Hypocaloric Nutrition: Theory, Evidence, Nuts, and Bolts

Introduction

Until recently there has been little evidence regarding the caloric target for feeding critically ill patients. In the absence of evidence, it has been assumed that we should aim to meet 100% of predicted energy needs. New multicenter RCTs challenge this dogma, particularly the PERMIT trial by Arabi et al.

Theory supporting hypocaloric nutrition

The nutrition paradox

Critically ill patients often don't have a good appetite, especially patients with sepsis. Patients with severe illness on a hospital diet often consume well below the recommended number of calories. This usually goes unnoticed. However, once a patient is intubated, enteral nutrition is initiated and it rapidly becomes obvious whether or not the patient can tolerate full caloric intake. If they cannot, it becomes a source of enormous consternation.

This is paradoxical for two reasons. First, if receiving 100% full caloric intake is essential, then this should be equally important before the patient is intubated. However, we intuitively feel that force-feeding a septic patient with no appetite is a bad idea. Second, there is considerable confusion regarding exactly how many calories critically ill patients burn (e.g., conflicting equations to predict caloric use), and what percentage of these calories we should replace. Consequently, when we target 100% caloric repletion, it is unclear whether we are chasing the right target.

Nutrition may not prevent muscle breakdown

In the acute phase of critical illness, systemic inflammation induces a catabolic state with breakdown of the patient's muscle protein. Ideally, administration of adequate nutrition would prevent this process entirely. However, muscle breakdown is a complex process driven by inflammation as well as malnutrition and disuse, which does not respond completely to nutritional supplementation. Beyond a certain point, aggressive nutritional support may promote fat gain instead of preventing muscle loss (Schetz 2013).

Autophagy may be a good thing in moderation.

Autophagy is a process wherein cells under stress digest and recycle organelles and proteins. This process is stimulated by starvation, and suppressed by feeding or insulin. Animal models suggest that autophagy could be beneficial in acute lung injury as well as septic shock (Mizumura 2012). It is possible that provision of excessive nutrition and insulin could inadvertently suppress autophagy with harmful consequences.

Landmark papers about hypocaloric nutrition

ARDS-NET investigators. Initial trophic vs. full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA 2012.

This is a prospective multicenter RCT of patients intubated for acute lung injury comparing full enteral feeding to lower-volume trophic feeding for six days (1). After six days, all patients received full enteral nutrition. Patients randomized to trophic feeds received 20 kCal/hour, equal to about 25% of the estimated daily caloric goal. One thousand adults were recruited.

There was no difference in mortality, ventilator-free days, infection, or other organ failures. Patients in the trophic feeding group experienced less regurgitation (0.4% vs. 0.7%; p=0.003), less vomiting (1.7% vs. 2.25; p=0.05), and on average two liters lower fluid balance. As shown below, patient in the trophic feeding group achieved superior glycemic control despite receiving less insulin. Note that after one week, insulin requirements decreased in the full feeding group, possibly reflecting a decrease in systemic inflammation and insulin resistance (more on this below).

Overall this study demonstrated that among patients with acute lung injury (mostly due to sepsis or pneumonia) a short period of underfeeding did not impact mortality or major organ function. As might be expected, lower nutritional targets improved gastrointestinal tolerance and glycemic control. This supports the practice of temporarily providing very low-level enteral nutrition if there are obstacles to providing a greater degree of nutritional support.

Arabi YM et al. Permissive underfeeding or standard enteral feeding in critically ill Adults (the PERMIT trial), NEJM 2015.

This is a prospective multicenter RCT comparing provision of 40-60% of estimated caloric requirements versus 70-100% of estimated requirements, with all patients receiving the same protein intake. 894 critically ill patients with medical, surgical, or trauma admission were included, of whom 97% were intubated.

