[Nutrition in intensive care]. / Ernährung in der Intensivmedizin.

Nutrition is a supportive therapy in critically ill patients. The caloric need of a patient is not static and may change during the clinical course. Early enteral nutrition helps preventing an energy deficit of the patient leading to an increased rate of secondary infections and prolonged length of stay. By using protocols early enteral nutrition may be improved with benefit for the critically ill. Patients should not receive hypercaloric nutrition. Supplemental parenteral nutrition should be used to minimize the gap between energy needs and enteral supplied calories. Nutrition should be supplied according to metabolic and enteral tolerance. A strict glucose control is not recommended to all patients any more. Hyperglycemia may be part of the adaptive response to stress, infection, and trauma. It is important to avoid hypoglycaemia and increased variability in glucose concentrations. To this end, structured local protocols with instructions for sampling density, glucose and insulin administration, avoidance and treatment of hypoglycaemia should be installed. There are contradictory data on the use of probiotics in critically ill patients. Among patients with severe acute pancreatitis, more patients died after having received probiotics. The use of probiotics should be evaluated in controlled trials. Adherence to guidelines may be improved, and their appliance should be followed by constant training and evaluation processes.

[Nutrition and immunonutrition in septic patients]. / Ernährung und Immunonutrition bei Sepsis.

Nutrition in septic patients is more than just caloric support. Not all nutritional concepts in general intensive care may be applied to septic patients. A tight glycemic control successfully used in post-operative intensive care patients has to be modified for the septic patient. Enteral immunonutrition leading to reduced length of stay in post-operative patients may be associated with increased mortality in patients suffering from severe sepsis. Newly developed lipid emulsions for parenteral nutrition became available. Application of these emulsions may prove to be beneficial in septic patients. An intravenous supplementation with glutamine of long-term exclusively parenterally fed intensive care patients may reduce their mortality. A nutrition individually optimized and adapted to the severity of the disease is considered to be an adjunct therapeutic measure in the treatment concept in sepsis.

[Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure]. / Sildenafil zur Therapie der schweren pulmonalen Hypertonie und des beginnenden Rechtsherzversagens.

Pulmonary hypertension (PHT) is mainly explained by four underlying pathophysiological phenomena: 1. Vasoconstriction, 2. reduction of pulmonary vascular bed, 3. reduction in vessel elasticity, and 4. obliteration of the vessel lumen by thrombotic material and subsequent cellular alterations of the vessel wall (vascular remodeling). Chronic right heart load is thus a consequence of increased pulmonary pressure and vascular resistance. Main targets of advanced therapeutic strategies are therefore first: resolution of chronically increased vascular tone by smooth muscle cell relaxation (vasodilators), second: reversal of vascular remodeling and third: prevention from pulmonary embolization and/or in-situ thrombosis (chronic anticoagulation). Long term administration of high dose calcium channel blockers (though operative only in a minority of 10 - 15 % of all patients), prostanoids (eg. prostacyclin, iloprost), and the recently approved unselective oral endothelin antagonist bosentan are regarded as established medical therapies for treatment of chronic PHT. However, applicability of these substances can be limited by potentially serious adverse events and/or necessity for elaborate parenteral application. Recent data are indicative for a strong pulmonary vasodilative potency of the selective phosphodiesterase-5 (PDE5) inhibitor sildenafil. Smaller clinical studies and numerous case reports underline the good tolerability of this orally applied substance in various form of PHT. Based on these encouraging results, the simple availability, and the low costs (in comparison to "established therapies") of the drug, sildenafil is currently widely used in an "off-label" indication for treatment of PHT. Controlled randomized studies have to confirm the current findings, before general recommendations regarding the use of sildenafil for treatment of PHT can be made.

Parenteral nutrition with n-3 lipids in sepsis.

Dietary supplements of n-3 fatty acids have long been used to influence chronic inflammatory disorders. Recent studies with an immune-enhancing diet partly based on n-3 fatty acids report beneficial effects in patients with acute hyper-inflammatory diseases, such as the sepsis syndrome or adult respiratory distress syndrome (ARDS). The possible suppression of exaggerated leucocyte activity, the improvement of microcirculatory events, as well as the opportunity to administer intravenous lipids enriched in n-3 fatty acids signal the possibility of a combination of parenteral caloric support and pharmacological intervention. Using parenteral administration of fish oil-based lipids, a new rapid and highly effective anti-inflammatory agent may allow the option to alter the immune status in hyper-inflammatory diseases such as sepsis and ARDS.

