Journal of Human Nutrition and Dietetics

REVIEW Impact of supplementation with amino acids or their metabolites on muscle wasting in patients with critical illness or other muscle wasting illness: a systematic review L. Wandrag,1 S. J. Brett,2 G. Frost1 & M. Hickson1 1

Department of Investigative Medicine, Nutrition and Dietetic Research Group, Imperial College London, London, UK Centre for Peri-operative Medicine and Critical Care Research, Imperial College Healthcare NHS Trust, London, UK

2

Keywords b-hydroxy-b-methylbutyrate, branched-chain amino acid, critical illness, essential amino acid supplement, leucine, muscle wasting. Correspondence L. Wandrag, Department of Nutrition & Dietetics, Charing Cross Hospital, Laboratory Block 13th Floor, Fulham Palace Rd, W6 8RF London, UK. Tel.: +44 (0)20 331 17844 Fax: +44 (0)20 331 11440 E-mail: [email protected] How to cite this article Wandrag L., Brett S. J., Frost G., Hickson M. (2014) Impact of supplementation with amino acids or their metabolites on muscle wasting in patients with critical illness or other muscle wasting illness: a systematic review. J Hum Nutr Diet. doi: 10.1111/jhn.12238

Abstract Muscle wasting during critical illness impairs recovery. Dietary strategies to minimise wasting include nutritional supplements, particularly essential amino acids. We reviewed the evidence on enteral supplementation with amino acids or their metabolites in the critically ill and in muscle wasting illness with similarities to critical illness, aiming to assess whether this intervention could limit muscle wasting in vulnerable patient groups. Citation databases, including MEDLINE, Web of Knowledge, EMBASE, the metaregister of controlled trials and the Cochrane Collaboration library, were searched for articles from 1950 to 2013. Search terms included ‘critical illness’, ‘muscle wasting’, ‘amino acid supplementation’, ‘chronic obstructive pulmonary disease’, ‘chronic heart failure’, ‘sarcopenia’ and ‘disuse atrophy’. Reviews, observational studies, sport nutrition, intravenous supplementation and studies in children were excluded. One hundred and eighty studies were assessed for eligibility and 158 were excluded. Twenty-two studies were graded according to standardised criteria using the GRADE methodology: four in critical care populations, and 18 from other clinically relevant areas. Methodologies, interventions and outcome measures used were highly heterogeneous and meta-analysis was not appropriate. Methodology and quality of studies were too varied to draw any firm conclusion. Dietary manipulation with leucine enriched essential amino acids (EAA), b-hydroxy-b-methylbutyrate and creatine warrant further investigation in critical care; EAA has demonstrated improvements in body composition and nutritional status in other groups with muscle wasting illness. High-quality research is required in critical care before treatment recommendations can be made.

Introduction Muscle wasting of patients on the intensive care unit (ICU) is of considerable concern, with patients losing between 1–2% of lean body mass per day (Gamrin et al., 1997; Plank & Hill, 2000), resulting in delayed recovery, as well as increased mortality and morbidity (Herridge et al., 2011; Bienvenu et al., 2012). Physical disability has been identified up to 5 years after ICU admission as a result of muscle weakness (Herridge et al., 2011). Muscle weakness acquired during critical illness has been independently associated with increased hospital mortality ª 2014 The British Dietetic Association Ltd.

(Ali et al., 2008). Muscle wasting is considered to contribute significantly to the muscle weakness experienced (Herridge et al., 2011). Muscle wasting is a multifactorial phenomenon, with the contributing factors comprising: the neuroendocrine response to trauma and critical illness; infection, sepsis and cytokine release (Soeters & Grimble, 2009); corticosteroid use; critical illness myopathy; nerve and neuromuscular junction changes; polyneuropathy; disuse atrophy (prolonged sedation and paralysis) and inadequate nutrition (Anzueto, 1999; Griffiths & Hall, 2010). Even with intense nutritional support, muscle wasting still occurs (Reid et al., 2004). 1

Amino acid supplementation in critical illness

Preservation of muscle mass is clearly crucial for patient rehabilitation [National Institute for Health & Care Excellence (NICE), 2009]; however the exact mechanisms involved with muscle wasting are still disputed and optimal nutritional support on the ICU has yet to be defined. Various strategies to minimise muscle wasting have been explored. Propranolol (a b-blocker) and oxandrolone (a testosterone analogue) increased lean body mass and protein synthesis in children after severe burns (Herndon et al., 2001, 2012; Jeschke et al., 2007). Many strategies have however failed, to show direct benefit and some were reported to worsen outcome (e.g. increased patient mortality observed with growth hormone administration in critically ill patients) (Takala et al., 1999). Studies looking at early mobilisation of ventilated patients have demonstrated feasibility, although prospective studies will be required to evaluate the impact of such stategies on muscle mass (Kress, 2009). Electrical muscle stimulation (EMS) has shown initial promise in terms of preservation of muscle mass (Gerovasili et al., 2009); however, larger prospective studies will be required to evaluate the exact role of EMS in muscle strength preservation (Parry et al., 2013). Similarly, numerous protein and amino acid preparations have been studied over the past decades with various levels of success. Branched-chain amino acids (BCAA; valine, leucine, isoleucine) were studied in the ICU population with some promise but studies often failed to address background nutrition. Furthermore, the ratio of BCAA used (valine : leucine : isoleucine of 1 : 1 : 1) now appears to be sub-optimal (Cynober & Harris, 2006). Importantly, leucine is known to promote muscle protein synthesis by stimulating the mammalian target of rapamycin (mTOR) signalling pathway involved with protein synthesis (Rennie et al., 2006). Studies using leucine supplementation demonstrate muscle protein synthesis in elderly subjects (Anthony et al., 2001); however, although muscle protein synthesis was observed in young subjects, this did not translate to an overall gain in protein balance (Glynn et al., 2010). Septic rats did not demonstrate an anabolic response either (Kazi et al., 2011). For populations with muscle wasting disorders, such as cachexia, b-hydroxy-b-methylbutyrate (HMB), a metabolite of leucine, has shown some promise in restoring lean body mass (Clark et al., 2000; May et al., 2002). Few amino acid supplementation studies exist in critical care; therefore, conditions with similarities to critical care have been assessed, including studies in patients with chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), age-related muscle wasting and bed rest studies. Although COPD and CHF as chronic diseases clearly differ from critical illness as an acute insult, many similarities in the pathophysiology of muscle wasting exist: muscle wasting during critical illness may be 2

