy.[16] The endogenous energy production in early critical illness cannot be abolished by nutrition therapy, and therefore, a progressive increase over days is recommended to prevent overfeeding.[17] This is further illustrated by the associations between the percentage of caloric target achieved during (early) ICU stay and energy expenditure (EE) measured by indirect calorimetry. The U-shaped relations found by Zusman and Weijs suggest that an energy intake of 70–80% of the measured EE is optimal, whereas lower and higher intakes both are associated with increased mortality.[8,18]

This U-shaped association was less clear when the results of the PERMIT trial on permissive underfeeding versus normocaloric feeding or energy-dense feeding versus normocaloric feeding in the TARGET trial are interpreted.[19,20] In both large randomized controlled trials (RCTs), no differences in relevant clinical endpoints after low, normal, or high caloric intake during early ICU stay were observed. It is important to consider that in these trials the protein intake was the same in the study arms. The results of these RCTs seem to contradict the findings of the observational studies. However, in the RCTs, energy targets were estimated by equations and were not based on indirect calorimetry. As equations are inaccurate, overfeeding and underfeeding may have occurred in both study arms. In the PERMIT trial, differences in caloric intake were limited (estimated at 11 vs. 16 kcal/kg/day) and possibly too small to detect differences.[21] Another speculative explanation could be that caloric groups in the TARGET trial were fed on the up- and downsloping part of the U-shaped relation and therefore no differences in mortality could be observed.

Available data suggest that early overfeeding should be prevented and that hypocaloric or normocaloric feeding does not confer major differences in outcome when protein intake is similar. Aggressive early caloric intake leads to more episodes of hyperglycemia and need for high-dose insulin therapy, as was observed in the TARGET and EAT-ICU trials.[20,22] As prolonged caloric deficits should be prevented, accepting a limited deficit (20–30% in the first ICU week) seems to be optimal. To estimate the caloric target after the initial phase, indirect calorimetry is strongly recommended.[11]

Refeeding Syndrome and Hypophosphatemia

Although refeeding syndrome (RFS) characterized by electrolyte shifts in response to reintroduction of nutrition after a period of starvation is ill-defined and many definitions are used, it can be best identified in ICU patients by refeeding hypophosphatemia (drop below 0.65 mmol/l within 72 h after the start of nutrition therapy).[23–25] Several studies have shown that caloric restriction to 500 kcal/day or less than 50% of target for 2–3 days is essential to prevent attributable mortality from RFS.[24,25]

Why are Proteins Important During Critical Illness?

Beneficial outcomes of critical illness are positively associated with the patients' muscle mass on ICU admission, the predominant endogenous source of amino acids.[26] Moreover, the catabolic response leads to reductions in muscle mass up to 1 kg/day during the first 10 days of ICU stay in patients with MODS.[27]

Mechanistic studies have shown beneficial effects on the loss of muscle mass and muscle protein synthesis induced by the administration of higher dosages of protein.[28] Many observational studies have shown that the provision of more protein as compared with lower intake of protein is associated with reductions in morbidity and mortality.[8,29–33] However, the number of RCTs on enhanced protein administration is low and studies only show limited effects on functional and clinical outcomes or are negative.[22,34–38] More evidence to prove improved outcomes is urgently warranted.[39]

Diverging or negative results may be a result of study design, the interactions with calorie administration and overfeeding, or refeeding syndrome or due to dose, composition, and timing of the intervention.[28] Recently also, studies, such as the PROCASEPT study, have suggested that effects of proteins on outcome may be different in sepsis patients compared with other ICU patients.[18,40]

Timing of Proteins and Progressive Administration of Proteins

Another explanation could be that very early high-protein intake in a post hoc analysis of the EPANIC trial, studying early versus late supplemental parenteral nutrition (SPN), was associated with negative effects on outcome.[41] This was confirmed in the retrospective PROTINVENT study showing increased mortality in patients treated with high-dose proteins during the first 3 days, although patients with an average intake below 0.8 g/kg/day showed the highest 6-month mortality after adjustment for relevant covariates.[42,43]

