Introduction
A historical perspective
Important protein-related concepts: a metabolic perspective
Adaptation to starvation
Adaptation of protein and amino acid metabolism under conditions of stress
Proteins are the major components of muscles, required for muscle dynamics and function | |
Enzymes are proteins. Therefore, proteins are essential for intermediary metabolism and energy production. Similarly, all cell carriers are proteins | |
Some proteins are involved in specific immunity (that is, immunoglobulins) and in nonspecific immunity (for example, opsonins) | |
Proteins contribute to the architecture and structure of organs and tissues. A typical example is collagen, which has a major architectural role, for example, in bone and skin | |
Proteins secreted into the blood by the liver are carriers of lipid-soluble molecules: hormones (for example, transthyretin for thyroxin), vitamins (for example, retinol binding protein for vitamin A), nutrients (for example, albumin for free fatty acids and tryptophan), and a number of drugs | |
Proteins in the blood, especially albumin, are involved in the control of oncotic (colloid osmotic) pressure | |
Proteins contribute physiologically to energy expenditure (12 to 15% of total daily expenditure) in the postabsorptive state, through release of amino acids following proteolysis. This may occur directly (for example, branched-chain amino acids in the muscles) or indirectly (through glucose (gluconeogenesis) or ketone body (ketogenesis)) |
Muscle proteins
Anabolic resistance
Interaction of protein with nonprotein energy
Amino acid transport
Potential adverse effects of amino acid provision
Methods for assessment of protein status
Nitrogen balance
Subject of measurement | Rationale | Usage |
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Plasma protein levels: albumin, transthyretin (formerly called prealbumin), and retinol binding protein | These proteins are selectively synthesized by the liver. Therefore, it is generally believed that their rate of synthesis parallels the supply of amino acids. In the case of inflammation, plasma levels of these proteins do not indicate nutritional status | Transthyretin measurements can be used to assess the efficacy of nutrition support [75], while albumin measurements can be used to assess the risk of complications associated with malnutrition. When used for this purpose, albumin may be used alone [76] or, ideally, as an index to be considered in combination with variations in body weight over time (nutritional risk index [77] in adults, geriatric nutritional risk index [78] in geriatric patients) |
Urinary 3-methylhistidine (3MH) | 3MH is derived from histidine with a post-transcriptional methylation at position 3. This amino acid is present mainly in myofibrillar proteins and, to a smaller extent, in intestinal smooth muscles. Following proteolysis, released 3MH is not reincorporated into proteins since there is no codon for this amino acid. Instead, 3MH is further eliminated into urine | There is a correlation between the 24-hour excretion of 3MH and myofibrillar proteolysis. Since the former will be dependent upon muscle mass, 3MH excretion must be expressed as a ratio to urinary creatinine. It has been clearly demonstrated that muscle myofibrillar proteins account for the entire increase in 3MH excretion during hypercatabolic states [79]. In chronic malnutrition, urinary 3MH is low due to restriction adaptation, and improvement in the nutritional state leads to an increase of this parameter because elevated protein synthesis leads to an increase in proteolysis |
Plasma phenylalanine | Phenylalanine is mainly catabolized in the liver, and not in the muscle. The arteriovenous difference in phenylalanine concentration is a marker of muscle proteolysis. Unfortunately, arterial puncture is an invasive procedure, and is associated with technical problems that complicate the use of this marker. In addition, interpretation of the data requires that blood flow is measured simultaneously. Alternatively, plasma phenylalanine can be measured as a marker of protein turnover. Some authors have suggested measuring the phenylalanine:tyrosine ratio for this purpose | It has been shown [80] that plasma phenylalanine correlates well with nitrogen balance in burn patients. At present, there are insufficient data available to recommend the use of plasma phenylalanine or of the phenylalanine:tyrosine ratio as a reliable marker of protein turnover |
Plasma citrulline | The amino acid citrulline is not included in proteins and it is almost absent in food. In the general circulation, most citrulline is formed in enterocytes and is mostly catabolized in the kidneys [81]. Of note, citrulline in the liver is strictly compartmentalized within periportal hepatocytes [61] and the liver neither takes citrulline up nor releases it, except in patients with liver cancer [82] |
Assessment of qualitative and quantitative amino acid requirements
Whole-body and muscle protein synthesis
Muscle mass and lean body mass
Protein nutrition support and outcome in critically ill patients
Muscle wasting and functional impairment
Level of protein nutrition support in critically ill patients
Current evidence for protein nutrition support and outcome
Citation | Patient population | Study design | Clinical outcome: recovery, survival and length of stay |
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Larsson and colleagues [114] | Severely injured patients (burn or fracture of more than two long bones). Randomized during the first week of trauma (n = 39) to five different amounts of N from 0 to 0.3 g/kg/day | Prospective randomized study | Daily and cumulative N balance increased in the groups with a N intake of up to 0.2 g/kg/day versus the no N group (P <0.001) |
Ishibashi and colleagues [15] | Immediate post-trauma patients (n = 18) or severely septic patients (n = 5) were divided into three groups (A, B, and C) receiving 1.1, 1.5, and 1.9 g/kg FFMc/day protein respectively | Retrospective study | Average loss of total body protein was 1.2 kg. Loss of body protein was greater in group A compared with groups B (P = 0.013) and C (P = 0.023). Protein loss in group B (1.5 g/kg FFMc/day), was half that of group A (1.1 g/kg FFMc/day). Protein loss in groups B and C was not different. An intake of 1.5 g/kg FFMc/day was equivalent to 1.0 g/day/kg body weight measured at the start of the study. Authors recommend the clinician obtains information on pre-illness bodyweight and prescribes 1.2 g/day/kg |
