Gary P. Zaloga

Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: Consensus statements from an international task force by the American College of Critical Care Medicine

Objective:To develop consensus statements for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients. Participants:A multidisciplinary, multispecialty task force of experts in critical care medicine was convened from the membership of the Society of Critical Care Medicine and the European Society of Intensive Care Medicine. In addition, international experts in endocrinology were invited to participate. Design/Methods:The task force members reviewed published literature and provided expert opinion from which the consensus was derived. The consensus statements were developed using a modified Delphi methodology. The strength of each recommendation was quantified using the Modified GRADE system, which classifies recommendations as strong (grade 1) or weak (grade 2) and the quality of evidence as high (grade A), moderate (grade B), or low (grade C) based on factors that include the study design, the consistency of the results, and the directness of the evidence. Results:The task force coined the term critical illness–related corticosteroid insufficiency to describe the dysfunction of the hypothalamic-pituitary-adrenal axis that occurs during critical illness. Critical illness–related corticosteroid insufficiency is caused by adrenal insufficiency together with tissue corticosteroid resistance and is characterized by an exaggerated and protracted proinflammatory response. Critical illness–related corticosteroid insufficiency should be suspected in hypotensive patients who have responded poorly to fluids and vasopressor agents, particularly in the setting of sepsis. At this time, the diagnosis of tissue corticosteroid resistance remains problematic. Adrenal insufficiency in critically ill patients is best made by a delta total serum cortisol of <9 &mgr;g/dL after adrenocorticotrophic hormone (250 &mgr;g) administration or a random total cortisol of <10 &mgr;g/dL. The benefit of treatment with glucocorticoids at this time seems to be limited to patients with vasopressor-dependent septic shock and patients with early severe acute respiratory distress syndrome (Pao2/Fio2 of <200 and within 14 days of onset). The adrenocorticotrophic hormone stimulation test should not be used to identify those patients with septic shock or acute respiratory distress syndrome who should receive glucocorticoids. Hydrocortisone in a dose of 200 mg/day in four divided doses or as a continuous infusion in a dose of 240 mg/day (10 mg/hr) for ≥7 days is recommended for septic shock. Methylprednisolone in a dose of 1 mg·kg−1·day−1 for ≥14 days is recommended in patients with severe early acute respiratory distress syndrome. Glucocorticoids should be weaned and not stopped abruptly. Reinstitution of treatment should be considered with recurrence of signs of sepsis, hypotension, or worsening oxygenation. Dexamethasone is not recommended to treat critical illness–related corticosteroid insufficiency. The role of glucocorticoids in the management of patients with community-acquired pneumonia, liver failure, pancreatitis, those undergoing cardiac surgery, and other groups of critically ill patients requires further investigation. Conclusion:Evidence-linked consensus statements with regard to the diagnosis and management of corticosteroid deficiency in critically ill patients have been developed by a multidisciplinary, multispecialty task force.

Immunonutrition in critically ill patients: a systematic review and analysis of the literature

BackgroundThe role of immuno-modulating diets (IMDs) in critically ill patients is controversial.ObjectiveThe goal of this meta-analysis was to determine the impact of IMD’s on hospital mortality, nosocomial infections and length of stay (LOS) in critically ill patients. Outcome was stratified according to type of IMD and patient setting.Data sourcesMEDLINE, Embase, Cochrane Register of Controlled Trials.Study selectionRCT’s that compared the outcome of critically ill patients randomized to an IMD or a control diet.Data synthesisTwenty-four studies (with a total of 3013 patients) were included in the meta-analysis; 12 studies included ICU patients, 5 burn patients and 7 trauma patients. Four of the studies used formulas supplemented with arginine, two with arginine and glutamine, nine with arginine and fish oil (FO), two with arginine, glutamine and FO, six with glutamine alone and three studies used a formula supplemented with FO alone. Overall IMD’s had no effect on mortality or LOS, but reduced the number of infections (OR 0.63; 95% CI 0.47–0.86, Pxa0=xa00.004, I2xa0=xa049%). Mortality, infections and LOS were significantly lower only in the ICU patients receiving the FO IMD (OR 0.42, 95% CI 0.26–0.68; OR 0.45, 95% CI 0.25–0.79 and WMD -6.28xa0days, 95% CI −9.92 to −2.64, respectively).ConclusionsAn IMD supplemented with FO improved the outcome of medical ICU patients (with SIRS/sepsis/ARDS). IMDs supplemented with arginine with/without additional glutamine or FO do not appear to offer an advantage over standard enteral formulas in ICU, trauma and burn patients.

