Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines

PURPOSE: To provide evidence-based guidelines for early enteral nutrition (EEN) during critical illness. METHODS: We aimed to compare EEN vs. early parenteral nutrition (PN) and vs. delayed EN. We defined "early" EN as EN started within 48 h independent of type or amount. We listed, a priori, conditions in which EN is often delayed, and performed systematic reviews in 24 such subtopics. If sufficient evidence was available, we performed meta-analyses; if not, we qualitatively summarized the evidence and based our recommendations on expert opinion. We used the GRADE approach for guideline development. The final recommendations were compiled via Delphi rounds. RESULTS: We formulated 17 recommendations favouring initiation of EEN and seven recommendations favouring delaying EN. We performed five meta-analyses: in unselected critically ill patients, and specifically in traumatic brain injury, severe acute pancreatitis, gastrointestinal (GI) surgery and abdominal trauma. EEN reduced infectious complications in unselected critically ill patients, in patients with severe acute pancreatitis, and after GI surgery. We did not detect any evidence of superiority for early PN or delayed EN over EEN. All recommendations are weak because of the low quality of evidence, with several based only on expert opinion. CONCLUSIONS: We suggest using EEN in the majority of critically ill under certain precautions. In the absence of evidence, we suggest delaying EN in critically ill patients with uncontrolled shock, uncontrolled hypoxaemia and acidosis, uncontrolled upper GI bleeding, gastric aspirate >500 ml/6 h, bowel ischaemia, bowel obstruction, abdominal compartment syndrome, and high-output fistula without distal feeding access.

Whole blood glutathione status and ICU morbidity in critically ill children.

BACKGROUND: A high reduced glutathione ratio is associated with high mortality in adult ICU patients. Whole blood glutathione status in critically ill children is less well characterized. In this study, whole blood glutathione status in pediatric intensive care (PICU) patients was determined and the relation between the redox status of whole blood glutathione and morbidity was investigated. METHODS: A prospective consecutive cohort of critically ill children (n = 146) admitted to the PICU of a tertiary university hospital, and a reference group of healthy children (n = 60) and healthy adults (n = 10) were included in the study. The concentrations of total and reduced whole blood were determined at admission and patient characteristics were recorded. RESULTS: A high fraction of reduced glutathione in the glutathione redox status was associated with longer dependency of mechanical ventilation and length of stay in the PICU (P = 0.02 and P = 0.03 respectively). In patients with a prolonged stay in the PICU (> 5 days), a more reduced state of glutathione was seen in patients who had more than two organ failures as compared to patients with one or two failing organs (P < 0.01 and P < 0.05), respectively. A positive correlation was also seen between numbers of organ failures and redox status of glutathione (r  = 0.45, P < 0.001). CONCLUSION: A high reduced glutathione ratio was associated with longer PICU stay, duration of mechanical ventilation, and multiple organ failure.

Continuous glucose monitoring by intravenous microdialysis: influence of membrane length and dialysis flow rate.

BACKGROUND: The benefit of tight glucose control in the intensive care unit is controversial. Part of the debate is around the frequency of glucose measurements, and therefore, a continuous glucose monitoring system is needed. Previously, we have shown that intravenous microdialysis has the potential for this purpose but that the accuracy must be improved. The aim of this study was to investigate the effects of the microdialysis membrane length and the perfusion rate on improving the accuracy. METHODS: Two volunteer studies were performed, one comparing intravenous microdialysis catheters with different lengths (10 and 20 mm) and one comparing different perfusion rates (0.5, 1 and 2 µl/min) with plasma glucose reference levels. Median values of seven samples taken over 70-min periods were compared using Bland-Altman plots. RESULTS: When microdialysis membranes of 10 and 20 mm perfused at a rate of 1 µl/min were used, the differences with measured plasma glucose levels were 30% ± 21% and 14% ± 13%. In comparison, plasma glucose measured in two different veins gave a difference of 3% ± 3%. In the second study, the differences between measured plasma glucose and that estimated with a microdialysis membrane of 30 mm perfused at 0.5, 1 and 2 µl/min were 8% ± 7%, 25% ± 19% and 39% ± 28%. Bland-Altman analyses gave the best line of equality (-0.11 mM) and the lowest limits of agreement (1.13 and -1.35 mM) when using the 30-mm membrane perfused with 0.5 µl/min. CONCLUSION: The agreement of the intravenous microdialysis with plasma glucose levels improved significantly when increasing the microdialysis membrane length, and thereby the membrane area, and decreasing the perfusion rate.

