Nutrition therapy in critical illness: a review of the literature for clinicians

In recent years, there has been much interest in the role of nutrition therapy in critical illness with an increase in publications and two updated international clinical guidelines [1, 2]. However, trial findings and guideline recommendations continue to be conflicting, making the translation of evidence into practice challenging. Further, it is becoming evident that the stage of critical illness and individual factors such as body composition may be important when considering how individuals might respond to nutrition interventions [3, 4]. This narrative review aims to provide a summary and interpretation of the adult critical care nutrition literature, with a particular focus on continuing practice gaps and areas with new data, to help clinicians make practical, yet evidence-based decisions regarding nutrition management during critical illness.

It is recognised that ‘one-size fits all’ and ‘set and forget’ approaches to nutrition do not adequately address the complex metabolic, hormonal, and immunological changes that occur with critical illness [3, 5]. It is essential that clinicians understand these processes and the impact on nutrient metabolism [4]. In 1942, Cuthbertson described two distinct metabolic phases during acute illness—the ‘ebb’ or early shock phase, followed by the ‘flow’ or catabolic phase [6]. In brief, the ‘ebb’ phase is characterised by haemodynamic instability and hormonal changes (including insulin resistance) in order to prioritise the delivery of energy substrates to vital tissues [6, 7]. This survival mechanism results in endogenous glucose production as well as lower energy expenditure compared to pre-injury [4]. The ‘flow’ phase involves the breakdown of tissue (including lean muscle tissue) in order to provide substrates to cover the immediate needs for the ‘fight or flight’ response and to reduce the risk of bleeding and infection [4]. More recently, a third, anabolic recovery phase has been described [3]. It is during this recovery phase when resynthesis of lost tissue can take place and the body may be more metabolically able to process delivered nutrients [3, 4]. Currently, there is no known clinical marker to identify when an individual shifts from one phase of critical illness to another. For the purposes of this review which aims to provide practical recommendations, we have adapted the terminology from the 2019 European Society of Parenteral and Enteral Nutrition (ESPEN) critical care guideline to describe the different stages of critical illness: ICU day 1–2 (acute early phase), ICU day 3–7 (acute late phase), and after ICU day 7 (recovery phase) [2].

While it is considered that nutrition may be more physiologically available and hence more important in the later phase of illness, due to the average intensive care unit (ICU) length of stay (LOS), the majority of nutrition trials have provided nutrition interventions in the acute phases of illness (regardless of the intended trial intervention period). Traditionally, it was thought that aggressive nutrition in the early stages of critical illness may improve clinical outcomes. However, evidence from recent randomised controlled trials (RCTs) does not support this, finding no benefit or harm with early nutrition delivery [8‐11]. An explanation for this may be because a substantial amount of energy was provided in a period of critical illness where energy expenditure is decreased and endogenous production is enhanced [4]. Specifically, harm was observed in The Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically ill Patients (EPaNIC) trial, the largest nutrition trial in critical illness [10]. In a study of 4640 mixed ICU patients (n = 2818 (61%) cardiac surgery patients) who were eligible to receive EN, late initiation of PN (started on day 8 of the ICU stay) led to an increase in the proportion of patients discharged alive and earlier from ICU and hospital (hazard ratio (HR) 1.06; 95% CI 1.00–1.13; p = 0.04 for both) when compared to PN commenced within 48 h of ICU admission [10]. Late initiation PN also led to a reduction in infectious complications (22.8% vs 26.2%, p = 0.008), cholestasis, duration of mechanical ventilation (MV), duration of renal replacement therapy, and health care costs [10]. Most recently, results from the largest enteral nutrition (EN) trial, The Augmented versus Routine approach to Giving Energy Trial (TARGET), support the theory that augmented energy delivery in the early phase of illness does not improve clinical outcomes compared to standard care [8]. This pragmatic prospective RCT of 3957 patients assessed 90-day mortality with augmented energy delivery (based on a predictive estimate of 1 ml/kg ideal body weight for height per day), compared to routine care [8]. Energy delivery was 50% higher in the intervention group (~ 30 kcal/kg ideal body weight/day) over the median 6-day nutrition delivery period (and approximated clinician estimated energy aims) but did not impact mortality or any secondary clinical outcomes [8]. However, it must be noted this study included a very ‘general’ (or unselected) population and that overfeeding may have occurred. Further post hoc work may increase the understanding and clinical implications of these results. Lack of benefit has also been observed with hypocaloric (low energy and adequate protein) and trophic (low energy and protein) feeding strategies compared to standard care, also provided early in critical illness and for short periods [9, 12]. The results of these trials support the hypothesis that for mixed ICU patients, nutrition interventions in the acute early and acute late phase of critical illness may not impact clinical outcomes and may cause harm in some groups. Therefore, less than 100% of energy expenditure should be targeted in this period due to endogenous glucose production. It remains unknown whether nutrition interventions continued for longer, impact functional recovery and quality of life [3].