Steroid treatment in ARDS: a critical appraisal of the ARDS network trial and the recent literature

ObjectivesTo compare the design and results of randomized trials investigating prolonged glucocorticoid treatment (≥u202f7 days) in patients with acute lung injury–acute respiratory distress syndrome (ALI–ARDS), and review factors affecting response to therapy, including the role of secondary prevention.DesignTrials were retrieved from the Cochrane Central Register of Controlled Trials (CENTRAL). Two investigators collected data on study characteristics, treatment intervention, and outcomes. The methodological quality of trials was determined and data were analyzed with Review Manager 4.2.3.Measurements and resultsFive selected trials (nu202f=u202f518) consistently reported significant improvement in gas exchange, reduction in markers of inflammation, and decreased duration of mechanical ventilation and intensive care unit stay (all pu202f<u202f0.05). Two early small clinical trials showed marked reductions in the relative risk (RR) of death with glucocorticoid therapy (RRu202f=u202f0.14, 95%xa0CIxa00.04–0.53; pu202f=u202f0.004, I2u202f=u202f0%). Three subsequent larger trials, when combined, although nominally beneficial, did not reproduce the marked reductions observed in the earlier trials (RRu202f=u202f0.84; 95%xa0CI 0.68–1.03; pu202f=u202f0.09, I2u202f=u202f9.1%), but achieved axa0distinct reduction in the RR of death in the larger subgroup of patients (nu202f=u202f400) treated before day 14 of ARDS [82/214 (38%) vs. 98/186 (52.5%), RRu202f=u202f0.78; 95%xa0CI 0.64–0.96; pu202f=u202f0.02, I2u202f=u202f0%].ConclusionsProlonged glucocorticoid treatment substantially and significantly improves meaningful patient-centered outcome variables, and has axa0distinct survival benefit when initiated before day 14 of ARDS.

Omega 3-Fatty Acids: Health Benefits and Cellular Mechanisms of Action

Epidemiological evidence has established that ingestion of long-chain polyunsaturated omega-3 fatty acids (omega-3 PUFAs), abundant in fish oils, have profound effects on many human disorders and diseases, including cardiovascular disease and cancer. Here we briefly review the dietary recommendations and the food sources that are naturally enriched by these fatty acids. There are also a number of products including eggs, bread, and cereals available to supplement omega-3 fatty acid dietary intake. Some of these supplements are proposed to aid different pathological conditions. While the beneficial effects of omega-3 fatty acids can no longer be doubted, their molecular mechanism of action remains elusive. Without question, the action of omega-3 fatty acids is complex and involves a number of integrated signaling pathways. This review focuses on one of the possible cellular mechanisms by which the omega-3 PUFAs, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), may function. Studies with cancer cells suggest that DHA induces cell cycle arrest and apoptosis by activating protein phosphatases, leading to dephosphorylation of retinoblastoma protein (pRB). Protein phosphatases are also involved with the protein Bcl2, which regulates the release of cytochrome c from mitochondria, and eventually, activation of the apoptotic enzyme caspase 3.

