Impact of sepsis, lung injury, and the role of lipid infusion on circulating prostacyclin and thromboxane A(2).

OBJECTIVE: To investigate whether plasma levels of prostacyclin (PGI2) and thromboxane A(2) (TxA2) are a function of the infusion rate of soybean-based fat emulsions, severity of systemic inflammation, and pulmonary organ failure. DESIGN: Prospective, randomized, crossover study. SETTING: Intensive care unit of a university hospital. PATIENTS: Eighteen critically ill patients, ten presenting with severe sepsis, eight with SIRS or sepsis complicated with ARDS. INTERVENTIONS: Patients were randomly assigned to receive rapid fat infusion over 6 h (rFI) or slow fat infusion over 24 h (sFI) along with parenteral nutrition. MEASUREMENTS AND RESULTS: The stable prostanoids 6-keto-PGF1alpha and TxB2 were measured in arterial and mixed venous blood samples, and at 6-h periods trans-pulmonary balances (TPB) were calculated. Free linoleic acid fraction was determined in arterial blood. rFI induced greater increase of linoleic acid than sFI in both groups. Enhanced prostanoid levels and correlations with linoleic acid availabilities were found, however, in ARDS patients only, revealing the highest sepsis- and lung injury scores. Averaged TPB per 24 h was positive in the sepsis group and negative in the ARDS group as rFI induced lowest TPB values for TxB2 at 6 h. CONCLUSION: The quantity of prostanoids formed and their subsequent utilization are dependent on the availability of precursor linoleic acid and are probably affected by the severity of SIRS or sepsis and the existence of pulmonary organ failure, respectively. Because TxA2 might be extracted by the injured lung, rapid infusion of soybean-based fat emulsions should be avoided in patients suffering from severe pulmonary organ failure.

Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway.

In mammals, the canonical nuclear factor kappaB (NF-kappaB) signaling pathway activated in response to infections is based on degradation of IkappaB inhibitors. This pathway depends on the IkappaB kinase (IKK), which contains two catalytic subunits, IKKalpha and IKKbeta. IKKbeta is essential for inducible IkappaB phosphorylation and degradation, whereas IKKalpha is not. Here we show that IKKalpha is required for B cell maturation, formation of secondary lymphoid organs, increased expression of certain NF-kappaB target genes, and processing of the NF-kappaB2 (p100) precursor. IKKalpha preferentially phosphorylates NF-kappaB2, and this activity requires its phosphorylation by upstream kinases, one of which may be NF-kappaB-inducing kinase (NIK). IKKalpha is therefore a pivotal component of a second NF-kappaB activation pathway based on regulated NF-kappaB2 processing rather than IkappaB degradation.

Effects of intravenous fat emulsions on lung function in patients with acute respiratory distress syndrome or sepsis.

OBJECTIVE: To investigate whether rapid or slowly infused intravenous fat emulsions affect the ratio of prostaglandin I2/thromboxane A2 in arterial blood, pulmonary hemodynamics, and gas exchange. DESIGN: Prospective, controlled, randomized, crossover study. SETTING: Operative intensive care unit of a university hospital. PATIENTS: Eighteen critically ill patients. Ten patients were stratified with severe sepsis, and eight patients had acute respiratory distress syndrome (ARDS). INTERVENTIONS: Patients were assigned randomly to receive intravenous fat emulsions (0.4 x resting energy expenditure) over 6 hrs (rapid fat infusion) or 24 hrs (slow fat infusion) along with a routine parenteral nutrition regimen, by using a crossover study design. MEASUREMENTS AND MAIN RESULTS: Systemic and pulmonary hemodynamics as well as gas exchange measurements were recorded via respective indwelling catheters. Arterial thromboxane B2 and 6-keto-prostaglandin-F1alpha plasma concentrations were obtained by radioimmunoassay, and 6-keto-prostaglandin-F1alpha/thromboxane B2 ratios (P/T ratios) were calculated. Data were collected immediately before and 6, 12, 18, and 24 hrs after onset of fat infusion. In the ARDS group, P/T ratio increased by rapid fat infusion. Concomitantly, pulmonary shunt fraction, alveolar-arterial oxygen tension difference [P(a-a)o2]/Pao2, and cardiac index increased as well, whereas pulmonary vascular resistance and Pao2/Fio2 declined. After slow fat infusion, a decreased P/T ratio was revealed. This was accompanied by decreased pulmonary shunt fraction, lowered P(a-a)o2/Pao2, and increased Pao2/Fio2. Correlations between plasma concentrations of 6-keto-prostaglandin-F1alpha or thromboxane B2 and measures of respiratory performance could be shown during rapid and slow fat infusion, respectively. In the sepsis group, the P/T ratio remained unchanged at either infusion rate, but pulmonary shunt fraction and P(a-a)o2/Pao2 decreased after rapid fat infusion, whereas Pao2/Fio2 increased. CONCLUSION: Pulmonary hemodynamics and gas exchange are related to changes of arterial prostanoid levels in ARDS patients, depending on the rate of fat infusion. In ARDS but not in sepsis patients clear of pulmonary organ failure, a changing balance of prostaglandin I2 and thromboxane A2 may modulate gas exchange, presumably via interference with hypoxic pulmonary vasoconstriction.