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initiated by systemic inflammation, as suggested by raised C-reactive protein (CRP), interleukin-6 (IL-6) and tumour necrosis factor (TNF)-a levels (Callahan & Supinski, 2009; McCarthy & Esser, 2010; Winkelman, 2010), whereas raised CRP, IL-6 and TNF-a levels have also been reported in COPD patients with muscle wasting (Jagoe & Engelen, 2003; Agusti et al., 2004; Yende et al., 2006) and systemic inflammation of both acute and chronic nature has been described in COPD patients (Oudijk et al., 2003). Oxidative stress with raised levels of nitric oxide and reactive oxygen species may contribute to muscle breakdown during critical illness (Dodd et al., 2010; McCarthy & Esser, 2010) as well as in COPD patients (Oudijk et al., 2003). Tissue hypoxia may also contribute, particularly because the nuclear factor kappaB catabolic pathway may be activated during hypoxia (de Theije et al., 2011; McCarthy & Esser, 2010), and this pathway has also been found to be activated in COPD patients with muscle wasting (Agusti et al., 2004; Ladner et al., 2003; Oudijk et al., 2003). Skeletal muscle apoptosis or programmed cell death has been observed in COPD and CHF patients (Agusti et al., 2002), as well as in the critically ill (Attaix et al., 2005; Jespersen et al., 2011). Muscle fibre atrophy and fibre type change have additionally been reported in the critically ill (Puthucheary et al., 2013), in COPD patients (Gosker et al., 2003) and in CHF patients (Vescovo et al., 1996). Quantitatively, muscle wasting in the critically ill may be more accelerated by 1–2% per day (Puthucheary et al., 2013; Reid et al., 2004), and by 20–40% during the disease process for COPD patients (Jagoe & Engelen, 2003). Age-related muscle wasting, or sarcopenia, also shares similarities to muscle wasting in critical illness not only because the elderly are increasingly being represented within critical care, but also because sarcopenia is characterised by diminished anabolic signals and the promotion of catabolic signals, such as pro-inflammatory cytokines, as well as the presence of oxidative stress and mitochondrial dysfunction (Roubenoff & Hughes, 2000; Carmeli et al., 2002; Kamel, 2003; Morley & Baumgartner, 2004). Lastly, although the muscle wasting experienced during bed rest or immobility cannot directly be compared to that of muscle wasting during critical illness, immobility during critical illness may contribute to muscle wasting (Ferrando et al., 2006) and bed rest studies may provide a model for studying disuse atrophy because cortisol has been infused into healthy subjects undergoing bed rest to simulate a stress response (Paddon-Jones et al., 2005). Understanding which amino acid component might play a role in ameliorating muscle wasting during critical illness may contribute to the successful rehabilitation of these patients. We reviewed the literature focusing on enteral supplementation with amino acids and amino acid ª 2014 The British Dietetic Association Ltd.

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metabolites in the critically ill or other muscle wasting illness with similarities to critical illness, aiming to assess whether this intervention can limit muscle wasting in vulnerable patient groups.

Amino acid supplementation in critical illness

Interventions Enteral supplementation with amino acid and amino acid metabolites were included: leucine and HMB (a leucine metabolite), as well as mixed preparations of amino acids, branched-chain amino acids or essential amino acids.

Methods A literature search was conducted using Pubmed, MEDLINE, Web of Knowledge (Web of Science, Biosis Citation Index and Journal Citation Reports), EMBASE, the meta-register of controlled trials and the Cochrane Collaboration library database. Keywords used in the search were ‘critical illness’, ‘critically ill patient’, ‘intensive care’, ‘chronic obstructive pulmonary disease’, ‘chronic heart failure’, ‘sarcopenia’, ‘bed rest’, ‘disuse atrophy’, ‘muscle wasting’, ‘amino acid supplementation’, ‘amino acid metabolite’, ‘enteral nutritional supplementation’, ‘muscle mass’, ‘lean mass’, ‘muscle breakdown’ and ‘muscle building’. Reference lists were hand searched. There were no restrictions for language of publication provided that an English abstract was available. Databases were searched from 1950 to 1 December 2013. Indices of current clinical trials were also accessed to identify current trials: Clinical trials (www.clinicaltrials.gov); current controlled trials (www.controlled-trials.com) and the meta-register of clinical trials (www.controlled-trials.com/mrct); INVOLVE via www.invo.org.uk/database and www.nihr.ac.uk. Inclusion criteria Interventional studies using enteral supplementation with amino acid or amino acid metabolites in the adult critically ill, in patients with chronic obstructive pulmonary disease, chronic heart failure, age-related muscle wasting (sarcopenia) or disuse atrophy (bed rest studies) were included. Studies were included if the aim of the study was to improve nitrogen balance, lean body mass and muscle function or strength with amino acid or metabolite supplementation. Exclusion criteria Papers were excluded if they were review papers; observational studies; interventional studies focusing on multiple nutritional supplementation (e.g. combination products containing fish oils, anti-oxidants and amino acids); studies where amino acids were used for immunonutrition purposes (i.e. glutamine); sport nutrition studies; intravenous supplementation studies; studies in children; studies in young subjects not undergoing bed rest; studies including cancer cachexia; liver disease; renal disease and HIV/ AIDS. Molecular and mechanistic discussions fall outside of the scope of this review. ª 2014 The British Dietetic Association Ltd.

Outcome measures These varied enormously and were placed into seven broad categories: ICU/hospital outcomes: length of stay; mortality and infectious outcomes including antibiotic use. Functional and strength testing: step, walk and stair tests; lung function tests; activities of daily living scores; grip strength; quadriceps twitch force and muscle function tests. Body composition: dual energy X-ray absorptiometry; weight, body mass index; bioelectrical impedance analysis; computed tomography; air displacement techniques; mid arm circumference; triceps skinfold and muscle biopsies. Nutritional: Mini Nutritional Assessment; resting energy expenditure via indirect calorimetry; food intake charts and enteral feed tolerance. Nitrogen balance/protein turnover: plasma amino acids; protein turnover studies; urinary studies including urinary nitrogen and 3-methyl histidine (3-MH). Blood markers/inflammation: inflammatory markers and cytokines; glucose; insulin. Quality of Life: mood questionnaires; depression scores; Short Form Health Survey (SF-36) and a respiratory symptom questionnaire.

