Protocol for a prospective cohort study on the use of clinical nutrition and assessment of long-term clinical and functional outcomes in critically ill adult patients.

BACKGROUND AND AIMS: Limited data are available on the impact of clinical nutrition over the course of critical illness and post-discharge outcomes. The present study aims to characterize the use of nutrition support in patients admitted to European intensive care units (ICUs), and its impact on clinical outcomes. Here we present the procedures of data collection and evaluation. METHODS: Around 100 medical, surgical, or trauma ICUs in 11 countries (Austria, Belgium, Czech Republic, Germany, France, Hungary, Italy, Poland, Spain, Sweden, United Kingdom) participate in the study. In defined months between November 2019 and April 2020, approximately 1250 patients are enrolled if staying in ICU for at least five consecutive days. Data from ICU day 1-4 are collected retrospectively, followed by a prospective observation period from day 5-90 after ICU admission. Data collection includes patient characteristics, nutrition parameters, complications, ICU and hospital length of stay, discharge status, and functional outcomes. For data analysis, the target is 1000 patients with complete data. Statistical analyses will be descriptive, with multivariate analyses adjusted for potential confounders to explore associations between nutritional balance and change in functional status, time-to-weaning from invasive mechanical ventilation, time to first clinical complication, and overall 15, 30 and 90-day survival. ETHICS AND DISSEMINATION: This non-interventional study was reviewed and approved by the ethics committee of the Medical University Vienna, Vienna, Austria (approval number 1678/2019), and the respective ethical committees from participating sites at country and/or local level, as required. Results will be shared with investigators on a country level, and a publication and results presentation at the 2021 ESPEN Congress is planned. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04143503.

Longitudinal pattern of glutamine/glutamate balance across the leg in long-stay intensive care unit patients.

BACKGROUND & AIMS: Progressive muscle wasting is a characteristic feature of patients treated at the intensive care unit (ICU). As a consequence, endogenous glutamine production by skeletal muscle may be compromised. We investigated the time pattern of the glutamine and glutamate net balance across the leg in long-stay ICU patients. METHODS: Critically ill patients with multiple organ failure that were expected to stay in the ICU for more than 3 days were included in a longitudinal study. Possible changes in amino acid net balance over the leg muscle were investigated overtime. The patients (n=20) were studied descriptively every third or fourth day, on a total of 2-7 occasions. MAIN RESULTS: The glutamine net release from leg muscles did not change significantly during the initial 2 weeks of ICU stay and was not related to the plasma concentration of glutamine. The net uptake of glutamate across the leg muscles was unaltered during this time period, but it was found to correlate statistically with both the arterial glutamate concentration and the glutamine net release. A continuous net release of phenylalanine indicated a progressive net loss of muscle protein in these patients. CONCLUSION: The net release of glutamine from skeletal muscle does not decrease in stabilized critically ill patients with multiple organ failure over the initial 2 weeks of ICU stay, despite progressive muscle wasting.

Total parenteral nutrition after surgery rapidly increases serum leptin levels.

OBJECTIVE: In humans, leptin is regulated by long-term changes in energy intake. However, short-term regulation of serum leptin by nutrients has been difficult to show. The aim of this study was to investigate whether short periods of fasting and stress sensitise the leptin response to nutrients. SUBJECTS AND EXPERIMENTAL PROTOCOL: Fourteen patients of normal weight undergoing elective open cholecystectomy were randomised into two groups. One group received saline infusion during surgery and for 24 h postoperatively. The other group also received saline during the surgical procedure, but total parenteral nutrition (TPN) was started immediately after surgery. Blood samples were drawn before as well as 2, 4, 8, 16, and 24 h after the start of surgery to determine the serum levels of leptin and other hormones. RESULTS: Postoperative TPN induced a significant rise in serum leptin within 6 h, reaching a more than fourfold increase within 14 h (P<0.001). Serum glucose and insulin levels increased within 2 h. Growth hormone and IGF-1 serum levels also increased significantly in the group receiving TPN. Serum cortisol levels increased postoperatively in both groups, which may explain why no significant reduction in serum leptin was observed in the group receiving saline. Free tri-iodothyronine (T3) decreased in both groups, while catecholamines were similar in the groups. CONCLUSION: During fasting and surgical stress, nutrients rapidly increased the serum leptin levels in humans in a manner similar to that previously reported in rodents. This may be mediated by increases in serum glucose, insulin and cortisol.

Determination of protein synthesis in lymphocytes in vivo after surgery.

