High-Protein Hypocaloric Nutrition for Non-Obese Critically Ill Patients.

High-protein hypocaloric nutrition, tailored to each patient's muscle mass, protein-catabolic severity, and exogenous energy tolerance, is the most plausible nutrition therapy in protein-catabolic critical illness. Sufficient protein provision could mitigate the rapid muscle atrophy characteristic of this disease while providing urgently needed amino acids to the central protein compartment and sites of tissue injury. The protein dose may range from 1.5 to 2.5 g protein (1.8-3.0 g free amino acids)/kg dry body weight per day. Nutrition should be low in energy (≈70% of energy expenditure or ≈15 kcal/kg dry body weight per day) because efforts to match energy provision to energy expenditure are physiologically irrational, risk toxic energy overfeeding, and have repeatedly failed in large clinical trials to demonstrate clinical benefit. The American Society for Parenteral and Enteral Nutrition currently suggests high-protein hypocaloric nutrition for obese critically ill patients. Short-term high-protein hypocaloric nutrition is physiologically and clinically sensible for most protein-catabolic critically ill patients, whether obese or not.

Will We Ever Agree on Protein Requirements in the Intensive Care Unit?

The precise value of the normal adult protein requirement has long been debated. For many reasons-one of them being the difficulty of carrying out long-term nutrition experiments in free-living people-uncertainty is likely to persist indefinitely. By contrast, the controlled environment of the intensive care unit and relatively short trajectory of many critical illnesses make it feasible to use hard clinical outcome trials to determine protein requirements for critically ill patients in well-defined clinical situations. This article suggests how the physiological principles that underlie our understanding of normal protein requirements can be incorporated into the design of such clinical trials. The main focus is on 3 principles: (1) the rate of body nitrogen loss roughly predicts an individual's minimum protein requirement and is thus essential to measure to identify individual patients and clinical situations in which the minimum protein requirement is importantly increased, (2) existing muscle mass sets an upper limit on the rate at which amino acids can be mobilized from muscle for transfer to central proteins and sites of injury and is thus important to monitor to identify patients who are at greatest risk of protein deficiency-related adverse outcomes, and (3) negative energy balance increases the dietary protein requirement, so calorie-deprived patients-whether obese or not-should be enrolled in hard clinical outcome trials that compare the current practice of "permissive underfeeding" (underprovision of all nutrients, including protein) with hypocaloric nutrition supplemented by a suitably generous amount of protein.

Summary Points and Consensus Recommendations From the International Protein Summit.

The International Protein Summit in 2016 brought experts in clinical nutrition and protein metabolism together from around the globe to determine the impact of high-dose protein administration on clinical outcomes and address barriers to its delivery in the critically ill patient. It has been suggested that high doses of protein in the range of 1.2-2.5 g/kg/d may be required in the setting of the intensive care unit (ICU) to optimize nutrition therapy and reduce mortality. While incapable of blunting the catabolic response, protein doses in this range may be needed to best stimulate new protein synthesis and preserve muscle mass. Quality of protein (determined by source, content and ratio of amino acids, and digestibility) affects nutrient sensing pathways such as the mammalian target of rapamycin. Achieving protein goals the first week following admission to the ICU should take precedence over meeting energy goals. High-protein hypocaloric (providing 80%-90% of caloric requirements) feeding may evolve as the best strategy during the initial phase of critical illness to avoid overfeeding, improve insulin sensitivity, and maintain body protein homeostasis, especially in the patient at high nutrition risk. This article provides a set of recommendations based on assessment of the current literature to guide healthcare professionals in clinical practice at this time, as well as a list of potential topics to guide investigators for purposes of research in the future.

Nutrition in critical illness: a current conundrum.

Critically ill people are unable to eat. What's the best way to feed them? Nutrition authorities have long recommended providing generous amounts of protein and calories to critically ill patients, either intravenously or through feeding tubes, in order to counteract the catabolic state associated with this condition. In practice, however, patients in modern intensive care units are substantially underfed. Several large randomized clinical trials were recently carried out to determine the clinical implications of this situation. Contradicting decades of physiological, clinical, and observational data, the results of these trials have been claimed to justify the current practice of systematic underfeeding in the intensive care unit. This article explains and suggests how to resolve this conundrum.

Appropriate vitamin D loading regimen for patients with advanced lung cancer.