Long-chain saturated fatty acids induce pro-inflammatory responses and impact endothelial cell growth

BACKGROUND & AIMSnSaturated fatty acids (SFAs), significant components of enteral and parenteral formulations, have been linked to cardiovascular complications. However, the effect of SFAs upon vascular inflammation is less clear. Endothelial cells (EC) play an important role in the acute inflammatory responses. We, therefore, evaluated the acute effects of different chain-length SFAs upon EC functions.nnnMETHODSnEndothelial cells were cultured with various SFAs. Growth and cytotoxicity were determined by WST-1 assay. Apoptosis and pro-inflammatory adhesion molecule (ICAM-1) expression was assayed using flow cytometry. Activation of NF-kappaB was analyzed using western blot analysis.nnnRESULTSnLong-chain SFAs (C14:0-C20:0) inhibited EC growth in a chain-length dependent manner. Medium-chain SFAs (C6:0-C12:0) did not significantly affect EC growth. In contrast, the short-chain SFA (C4:0) stimulated cellular growth. Stearic acid induced significantly more EC apoptosis and necrosis than palmitic acid or myristic acids. Stearic acid (>10muM) treatment also significantly increased ICAM-1 expression. Stearic acids pro-inflammatory response was confirmed by phosphorylation of IkappaB-alpha and NF-kappaB in a dose dependent manner.nnnCONCLUSIONSnLong-chain SFAs can induce pro-inflammatory responses and significantly impact growth and viability of EC. Our data suggest that the presence of long-chain SFAs in parenteral formulations may have harmful effects on the vascular system.

An Improved Method for Determining Medium- and Long-Chain FAMEs Using Gas Chromatography

The existing protocols for analyzing fatty acid methyl esters (FAMEs) using a one-step acetyl chloride (AC) catalyzed transesterification and extraction procedure cannot accurately determine the medium- and long-chain fatty acids simultaneously in clinical (enteral, parenteral) formulations. For example: (1) addition of AC at room temperature generates an exothermic reaction that often results in loss of sample and possible injury to the analyst; (2) certain polyunsaturated fatty acids (PUFAs) are less stable at elevated temperatures during the transesterification and contribute to the over-estimation of the C16:0 and C18:1 fatty acids; and (3) the flame-ionization detector (FID) response varies depending on the carbon chain length of the fatty acids, that consequently impacts the underestimation of medium-chain fatty acid (C6–C10) recoveries. To overcome these deficiencies and accurately determine FAMEs, we have developed an improved one-step transesterification method that employs the addition of AC in tubes kept on a dry ice bath, the transesterification at room temperature, and the data analysis using relative response factors. Using this modified protocol, we determined the fatty acid composition of lipid emulsions (Omegaven® and Lipidem®) on a Shimadzu GC2010 gas chromatography (GC) system using a capillary GC column (Zebron ZB-WAX plus, 30xa0m, 0.25xa0mmxa0ID, 0.25xa0μm). Our data suggest that the improved method can be easily used to accurately determine fatty acids (C6–C24) in functional foods and lipid emulsions.

N-3 Fatty acids prevent whereas trans-fatty acids induce vascular inflammation and sudden cardiac death

n-3 PUFA have well-recognised cardio-beneficial effects. In contrast, premature coronary deaths are associated with consumption of high levels of trans-fatty acids (TFA). The present study determined the effects of n-3 PUFA and TFA on sudden cardiac death and vascular inflammation. A rat coronary ligation model was used to study the effect of fatty acids on sudden cardiac death, whereas a mouse femoral artery ligation model was used to study compensatory vascular remodelling. Human aortic endothelial cells (HAEC) were utilised for the in vitro studies to investigate expression of inflammatory molecules. Feeding animals an n-3 PUFA-enriched diet caused a sevenfold increase in plasma n-3 PUFA compared with that of the TFA-fed group, whereas a TFA-enriched diet caused a 2.5-fold increase in plasma TFA compared with the n-3 PUFA group. Animals on a TFA diet had a lower survival rate due to sudden cardiac death and exhibited variable degrees of aortic atherosclerotic lesions. Animals on a TFA diet had diminished hindlimb collateral growth, whereas animals on the n-3 PUFA diet exhibited extensive collateral growth about ligated regions. HAEC treated with TFA (trans-18 : 2) showed significantly increased expression of intracellular adhesion molecule-1 and nitrosylation of cellular proteins than those treated with DHA (n-3 PUFA, 22 : 6). The in vivo study demonstrates that, in contrast to TFA, n-3 PUFA improve animal survival after myocardial infarction, prevent development of atherosclerotic lesions and stimulate compensatory vascular remodelling. The in vitro study demonstrates that TFA induce, while n-3 PUFA prevent, vascular inflammation.