There are currently four international clinical practice guidelines available to inform the nutrition management of critically ill patients [1, 2, 13, 14]. Table 1 summarises each guideline and outlines key recommendations and their level of supporting evidence.

Determination of energy requirements is one of the most significant challenges in critical illness and is of vital importance as prescribed targets are used to guide nutrition delivery. Predictive equations that estimate energy expenditure are the most commonly used method due to their ease of application but are often inaccurate compared to measured energy expenditure using indirect calorimetry [15]. Table 2 summarises why predictive equation estimates vary from measured energy expenditure [16, 17]. Importantly, inaccuracies increase at the extremes of weight, in the most severely unwell, and in older and more malnourished populations [16, 18]. Despite these failings, predictive equations continue to be widely used and are recommended in international clinical guidelines in the absence of indirect calorimetry [1, 2].

In states of stress, such as in critical illness, the synthesis of acute phase proteins and those involved in immune function increase to support recovery [30]. Rapid and significant loss of skeletal muscle mass occurs to provide precursor amino acids to aid this process [31]. Despite a lack of definitive evidence, clinical guidelines recommend protein delivery of between 1.2 and 2 g/kg/day (Table 1) based on the assumption that like energy, delivery of adequate protein will attenuate skeletal muscle wasting and improve clinical outcomes. The ASPEN/SCCM guidelines also make recommendations for higher protein provision in specific clinical conditions (i.e. burns, obesity, and multi-trauma), which again are based on limited, primarily observational data and expert opinion [1]. The variation in the clinical guideline recommendations for protein delivery reflects the lack of good quality trials investigating the role of protein provision on clinical outcomes.

One of the most important pieces of information that clinicians should consider is that patients do not receive the energy and protein dose that is prescribed. In a recent retrospective observational study of 17,524 patients, the mean ± standard deviation energy and protein received was 56 ± 30% and 52 ± 30% of the intended aim, respectively [43]. This has consistently been shown across different time periods and geographical regions [44]. The reasons for this are multifactorial, including interruptions to EN for procedures, delayed initiation of nutrition, and gastrointestinal intolerance [45].

In light of the current evidence, the authors support the gradual introduction of nutrition therapy during the acute phases of critical illness, with energy and protein targets outlined in Fig. 1. In patients who are ‘at risk’ of refeeding syndrome, it is crucial that nutrition therapy is introduced slowly, and electrolytes are monitored closely and replaced as necessary [46]. If hypophosphatemia is present (e.g. < 0.65 mmol/l) in the first few days after starting nutrition therapy, then energy delivery should be restricted to ~ 50% requirements for 2–3 days [47].