BACKGROUND: Most patients attending cancer clinics have hypovitaminosis D. Correcting or preventing this abnormal condition could mitigate the emotional and physical complications of their disease, but clinical trials of vitamin D therapy in this setting are hindered by the unavailability of safe, effective and practical loading dose regimens. METHODS: In this single arm open-label pharmacokinetic trial, outpatients with advanced lung cancer consumed 20,000 IU vitamin D daily with the largest meal of the day for 14 days followed by 10,000 IU per day for a further 7 days. Plasma concentrations of 25-hydroxyvitamin D [25(OH)D], parathyroid hormone, calcium, vitamin C and C-reactive protein were measured on protocol days 0, 14 and 21, and serum vitamin D binding protein (VDBP) concentrations on days 0 and 21. As a secondary objective, preliminary information was obtained regarding clinical effects of rapid vitamin D loading on mood and symptoms by administering appropriate questionnaires two times at baseline and after 14 and 21 days of vitamin D therapy. RESULTS: Of the 91 patients enrolled in the study, 85 % had hypovitaminosis D and 41 % had hypovitaminosis C. Plasma VDBP concentrations were in the normal range. The vitamin D load increased the average plasma 25(OH)D concentration to 116 ± 34 nmol/L (mean ± SD); the median concentration was 122 nmol/L (interquartile range 103-134); VDBP concentrations did not change. Final plasma 25(OH)D concentrations were subnormal (<75 nmol/L) for 13 % of the patients and sub-target (<120 nmol/L) for 44 % of them. In most cases, subnormal and sub-target 25(OH)D concentrations were attributable to obesity and/or a low baseline 25(OH)D concentration. Mood and symptom scores did not change significantly throughout the 3-week protocol. CONCLUSION: Hypovitaminosis D and C are very common in outpatients with advanced lung cancer. A vitamin D load of 20,000 IU per day for 14 days failed to achieve the target concentration in 44 % of the participants in this trial. These results suggest that a loading dose of 30,000 IU per day for 14 days would be safe and effective for patients who are obese or at risk of severe hypovitaminosis D. The preliminary nature of the study design, and the failure to achieve target 25(OH)D concentrations for a large proportion of the patients, do not allow any firm conclusion about the clinical effects of correcting hypovitaminosis D in this patient population. Nevertheless, no evidence was obtained that partial correction of hypovitaminosis D greatly improved mood, reduced distress or relieved cancer-related symptoms. This trial was registered at clinicaltrials.gov as NCT01631526.

A simple method for plasma total vitamin C analysis suitable for routine clinical laboratory use.

BACKGROUND: In-hospital hypovitaminosis C is highly prevalent but almost completely unrecognized. Medical awareness of this potentially important disorder is hindered by the inability of most hospital laboratories to determine plasma vitamin C concentrations. The availability of a simple, reliable method for analyzing plasma vitamin C could increase opportunities for routine plasma vitamin C analysis in clinical medicine. METHODS: Plasma vitamin C can be analyzed by high performance liquid chromatography (HPLC) with electrochemical (EC) or ultraviolet (UV) light detection. We modified existing UV-HPLC methods for plasma total vitamin C analysis (the sum of ascorbic and dehydroascorbic acid) to develop a simple, constant-low-pH sample reduction procedure followed by isocratic reverse-phase HPLC separation using a purely aqueous low-pH non-buffered mobile phase. Although EC-HPLC is widely recommended over UV-HPLC for plasma total vitamin C analysis, the two methods have never been directly compared. We formally compared the simplified UV-HPLC method with EC-HPLC in 80 consecutive clinical samples. RESULTS: The simplified UV-HPLC method was less expensive, easier to set up, required fewer reagents and no pH adjustments, and demonstrated greater sample stability than many existing methods for plasma vitamin C analysis. When compared with the gold-standard EC-HPLC method in 80 consecutive clinical samples exhibiting a wide range of plasma vitamin C concentrations, it performed equivalently. CONCLUSION: The easy set up, simplicity and sensitivity of the plasma vitamin C analysis method described here could make it practical in a normally equipped hospital laboratory. Unlike any prior UV-HPLC method for plasma total vitamin C analysis, it was rigorously compared with the gold-standard EC-HPLC method and performed equivalently. Adoption of this method could increase the availability of plasma vitamin C analysis in clinical medicine.

Human Protein and Amino Acid Requirements.

Human protein and amino acid nutrition encompasses a wide, complex, frequently misunderstood, and often contentious area of clinical research and practice. This tutorial explains the basic biochemical and physiologic principles that underlie our current understanding of protein and amino acid nutrition. The following topics are discussed: (1) the identity, measurement, and essentiality of nutritional proteins; (2) the definition and determination of minimum requirements; (3) nutrition adaptation; (4) obligatory nitrogen excretion and the minimum protein requirement; (5) minimum versus optimum protein intakes; (6) metabolic responses to surfeit and deficient protein intakes; (7) body composition and protein requirements; (8) labile protein; (9) N balance; (10) the principles of protein and amino acid turnover, including an analysis of the controversial indicator amino acid oxidation technique; (11) general guidelines for evaluating protein turnover articles; (12) amino acid turnover versus clearance; (13) the protein content of hydrated amino acid solutions; (14) protein requirements in special situations, including protein-catabolic critical illness; (15) amino acid supplements and additives, including monosodium glutamate and glutamine; and (16) a perspective on the future of protein and amino acid nutrition research. In addition to providing practical information, this tutorial aims to demonstrate the importance of rigorous physiologic reasoning, stimulate intellectual curiosity, and encourage fresh ideas in this dynamic area of human nutrition. In general, references are provided only for topics that are not well covered in modern textbooks.