IKKbeta is essential for protecting T cells from TNFalpha-induced apoptosis.

Transcription factor NF-kappaB, whose activation depends on the IKKbeta catalytic subunit of the IkappaB kinase, was assigned with both anti- and proapoptotic functions in T lymphocytes. To critically evaluate these functions, we transferred Ikkbeta-/- or wild-type (wt) fetal liver (FL) stem cells into lethally irradiated mice. Ikkbeta-/- radiation chimeras show thymic rudiments, aberrant lymphoid organs, and absence of T cells. T lymphopoiesis is rescued when Ikkbeta-/- stem cells are cotransferred with wt bone marrow, suggesting that IKKbeta may mediate its lymphopoietic function via extrinsic factors. However, almost normal development of Ikkbeta-/- T cells is observed upon removal of type 1 TNFalpha receptor, indicating that TNFalpha signaling accounts for the absence of Ikkbeta-/- T cells. Indeed, Ikkbeta-/- radiation chimeras exibit elevated circulating TNFalpha, and Ikkbeta-/- thymocytes display increased TNFalpha sensitivity.

Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis.

Activity of the p38alpha MAP kinase is stimulated by various stresses and hematopoietic growth factors. A role for p38alpha in mouse development and physiology was investigated by targeted disruption of the p38alpha locus. Whereas some p38alpha(-/-) embryos die between embryonic days 11.5 and 12.5, those that develop past this stage have normal morphology but are anemic owing to failed definitive erythropoiesis, caused by diminished erythropoietin (Epo) gene expression. As p38alpha-deficient hematopoietic stem cells reconstitute lethally irradiated hosts, p38alpha function is not required downstream of Epo receptor. Inhibition of p38 activity also interferes with stabilization of Epo mRNA in human hepatoma cells undergoing hypoxic stress. The p38alpha MAP kinase plays a critical role linking developmental and stress-induced erythropoiesis through regulation of Epo expression.

[Immune function and organ failure. Immunomodulation with nutritional support--an update]. / Immunfunktion und Organversagen. Immunmodulation durch Ernährungssubstrate--"update".

Today, substrates with immunomodulatory effects are not only identified in all groups of macronutrients, but also in the domains of vitamins and traceelements. Mainly they interfere with 3 areas of the immune response: 1. the mucosal barrier function, 2. the cellular defense function, and 3. the local or systemic inflammatory response. Enteral formulas enriched with immune-enhancing diets are already in clinical use to encounter "immunoparalysis" of cellular defense during critical illness. Considering defined outcome variables, indeed, current clinical studies point out some improvements. Using an evidence based approach, a grade A recommendation was proclaimed for its broad clinical use. For defined subgroups of patients, however, presenting with most severe appearances of SIRS and consecutive organ failure, the current concept of enteral immunonutrition remains to be a matter of debate, and the evidence of clinical benefits persist to be questionable.