• • • • • • •

Quality assessment Studies were initially assessed by the lead investigator (LW) in accordance with the GRADE methodology (Atkins et al., 2004) and, subsequently, consensus on inclusion, exclusion and classification was achieved amongst the whole study group. Briefly, studies were initially graded according to whether they were blinded, controlled, whether a placebo product was used and whether they were adequately powered. Randomised controlled trials were given a high grade and nonrandomised studies were given a moderate or low grade. Subsequently, studies were marked down on limitations of methodology or risk of bias. If a study title contained the words ‘randomised study’ but randomisation was not described adequately in the methodology, the study was downgraded to moderate. Synthesis of results Results were described using the ‘PICO’ framework (population, intervention, comparator, outcome) and quality assessment of individual studies was performed by using 3

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Amino acid supplementation in critical illness

GRADE criteria. Results for ICU studies are presented in Table 1 and those for non-ICU studies are presented in Table 2. Meta-analysis was not performed as a result of the heterogeneous populations, interventions and outcome measures studied. Risk of bias was assessed per GRADE criteria based on study randomisation, blinding and use of control group and placebo. The PRISMA 2009 checklist was used to guide the design of this systematic review (Moher et al., 2009). Results One hundred and eighty articles were assessed for eligibility and 158 were excluded with reason. Twenty-two studies were included and graded. Four ICU studies included two studies in trauma patients, one in general ICU patients and one in critically ill COPD patients. The 18 non-ICU studies included three studies in patients with COPD, one study in chronic heart failure patients, nine studies in elderly subjects with sarcopenia and five studies in subjects undergoing bed rest. The process of study selection is shown in Fig. 1. Intensive care unit studies No ICU studies were graded as high quality. One study was classed as moderate quality (Kuhls et al., 2007) and three as low quality (Jensen et al., 1996; Hsieh et al., 2006; Mansoor et al., 2007). A summary of each study is provided in Table 1. Moderate quality intensive care unit study Kuhls et al. (2007) studied 100 trauma ICU patients comparing HMB supplementation, HMB with additional arginine and glutamine (HMB+) or an iso-caloric, isonitrogenous placebo product. The aim of the study was to assess whether HMB alone or HMB in combination with arginine and glutamine had any effect on nitrogen balance and muscle breakdown. The HMB supplement contained 3 g of HMB, whereas HMB+ contained an additional 14 g of L-arginine and 14 g of L-glutamine. The findings indicate that nitrogen balance improved with the intervention; the mean nitrogen balance was 9, 10.9 and 6.5 g day–1 for the control, HMB+ and HMB groups, respectively (P = 0.05). Interestingly, the HMB+ group appeared to remain in a more negative nitrogen balance throughout the study (P < 0.05), suggesting a possible detriment to added arginine or glutamine. The 3-MH and urinary nitrogen results combined suggest that supplementation did not affect muscle breakdown. There were no significant differences between groups for mortality, 28-day antibiotic use, inflammatory 4

markers, hospital and ICU length of stay, ventilator days and number of new infections. The study followed a randomised, double-blinded and placebo-controlled design; however, the study did have some important limitations. Although a sample size of 100 was reported, only data for 72 patients were analysed, leading to a potential type II error. Twenty-eight subjects were excluded from statistical analysis because they did not meet 50% compliance for supplementation. Additionally, 3-MH was used as a sole marker for muscle proteolysis despite some of its known limitations as a biomarker (i.e. not being a sensitive marker of specific tissue pools), whereas prealbumin was used as a surrogate for protein synthesis. Despite the limitations, HMB supplementation appeared to improve nitrogen balance in severely injured trauma patients, and the addition of arginine and/or glutamine appeared to neutralise any benefit of HMB alone. Low-quality intensive care unit studies Twenty-eight ICU patients were given EAA or non-EAA supplements over 10 days with the aim of comparing plasma amino acid differences and nitrogen balance (Jensen et al., 1996). No clinical benefit was found with enteral glutamine-enriched EAA supplementation (i.e. no difference found in immune function, plasma amino acid levels or nitrogen balance). Mansoor et al. (2007) performed a study in 12 trauma ICU patients and nine healthy controls where supplementation with threonine, serine, cysteine and aspartic acid was assessed to determine the effects on protein metabolism. This unusual mixture of amino acids was selected based on previous work demonstrating a demand for these particular amino acids in septic rats (reduced weight loss, muscle catabolism and an enhanced recovery) (Breuille et al., 2006). No significant differences between the two ICU groups were found. The study was limited mainly by the small sample size, a lack of statistical power and the short interventional period. The final ICU study included 34 ventilated COPD patients given 3 g day–1 HMB supplementation over 7 days to examine effects on inflammation, protein metabolism and pulmonary function (Hsieh et al., 2006). Anti-catabolic effects were reported; however, protein metabolism was not adequately assessed. The study was further limited by the small sample size, with a lack of statistical power analysis, a short interventional period, a nonrandomised design and a lack of placebo product. Thus, although these data again point to the potential benefits of HMB, the design flaws limit the value of the data. ª 2014 The British Dietetic Association Ltd.

ª 2014 The British Dietetic Association Ltd.

Low Block randomised Double-blinded Placebo controlled Small (n = 19 analysed) Low Block randomised double-blinded controlled Small n = 12 Short study

Jensen et al. (1996)

Intervention 3 g HMB (n = 28) 3 g HMB+ (Arg, Gln) (n = 22) + standard feed (105 kJ kg–1 or 25 kcal kg–1 and 1.5 g protein kg–1) 14, 28 days follow-up

EN with EAA (6 9 Gln amount) (10 days) BCAA ratio: Val : Leu : Iso of 1 : 4 : 1 EN at 125–146 kJ (30–35 kcal kg–1) No mention of protein in feed

Enteral nutrition + Threonine, Serine, Cysteine, Aspartic acid (n = 6) EN: 146 kJ kg–1 (35 kcal kg–1) and 1.55 g protein kg–1

3 g HMB supplement via NGT (1.5 g b.d.) over 7 days No mention of composition of enteral feed

Population

n = 100 trauma ICU patients n = 72 analysed

n = 28 ICU patients (18–75 years)

n = 12 Trauma ICU patients eight healthy controls

n = 34 ventilated COPD patients

Standard enteral feed with no supplement over 7 days

Feed + Alanine (Ala) (n = 6), 10 days Same kcal and nitrogen

Same enteral nutrition with non-EAA instead of extra Gln

Placebo + standard feed, 14 days with 28 days follow-up (n = 22)

Comparison

CRP, WCC BUN, Lung function Body weight

Plasma proteins TNF-a, IL1-b, IL-6 Protein turnover N2 balance, 3-MH Muscle biopsies Indirect calorimetry

