Critical Care 2009, 13:R74

The protective effect of glutamine, as a pharmacological agent against lung injury, has been reported in experimental sepsis; however, its efficacy at improving oxygenation and lung mechanics, attenuating diaphragm and distal organ injury has to be better elucidated. In the present study, we tested the hypothesis that a single early intravenous dose of glutamine was associated not only with the improvement of lung morpho-function, but also the reduction of the inflammatory process and epithelial cell apoptosis in kidney, liver, and intestine villi.

Methods
Seventy-two Wistar rats were randomly assigned into four groups. Sepsis was induced by cecal ligation and puncture surgery (CLP), while a sham operated group was used as control (C). One hour after surgery, C and CLP groups were further randomized into subgroups receiving intravenous saline (1 ml, SAL) or glutamine (0.75 g/kg, Gln). At 48 hours, animals were anesthetized, and the following parameters were measured: arterial oxygenation, pulmonary mechanics, and diaphragm, lung, kidney, liver, and small intestine villi histology. At 18 and 48 hours, Cytokine-Induced Neutrophil Chemoattractant (CINC)-1, interleukin (IL)-6 and 10 were quantified in bronchoalveolar and peritoneal lavage fluids (BALF and PLF, respectively).

Results
CLP induced: a) deterioration of lung mechanics and gas exchange; b) ultrastructural changes of lung parenchyma and diaphragm; and c) lung and distal organ epithelial cell apoptosis. Glutamine improved survival rate, oxygenation and lung mechanics, minimized pulmonary and diaphragmatic changes, attenuating lung and distal organ epithelial cell apoptosis. Glutamine increased IL-10 in peritoneal lavage fluid at 18 hours and bronchoalveolar lavage fluid at 48 hours, but decreased CINC-1 and IL-6 in BALF and PLF only at 18 hours.

Conclusions
In an experimental model of abdominal sepsis, a single intravenous dose of glutamine administered after sepsis induction may modulate the inflammatory process reducing not only the risk of lung injury, but also distal organ impairment. These results suggest that intravenous glutamine may be a potentially beneficial therapy for abdominal sepsis.

Critical Care Medicine 2009;37:1866-1872

To determine whether medical intensive care unit (ICU) patients receiving nasoduodenal (ND) feedings achieve optimal nutritional support and better clinical outcomes compared with patients receiving nasogastric (NG) feedings.

Design
A prospective, randomized, clinical study.

Setting
Medical ICU of a university-affiliated tertiary medical center.

Patients
One hundred twenty-one medical ICU patients required enteral feeding.

Interventions
Patients were randomized to receive enteral feeding. One group received ND feedings and the other group received NG feedings. All patients followed the same protocol.

Measurements and main results
The primary outcome of optimal nutritional support was assessed by measurement of time to goal tube feed rate and daily calorie and protein intake. Secondary clinical outcomes included number of ICU, hospital and ventilator days, number of the days in the study, blood-glucose levels, incidence of vomiting, diarrhea, gastrointestinal bleeding, tube replaced, tube clogged, fever, bacteremia, and ventilator-associated pneumonia (VAP), and mortality rate. Results showed that the ND group had a higher average daily calorie and protein intake compared with NG group and achieved nutritional goals earlier. In terms of clinical outcomes, patients in the ND group had a lower rate of vomiting and VAP. The other clinical outcomes such as number of ICU days, hospital days, ventilator days, blood-glucose level, tube replaced or clogged, diarrhea, gastrointestinal bleeding, fever, bacteremia, and mortality rate were not significantly different between two groups.

Conclusions
Patients who received ND feedings achieved nutritional goals earlier than those who received NG feeding. ND feeding group also has a lower rate of vomiting and VAP in the medical ICU setting.

Crit Care Med 2009;37:1757-1761

The guidelines are intended for the adult medical and surgical critically ill patient populations expected to require an ICU stay of > 2 or 3 days and are not intended for those patients in the ICU for temporary monitoring or those who have minimal metabolic or traumatic stress. The guidelines are based on populations, but like any other therapeutic treatment in an ICU patient, nutrition requirements and techniques of access should be tailored to the individual patient.