Proteins and feeding in general are known to suppress autophagy, an important intracellular cleaning mechanism. Whether this should lead to the prevention of an autophagy-deficient state is a matter of debate.[28] Recently, a retrospective study did not show negative effects of early protein administration during ICU stay as it was shown to improve 60-day survival. In this study, moderate intake during the first 3 days was provided.[44] Based on the limited information and not to do harm, gradual progression to the protein target can be recommended.[11,45] As this is also recommended for calories, step-wise increase to target in a few days can be performed using enteral nutrition (Figure 1). Following the ESPEN guidelines, the protein target after progression should be at least 1.3 g/kg/day.[11]

Figure 1.

Practical approach to provide proteins and calories during the phases of critical illness and convalescence. g/kg/day grams of proteins per kilogram per day, kcal/day total kilocalories per day, BIA bioelectrical impedance analysis, DEXA dual-energy X-ray absorptiometry, CT computed tomography scanning. During the first 3 days, calories and proteins are gradually progressed to target 1 on day 4 in steps of 25% daily increase. Target 1 is 1.3 g/kg/day for proteins and for calories 70% of calculated targets or 100% of target when measured by indirect calorimetry. Target 2 should be met during chronic critical illness and after ICU discharge on general wards. For target 2, calories are increased to 125% of predictive equations or indirect calorimetry or 30 kcal/kg/day and for proteins 1.5–2.0 g/kg/day should be targeted. After hospital discharge, target 3 recommends a higher caloric target (150% of predictive equations or 35 kcal/kg/day) and a higher protein intake of 2.0–2.5 g/kg/day

How to Reach the Protein Target?

A step-wise approach to meet the protein targets during critical illness is proposed to enhance a better performance (Table 2). This approach is based on the optimization of EN as a first step. However, it is challenging to meet the protein targets without overfeeding. Most tube feeds (and parenteral nutrition products) have a low-protein-to-energy ratio. Recently, a very-high-protein-to-energy ratio enteral feed based on intact protein was studied in an international randomized controlled trial compared with an isocaloric standard high-protein product.[48] With this new product, an average intake of 1.5 g/kg/day on day 5 was achieved, with a significantly higher amino acid concentration in the blood compared with the control product (mean protein intake 0.75 g/kg/day). The study clearly shows that using a standard high-protein product it is not possible to achieve intakes above 1.0–1.2 g/kg/day. Other ways to improve the protein intake is by using enteral protein supplements or supplemental amino acid solutions.

Should we use Intact Proteins or Hydrolyzed Protein in the ICU?

Based on the available literature, there is no indication that pre-digested or hydrolyzed enteral feeds are better tolerated than intact protein feeds.[52] In some studies, the tolerance seems even worse and the target achieved lower compared with polymeric feeds.[53,54] At present, recommendations are against the routine use of these semi-elemental formulations.[49] Whether semi-elemental formulations are superior in specific groups of patients at risk of enterocyte mass reduction and gut dysfunction, in particular patients with shock or sepsis, could be addressed in future studies.

Timing of SPN

Early initiation of supplemental parenteral nutrition (SPN), before days 3–7, is not recommended based on a meta-analysis and recent guidelines.[11,50] Only in patients with reasons to delay enteral nutrition and high nutritional risk early PN should be considered.[11,49] SPN may increase infectious morbidity possibly due to the risk of overfeeding.[55] However, the recent TOP-UP trial suggested a benefit on Barthel Index-measured functional capacity (p < 0.08) in ICU patients at higher nutrition risk with low and high BMIs.[51] The role of earlier SPN use in malnourished or low BMI patients to improve functional outcomes requires further study.

Monitoring of Nutrition

No studies are available comparing outcomes with monitoring versus not monitoring nutrition therapy. However, the potential for abnormal values to be associated with harm was clearly recognized by a group of international experts.[56] Locally adapted standard operating procedures for the follow-up of EN and PN are recommended. Clinical observations, laboratory parameters (including blood glucose, electrolytes, triglycerides, liver tests), and monitoring of energy expenditure and body composition are essential to prevent and detect nutrition-related complications.[56]