The study was well executed, with clear separation between the two groups (panel A above). The primary outcome was mortality at 90 days, which was 27.2% in the hypocaloric group vs. 28.9% in the full nutrition group (p=0.58). Similar to the EDEN trial, patients in the hypocaloric nutrition group achieved better glycemic control despite requiring less insulin, and had a slightly lower fluid balance (panels C-E above). There were no differences in ventilator-free days or overall severity of illness (panel F above).

Hypocaloric nutrition caused a slight increase in endogenous protein loss at 7 days with no difference at 14 days (as measured by nitrogen balance; panel I above). This supports the concept that above a certain threshold, additional caloric intake doesn't strongly affect breakdown of muscle proteins.

Although the benefits of hypocaloric nutrition shown in this study are debatable, the study provides evidence that administration of 50% predicted caloric needs is safe for two weeks. However, it must be noted that the investigators used a specifically designed formulation to target providing 100% of protein requirements using protein supplements.

Limitations of both EDEN and the PERMIT trial

Although these are both well-performed prospective RCTs, they do share some limitations in common. Both studies excluded patients with pre-existing malnutrition, severe shock, or burns. EDEN also excluded patients with neuromuscular disease, severe chronic respiratory failure, or obesity, with PERMIT excluding patients with pregnancy. Thus, these findings may not apply to all patients, especially patients with pre-existing debilitation or unusually high metabolic demands.

Another limitation of these studies was that they were performed in research centers with extremely close attention to the number of calories the patient was receiving. Even in this setting, patients received less than target caloric intake (e.g. in the PERMIT trial, the “100% nutrition” group only received 70% of the calorie goal). In real-world settings, interruptions in tube feeding would likely be a greater problem, potentially leading to a risk of substantial under-feeding. Therefore, if hypocaloric nutrition is performed, special attention is required to the number of calories the patient is actually receiving.

Nuts & bolts of providing hypocaloric enteral nutrition

Some early studies showed an increased risk of infection with hypocaloric nutrition. However, upon closer examination this was linked to administration of lower amounts of protein, rather than lower numbers of calories (Tian 2015). Therefore, when providing hypocaloric nutrition it appears important to provide 100% of the daily requirement of protein (Weijs 2013). This cannot be achieved by simply cutting the rate of tube feeds in half.

If a nutritionist is not immediately available, the following approach may be used with most patients (excluding, for example, patients with renal failure or morbid obesity). This approach is not completely precise. However, since our nutritional targets are rough estimates, the entire concept of precision may be moot. In a busy ICU, complex equations are often a barrier to implementing an evidence-based nutritional strategy at the bedside. The approach used here is designed to be a fast and easy way to obtain a reasonablenutritional prescription.

First, a type of tube feed should be selected. This gets confusing because several dozen tube feed formulations exist from a variety of brands. Below is a classification of common tube feeds. For patients with high residuals or emesis, a more concentrated formulation may be useful.

Rough classification of tube feed formulations

1 kCal/kg, low-protein (~0.04 grams/ml)
- Osmolite 1-cal
- Peptamen
- Nutren 1.0
1 kCal/kg, high-protein (~0.065 grams/ml)
- Promote, Promote with fiber
- Replete, Replete with fiber
- Peptamen VHP
1.5 kCal/kg concentrated (~0.065 grams/ml)
- Isosource 1.5
- Nutren 1.5
- Peptamen 1.5
- Osmolite 1.5
- Jevity 1.5
- Respalor 1.5
2 kCal/kg concentrated (~0.08 grams/ml)
- TwoCal HN
- Nutren 2.0
- NutriRenal 2.0
- NovaSource Renal

The table below provides nutritional prescriptions based on gender, height, and tube feed formulation. The resulting prescription is a rateof the tube feed along with an additional amount of pure protein supplementation (available in different hospitals as either scoops of protein powder or packets of protein paste). This table is based on approximating the caloric requirements as 25 kCal/kg/day and the protein requirement in critical illness as 1.5 grams/kg/day, both using the ideal body weight (2).

