The Role of Nutritional Support in the Physical and Functional Recovery of Critically Ill Patients

A Narrative Review

Danielle E. Bear; Liesl Wandrag; Judith L. Merriweather; Bronwen Connolly; Nicholas Hart; Michael P. W. Grocott


Crit Care. 2017;21(226) 

In This Article

Timing of Nutrition Support

Most experts and guidelines agree that EN should be commenced within 24–48 hours of admission to the ICU.[1,8,20,21] Early EN is encouraged to assist with the maintenance of gut integrity, modulation of the stress and immune response and attenuation of disease severity,[22,23] which may, in turn, improve overall outcome.[24] The most recent meta-analysis of trials investigating the effect of early EN was performed as part of the joint American Society for Parenteral Nutrition (ASPEN) and Society of Critical Care Medicine (SCCM) guidelines for the provision of nutrition support in critical illness.[8] This systematic review identified 21 RCTs meeting their inclusion criteria and found that provision of early EN was associated with a significant reduction in mortality and infectious morbidity compared with withholding early EN (delayed EN or standard care).[8]

In contrast to this convincing evidence, others argue that anorexia may be a preserved evolutionary response and that early starvation or limiting nutritional intake over the first 48–72 hours to the first week of critical illness is beneficial.[25,26] This notion contrasts with results of many observational studies reporting that feeding via the enteral route alone leads to significant underfeeding which in turn is negatively associated with the standard outcome measures of mortality, length of stay and infection frequency.[27,28,29,30] As a consequence of these findings, the use of PN has increased over recent years, which raises further questions in relation to the timing of nutrition support.

In the large EPaNIC trial (Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients),[7] the use of early PN to supplement early insufficient EN led to greater muscle weakness, thought to be related to impaired autophagy.[31] For this reason, the use of PN (either exclusive or supplemental) is not recommended over the first 7 days of ICU admission in patients who are not considered to be at high nutritional risk.[8]

Despite these opposing views, studies investigating the impact of withholding nutrition completely over the first week of critical illness do not exist and guidelines continue to recommend increasing nutrition support over the first week of critical illness to meet target recommendations.[8,20,21] Additionally, studies undertaken after the first week of critical illness, and indeed in the post-ICU phase, are lacking. This will be discussed later in the review, but essentially the impact of usual nutritional practice in the ICU on the physical and functional recovery of ICU patients is unknown.

The presumed benefit of nutritional support during critical illness, in order to reduce muscle wasting, is based on three assumptions. The first assumption is that all patients absorb all of the nutrients delivered; the second is that the critically ill skeletal muscle can utilise the nutrients which are delivered; and the third assumption is that the consequence of these processes is always an anabolic and never a catabolic effect.[32] Contrary to these assumptions, delays in gastric emptying[33] and incomplete absorption from the small bowel[34] may significantly alter the presumed benefit. In addition, little is known about the ability of skeletal muscle to utilise these nutrients at different time points over the ICU admission. It is possible that current feeding methods may not physiologically be able to produce the desired outcome benefit or that provision of nutrients does not result in anabolism, particularly in the earliest phase of critical illness (e.g. first 48–72 hours)[35] or in clinical conditions defined by persistent inflammation and hypoxia.[16] Studies investigating the anabolic effect of nutrition at different time points over the course of critical illness and recovery are required to provide further guidance on the most appropriate timing of nutrition support in order to influence these outcomes.

Dose of nutrition support


In general, critically ill patients do not meet recommended levels of nutritional intake, particularly when the enteral route is used alone.[36] This is true both in routine clinical practice[36] and in the setting of RCTs.[2,3,4] The effect of underfeeding during the period of critical illness on skeletal muscle wasting and physical function is wholly unclear. One-year follow-up from the EDEN trial (Early vs Delayed Enteral Feeding to Treat People with Acute Lung Injury or Acute Respiratory Distress Syndrome) suggested that there was no beneficial effect on physical function from target compared with trophic enteral feeding over the first 6 days of critical illness,[37] albeit in the context of a number of confounders that would need further consideration. However, more patients in the trophic feeding group were discharged to rehabilitation centres, suggesting that there may be some beneficial effect to improving nutritional intakes.[37] Noteworthy in this trial is that patients in the full feeding group only met 70% of the energy targets which may not be sufficient to produce an outcome benefit, at least when predictive equations are used.[30] In contrast, a sub-group analysis from the Reducing Deaths due to Oxidative Stress Study (REDOXs) found that increasing nutritional adequacy led to improvements in 3-month Short Form-36 (SF-36) scores relating to the physical domains. However, this effect was diminished by 6 months.[38] Other large RCTs have also included physical or quality of life outcomes with varying results (Table 1).[2,3,31,38,39,40,41,42]

Two pre-planned sub-group analyses from the EPaNIC study investigated the impact of the macronutrient dose (in the form of early vs late supplemental PN) on rates of skeletal muscle wasting.[31,39] The first of these[31] found that muscle wasting, measured from muscle biopsies, was not different between the two groups. In addition, using the Medical Research Council (MRC) sum-score, weakness was found to recover faster in the group receiving late PN. In the second of these sub-group analyses,[39] early PN was shown to adversely impact on femoral muscle quality, measured using computed tomography (CT) scans, but did not affect the rates of wasting observed in 15 neurosurgical patients.