High-dose intravenous vitamin C combined with cytotoxic chemotherapy in patients with advanced cancer: a phase I-II clinical trial.

BACKGROUND: Biological and some clinical evidence suggest that high-dose intravenous vitamin C (IVC) could increase the effectiveness of cancer chemotherapy. IVC is widely used by integrative and complementary cancer therapists, but rigorous data are lacking as to its safety and which cancers and chemotherapy regimens would be the most promising to investigate in detail. METHODS AND FINDINGS: We carried out a phase I-II safety, tolerability, pharmacokinetic and efficacy trial of IVC combined with chemotherapy in patients whose treating oncologist judged that standard-of-care or off-label chemotherapy offered less than a 33% likelihood of a meaningful response. We documented adverse events and toxicity associated with IVC infusions, determined pre- and post-chemotherapy vitamin C and oxalic acid pharmacokinetic profiles, and monitored objective clinical responses, mood and quality of life. Fourteen patients were enrolled. IVC was safe and generally well tolerated, although some patients experienced transient adverse events during or after IVC infusions. The pre- and post-chemotherapy pharmacokinetic profiles suggested that tissue uptake of vitamin C increases after chemotherapy, with no increase in urinary oxalic acid excretion. Three patients with different types of cancer experienced unexpected transient stable disease, increased energy and functional improvement. CONCLUSIONS: Despite IVC's biological and clinical plausibility, career cancer investigators currently ignore it while integrative cancer therapists use it widely but without reporting the kind of clinical data that is normally gathered in cancer drug development. The present study neither proves nor disproves IVC's value in cancer therapy, but it provides practical information, and indicates a feasible way to evaluate this plausible but unproven therapy in an academic environment that is currently uninterested in it. If carried out in sufficient numbers, simple studies like this one could identify specific clusters of cancer type, chemotherapy regimen and IVC in which exceptional responses occur frequently enough to justify appropriately focused clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT01050621.

What is the best nutritional support for critically ill patients?

Optimum nutritional support in critical illness remains controversial. A recent review of nutritional interventions in the ICU concluded that few of them improved clinical outcomes. In our view, it is a serious shortcoming of these trials that they focused on calories, falling far short of current recommendations for protein provision. Well designed clinical trials that ensure sufficient protein provision are urgently needed if we are to improve the quality of nutritional support in the ICU.

Effects of vitamin C and vitamin D administration on mood and distress in acutely hospitalized patients.

BACKGROUND: Hypovitaminosis C and D are highly prevalent in acute-care hospitals. Malnutrition with regard to these vitamins has been linked to mood disturbance and cognitive dysfunction. OBJECTIVE: The objective was to determine whether vitamin C or D supplementation improves mood state or reduces psychological distress in acutely hospitalized patients with a high prevalence of hypovitaminosis C and D. DESIGN: A randomized, double-blind, active-control clinical trial compared the effects of vitamin C (500 mg twice daily) with those of high-dose vitamin D (5000 IU/d) on mood (Profile of Mood States) and psychological distress (Distress Thermometer). RESULTS: Vitamin C provided for a mean of 8.2 d increased plasma vitamin C concentrations to normal (P < 0.0001) and was associated with a 71% reduction in mood disturbance (P = 0.0002) and a 51% reduction in psychological distress (P = 0.0002). High-dose vitamin D provided for a mean of 8.1 d increased plasma 25-hydroxyvitamin D [25(OH)D] concentrations (P < 0.0001), but not into the normal range, and had insignificant effects on mood (P = 0.067) and distress (P = 0.45). The changes in mood and distress in the vitamin C group were greater than those in the vitamin D group (P = 0.045 for mood; P = 0.009 for distress). CONCLUSIONS: Short-term therapy with vitamin C improves mood and reduces psychological distress in acutely hospitalized patients with a high prevalence of hypovitaminosis C and D. No conclusion is possible regarding the effects of vitamin D because the dose and duration of therapy were insufficient to raise 25(OH)D concentrations into the normal range. This trial was registered at clinicaltrials.gov as NCT01630720.