CRP, TLC, Alb Plasma AA Indirect Calorimetry N2 balance

24-h urine collection 3-MH (muscle breakdown) Prealbumin

Outcome measures

AA did not change plasma protein synthesis, nor whole body protein synthesis or 3-MH excretion Trend towards increased muscle protein synthesis in the interventional group (P = 0.065) Nitrogen balance: 35 g kg–1 in the Ala group and 32 g kg–1 in the interventional group, P > 0.05 Significant ↓ in CRP (P < 0.05) and WCC (P < 0.01) in HMB group. ↓ BUN (not significant)

Urinary excretion of N2: no significant difference between groups (P = 0.23) Nitrogen balance was affected by Rx (P = 0.05) Mean N2-bal (g day–1): 9 Controls 10.9 HMB+ group 6.5 HMB group (P < 0.05) No Rx difference for mortality, 28-day antibiotic use, LOS, ICU LOS, ventilator days, or number of infections No difference: Albumin, prealbumin, N2 balance or energy expenditure

Outcomes

3-MH, 3-methyl-histadine; Alb, Albumin; Arg, Arginine; b.d., twice daily; BUN, blood urea nitrogen; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; EN, enteral nutrition; Gln, glutamine; HMB, b-hydroxy-b-methylbutyrate; IL, interleukin; Iso, isoleucine; LOS, Length of stay; Leu, leucine; N2 Bal, nitrogen balance; NGT, nasogastric tube; REE, resting energy expenditure; Rx, treatment; TLC, total lymphocyte count; TNF, tumour necrosis factor; Val, valine; WCC, white cell count.

Hsieh et al. (2006)

Low not randomised Blinded controlled No placebo Small sample

Moderate Randomised Double-blinded Placebo controlled Power calculation (n = 100)

Kuhls et al. (2006)

Mansoor et al. (2007)

Quality markers

Study

Table 1 Amino acid supplementation studies in the intensive care unit (ICU) L. Wandrag et al. Amino acid supplementation in critical illness

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Quality markers

Moderate Randomised Double-blinded Placebo-controlled Power calculation: n = 60 n = 38: Underpowered

Moderate Block randomisation, Blinded, Placebo-controlled

Moderate Randomised Controlled Small sample size

Study

Fuld et al. (2005)

Rondanelli et al. (2011)

Brooks et al. (2008)

Intervention Oral creatine + glucose polymer Loading phase: 3 9 day over 14 days, then od for 10 weeks during exercise based rehab programme

4 g EAA 9 2 day–1 for 8 weeks BCAA ratio: Val : Leu : Iso of 1 : 2 : 1 Diet: 6485 kJ day–1 (1550 kcal kg–1) and 50 g protein–1 day–1

1. EAA (n = 7) 2. EAA 3 h after resistance training, n = 12 3. EAA 5 min before resistance training, n = 12 BCAA: 1 : 2 : 1 Diet: REE, 54% CHO, 33% fat, 15% protein

Population n = 38 COPD outpatients

n = 41 Elderly nursing home patients (75–95 years)

n = 31 Healthy men (31– 55 years) 28-day bed rest followed by 14 days recovery

EAA without resistance exercise Diet same as interventional group

4 g Maltodextrin placebo (isocaloric) Diet: 8158 kJ day–1 (1950 kcal kg–1) and 59 g protein day–1

Oral glucose polymer as placebo Loading phase: 3 9 day over 14 days, then o.d. for 10 weeks

Comparison

Body Comp: DEXA Weight, BMI CT: thigh muscle/fat Muscle strength REE Monitored food intake

ADL and SF-36 Grip strength Weight, ht, BMI MNA Weighed food intake QoL

Body composition Lower limb muscle performance Shuttle walk test Pulmonary Rehab sessions: 2 9 week

Outcome measures

Table 2 Amino acid supplementation: chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), sarcopenia and bed rest studies

Post-loading: Creatine group: increase lower limb strength (P < 0.05), lower limb endurance (P < 0.01) and handgrip endurance (P < 0.05), Weight and FFM increase (P < 0.05 in both) Post-rehab: Creatine group: increase lower limb strength, endurance, weight, FFM and handgrip strength (all P < 0.05) Activity decreased in placebo group (P < 0.01) Both groups improved MNA and prealbumin Both groups improved grip, more so in EAA (P = 0.001) ADL better in EAA group (P = 0.044) EAA improved QoL (P = 0.02 and 0.03) Body weight: ↓ all groups, (P < 0.01) LBM: ↓ all groups, no difference between groups Thigh muscle area ↓ all groups after bed rest (P < 0.001). Most change in EAA group Muscle strength ↓all (no significant difference between groups)

Outcomes

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Quality markers

Low ‘Randomly assigned’ Blinded Placebo-controlled No sample size calculation

Low Not randomised Cross-over design Small sample Short study period

Low Randomised Blinded Controlled No placebo

Low ‘Randomly assigned’ Placebo-controlled

Study

Dal Negro et al. (2010)

Engelen et al. (2007)

Aquilani et al. (2008)

Verhoeven et al., (2009)

Table 2 (Continued)

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n = 8 Healthy elderly Same liquid test meal

n = 8 COPD outpatients Soy + BCAA liquid test meal, over 2 days BCAA ratio: Val : Leu : Iso of 1 : 2 : 1 to 1 : 4 : 1 4 g EAA supplement twice daily (n = 22) over 2 months BCAA ratio: Val : Leu : Iso of 1:2:1

7.5 g day–1 Leu meals over 12 weeks Diet: 8192 kJ day–1 (1958 kcal kg–1) 60% CHO, 28% fat and 12% protein

n = 16 COPD and healthy elderly

n = 44 CHF patients with depleted skeletal muscle mass

n = 29 healthy elderly men (mean 71 years)

Placebo capsules (wheat flour), same standard meal

No placebo n = 22, no supplement over 2 months, only regular diet

Placebo over 3 months (n = 16)

4 g EAA twice daily over 3 months (n = 16) No information on BCAA ratio

n = 32 COPD outpatients with sarcopenia 25 ♂ 7♀

Comparison

Intervention

Population

Height, weight, leg volume Body comp (CT, DEXA) Muscle biopsies Dietary intake

Weight/BMI AMA (TSF and MAMC) N2-bal (urinary N) 7-day food diary 6-min walk test REE