JAMA. 2008;300:2731-2741

Evidence demonstrates that providing nutritional support to intensive care unit (ICU) patients within 24 hours of ICU admission reduces mortality. However, early feeding is not universally practiced. Changing practice in complex multidisciplinary environments is difficult. Evidence supporting whether guidelines can improve ICU feeding practices and patient outcomes is contradictory.

Objective
To determine whether evidence-based feeding guidelines, implemented using a multifaceted practice change strategy, improve feeding practices and reduce mortality in ICU patients.

Design, setting, and patients
Cluster randomized trial in ICUs of 27 community and tertiary hospitals in Australia and New Zealand. Between November 2003 and May 2004, 1118 critically ill adult patients expected to remain in the ICU longer than 2 days were enrolled. All participants completed the study.

Interventions
Intensive care units were randomly assigned to guideline or control groups. Guideline ICUs developed an evidence-based guideline using Browman’s Clinical Practice Guideline Development Cycle. A practice-change strategy composed of 18 specific interventions, leveraged by educational outreach visits, was implemented in guideline ICUs.

Main outcome measures
Hospital discharge mortality. Secondary outcomes included ICU and hospital length of stay, organ dysfunction, and feeding process measures.

Results
Guideline and control ICUs enrolled 561 and 557 patients, respectively. Guideline ICUs fed patients earlier (0.75 vs 1.37 mean days to enteral nutrition start; difference, ñ0.62 [95% confidence interval {CI}, ñ0.82 to ñ0.36]; P < .001 and 1.04 vs 1.40 mean days to parenteral nutrition start; difference, ñ0.35 [95% CI, ñ0.61 to ñ0.01]; P = .04) and achieved caloric goals more often (6.10 vs 5.02 mean days per 10 fed patient-days; difference, 1.07 [95% CI, 0.12 to 2.22]; P = .03). Guideline and control ICUs did not differ with regard to hospital discharge mortality (28.9% vs 27.4%; difference, 1.4% [95% CI, ñ6.3% to 12.0%]; P = .75) or to hospital length of stay (24.2 vs 24.3 days; difference, ñ0.08 [95% CI, ñ3.8 to 4.4]; P = .97) or ICU length of stay (9.1 vs 9.9 days; difference, ñ0.86 [95% CI, ñ2.6 to 1.3]; P = .42).

Conclusions
Using a multifaceted practice change strategy, ICUs successfully developed and introduced an evidence-based nutritional support guideline that promoted earlier feeding and greater nutritional adequacy. However, use of the guideline did not improve clinical outcomes.

Crit Care Med. 2008;36:1762-1767

To identify current clinical practice regarding nutrition and its association with morbidity and mortality in patients with severe sepsis or septic shock in Germany.

Design
Nationwide prospective, observational, cross-sectional, 1-day point-prevalence study.

Setting
The study included 454 intensive care units from a representative sample of 310 hospitals stratified by size.

Patients
Participants were 415 patients with severe sepsis or septic shock (according to criteria of the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference).

Interventions
None.

Measurements and Main Results
Data were collected by on-site audits of trained external study physicians during randomly scheduled visits during 1 yr. Valid data on nutrition were available for 399 of 415 patients. The data showed that 20.1% of patients received exclusively enteral nutrition, 35.1% exclusively parenteral nutrition, and 34.6% mixed nutrition (parenteral and enteral); 10.3% were not fed at all. Patients with gastrointestinal/intra-abdominal infection, pancreatitis or neoplasm of the gastrointestinal tract, mechanical ventilation, or septic shock were less likely to receive exclusively enteral nutrition. Median Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment scores were significantly different among the nutrition groups. Overall hospital mortality was 55.2%. Hospital mortality was significantly higher in patients receiving exclusively parenteral (62.3%) or mixed nutrition (57.1%) than in patients with exclusively enteral nutrition (38.9%) (p = .005). After adjustment for patient morbidity (Acute Physiology and Chronic Health Evaluation II score, presence of septic shock) and treatment factors (mechanical ventilation), multivariate analysis revealed that the presence of parenteral nutrition was significantly predictive of mortality (odds ratio, 2.09; 95% confidence interval, 1.29-3.37).