This table looks busy, but it's easy to use. For example, suppose that we wanted to provide hypocaloric nutrition to a man with height 68 inches using Nutren 1.5. As shown below, this can be provided using a rate of 15 ml/hour plus 78 grams of supplemental protein per day.

Discussion

For decades it has been dogmatically accepted that nutritional support must provide 100% of the estimated caloric requirement at all times. Although this may seem to be physiologic, it is not the body's natural response to inflammation. Normally inflammation causes a reduction in appetite with negative caloric balance and weight loss. Although this is not sustainable chronically, it is possible that having a negative caloric balance temporarily during acute illness could be beneficial (e.g. due to stimulation of autophagy and avoidance of aspiration).

The ideal caloric intake during acute illness remains unclear. The EDEN trial shows that it is safe to provide 25% of the caloric goal for five days. The PERMIT trial shows that targeting 50% of the caloric goal for two weeks was similarly safe. Although neither trial showed improved mortality, there were some signals of benefit from hypocaloric nutrition (improved gastrointestinal tolerance, improved glycemic control, and more negative fluid balance).

It is possible to imagine that the ideal caloric administration could be dynamic over time (figure below). Initially when the patient is severely ill, it might be unwise or difficult to provide 100% of the estimated caloric requirement. Over time, as the patient recovers, the amount of nutrition could be increased. Acute illness involves characteristic evolution in hemodynamic, endocrine, and fluid shifts so it makes sense that nutritional requirements would be dynamic as well.

This evidence may not be strong enough to indicate that hypocaloric nutrition should be used for most ICU patients. However, hypocaloric nutrition may be a reasonable strategy when managing an acutely ill patient with difficulty tolerating tube feeds (e.g. due to emesis and distension). It is possible that the patient may simply not be ready to tolerate 100% caloric nutrition, so attempts to force this intake (e.g. with prokinetic agents) may be ill-conceived. Rather than continuing to chase a target 100% caloric provision, it may be safer and more successful to temporarily target 50% caloric provision with 100% protein administration. This could reduce the likelihood of distension, vomiting, or complete failure of enteral nutrition (with transition to parenteral nutrition).

Nutrition has a variety of effects on the endocrine and immune systems. Clinical evidence is required to determine the ideal nutritional target during acute illness, rather than assuming that 100% nutritional provision is ideal all the time.
The PERMIT trial provides evidence that hypocaloric nutrition is safe among most acutely ill ICU patients for limited periods of time (e.g. 50% calorie provision for two weeks with administration of 100% of protein requirements).
Currently it is unclear whether hypocaloric or full nutrition is superior upon admission to the ICU. The ideal nutritional strategy likely varies between patients based on several variables (e.g. pre-existing malnutrition, difficulty tolerating feeds).
Hypocaloric nutrition may be a reasonable short-term approach for many patients who are having difficulty tolerating 100% caloric administration.
For most ICU patients (e.g. without morbid obesity or renal failure), the following table may be used to quickly estimate a prescription for enteral nutrition which provides 100% of estimated protein requirements despite varying levels of calories.

Same figure on its side (may be easier to read with a smartphone):

Additional reading

Schetz M et al. Does artificial nutrition improve outcome of critical illness? Critical Care 2013.
Wischmeyer PE. The evolution of nutrition in critical care: how much, how soon? Critical Care 2013.

Notes

(1) The term “trophic” feeding refers to very low levels of enteric feeding intended to prevent atrophy of the gut border. This may also be referred to as “trickle” feeding.

(2) Note that 1.5 grams/kg/day protein and 25 kCal/kg are consistent with both ASPEN and ESPEN Guidelines (American & European nutritional societies)(Weijs 2013). There seems to be a bit more consensus about protein requirements, with the 1.5 g/kg/day figure consistent with recommendations and most articles on the topic. There are a wider variety of equations and methods used for determining total energy requirement.