Protein turnover

BMI FFM via BIA Total protein and Alb QoL Activity monitor

Outcome measures Body weight increased in EAA group by 6 kg, 11%). No P-value reported 3.6 kg (8.9%) increase in FFM reported in EAA group, no P-value reported Whole body protein synthesis: increased in COPD group with soy + BCAA supplement, not soy feed alone (P < 0.05) Weight increase by 1 kg in 80% CHF patients in EAA group, (P < 0.01) AMA increase in both groups (P < 0.02) 6-min walking test increase in EAA group only (P < 0.001) Protein intakes were higher in EAA group 1.3 versus 1.1 g kg–1 (not significant) Muscle strength: No difference between groups or after 12week supplementation Leg volume, FM/FFM: No difference Muscle Tissue: No difference between groups and no change from baseline to 12 weeks

Outcomes

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Quality markers

Low Randomised Double-blinded Placebo-controlled Small sample, No sample size calculation

Low Randomisation not described: ‘assigned’ Power calculation (n = 5 per group) Short study period

Low Randomisation not described Placebo used Small sample

Low Not randomised Small sample Short study period

Study

Dillon et al. (2009)

Volpi et al. (2003)

Freyssenet et al. (1996)

Rieu et al. (2006)

Table 2 (Continued)

Same training + Lactose placebo, n=8 Diet: 11 300 kJ day–1 (15.6% protein, 34.8% fat, 49.6% CHO) 0.071 g kg–1 Alanine as placebo over 5 h only

18 g EAA (n = 6) boluses every 10 min over 3 h + standardised diet pretesting No information on BCAA ratio

6 week endurance training + BCAA (n = 9) val : leu : iso of 1 : 8 : 1 Diet: 11 000 kJ day–1 (18.3% protein, 34.7% fat, 47.1% CHO)

Leu: 0.052 + 0.0116 g kg–1 Iso + 0.0068 g kg–1 Val over 5 h only BCAA ratio: Val : Leu : Iso of 1 : 5 : 1

n = 14 Healthy elderly

n = 17 Elderly men (55–73 years)

n = 20 Healthy elderly (70 years)

40 g Non-EAA + EAA (n = 8) every 10 min over 3 h + standardised diet pretesting

Placebo capsule: lactose, isocaloric (3 months)

Baseline = all subjects 7.5 g EAA for acute response 3/12: 15 g EAA in capsules (7.5 g b.d. in between meals) Val : Leu : Iso of 1 : 1.6 : 1

n = 14 elderly females with sarcopenia (67–69 years)

Comparison

Intervention

Population

Protein turnover Muscle biopsies

Muscle biopsies Dietary intake (3 days food diary + weighed intake)

Strength testing Body composition via DXA Stable isotope study (during acute tests of 7.5 g EAA all subjects) Muscle biopsies pre- and post-EAA Muscle protein metabolism via stable isotopes Muscle biopsies

Outcome measures

Whole body protein turnover: no significant differences between groups Fractional synthesis rates: no significant differences between groups (P = 0.77) Net protein balance across the leg: protein synthesis observed in both groups, no difference between groups No microscopic structural change or other dietary change as a result of BCAA Skeletal muscle structural changes as a result of endurance exercise alone ↑MPS (↑FSR by 55%) after 5 h leucine supplement versus controls (P < 0.05), no change in whole body protein turnover

LBM increased over 3 months in the EAA group only (P < 0.05) Muscle fractional synthesis rate after 3 months in the EAA group (P < 0.05)

Outcomes

Amino acid supplementation in critical illness L. Wandrag et al.

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Quality markers

Low Not randomised No blinding No controls No placebo Small sample

Low Not randomised Single blinded No placebo Small sample

Low Not randomised No placebo Small sample Short study period

Low Not randomised Single blinded Placebo-controlled Small sample

Study

Borsheim et al. (2008)

Casperson et al. (2012)

Katsanos et al. (2005)

Ferrando et al. (2010)

Table 2 (Continued)

n = 8 healthy young 6.7 g EAA over 1 day only

Diet soda (n = 11) + normal diet (0.8 g protein kg–1 day–1), 10 days

4 g 9 3 day–1 Leucine over 2 weeks + simulated meal day 1 and day 15 (7 g of EAA + 10 g CHO) Val : Leu : Iso of 1 : 2 : 1

n = 11 healthy elderly 6.7 g EAA over 1 day only BCAA ratio: Val : Leu : Iso of 1:2:1

45 g EAA (15 g 9 3 day–1) in diet soda (n = 10) + normal diet, 10 days BCAA ratio: 1 : 4 : 1 Diet: weight maintenance

n = 8 Healthy, sedentary elderly subjects (mean age 68 years)

ª 2014 The British Dietetic Association Ltd.

n = 19 healthy subjects (11 elderly and eight young)

n = 21 Elderly Bed rest study

Subjects served as own controls No placebo Diet: 7698 kJ day–1 (1840 kcal kg–1), 62 g protein day–1

No controls No placebo Normal diet = 7250 kJ day–1 (1733 kcal kg–1), 1 g protein kg–1 day–1

11 g 9 2 day–1 EAA + arginine, Normal diet 16 weeks BCAA ratio: Val : Leu : Iso of 1:5:1

n = 12 Glucose intolerant elderly adults + sarcopenia

Comparison

Intervention

Population

DEXA Muscle protein synthesis (isotopes and biopsy) Functional assessment REE

Leg volume, flow Leg lean mass, fat mass (DEXA) Muscle biopsies

FM/FFM via DEXA Prot turnover Muscle FSR Muscle biopsy 9 4 Dietary log

Muscle strength Physical activity DEXA (week 0, 4, 8, 12, 16) Plasma AA

Outcome measures N/s change: physical activity, food intake, plasma AA, weight LBM increased over 16 weeks (P = 0.038) Leg strength increased (P < 0.001) Walk test: speed increased (P = 0.002) Functional test increased (P = 0.007) ↑in MPS after 2 weeks on leucine supplement, day 1 : 0.063 versus day 15: 0.074%/h, (P = 0.004) 2 weeks on leucine supplement ↑mTOR, day 1: 1.03 versus day 15: 1.23, (P = 0.01) Young 2.5 times more leg phenylalanine than elderly (P = 0.010) No significant differences between groups for leg blood flow and plasma amino acid levels Fractional synthesis rate maintained in EAA group (P = 0.025) and not in control group No effect of EAA in total and leg lean mass maintenance

Outcomes

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Low ‘Randomly assigned’ Placebo-controlled Small sample

Low Randomised Placebo-controlled Not blinded Small sample Short study period

Low ‘Randomly assigned’, not described No blinding Small sample Short study period

Paddon-Jones et al., (2004)

Stein et al. (1999)