Phytosterols, Lipid Administration, and Liver Disease During Parenteral Nutrition

Phytosterols are plant-derived sterols that are structurally and functionally analogous to cholesterol in vertebrate animals. Phytosterols are found in many foods and are part of the normal human diet. However, absorption of phytosterols from the diet is minimal. Most lipid emulsions used for parenteral nutrition are based on vegetable oils. As a result, phytosterol administration occurs during intravenous administration of lipid. Levels of phytosterols in the blood and tissues may reach high levels during parenteral lipid administration and may be toxic to cells. Phytosterols are not fully metabolized by the human body and must be excreted through the hepatobiliary system. Accumulating scientific evidence suggests that administration of high doses of intravenous lipids that are high in phytosterols contributes to the development of parenteral nutrition-associated liver disease. In this review, mechanisms by which lipids and phytosterols may cause cholestasis are discussed. Human studies of the association of phytosterols with liver disease are reviewed. In addition, clinical studies of lipid/phytosterol reduction for reversing and/or preventing parenteral nutrition associated liver disease are discussed.

Is there a difference in bloodstream infections in critically ill patients associated with ready-to-use versus compounded parenteral nutrition?

BACKGROUND & AIMSnParenteral nutrition is widely used in critically ill patients receiving nutritional support. Several previous studies associated the use of parenteral nutrition with the development of bloodstream infections. This study compared bloodstream infections in critical care patients receiving parenteral nutrition (PN) prepared via conventional compounding versus premixed multichamber bags.nnnMETHODSnRecords in the Premier Perspective™ database for all in patients ≥ 18 years of age, with a minimum 3-day intensive care unit stay, who received PN between 2005 and 2007 were analyzed (n = 15,328). Statistical analysis of data, grouped according to preparation method, compared differences in both observed bloodstream infection rates and adjusted rates, using logistic regression to examine the impact of hospital and patient baseline characteristics.nnnRESULTSnPatients receiving compounded parenteral nutrition had longer intensive care unit stays (11.3 vs. 9.1 days) and longer hospital stays (22.6 vs. 19.4 days); both P < .001. After adjusting for baseline differences, the probability for bloodstream infections was 19% higher when using compounded parenteral nutrition vs. multichamber bags (29.6 vs. 24.9%; odd ratio = 1.29; 95% confidence interval = 1.06-1.59).nnnCONCLUSIONnIn this retrospective review of a large patient database the adjusted probability of bloodstream infection was significantly lower in patients receiving multichamber bags than compounded parenteral nutrition. These findings need to be investigated further in high quality observational studies and prospective clinical trials.

The ratio of energy expenditure to nitrogen loss in diverse patient groups – A systematic review

BACKGROUND & AIMSnThe ratio of energy expenditure to nitrogen loss respectively of energy to nitrogen provision (E/N) is considered a valuable tool in the creation of an enteral or parenteral formulation. Specific E/N ratios for parenteral nutrition (PN) have not yet been clearly defined. To determine the range of energy expenditure, nitrogen (protein) losses, and E/N ratios for various patient groups, we performed a systematic review of the literature.nnnMETHODSnMedline 1950-2011 was searched for all studies on patients or healthy controls reporting energy expenditure and nitrogen loss at the same time.nnnRESULTSnWe identified 53 studies with 91 cohorts which comprised 1107 subjects. Mean TEE ± standard deviation (SD) was 31.2 ± 7.2 kcal/kg BW/day in patients (n = 881) and 35.6 ± 4.3 kcal/kg BW/day in healthy controls (n = 266). Mean total protein loss (TPL) was 1.50 ± 0.57 g/kg BW/day in patients and 0.94 ± 0.24 g/kg BW/day in healthy controls. A non-linear significant correlation was found between TPL and the E/N ratio.nnnCONCLUSIONnThe E/N ratio is not a constant value but decreases continuously with increasing protein loss. These variations should be considered in the nutritional support of patients.