Continuous glucose monitoring by intravenous microdialysis.

BACKGROUND: The conflicting results from studies over tight glucose control in intensive care unit (ICU) patients ask for a continuous on-line real-time glucose monitoring in future. Here, intravenous microdialysis was tested in ICU patients and healthy volunteers. Primary aims were technical feasibility and accuracy. METHODS: A microdialysis catheter was inserted into a peripheral vein. ICU patients (n=10) were studied for up to 5 days. Healthy volunteers (n=6) were studied on one occasion. Recordings were monitored during 70 min each 24-h period to allow for an estimate of variability over time. Microdialysis glucose and lactate were compared with plasma glucose and whole blood lactate. Results are presented as medians (quartiles) of the differences between microdialysis and plasma concentrations over each of the 70-min recording periods. RESULTS: Out of the included ICU patients, no exclusions or early terminations were due to failure of the microdialysis catheter. The concordance was highly variable. The difference of medians over the recording periods differed by -34% (-40, -16) in patients and -22% (-31, -15) for the volunteers. In contrast, the overall variability within the individual measurement periods was low. CONCLUSION: Technical feasibility was good, but the accuracy was not sufficient and the variability between the recording periods was high without calibrations. The non-availability of suitable peripheral veins was a problem in many patients screened but not included in the study. Intravenous microdialysis to obtain continuous on-line real-time glucose monitoring is technically feasible, but accuracy needs to be improved.

Muscle mitochondrial activity increases rapidly after an endotoxin challenge in human volunteers.

BACKGROUND: Mitochondrial derangements in muscle of patients suffering from sepsis have been established in several studies and have been related to muscle dysfunction and organ failure. It is not possible to study the early phase of sepsis in patients; therefore, we used a human endotoxaemia model to study the effect of early sepsis on muscle mitochondria. METHODS: Seven healthy male volunteers received a standardised endotoxin challenge. Muscle biopsies were obtained immediately before the challenge, and at 2 and 4 h following the endotoxin challenge. The muscle biopsies were analysed for maximal activities of citrate synthase and complexes I and IV of the respiratory chain. In addition, total and mitochondrial superoxide dismutase (SOD) activities were analysed. The concentrations of ATP, creatine phosphate and lactate were analysed to assess the cellular energy status. Total and phosphorylated AMP-activated protein kinase (AMPK-P), a key regulator in intracellular energy metabolism, was measured. RESULTS: Activities of citrate synthase and complex I were significantly increased 2 h after the endotoxin challenge. SOD activities were unaffected by the endotoxin challenge. No changes in ATP, creatine phosphate or lactate were observed. Neither total nor AMPK-P changed. CONCLUSIONS: An endotoxin challenge given to healthy volunteers rapidly increases mitochondrial enzyme activity in skeletal muscle. The results of this human model indicate that possibly early during sepsis, mitochondrial activity might be increased in contrast to what has been shown in the later phases of sepsis. It is possible that this early activation leads to exhaustion of the mitochondria and a decreased function later during sepsis.

Glutamine kinetics during intravenous glutamine supplementation in ICU patients on continuous renal replacement therapy.

OBJECTIVE: To investigate glutamine kinetics during continuous renal replacement therapy (CRRT) in multiple organ failure (MOF) patients with and without exogenous intravenous glutamine supplementation. DESIGN AND PATIENTS: In a pragmatic clinical study 12 patients without urine production receiving CRRT were prospectively randomized in a cross-over design to receive glutamine intravenously for 20 h before placebo or placebo before glutamine on two consecutive days. Alanyl-glutamine or placebo (saline) was infused. MEASUREMENTS: Plasma glutamine concentration was measured in artery, femoral vein, and filtration fluid. Blood flow across the leg was measured and the efflux of glutamine calculated. The rate of appearance of glutamine was calculated from the plasma decay curve of glutamine concentration on the day of treatment. RESULTS: Glutamine supplementation increased plasma concentrations from 570+/-252 to 831+/-367 micromol l(-1). Glutamine losses into the filtration fluids were similar during treatment and control days: 25+/-13 vs. 24+/-11 mmol 24 h(-1), corresponding to 3.6+/-1.9 and 3.5+/-1.6 g 24 h(-1), respectively. Net glutamine balance across the leg was also similar on treatment and control days: 150+/-138 and 188+/-205 nmol min(-1) 100 ml(-1), respectively. The rate of appearance of glutamine was 54+/-17 g 24 h(-1). CONCLUSION: The loss of glutamine into the ultrafiltrate during CRRT in MOF patients suggests a greater need for exogenous glutamine than in patients without renal failure. The leg efflux and the filtration losses of glutamine were not affected in response to intravenous glutamine supplementation.