Conclusions
Patients with severe sepsis or septic shock in German intensive care units received preferentially parenteral or mixed nutrition. The use of parenteral nutrition was associated with an increased risk of death.

Critical Care Medicine 2007;35:S541-S544

A recent editorial in Critical Care Medicine was titled Glutamine, a life-saving nutrient, but why? (2003; 31:2555-2556). This review will attempt to utilize new understanding of gene-nutrient interactions and molecular medicine to address potential mechanisms by which glutamine may be lifesaving after critical illness and injury. Recent meta-analysis data reveal that glutamine seems to exert a beneficial effect on mortality in critically ill patients. However, this effect seems to be dose and route dependent. The questions that remain to be answered are in what settings and via what method of administration does this phamaconutrient show optimal benefit? It is likely that examination of the molecular mechanisms by which glutamine exerts its effects will lead to an understanding of how best to utilize glutamine as both a pharmacologic and a nutritional agent. Clearly, clinical critical illness leads to a marked deficiency in glutamine that is correlated with mortality in the intensive care unit setting. It makes obvious sense that the deficiency of this vital stress nutrient should be replaced. In addition, recent laboratory data reveal glutamine may act via mechanisms independent of its role as a metabolic fuel. These include enhanced stress protein response, attenuation of the inflammatory response, improved tissue metabolic function, and attenuation of oxidant stress. Present data indicate that glutamine functions as a metabolic fuel and stress-signaling molecule after illness and injury. Thus, deficiencies observed in critical illness demand replacement for both pharmacologic and metabolic optimization. Presently, randomized, multicenter, clinical trials utilizing glutamine as a pharmacologic and a nutritional agent are ongoing.

Critical Care Medicine 2007;35:S535-S540 

Hypermetabolism and malnourishment are common in the intensive care unit. Malnutrition is associated with increased morbidity and mortality, and most intensive care unit patients receive specialized nutrition therapy to attenuate the effects of malnourishment. However, the optimal amount of energy to deliver is unknown, with some studies suggesting that full calorie feeding improves clinical outcomes but other studies concluding that caloric intake may not be important in determining outcome. In this narrative review, we discuss the studies of critically ill patients that examine the relationship between dose of nutrition and clinically important outcomes. Observational studies suggest that achieving targeted caloric intake might not be necessary since provision of approximately 25% to 66% of goal calories may be sufficient. Randomized controlled trials comparing early aggressive use of enteral nutrition compared with delayed, less aggressive use of enteral nutrition suggest that providing increased calories with early, aggressive enteral nutrition is associated with improved clinical outcomes. However, energy provision with parenteral nutrition, either instead of or supplemental to enteral nutrition, does not offer additional benefits. In summary, the optimal amount of calories to provide critically ill patients is unclear given the limitations of the existing data. However, evidence suggests that improving adequacy of enteral nutrition by moving intake closer to goal calories might be associated with a clinical benefit. There is no role for supplemental parenteral nutrition to increase caloric delivery in the early phase of critical illness. Further high-quality evidence from randomized trials investigating the optimal amount of energy intake in intensive care unit patients is needed.

To describe the current status and the clinical data related to the effects of tight glucose control by intensive insulin therapy in critically ill patients.

Design
Review article.

Setting
University hospital.

Patients
Medical and surgical critically ill patients in whom a correlation between blood glucose and outcome variables were searched.

Interventions
Tight glucose control by intensive insulin therapy.

Measurements and Main Results
In contrast to the decreases in mortality and to low severity of adverse effects reported when insulin rate was titrated to keep blood glucose between 80 and 110 mg/dL, the benefits were not confirmed in multicenter prospective studies. Retrospective data found an association between a mean blood glucose level of <140-150 mg/dL and improved outcome. Currently unanswered issues include the optimal target for blood glucose, the effects of high blood glucose variability, the risks and hazards of hypoglycemia, and the potential influence of the underlying disorder on the effects of tight glucose control.