The measurement of weight and muscularity is important in the assessment of nutrition status and monitoring the effectiveness of nutrition interventions [61]. However, due to the extreme fluid shifts that critically ill patients experience, measured weight and/or muscularity assessed by traditional bedside methods (e.g., subjective physical assessment, mid-arm muscle circumference) may be inaccurate in this patient population [62‐64]. Table 4 summarises the emerging tools for assessment of muscularity in the ICU setting: computed tomography image analysis, bioimpedance analysis, and ultrasound. Currently, these methods for assessing muscle mass and quality are mostly limited to research [64‐66]. There is an essential need to evaluate which bedside tools can accurately measure muscle mass, and identify those individuals with lower than normal muscularity, as well as to better understand the clinical importance of changes in muscle health and the interface with nutrition interventions in critical illness.

RCTs conducted to date have focused on key practice questions, but included heterogenic populations. These studies have not shown clinical benefit with nutrition interventions for reasons previously discussed though there are several patient subgroups that may still benefit from nutrition interventions. In an attempt to investigate such groups, a number of large RCTs have included pre-planned subgroup analysis (e.g. response to the intervention according to differing BMI category). However, results from these types of analyses must be interpreted with caution as the sample size may be small. Moreover, if a benefit or harm is observed in a subgroup, but the overall trial result suggests no difference, it must be considered that another subgroup hidden in the heterogeneous population may have experienced the opposite effect.

The limited data available indicates that the predominant mode of nutrition following an ICU admission is via the oral route and nutrition intake in this period remains below clinician recommendations. In 32 patients from 2 centres, nutrition intake was assessed 3 times per week in the post-ICU phase [71]. Oral nutrition was the most common type of nutrition therapy (55% of study days) [71]. The median [interquartile range] energy and protein intake was 79% [41–108%] and 73% [44–98%], respectively; however, considerable variation was observed depending on the type of nutrition therapy provided, with energy and protein provision the lowest in patients who received no additional oral nutrition supplements (37% [21–66%] of target energy and 48% [13–63%] protein) [71]. A second single-centre study of patients with traumatic brain injury indicated poorer intake post-ICU compared to in ICU, and nutritional deficit was significantly greater in patients who consumed oral nutrition alone compared to those receiving artificial nutrition support [72]. Despite this, dietitians spent just 20% of their time managing patients receiving oral nutrition therapy and saw the patients a mean of 2.2 (1.0) times per week for 34 (20) min per occasion on the post-ICU ward [72]. The predominant issues impacting nutrition intake are reported as appetite, disinterest in food, and taste changes [73].

Unfortunately, non-individualised, ‘one-size fits all’ processes to the management of nutrition are likely impacting on nutrition adequacy in the post-ICU period. In one of the only studies investigating processes that impact nutrition in the post-ICU period, it was found that of nine patients transferred to the post-ICU ward, six had their gastric tube removed on the advice of the medical team without assessment of nutrition intake [73]. Early removal of gastric tubes may improve patient comfort and is encouraged by many post-surgical protocols, but has the potential to negatively impact nutrition intake [73]. The decision to remove a tube should be made on a case-by-case basis and after consultation with the patient, the treating team, and the dietitian [74]. Among other possible causes, it is plausible that inadequate nutrition following critical illness may result in significant energy and protein deficit and may explain the lack of benefit in long-term outcomes observed in nutrition studies that have delivered an intervention in the acute early and late phases. This is an important knowledge gap for investigation and to provide initial insights; a multicentre RCT is underway (ClinicalTrials.​gov NCT03292237).

Results from recent large-scale trials highlight that in heterogeneous groups of patients, full feeding in the acute phases of critical illness does not provide an advantage over trophic feeding and may be harmful. It remains uncertain what impact specific nutrition interventions have in the recovery phase of illness and in specific subgroups who may respond differently to nutrition interventions. The effect of nutrition delivery on other clinically meaningful outcomes, such as muscle health and physical function, is also insufficiently studied. We recommend nutrition prescriptions that tailor for pre-admission nutrition status, and severity and stage of illness. Particular attention should be paid to patients that are in (or likely to stay in) ICU for greater than a week, with ongoing monitoring of nutrition delivery and regular review of measured or estimated nutrition requirements.