Intravenous glutamine supplementation to head trauma patients leaves cerebral glutamate concentration unaffected.

OBJECTIVE: There is reluctance to use glutamine-containing i.v. nutrition for neurosurgical patients, as this may result in elevated intracerebral glutamate levels, which are thought to be associated with neuronal injury and cell swelling, causing an increase in ICP and an unfavourable outcome. As general ICU patients benefit from i.v. glutamine supplementation in terms of reduced mortality and morbidity, neurosurgical patients might also be candidates for such treatment, if the possible relation between i.v. glutamine supplementation and a possible increase in cerebral glutamate could be sorted out. DESIGN AND SETTING: The study protocol had a crossover design with a 24h treatment period and a 24h placebo period in random order. Treatment was a glutamine containing dipeptide, L-alanyl-L-glutamine 200mg/ml, for 20h; placebo was saline. The rate of infusion was 0.125ml/kg/h, which is equal to 0.34g/kg of glutamine over the 20h period. Microdialysate was collected for analysis in 120min portions. The flow through the microdialysis catheter was 0.3microl/min. SUBJECTS: Patients with severe head trauma (GCS

Muscle glutathione metabolism during ischemia and reperfusion in patients undergoing aorto-bifemoral bypass surgery.

BACKGROUND: After an ischemia time of 1 h during aortic aneurysm surgery, muscle glutathione redox-status is not altered, indicating that this ischemic insult is well within the scavenging capacity of muscle glutathione, the most important endogenous scavenger. In the present study, the impact of elective aorto-bifemoral bypass surgery, involving a longer ischemia time, on muscle glutathione and its redox-status was investigated. METHODS: Leg muscle biopsies were obtained pre-operatively, at maximal ischemia, after 10 min and 24 h of reperfusion from 12 patients undergoing aorto-bifemoral bypass surgery. Muscle glutathione, free amino acids and energy-rich compounds were determined. RESULTS: Clamping times were 113 (99-120 min); median (quartiles). At maximal ischemia, muscle lactate increased by 7.5 (4.0-10.7) mmol/kg dry weight (dw) (P < 0.001) and phosphocreatine (PCr) decreased by 14.6 (8.9-23.3) mmol/kg dw (P < 0.001). At maximal ischemia, reduced glutathione (GSH) was unaltered but muscle glutamate decreased by 0.51 (0.30-0.85) mmol/kg wet weight (ww) (P < 0.001). At 24 h post-operatively, the reduced glutathione decreased by 0.47 (0.34-0.65) mmol/kg (ww) (P < 0.001) without changes in oxidized glutathione (GSSG) or in glutathione redox-status. Cysteine and glycine, the two other constituent amino acids to glutathione, did not change during the study period. CONCLUSION: Ischemia of 2 h during aorto-bifemoral bypass was associated with changes in muscle energy-rich compounds but without any changes in glutathione redox-status. A decreased antioxidative capacity, as reflected by a decrease in muscle glutathione concentrations, was seen 24 h post-operatively, still without changes in glutathione redox-status. This is not different from the changes seen after abdominal surgery not involving ischemia-reperfusion.

ESPEN Guidelines on Enteral Nutrition: Intensive care.

Enteral nutrition (EN) via tube feeding is, today, the preferred way of feeding the critically ill patient and an important means of counteracting for the catabolic state induced by severe diseases. These guidelines are intended to give evidence-based recommendations for the use of EN in patients who have a complicated course during their ICU stay, focusing particularly on those who develop a severe inflammatory response, i.e. patients who have failure of at least one organ during their ICU stay. These guidelines were developed by an interdisciplinary expert group in accordance with officially accepted standards and are based on all relevant publications since 1985. They were discussed and accepted in a consensus conference. EN should be given to all ICU patients who are not expected to be taking a full oral diet within three days. It should have begun during the first 24h using a standard high-protein formula. During the acute and initial phases of critical illness an exogenous energy supply in excess of 20-25 kcal/kg BW/day should be avoided, whereas, during recovery, the aim should be to provide values of 25-30 total kcal/kg BW/day. Supplementary parenteral nutrition remains a reserve tool and should be given only to those patients who do not reach their target nutrient intake on EN alone. There is no general indication for immune-modulating formulae in patients with severe illness or sepsis and an APACHE II Score >15. Glutamine should be supplemented in patients suffering from burns or trauma.