Paddon-Jones et al., (2003)

n = 6 Diet soft drink + sucrose, no EAA 28 days

30 mmol day–1 non BCAA at 1.3 9 REE over 6 day bed rest

n = 7: 49.5 g EAA day–1 + sucrose in diet drink, 28 days Val : Leu : Iso of 1 : 1.5 : 1 Diet: 59% CHO, 27% fat and 14% protein Energy: estimated

30 mmol day–1 BCAA at 1.3 9 REE, over 6-day bed rest No information on BCAA ratio

15 g EAA + normal diet + cortisol over 1 day BCAA ratio: Val : Leu : Iso of 1:6:1

n = 13 Healthy males Bed rest study

n = 19 Healthy subjects, bed rest (22–37 years), five dropouts

n = 12 Healthy adults Bed rest study

15 g EAA + normal diet (1 day)

Comparison

Intervention

Population

Protein turnover Cortisol Muscle biopsy

Urinary N2 and 3MH Plasma samples N2 Bal (no correction for urinary/faecal losses)

Protein turnover, day 1 and day 28 Muscle biopsies Body composition (DEXA) Strength testing Cortisol and plasma AA

Outcome measures Weight stable in interventional group, ↓in control group (86 versus 83.7 kg, P < 0.01) And leg lean mass maintained where lost in control group, (P < 0.05) FSR ↑in EAA group, not in control group, both day 1 and day 28 (both P < 0.05) ⇒ Muscle mass loss minimised with EAA, strength not preserved N2 retention better in BCAA group, P < 0.03 No effect of BCAA on 3MH BCAA group had 10 mg kg–1 day–1 higher N2 intake (P = 0.51) Protein turnover: increased both groups (not significant) Cortisol: increased in both groups (P < 0.05) Mixed muscle FSR: ↑in both groups in response to EAA (P < 0.05), no between group difference evident

Outcomes

AA, amino acids; ADL, activities of daily living; Alb, albumin; AMA, arm muscle area; Arg, Arginine; b.d., twice daily; BIA, bio-electrical impedance analysis; BMI, body mass index; BUN, blood urea nitrogen; CHO, carbohydrate; CRP, C-reactive protein; CT, computed tomography; DEXA, dual energy X-ray absorptiometry; EN, enteral nutrition; FFM, fat free mass; FM, fat mass; Gln, glutamine; Iso, Isoleucine; Leu, Leucine; LOS, length of stay; MNA, Mini Nutritional Assessment; MPS, muscle protein synthesis; o.d., once daily; QoL, quality of life; REE, resting energy expenditure; TSF, triceps skinfold; Val, valine.

Quality markers

Study

Table 2 (Continued) Amino acid supplementation in critical illness L. Wandrag et al.

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L. Wandrag et al.

Identification

Amino acid supplementation in critical illness

628 records idenfied through database searching

Eligibility

Screening

415 records aer duplicates removed

415 records screened

180 full-text arcles assessed for eligibility

235 excluded

158 excluded with reason

Included

22 studies included and graded

4 ICU studies

18 non-ICU studies

Figure 1 Process of study selection in accordance with the PRISMA 2009 guidelines (Moher et al., 2009). ICU, intensive care unit.

Overall, the data from ICU studies are very limited but suggest that HMB may improve nitrogen balance, although this improvement was marginal. Nevertheless, ICU is an extremely challenging environment in which to carry out research and so an exploration of other clinically relevant areas may be warranted. Non-intensive care unit studies Eighteen studies were identified in non-ICU settings. No studies were graded as high quality, three were of moderate quality (Fuld et al., 2005; Brooks et al., 2008; Rondanelli et al., 2011) and fifteen studies were of low quality (Freyssenet et al., 1996; Stein et al., 1999; Paddon-Jones et al., 2003, 2004; Volpi et al., 2003; Katsanos et al., 2005; Rieu et al., 2006; Engelen et al., 2007; Aquilani et al., 2008; Borsheim et al., 2008; Dillon et al., 2009; Verhoeven et al., 2009; Dal Negro et al., 2010; Ferrando et al., 2010; Casperson et al., 2012). A summary of each study is provided in Table 2. Chronic obstructive pulmonary disease One moderate quality study and two low-quality studies were assessed. In a moderate quality study in 38 COPD patients undergoing pulmonary rehabilitation, the use of 5.7 g of oral creatine monohydrate (a metabolite of arginine, glycine and methionine, which is widely used in the ª 2014 The British Dietetic Association Ltd.

exercise arena to support muscle anabolism) was assessed on muscle function, strength, lung function and quality of life (Fuld et al., 2005). Creatine increased fat-free mass, lower limb strength and endurance in the post-loading and post-rehabilitation phase. The limitations of the study include a small sample size, a high drop-out rate (39% for the placebo group and 22% for creatine), and no assessments of nutrient intake, nor baseline nutritional status. Thus, creatine may offer an option for supplementation in ICU patients that could be tested. Muscle wasting is commonly observed in COPD patients, contributing to poor physical function. Dal Negro et al. (2010) assessed whether 4 g of EAA supplementation would improve body composition, muscle metabolism, physical activity and health status in 32 COPD outpatients with sarcopenia. Body weight and fatfree mass increased in the supplemented group (Table 2); however, P-values were not reported. The study was limited by a small sample size and dietary intakes were not assessed. Nevertheless, interventions aimed at ameliorating muscle wasting in COPD patients with sarcopenia may offer some suggestion of what intervention might minimise muscle wasting during critical illness. A soy test meal with additional BCAA was studied to assess differences in protein metabolism between healthy elderly subjects and COPD patients (Engelen et al., 2007). Whole body protein synthesis increased in the group consuming soy + BCAA compared to soy feeding alone 11

Amino acid supplementation in critical illness

(P < 0.05). The study received a low grade because the sample size was small, the study period was short and the study was nonrandomised, although a cross-over design was followed. Chronic heart failure One low quality study in CHF patients was included. Aquilani et al. (2008) examined whether diet combined with 4 g of EAA supplementation had a positive effect on nutritional and metabolic status of chronic heart failure patients. These patients are another group where muscle wasting is common and related to hypoxia or systemic inflammation; in the study, patients were specifically selected for depleted muscle mass. An increase in weight and body mass index was found in the EAA group compared to the control group (P < 0.01). Limitations to the study include the small sample size, a lack of blinding, no placebo product being used, the control group having a higher baseline body weight, and body composition being measured by anthropometric measures alone. The study used a higher ratio of leucine within the BCAA composition (Table 2), which may require further investigation when formulating future supplements to prevent muscle wasting. Elderly One moderate quality study and eight low quality studies were included. Rondanelli et al. (2011) explored whether 4 g of EAA supplementation twice daily would improve nutritional status, muscle function, activity levels and health-related quality of life in elderly institutionalised patients potentially suffering from sarcopenia. The results showed that the EAA mixture improved nutritional status, physical performance, muscle function and levels of depression significantly. This was a well conducted study; however, the sample size was small. Sarcopenia, although not identical to ICU-related muscle wasting, shares some similarities as a result of deranged anabolic signals and the presence of pro-inflammatory cytokines (Ershler & Keller, 2000). Clearly, this differs from the dramatic muscle wasting observed in ICU patients, although positive results in this group may offer clues to a useful supplement in critical illness. Verhoeven et al. (2009) studied the effect of 2.5 g of leucine supplementation over 3 months on muscle mass and strength in 29 healthy elderly men. No differences were observed after 3 months of supplementation for any of the outcome measures. This adds useful data showing that leucine supplementation alone does not increase muscle mass or strength and may be most beneficial when given in addition to the other branched-chain