[Cerebral protection. The role of nutritional therapy]. / Zerebrale Protektion. Stellenwert der Ernährungstherapie.

Prevention of secondary cerebral insults has the highest priority as far as therapeutic interventions of the patient with brain lesions are concerned. Patients with cerebral lesions have to overcome both, cerebral and systemic insults. The intensity of the neuronal injury determines the grade of hypermetabolism. Optimal metabolic and nutritional therapy for patients with cerebral lesions should be accomplished to minimize secondary brain damage. Frequently, the systemic hypermetabolic response is associated with cerebral ischemic metabolism. Therefore systemic blood glucose levels should be less than 150 mg/dl to prevent intracellular anaerobic accumulation of lactate. Individual utilization capacity of substrates is determined by the grade of hypermetabolism. Substrate load has to be adapted to the individual utilization capacity to avoid side effects of nutritional therapy like substrate and volume overload, imbalances of electrolytes as well as enhanced application of excitatoric substrates. In addition, whenever possible enteral nutrition should be applied to profit from reduced bacterial translocation and improved glucose hemostasis. Oxygen radical production and lipid peroxidation are important pathophysiologic mechanisms concerning cerebral lesions. More recent data show reduced antioxidative status in patients with brain injuries which favors lipid peroxidation. Further studies must be carried out to evaluate the potential neuro-protective effect of an antioxidative nutritional regimen in patients with cerebral lesions.

Enteral versus parenteral nutrition: effects on gastrointestinal function and metabolism.

The effects of total parenteral nutrition (TPN) versus enteral nutrition (TEN) were studied in 34 patients following major neurosurgery. Measurements were made of resting energy expenditure (REE), urea production rate (UPR), visceral proteins, parameters of liver and pancreas function, as well as gastrointestinal absorption. To predict nutritional status, nutritional index (NI) was calculated. UPR revealed no significant differences between the groups. After 12 days of TEN, however, synthesis of visceral proteins increased significantly. In addition, NI improved after TEN (p < 0.05), whereas it remained unchanged after TPN. Thrombocyte and lymphocyte counts rose predominately during enteral nutrition. Only in the TEN group was REE increased by 18% and Glasgow Coma Scale (GCS) enhanced from Day 6 on. Exogenous insulin demand was enhanced in the parenterally fed group, and bilirubin (p < 0.05), amylase (p < 0.05), and lipase (p < 0.01) rose significantly, as did gamma-glutamyl-transferase (p < 0.0005) and alkaline phosphatase (p < 0.0005). After 12 d of TPN, vitamin A absorption was significantly attenuated, indicating reduced fat absorption compared to TEN. Carbohydrate absorption did not show significant changes between the groups. Only during TPN did mean values of xylose absorption remain below the normal range. Therefore, enteral nutrition following neurosurgical procedures is associated with an accelerated normalization of nutritional status and an improved substrate tolerance. TEN opposes early postoperative absorption disturbances of the small intestine.

Immune modulation by polyunsaturated fatty acids during nutritional therapy: interactions with synthesis and effects of eicosanoids.

OBJECTIVE: Review of the range of action of polyunsaturated fatty acids (PUFAs) on the basis of interactions with eicosanoids. Discussion of the clinical relevance of these actions. DATA SOURCES: Original papers and reviews of the pertinent literature in German and English, covered by repeated MEDLINE searchers. SELECTION CRITERIA: Pertinent original papers and review articles from 1983 on, as well as some significant original papers of earlier origin with main emphasis on studies concerned with the pharmacodynamic interactions between PUFAs, eicosanoids and the immune system. RESULTS: PUFAs are precursors of eicosanoid formation. Interactions between PUFAs and the immune system are influenced by the rate of synthesis as well as by the efficacy of the various eicosanoids. The rate of eicosanoid synthesis is determined by PUFA turnover. In the absence of essential fatty acid deficiency (EFAD), PUFA turnover depends on the activity of phospholipases. Activities are enhanced under the influence of stress factors such as trauma and sepsis. The efficacy of eicosanoids is determined by the availability of different PUFAs in the cellular phospholipid pool, whereby n-6 and n-3 PUFAs give rise to eicosanoids of different series. The eicosanoids formed from n-3 PUFAs, compared to those derived from n-6 PUFAs, develop similar quality but less intensity of action. Therefore, eicosanoids of different origin induce different effects at a given rate of synthesis. CONCLUSIONS: Appropriate dietary alterations of the availability of n-6 and n-3 PUFAs together with the resulting influence on synthesis and action of mediators, possibly might serve as a pharmacological tool to influence systemic functions in critically ill patients in the future.