Conclusions
Recommendations regarding the practical aspects of tight glucose control by intensive insulin therapy cannot be presently issued. An intermediate target level for blood glucose of 140-180 mg/dL seems to be associated with the lowest risk-to-benefit ratio.

Critical Care Medicine 2007;35:S496-S502

In two large, randomized studies, maintenance of normoglycemia with intensive insulin therapy largely prevented morbidity and reduced mortality of critically ill patients. Recently, questions have been raised about the efficacy and safety of this therapy. These issues are systematically addressed and discussed with the evidence available from these and other studies. The available studies show that an absolute reduction in risk of hospital death of 3% to 4% is to be expected from intensive insulin therapy in an intention-to-treat analysis. Future studies designed to confirm a statistically significant survival benefit should be adequately powered, with inclusion of ≥5,000 patients. When patients are treated with intensive insulin therapy for >3 days, the absolute reduction in the risk of death increases to approximately 8%. Insulin therapy also improves morbidity, more so when continued for >3 days. Strict blood glucose control to normoglycemia (<110 mg/dL) is required to obtain the most clinical benefit, but this inherently increases the risk of hypoglycemia. It remains unclear whether short hypoglycemic episodes are truly harmful for these patients. In conclusion, demonstration of the clinical benefits of intensive insulin therapy depends on the quality of blood glucose control and the statistical power of the studies.

There is still insufficient knowledge about in vivo glutamine metabolism and the regulation of glutamine homeostasis, particularly during metabolic stress. A shortage of glutamine is associated with a poor outcome, whereas for septic patients in the intensive care unit an increased availability of glutamine can prevent mortality and morbidity. Cellular defense mechanisms depend on normal glutamine availability to respond adequately to challenges presented. In clinical practice, treatment of plasma glutamine depletion improves outcome for the critically ill patient. An increased metabolic need for glutamine must be met with an increased consumption of glutamine. Ordinary food is not a sufficient supply of glutamine for the patient with multiple organ failure in the intensive care unit, but that is also true for several other nutrients. It is, therefore, debatable whether an exogenous supply of glutamine should be regarded as a pharmacologic treatment or whether this just represents physiology in stressed states. If a glutamine shortage requires substitution, supplementation to the normal concentration is compensation of a shortage, and the effect is physiological.

Critical Care Medicine 2007;35:S545-S552

We know that critically ill patients suffering from undernutrition with a limited nutritional reserve have a poorer outcome. Furthermore, having a low body mass index has been shown to be an independent predictor of excess mortality in multiple organ failure. Therefore, nutritional support has gained increasing interest in critical illness with the hope of preventing or attenuating the effects of malnutrition. A negative nitrogen balance is the characteristic metabolic feature in critical illness, with the major protein loss derived from skeletal muscle. In particular, glutamine concentrations are rapidly reduced in plasma and muscle.

Over the last 20 yrs or so, increasing evidence is emerging to support the use of glutamine supplementation in critical illness. Clinical trials have found a mortality and morbidity advantage with glutamine supplementation. The advantage appears to be greater the more glutamine is given and greater again when given parenterally. Various modes of action have been postulated. Glutamine seems to have an effect on the immune system, antioxidant status, glucose metabolism, and heat shock protein response. However, the benefit of exogenous glutamine on morbidity and mortality is not universally accepted. This review critically appraises the current clinical evidence regarding glutamine supplementation in critical illness.

Critical Care Medicine 2007;35:S557-S563

Sepsis is a severe condition in critically ill patients and is considered an arginine deficiency state. The rationale for arginine deficiency in sepsis is mainly based on the reduced arginine levels in sepsis that are associated with the specific changes in arginine metabolism related to endothelial dysfunction, severe catabolism, and worse outcome.

Exogenous arginine supplementation in sepsis shows controversial results with only limited data in humans and variable results in animal models of sepsis. Since in these studies the severity of sepsis varies but also the route, timing, and dose of arginine, it is difficult to draw a definitive conclusion for sepsis in general without considering the influence of these factors.