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amino acids but not as a sole supplement (Cynober & Harris, 2006). Elderly females with sarcopenia were given a 7.5 g of EAA supplement over a 3-month period to assess anabolic response (Dillon et al., 2009). Muscle fractional synthesis rate and lean body mass were both significantly higher after 3 months of EAA supplementation compared to placebo (Table 2). The study was limited by small sample size but, again, shows that a BCAA supplement with a higher ratio of leucine appears to have an effect on muscle synthesis. The study is relevant to the ICU population because sarcopenia involves alterations in the mechanisms of muscle breakdown and synthesis. Volpi et al. (2003) studied 14 healthy elderly subjects, of whom six were given 18 g of EAA supplement in 10min boluses over 3 h and eight were given 40 g of EAA and non-EAA. Although both groups demonstrated increased protein synthesis, no difference was reported between the two groups (Volpi et al., 2003). Freyssenet et al. (1996) looked at the combined effect of a BCAA supplement and endurance exercise on skeletal muscle structural characteristics in elderly men with sarcopenia. The supplement contained a high leucine component of 1 : 8 : 1 for the BCAA ratio. The number of capillaries per fibre was the only significant change observed after the 6-week endurance exercise programme, this was considerd to be a result of endurance exercise and not the BCAA supplementation. The study was limited by the small sample size and unclear randomisation. Rieu et al. (2006) studied subjects over 5 h to assess the effect of a complete meal with or without additional leucine on muscle protein synthesis and whole body protein metabolism in 20 healthy elderly men. An increase in muscle fractional synthesis rate of 55% was observed in the leucine group after 5 h (P < 0.05) with no change in whole body protein turnover observed. Limitations to the study include a nonrandomised design, a small sample size and a short study period. Borsheim et al. (2008) studied twelve elderly glucose intolerant subjects to assess whether 11 g of EAA + arginine taken twice daily over 16 weeks would increase lean body mass, strength and functional capacity. Significant improvements in lean body mass (P = 0.038), leg strength (P < 0.001), walking speed (P = 0.002) and functional assessment (P = 0.007) were seen after 16 weeks on EAA + arginine. The leucine content in this supplement was high, with a BCAA ratio of 1 : 5 : 1 (Val : Leu : Iso). The study has several limitations, including a nonrandomised design, a lack of blinding, the lack of a control group and a small sample size. Elderly glucose intolerant participants again cannot be directly compared with ICU patients; however, the anabolic effect of this supplement

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in insulin-resistant participants may indicate strategies that could be explored in insulin-resistant ICU patients. Casperson et al. (2012) used 12 g of leucine supplementation to assess the effects on muscle protein synthesis and mTOR signalling in elderly subjects. Two weeks of leucine supplementation significantly activated the mTOR signalling pathway (day 1 = 1.03 versus day 15 = 1.23 phosphorylated/total, P = 0.01), demonstrating nutrient anabolic signalling, as well as increasing postabsorptive muscle protein synthesis (day 1 = 0.063 versus day 15= 0.074% h–1, P = 0.004). Limitations to the study include a nonrandomised, single-blinded design, a small sample size and the lack of use of a placebo product. The elderly are increasingly represented in the ICU population, and interventions shown to be effective in the elderly could potentially be explored in an ICU population. Katsanos et al. (2005, 2006) assessed whether elderly and young subjects responded differently to a bolus of 6.7 g EAA in terms of leg muscle protein synthesis. Lower muscle protein synthesis was reported in elderly compared to young subjects (Table 2). The methodology has several limitations in that it was nonrandomised, not blinded and included a small sample size. Examining whether young and elderly participants differ in anabolic response to EAA supplementation could broaden the applicability of the supplement use, particularly if this intervention is explored in a heterogeneous ICU population. Disuse atrophy One moderate quality study and four low quality studies were assessed. Disuse atrophy studies are pertinent to this topic because critically ill patients experience long periods of immobility and, despite the fact that catabolism is far more severe and rapid in critical illness, this group may offer insights with respect to a suitable supplement for testing. In the moderate quality study, Brooks et al. (2008) compared the effects of 15 g of EAA supplement daily (alone, before or after resistance exercise) in healthy men undergoing a 28-day bed rest period to determine whether this combined treatment would affect muscle strength and body composition. Results showed that the EAA supplementation along with resistance training provided greater protection against muscle and strength loss during 28 days of bed rest. The EAA-only group showed no protection against muscle or strength loss, suggesting that resistance training is a critical part of the effective strategy (Table 2). Limitations of the study included a small sample size and no comparator group receiving resistance training only. Ferrando et al. (2010) examined whether 15 g of EAA in addition to a standard diet during 10 days of bed rest would maintain muscle mass and function in elderly ª 2014 The British Dietetic Association Ltd.