[Effect of polyunsaturated fatty acids on immune status: importance as structural and mediator building blocks]. / Effekte von mehrfach ungesättigten Fettsäuren auf den Immunstatus: Bedeutung als Struktur- und Mediatorbausteine.

OBJECTIVE: A review of pharmacodynamic effects induced by polyunsaturated fatty acids (PUFA) with special emphasis on their significance as components of biomembranes and as precursors for mediator formation. DATA SOURCES: Original papers as well as review articles in German and English were retrieved by repeated MEDLINE research. SELECTION CRITERIA: Pertinent original papers as well as review articles since 1983 as well as some significant original papers of earlier origin were used. RESULTS: The current classification of different groups of fatty acids, due to their degree of desaturation, implies that various classes of fatty acids can be correlated to either energetic or structural or functional tasks, respectively. PUFAs are an integral part of membrane structures and serve as precursors of mediator synthesis. They are therefore prone to have major impact on cell function. In particular, interactions between PUFAs and the immune system are substantially determined by the effects of different eicosanoids, which are also derived from PUFAs. However, their impact on various immune functions is dose dependent as well as quantitatively different. If the immune response mediated by eicosanoids is under consideration, actions on the specific immune system have to be discriminated from effects on nonspecific immunity. CONCLUSION: During homeostasis, PUFAs as well as their derived mediators are important factors for a well-operating immune system. If, however, eicosanoid synthesis becomes either diminished or augmented, functions related to the specific immune response are impaired. By contrast, the intensity of the nonspecific immune response is strongly related to the amount of mediators released. During nutritional therapy, lipids not only provide an energetic source but also interfere with structural integrity and functional performance of the cell.

[Enteral nutrition of critically ill patients]. / Enterale Ernährung bei kritisch kranken Patienten.

OBJECTIVE: The purpose of this article is to review the facilities of early enteral nutrition in critically ill patients. DATA SOURCES: Review articles as well as original papers are the main sources for this contribution. SELECTION CRITERIA: Pathophysiologic conditions of intestinal substrate assimilation during hypermetabolism are described. The resulting consequences for enteral alimentation are discussed. Practical aspects such as classification and different indications of formulas, performance of enteral nutrition as well as management of tube feeding complications are further subjects of this review. RESULTS: Paying attention to tolerance, enteral nutrition can be started early in the postoperative or posttraumatic course. Jejunal substrate application, however, reveals to be a major issue for successful management. CONCLUSION: Clinical performance as well as efficiency of enteral nutrition seem to be essentially dependent on the intestinal blood flow. New methods for estimating intestinal blood flow, such as tonometry, will have to be evaluated especially in critically ill patients to improve the indications for enteral nutrition.

[The non-energetic importance of enteral nutrition of critically ill patients]. / Nichtenergetische Bedeutung der enteralen Ernährung bei kritisch kranken Patienten.

OBJECTIVE: The aim of this review is to describe recently discussed nonenergetic effects of enteral nutrition. DATA SOURCES: Results of current animal and clinical studies are summarized and the place of enteral nutritional regimen in critically ill patients is discussed. SELECTION CRITERIA: The possible protective effect of early enteral nutrition in critically ill patients concerning stress ulcus prophylaxis, infections, and the pathogenesis of multiple organ failure is gaining particular attention in this review. RESULTS: The reduction of intestinal bacterial translocation and the decline of catabolism during enteral substrate application seems to be proven by animal experiments. CONCLUSION: The relevance of early enteral nutrition in critically ill patients, however, needs to be investigated in further clinical studies.