Enhanced nitric oxide production in sepsis is related to suggested detrimental effects on hemodynamic instability and enhanced oxidative stress. Potential mechanisms for beneficial effects of exogenous arginine in sepsis include enhanced (protein) metabolism, improved microcirculation and organ function, effects on immune function and antibacterial effects, improved gut function, and an antioxidant role of arginine. We recently performed a study indicating that arginine can be given to septic patients without major effects on hemodynamics, suggesting that more studies can be conducted on the effects of arginine supplementation in septic patients.

Critical Care Medicine 2007;35:S564-S567

Given the multiple biological, metabolic, and pharmacologic effects of supplemental arginine, much effort has been devoted to defining its role in numerous clinical conditions. Herein, we review the multiple pathways of arginine metabolism with its various enzyme systems; the effect of arginine on nutrition, healing, and immune system; and its clinical use. Sepsis has been postulated to be an arginine-deficient state and/or a syndrome with elevated levels of nitric oxide. So-called immunonutritional formulations containing various nutritional components have been used most often, yet the effects often are attributed to arginine alone. Such conclusions led to guidelines recommending against the use of arginine-supplemented diets in critically ill patients. While caution in the face of a lack of evidence for benefit in sepsis is commended, well-defined studies examining arginine monotherapy in the context of full nutritional support should be carried out so as to define the possible clinical uses of arginine in critically ill and septic patients.

Critical Care 2007, 11:R79

Early nutrition is recommended for patients with sepsis, but data are conflicting regarding the optimum route of delivery. Enteral nutrition (EN), compared with parenteral nutrition (PN), results in poorer achievement of nutritional goals but may be associated with fewer infections. Mechanisms underlying differential effects of the feeding route on patient outcomes are not understood, but probably involve the immune system and the anabolic response to nutrients. We studied the effect of nutrition and the route of delivery of nutrition on cytokine profiles, the growth hormone–insulin-like growth factor-1 (IGF-I) axis and a potential mechanism for immune and anabolic system interaction, the suppressors of cytokine signaling (SOCS), in rodents with and without sepsis.

Methods
Male Sprague–Dawley rats were randomized to laparotomy (Sham) or to cecal ligation and puncture (CLP), with postoperative saline infusion (Starve), with EN or with PN for 72 hours. Serum levels of IL-6 and IL-10 were measured by immunoassay, and hepatic expressions of cytokine-inducible SH2-containing protein, SOCS-2, SOCS-3, IGF-I and the growth hormone receptor (GHR) were measured by real-time quantitative PCR.

Results
IL-6 was detectable in all groups, but was only present in all animals receiving CLP-PN. IL-10 was detectable in all but one CLP-PN rat, one CLP-EN rat, approximately 50% of the CLP-Starve rats and no sham-operated rats. Cytokine-inducible SH2-containing protein mRNA was increased in the CLP-EN group compared with the Sham-EN group and the other CLP groups (P < 0.05). SOCS-2 mRNA was decreased in CLP-PN rats compared with Sham-PN rats (P = 0.07). SOCS-3 mRNA was increased with CLP compared with sham operation (P < 0.03). IGF-I mRNA (P < 0.05) and GHR mRNA (P < 0.03) were greater in the fed CLP animals and in the Sham-PN group compared with the starved rats.

Conclusion
In established sepsis, nutrition and the route of administration of nutrition influences the circulating cytokine patterns and expression of mRNA of SOCS proteins, GHR and IGF-I. The choice of the administration route of nutrition may influence cellular mechanisms that govern the response to hormones and mediators, which further influence the response to nutrients. These findings may be important in the design and analysis of clinical trials of nutritional interventions in sepsis in man.

See related commentary by Stehle.

Liver dysfunction associated with artificial nutrition in critically ill patients is a complication that seems to be frequent, but it has not been assessed previously in a large cohort of critically ill patients.