Amino acid supplementation in critical illness

subjects. It was concluded that muscle function may be preserved with EAA supplementation during periods of compulsory bed rest (Table 2). Limitations to the study include a nonrandomised design, single blinding and a small sample size. Disuse atrophy from bed rest studies again cannot be directly compared with muscle wasting after critical illness; however, these types of studies may suggest potential interventions for minimising muscle wasting during critical illness. In a further bed rest study, 49.5 g day–1 EAA with carbohydrate was examined for anabolic stimulus during 28 days of bed rest (Paddon-Jones et al., 2004). Muscle wasting appeared to be minimised with this EAA supplement; however, strength was not fully preserved. The study was limited by a small sample size and an inadequate description of randomisation. These data support the theory that the ratio of BCAA should include higher levels of leucine compared to the other amino acids. Stein et al. (1999) conducted a bed rest study to assess whether 30 mmol day–1 supplemental BCAA during 7 days of bed rest prevented nitrogen loss. Higher nitrogen retention was observed in the BCAA group compared to control subjects (62.5  8.0 mg kg–1 day–1 in the BCAA group versus 21.6  14.7 mg kg–1 day–1 in controls, P < 0.03). Limitations include a small sample size, a high dropout rate, a short study period, exclusion of faecal and insensible losses from nitrogen balance calculations and the lack of robust protein turnover work. Paddon-Jones et al. (2003) studied 12 healthy subjects to examine whether a 27-h cortisol infusion (to simulate a stress response) changed muscle protein metabolism after a bolus ingestion of 15 g of EAA (Table 2). Anabolic response to EAA ingestion was increased during acute hypercortisolaemia. Whether this response will be observed after actual trauma requires further investigation in a larger, prospective randomised controlled trial with a much longer interventional period. Again, this simulated stress response cannot directly be compared with ICU-related muscle wasting; however, these studies may suggest potential interventions for minimising muscle wasting after critical illness. The moderate quality studies suggest that improvements in nutritional status, body composition, physical performance and muscle function with EAA and creatine supplementation are possible in patient groups relevant to ICU muscle wasting, although considerable work is required to determine the dose and BCAA ratio of EAA supplementation, and that more leucine appeared to be more beneficial. Two studies indicate that resistance training is required along with EAA supplementation to protect against muscle wasting. An important caveat is that the subjects in these studies will not have been experiencing the degree of infective or inflammatory challenge commonly exhibited by ICU patients. 13

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Amino acid supplementation in critical illness

Low-quality studies suggest that EAA and BCAA supplements in COPD patients may increase protein synthesis, body weight and lean body mass. In the elderly, EAA may improve muscle protein synthesis, muscle fractional synthesis rate, lean body mass and function and, in participants undergoing bed rest, EAA may maintain weight and fractional synthesis rate, whereas strength is unlikely to be preserved. Leucine supplementation stimulated the mTOR pathway and increased muscle protein synthesis in the elderly; however, leucine alone does not appear to protect against muscle wasting. Discussion The evidence from ICU studies suggests that HMB supplementation may be the only amino acid supplement tested to date that could lead to improvement in nitrogen balance in severely injured trauma patients. However, because the pool of data is extremely limited, further exploration of other EAA ratios and doses is justified. Non-ICU studies suggest that EAA mixtures may well have a beneficial effect on lean body mass, although the data for function and strength are less clear. Leucine, in particular, appears to be the critical amino acid, although the amount of leucine required in the supplement remains to be determined, along with the formulation of the mixture of other amino acids accompanying the leucine. This conclusion is also supported by the lower-quality studies. As alluded to earlier, the other diseases with similarities to ICU are used because they may inform the design of future supplementation studies in ICU patients; however, the comparisons are provisional in nature. The ratio of BCAA also appears to be important and higher ratios of leucine appear to be more effective. Some of the studies reviewed used BCAA ratios as high as 1 : 5 : 1 and 1 : 8 : 1 because additional leucine is considered to promote muscle protein synthesis (Anthony et al., 2001; Breen & Phillips, 2011; Crozier et al., 2005; Dickinson et al., 2011); however, the results did not always support this theory. Leucine, which is known to promote muscle protein synthesis by stimulating the mTOR signalling pathway, does not necessarily demonstrate a protein synthetic response in healthy subjects. The 3-month supplementation study noted the healthy elderly subjects’ mean daily protein intake (1 g kg–1 day– 1 ), as well as how this exceeded that of the recommended daily protein intake for the elderly (0.85 g kg–1 day–1). This may have led to already maximised muscle protein synthesis in this group (Verhoeven et al., 2009). Equally, young healthy subjects do not appear to demonstrate net protein synthesis as the elderly do after leucine supplementation (Glynn et al., 2010). Data on the potential muscle building capacity of leucine enriched essential 14

amino acid supplementation (BCAA ratio of 1 : 2 : 1 or higher), HMB and also creatine are still the most intriguing of all the data presented. The strengths of this review include the systematic approach employed, the grading of each study to set criteria and the comprehensive list of studies provided that could be used to integrate current knowledge or to plan future interventional studies. Because the data do not provide suitable evidence, no firm conclusions or treatment recommendations can be made for supplementation in the critically ill. Future studies need to be adequately powered, conducted in more homogeneous patient subgroups on the ICU, use clearly defined interventions that control for baseline nutrition, as well as provide supplementary EAA, which are also provided for a sufficiently long period to assess clinical outcomes, as well as the acute anabolic response or metabolic change. Yet trying to influence clinical outcomes such as length of stay or mortality requires very large sample sizes. One ongoing enteral amino acid supplementation study has been identified on the clinical trials register in survivors of critical illness (study number: NCT01063738). The study is investigating EAA supplementation during rehabilitation after critical illness, aiming to recruit 180 subjects and to examine the effect of both diet and physical rehabilitation in a randomised, single-blinded design. The results obtained will add to current evidence. Limitations The present review is limited by the published data available; in particular, it was not possible to conduct metaanalyses as a result of the heterogeneity of the published ICU studies. Many publications suffered from poor methodological quality and/or reporting, particularly the process of randomisation, and this means that there is a risk of bias in this review. In addition, bed rest studies and studies in the elderly, in patients with COPD and in patients with CHF, may not present the best models for studying ICU-related muscle wasting because the muscle wasting in the critically ill is clearly so multifaceted. However, these groups were included because the data may offer pointers to the most promising interventions to investigate. Clearly, more high-quality research in ICU patients is needed to identify whether nutritional supplementation can limit muscle wasting and improve clinical outcomes. Conclusions Dietary manipulation with leucine enriched EAA, HMB or creatine warrants further investigation in the critically ª 2014 The British Dietetic Association Ltd.

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ill and may offer a supportive strategy towards minimising muscle mass loss in these vulnerable patients. Variability in quality and methodology of current evidence does not allow for formulation of any clinical recommendations. Studies in other muscle wasting illnesses with similarities to critical illness suggest that EAA mixtures may have a beneficial effect on lean body mass; however, the data for function and strength are less clear.

Conflict of interests, source of funding and authorship The authors declare that there are no conflicts of interest. The authors acknowledge support from the Department of Health via the National Institute of Health Research who supported this work through the provision of a Clinical Doctoral Research Fellowship for LW. The research was further supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. All authors have made substantial contributions to the concept and design of the systematic review, with the grading of the studies and interpretation of the data, the drafting of the article and critical revision. All authors have approved the final version submitted for publication.

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