Elimination kinetics of L-alanyl-L-glutamine in ICU patients.

A randomised, double blind, placebo-controlled study was performed giving 0.5 g x kg(-1) x day(-1) of undiluted alanyl-glutamine (20%) or saline in a peripheral vein during 4 hours in ICU patients (n = 20). During the infusion period a steady state in plasma concentration was reached for alanyl-glutamine, but not for alanine, glutamine or glutamate. On the other hand there was no accumulation of any of the amino acids, as the pre-infusion concentrations were reached within 8 hours after the end of infusion. The half-life of the dipeptide was 0.26 hours (range, 0.15-0.63 h). The distribution volume of alanyl-glutamine was larger than the extracellular water volume, indicating a rapid hydrolysis of the dipeptide. There was no detectable alanyl-glutamine in the urine of any of the patients. All patients had excretion of small amounts of amino acids in urine, but the renal clearance of alanine, glutamine and glutamate were not different between the two groups.

Temporal changes in whole-blood and plasma glutathione in ICU patients with multiple organ failure.

OBJECTIVE: This study investigated the temporal changes in whole-blood and plasma glutathione in ICU patients with multiple organ failure. DESIGN AND SETTING: Prospective and descriptive pilot study performed in an ICU with eight beds at a university hospital. PATIENTS: Critically ill patients (n=11) with multiple organ failure and ICU stay of at least 6 days were consecutively included. Patients with chronic obstructive pulmonary disease (n=21) and healthy volunteers (n=10) were used as reference groups. MEASUREMENTS AND RESULTS: Whole-blood and plasma glutathione were measured every 72 h. Total glutathione and the reduced fraction were determined in whole blood. The oxidized fraction and the redox status were calculated from these values. In plasma only the total concentration was determined. Patients were studied for 6-15 days. Nutrition was supplied according to routines supplying basal needs including glutamine. Both total and reduced glutathione was found to be depleted in whole blood compared to the reference groups. Redox status indicated continuing oxidative stress. Plasma glutathione showed higher values in total concentrations than the reference groups. CONCLUSIONS: This study demonstrates that glutathione remains depleted in whole blood. This contrasts to what has previously been shown in skeletal muscle where a restitution of glutathione concentration is seen.

Contractile protein breakdown in human leg skeletal muscle as estimated by [2H3]-3-methylhistidine: a new method.

3-Methylhistidine urinary excretion and net balances across the leg or forearm have been used as markers of contractile protein breakdown in muscle tissue. Here we investigate whether infusion of labeled 3-methylhistidine and the measurement of the arteriovenous dilution of the tracer with unlabeled 3-methylhistidine will result in more consistent and precise measurements of 3-methylhistidine rates of appearance and consequently muscle contractile protein breakdown rates in comparison with conventional arteriovenous concentration difference measurements. Six healthy volunteers were studied in the postabsorptive state and received a primed continuous infusion of 3-[2H3-methyl]- methylhistidine and L-[ring-2H5]-phenylalanine for 4 hours. 2H3-3-methylhistidine reached an isotopic steady state after 210 minutes in all subjects. Arteriovenous differences of 3-methylhistidine, measured by high-performance liquid chromatography (HPLC), showed both uptake and release from skeletal muscle, which is theoretically not likely to occur. The enrichment of 2H3-3-methylhistidine was consistently lower in the femoral vein than in the artery, and therefore a constant net release of 3-methylhistidine from the leg was observed. The mean rates of appearance for 3-methylhistidine and phenylalanine were 0.44 +/- 0.30 nmol x min(-1) x 100 mL(-1) and 11.2 +/- 5.7 nmol x min(-1) x 100 mL(-1), respectively. In summary, arteriovenous difference measurement of 2H3-3-methylhistidine enrichment is more reliable than measurement of arteriovenous difference of unlabeled 3-methylhistidine. Consequently, measuring rates of appearance from leg muscle using labeled 3-methylhistidine resulted in more consistent and accurate values of contractile protein degradation rates in human skeletal muscle.