Methods
We conducted a prospective cohort study of incidence in 40 intensive care units. Different liver dysfunction patterns were defined: (a) cholestasis: alkaline phosphatase of more than 280 IU/l, gamma-glutamyl-transferase of more than 50 IU/l, or bilirubin of more than 1.2 mg/dl; (b) liver necrosis: aspartate aminotransferase of more than 40 IU/l or alanine aminotransferase of more than 42 IU/l, plus bilirubin of more than 1.2 mg/dl or international normalized ratio of more than 1.4; and (c) mixed pattern: alkaline phosphatase of more than 280 IU/l or gamma-glutamyl-transferase of more than 50 IU/l, plus aspartate aminotransferase of more than 40 IU/l or alanine aminotransferase of more than 42 IU/l.

Results
Seven hundred and twenty-five of 3,409 patients received artificial nutrition: 303 received total parenteral nutrition (TPN) and 422 received enteral nutrition (EN). Twenty-three percent of patients developed liver dysfunction: 30% in the TPN group and 18% in the EN group. The univariate analysis showed an association between liver dysfunction and TPN (p < 0.001), Multiple Organ Dysfunction Score on admission (p < 0.001), sepsis (p < 0.001), early use of artificial nutrition (p < 0.03), and malnutrition (p < 0.01). In the multivariate analysis, liver dysfunction was associated with TPN (p < 0.001), sepsis (p < 0.02), early use of artificial nutrition (p < 0.03), and calculated energy requirements of more than 25 kcal/kg per day (p < 0.05).

Conclusion
TPN, sepsis, and excessive calculated energy requirements appear as risk factors for developing liver dysfunction. Septic critically ill patients should not be fed with excessive caloric amounts, particularly when TPN is employed. Administering artificial nutrition in the first 24 hours after admission seems to have a protective effect.

Critical Care 2006, 10:R153

Nosocomial pneumonia is a major source of morbidity and mortality after severe burns. Burned patients suffer trace element deficiencies, depressed antioxidant and immune defences. The study aimed at determining the effect of trace element supplementation on nosocomial or ICU-acquired pneumonia.

Material and methods
Two consecutive, randomised double-blinded, supplementation studies including two homogeneous groups of 41 severely burned patients (20 placebo and 21intervention) admitted to the Burn centre of a University hospital were combined. Intervention: intravenous trace element supplements (copper 2.5-3.1 mg/d, selenium 315-380 mcg/d, zinc 26.2-31.4 mg/d) for 8 to 21 days versus placebo. Endpoints were infections during the first 30 days (predefined criteria for pneumonia, bacteremia, wound, urine, other), wound healing, length of ICU stay. Plasma and skin (study 2) concentrations of Se and Zn were determined on days 3, 10 and 20.

Results
The patients, aged 42+/-15 years were burned on 46+/-19% of body surface: the combined characteristics of the patients did not differ between the groups. Plasma trace element concentrations and antioxidative capacity were significantly enhanced with normalization of plasma selenium, zinc and glutathione peroxidase concentrations in plasma and skin in the trace element supplemented group. A significant reduction in number of infections was observed in the supplemented patients, which decreased from 3.5+/-1.2 to 2.0+/-1.0 episodes per patient in placebo group (p <0.001). This was related to a reduction of nosocomial pneumonia, which occurred in 16 (80%) patients versus 7 (33%) patients respectively (p<0.001), and of ventilator-associated pneumonia from 13 to 6 episodes respectively (p=0.023).

Conclusions
Enhancing trace element status and antioxidant defences by selenium, zinc and copper supplementation was associated with a decrease of nosocomial pneumonia in critically ill severely burned patients.

Objective
To discuss certain important features of nutrition and metabolism in the intensive care unit.

Data Source
Prospective clinical trials examining issues related to glucose control, immunonutrition, and comparison of enteral and parenteral nutrition.

Conclusions
It remains unclear which glycemic threshold should be used in many patients for insulin initiation, but surgical patients receiving adequate nutrition should probably be treated to true normoglycemia. Immunonutrition may be beneficial in some populations, but the evidence does not justify its use in the intensive care unit. Contrary to popular belief, appropriately administered parenteral nutrition may provide similar or more benefit than enteral and clearly needs more widespread acceptance in cases where initiation of enteral nutrition is slow to start or is contraindicated.