It is likely that the timing and dose of energy provision go hand in hand. Indeed, recent thinking suggests that consideration of the endogenous production of energy in early critical illness is essential to the timing and dose of nutritional supplementation.[1] However, with no bedside method to measure endogenous energy production, it is impossible to account for this when calculating energy expenditure and devising feeding regimens. It has been postulated that in early critical illness (e.g. within the first 72–96 hours) permissive underfeeding to approximately 15 kcal/kg with full protein nutrition support may be warranted,[43] but this awaits confirmation of benefit in RCTs. In addition, the use of predictive equations to determine energy targets may heavily influence the results of nutrition trials in the ICU as they are known to produce results which are less accurate than measured energy expenditure (MEE) using indirect calorimetry.[44] Indeed, studies feeding to MEE have consistently shown positive benefits and a recent observational study found that feeding to 70% of MEE was optimal in terms of mortality.[45] However, limitations preclude the frequent use of indirect calorimetry in clinical practice. These include availability of accurate metabolic monitors, costs, time taken to undertake the measurement and specific exclusions meaning that some of the sickest patients are unsuitable for measurement (e.g. those on continuous renal replacement therapy and those with high oxygen requirements).[46] However, the introduction to the market of a metabolic monitor designed specifically for mechanically ventilated patients, with a reasonable cost, is under development and may bypass some of these limitations for future trials.[46] This is particularly pertinent as the effect of this targeted energy feeding on physical and functional recovery remains unknown.


Inadequate protein provision has been considered a contributing factor explaining why RCTs, such as the EDEN trial mentioned earlier,[3] do not show any beneficial impact of nutrition in the critically ill.[47] Early studies investigating protein intake in critically ill patients reported an improvement in whole-body nitrogen balance or whole-body protein turnover, with higher protein intakes.[48] Since then, several large observational studies have reported mortality benefits when higher protein delivery is achieved.[49,50,51] Whilst this may, in part, be because less sick patients may be able to have more protein delivered, this important confounder is accounted for in many of the more recent studies. For this reason, current recommendations range between 1.2 and 2.5 g/kg/day.[8] Whilst it seems plausible that higher protein delivery may attenuate skeletal muscle loss, the data supporting enhancement of muscle strength and function are lacking.[52] Secondary outcome results relating to the physical function component of the SF-36 score from the Nephro-Protective Trial,[53] investigating the effect of intravenous amino acid supplementation on development of acute kidney injury, are awaited to contribute to the current evidence base.

One recent RCT investigated the effect of different protein intakes on muscle strength, wasting and fatigue in critically ill patients receiving PN.[42] In this study, 119 patients were randomised to receive 0.8 or 1.2 g/kg protein. There was no difference in the primary outcome of handgrip strength at ICU discharge. However, despite a smaller than planned difference in the delivery of protein (0.9 g/kg vs 1.1 g/kg), the study found that a higher protein intake resulted in differences in secondary outcomes including greater handgrip strength at day 7, improved measures of forearm muscle thickness and rectus femoris cross-sectional area and reduced fatigue scores. These results support the concept that a higher protein intake, at least when supplied via the parenteral route, leads to a reduction in muscle wasting during the first week of critical illness. However, such preliminary findings await confirmation in larger studies that would, in particular, need to correct for baseline heterogeneity, as these results are in contrast to observational data from the EPaNIC Study[31,39] and from the MUSCLE-UK group where higher protein delivery was observed to be associated with greater skeletal muscle wasting.[16]

Taken together, these data have led to the hypothesis that it may not be the amount of protein delivered, but the way in which we deliver the feed in a continuous manner that drives skeletal muscle wasting.[32] In healthy subjects, muscle protein synthesis increases from 45 to 90 minutes after provision of amino acids, either oral or intravenous, but then decreases after 90 minutes.[54,55] This effect is observed despite the continued availability of amino acids in both the plasma and muscle, and has been termed the 'muscle full effect'. It is not unreasonable to consider that this effect is also relevant in critically ill patients, and this hypothesis underpins the rationale for the current multi-centre RCT comparing intermittent and continuous feeding to investigate the effect on skeletal muscle wasting.[35]