1. The stimulation and depression of peripheral blood lymphocytes has previously been studied in vitro, showing an immune depression postoperatively; however, it is difficult to interpret these in vitro findings. Therefore, an in vivo technique has been established for determination of the fractional protein synthesis rate, as an index of metabolic activity in human peripheral blood lymphocytes, by using a stable isotope technique. 2. The rate of protein synthesis was calculated from the increase in enrichment of L-[2H5]phenylalanine in protein of a mixed population of mononuclear leucocytes, isolated by density gradient, after an intravenous flooding dose of L-[2H5]phenylalanine. A linear time course of isotopic incorporation into the cells was demonstrated. 3. The fractional rate of protein synthesis of a mixed population of mononuclear leucocytes was studied in relation to surgical interventions and to potential modifiers of the response. The fractional synthesis rate increased 24 h after open and laparoscopic cholecystectomy (49 +/- 19% and 40 +/- 14% respectively, P < 0.02), irrespective of postoperative total parenteral nutrition or preoperative glucose infusion. In contrast to surgery, insulin did not stimulate protein synthesis in peripheral mononuclear leucocytes.

Muscle protein synthesis rate decreases 24 hours after abdominal surgery irrespective of total parenteral nutrition.

BACKGROUND: Muscle protein synthesis rate is known to decrease postoperatively as a part of the catabolic response to trauma. Conventional total parenteral nutrition (TPN) in the postoperative period does not seem to counteract the decrease in protein synthesis. However, it is still unclear if ongoing TPN given continuously after surgery would inhibit this fall in muscle protein synthesis. METHODS: The rate of protein synthesis in skeletal muscle was determined before and 24 hours after open cholecystectomy, used as a standardized human model of trauma. Patients (n = 14) were randomized to receive either TPN continuously throughout the postoperative period or saline as postoperative fluid therapy. The protein synthesis rate was calculated from the increase in enrichment of labeled phenylalanine in protein after an IV flooding dose of [2H5] phenylalanine, 45 mg/kg body weight. RESULTS: The fractional synthesis rate decreased by 31% from 1.74 +/- 0.13% to 1.15 +/- 0.10% per 24 hours in the saline group (p < .02) and by 23% from 1.59 +/- 0.10% to 1.22 +/- 0.07% per 24 hours in the group receiving TPN (p < .01), showing no significant difference between the two groups. CONCLUSION: A continuous and ongoing infusion of conventional TPN started immediately after surgery did not counteract the obligatory decline of muscle protein synthesis, observed 24 hours postoperatively.

Response of protein synthesis in human skeletal muscle to insulin: an investigation with L-[2H5]phenylalanine.

The role of insulin in the regulation of muscle protein synthesis in adult humans has been investigated with intravenous infusion of insulin at levels comparable with those observed after normal feeding. Glucose was also infused to maintain euglycemia. Muscle protein synthesis was measured in six healthy subjects before and during insulin and glucose infusion from the incorporation of L-[2H5]phenylalanine into the protein of vastus lateralis sampled by percutaneous biopsy. L-[2H5]phenylalanine was given as a single injection of a flooding amount (45 mg/kg). The relatively low levels of enrichment of phenylalanine in protein (0.005 atom%) were measured by modified gas chromatography-mass spectrometry and verified by comparison with incorporation of L-[2,6-3H]phenylalanine. Similarity of enrichment in tissue-free and plasma pools (flooding) and linear incorporation over the period of measurement were also verified. The fractional rate of muscle protein synthesis in the group of postabsorptive subjects was 1.65 +/- 0.11% (SE)/day. The rate was unaltered by insulin and glucose infusion, 1.66 +/- 0.16%/day.

Lipolysis during abdominal surgery.

Subcutaneous adipose tissue lipolysis has been monitored with microdialysis during elective cholecystectomy by laparotomy in otherwise healthy nonobese subjects. Eight of the subjects received saline and seven received glucose iv during the operation. In both groups the glycerol level in the microdialysate (lipolysis index) started to increase steadily from the start of the general anesthesia until the abdominal wall was closed. Thereafter it leveled off and remained elevated until after extubation. Plasma glycerol started to rise after the surgical incision. The levels of noradrenaline and adrenaline, but not of insulin, glucagon, and cortisol in plasma, changed in parallel with that of glycerol in the microdialysate. The glycerol response in adipose tissue in the group receiving iv glucose was three times more marked than in the saline group (P = 0.01) in spite of marked hyperinsulinemia, but there was no difference between the groups in plasma glycerol response. The plasma noradrenaline response was 50% higher (P = 0.03) in the glucose group than in the saline group, but there was no difference between the groups in the plasma adrenaline, glucagon, or cortisol responses. Adipose tissue blood flow was measured by the escape of ethanol from the dialysis solvent into the extracellular space. It was constant throughout the experimental period in both groups. In conclusion, the lipolysis rate is accelerated during general anesthesia and abdominal surgery because of increased catecholamine production. Perioperative glucose infusion is associated with a further acceleration of the lipolytic rate in subcutaneous adipose tissue due to an additional activation of the sympathetic nervous activity that overrides the antilipolytic effect of the glucose-induced hyperinsulinemia. Other adipose regions may be less sensitive to glucose infusions and anesthesia.