Barr and colleagues [118] | 200 ICU patients (npo >48 hours after their admission): 100 before implementation of a nutritional management protocol, 100 afterwards | Prospective evaluation | Risk of death was 56% lower in patients who received EN (HR: 0.44, 95% CI: 0.24, 0.80, P = 0.007) |
Martin and colleagues [119] | 499 ICU patients with an expected ICU stay of at least 48 hours. Introduction of evidence-based recommendations | Cluster-randomized controlled trial | Implementation of evidence-based recommendations led to more days of EN (P = 0.042), shorter mean hospital stay (P = 0.003) and a trend towards reduced mortality (P =0.058). The mean ICU stay did not differ significantly |
Doig and colleagues [117] | 1,118 patients in the ICU >2 days. Randomization to guideline or control groups. Guideline ICUs used an evidence-based guideline | Cluster-randomized controlled trial | Guideline ICU patients were fed earlier and reached nutritional goals more often compared with control subjects, but did not show significantly different hospital discharge mortality (P = 0.75), hospital LOS (P = 0.97), or ICU LOS (P = 0.42) |
Alberda and colleagues [14] | 2,772 mechanically ventilated patients. Prescribed and received energy was reported | Observational cohort study | Patients received only 56 to 64% of the nutritional prescription for energy and 50 to 65% for protein. Increased provision of energy and protein appear to be associated with improved clinical outcomes, particularly when BMI <25 or ≥35 kg/m2. A 1,000 kcal increase is associated with improved mortality (P = 0.014) and more ventilation-free days (P = 0.003) |
Strack van Schijndel and colleagues [120] | 243 sequential mixed medical-surgical patients. Nutrition according to indirect calorimetry and at least 1.2 g protein/kg/day | Prospective observational cohort study | Reaching nutritional goals improves ICU (P = 0.027) and 28-day mortality (P = 0.005) and hospital survival (P = 0.04) in female patients. When only energy goals but not protein goals are met, ICU mortality is not changed. No differences could be observed for male patients |
Casaer and colleagues [123] | 4,640 ICU patients: 2,312 patients received PN within 48 hours after ICU admission, 2,328 patients received no PN before day 8 | Randomized, multicenter trial | Early provision of PN shows a higher complication rate (26.2% vs 22.8% for ICU infections, P = 0.008), longer mechanical ventilation time (9.7% longer, P = 0.006) and renal replacement therapy (3 days' longer, P = 0.008), and a longer mean hospital duration (6.4% higher likelihood to discharge later, P = 0.04), but no significant impact on mortality |
Weijs and colleagues [121] | 886 mechanically ventilated patients; stratified into three groups: reaching energy and protein target; reaching energy target; and reaching no target | Prospective observational cohort study | Reaching the energy and protein target is associated with a 50% decrease in 28-day mortality. Reaching only the energy target is not associated with an improvement |
Arabi and colleagues [124] | 240 ICU patients randomly assigned to permissive underfeeding or target feeding | Randomized, controlled trial | Permissive underfeeding may be associated with lower mortality rates. Hospital mortality was lower in the permissive feeding group (30.0% vs 42.5%; relative risk: 0.71; 95% CI: 0.50, 0.99; P = 0.04). However, 28-day all-cause mortality was not significantly different between groups (18.3% vs 23.3%; relative risk: 0.79; 95% CI: 0.48, 1.29; P = 0.34) |
Rice and colleagues [125] | 200 mechanically ventilated patients with acute respiratory failure, expected to require mechanical ventilation for at least 72 hours randomized to receive initial trophic (10 ml/hour) or full-energy EN for the initial 6 days | Randomized, open-label study | Mortality to hospital discharge was 22.4% for trophic vs 19.6% for full energy (P = 0.62). The trophic group showed a trend for less diarrhea in the first 6 days (19% vs 24% of feeding days; P =0.08) and significantly fewer episodes of elevated gastric residual volumes (2% vs 8% of feeding days; P <0.001) |
Singer and colleagues [126] | 130 patients expected to stay in ICU >3 days. Randomization to EN with a target determined by indirect calorimetry (study group) or with 25 kcal/kg/day (control group) | Prospective, randomized, controlled trial | Patients in the study group had a higher mean energy (P =0.01) and protein intake (P =0.01) than the control group. They also showed a trend towards reduced mortality (32.3% vs 47.7%, P =0.058), but the number of infectious complications were higher (37 in the study vs 20 in the control group P =0.05) |
Allingstrup and colleagues [122] | 113 ICU patients. Analyzed according to provided amount of protein and AA | Prospective, observational, cohort study | In the low protein and AA provision group, the Kaplan-Meier survival probability was 49% on day 10, compared with 79% and 88% in the medium and high protein and AA groups on day 10, respectively |
Rice and colleagues [127] | 1,000 patients with acute lung injury requiring mechanical ventilation. Randomization to trophic or full enteral feeding for the first 6 days | Randomized, open-label, multicenter trial | Initial trophic feeding did not improve 60-day mortality (23.2% vs 22.2%, P =0.77) or infectious complications (P =0.72, P =0.77, and P =0.24 for ventilator-associated pneumonia, Clostridium difficile colitis and bacteremia, respectively) compared with full enteral feeding |
Heidegger and colleagues [128] | ICU patients who had received less than 60% of their energy target from EN, were expected to stay >5 days, and to survive >7 days. Randomization to SPN (n =153) or EN (n =152). Protein administration was set to 1.2 g/kg ideal bodyweight/day during the study | Randomized controlled trial | Mean energy delivery between days 4 and 8 was higher for the SPN group (103% vs 77% of energy target). Nosocomial infections, between days 9 and 28, were more frequent in the EN group patients (38% vs 27%, P =0.0248). Overall nosocomial infections were not different |