Cellular pathophysiology and therapy of pulmonary hypertension.

The identification of several mutations of the bone morphogenetic protein receptor 2 (BMPR2) gene, a member of the transforming growth factor beta receptor family, gives hope for new insights into the pathophysiology of pulmonary hypertension. Genetic predisposition might dictate the responses of pulmonary artery fibroblasts, smooth muscle cells, and endothelial cells, as well as platelets and leukocytes, or their specific interactions with different extrinsic factors. These cells possess distinct subtypes and interact with each other. Pulmonary hypertension is associated with vasoconstriction, remodeling, and in situ thrombosis of the pulmonary arteries, but the initial events and their relationship to the genetic background are presently unknown. Current therapeutic approaches are based on our knowledge of the physiologic regulation of pulmonary artery tone, pathophysiologic changes, and our clinical experience with different treatment strategies. Beyond diuretics and anticoagulants, prostaglandins are generally accepted therapeutic agents for primary pulmonary hypertension and related diseases, whereas high-dose calcium-channel blockers are reserved for a small subset of patients, those who respond favorably to vasodilators in an acute test. Long-term intravenous prostacyclin infusion has become the most important specific therapy for primary pulmonary hypertension and associated diseases. However, this therapy is hampered by catheter complications and systemic side effects. Alternative application routes of prostacyclin or its stable analogs may avoid these problems. Inhaled application of the prostacyclin analog iloprost results in predominant pulmonary vasodilation with few systemic side effects and may possess clinical efficacy similar to that of intravenous prostacyclin. Inhaled nitric oxide is widely accepted as a screening agent for active responders to vasodilators and has a similar hemodynamic profile as inhaled iloprost, although the percentage of responders is considerably lower. However, there are unsolved toxicologic questions and practical difficulties concerning the safe long-term application of nitric oxide. Combining inhaled vasodilators with phosphodiesterase inhibitors may prolong the duration of the effects and improve the convenience of inhaled therapy for pulmonary hypertension. Therapeutic approaches in the future may aim at the transforming growth factor beta pathway and at the identification of early stages of the disease to prevent further disease progression.

Alteration of fatty acid profiles in different pulmonary surfactant phospholipids in acute respiratory distress syndrome and severe pneumonia.

Impairment of alveolar surfactant function has been documented in the acute respiratory distress syndrome (ARDS) and in severe pneumonia (PNEU); however, the underlying mechanisms are not completely understood. In the current report we present a detailed analysis of fatty acid (FA) profiles of different surfactant phospholipid (PL) classes isolated from bronchoalveolar lavage fluids (BALF) and large surfactant aggregates (LSA) from mechanically ventilated patients with ARDS (n = 8), ARDS associated with lung infection (ARDS + PNEU, n = 9), and PNEU (n = 22). Healthy volunteers served as control subjects (n = 8). PLs were isolated by thin-layer chromatography, and the FA profile of each PL class was assessed by gas chromatography. In addition, the minimal surface tension (gamma min) of untreated LSA and of LSA after supplementation with additional dipalmitoylated phosphatidylcholine (DPPC) was analyzed (pulsating bubble surfactometer). As compared with control LSA, the percentage of palmitic acid in phosphatidylcholine (PC) was significantly decreased in all patient groups (ARDS 63.0 +/- 2.0%, ARDS + PNEU 64.6 +/- 4.9%, PNEU 65.6 +/- 1.5%, control subjects 80.1 +/- 1.7%), whereas the relative amount of unsaturated species in PC increased significantly in all groups. Phosphatidylglycerol (PG) and phosphatidylinositol (PI) presented similar FA profiles in control subjects, but differed in the patients. The FA pattern of sphingomyelin (SPH) and phosphatidylethanolamine (PE) displayed only minor changes under conditions of respiratory failure. As compared with control subjects a highly significant increase of gamma min from near zero to approximately 16 mN/m was observed in all patients and was found to be inversely correlated to the percentage of palmitic acid in PC of LSA or BALF. Accordingly, values for gamma min were significantly improved upon secondary supplementation of LSA with DPPC up to control values. We conclude that marked changes in the FA composition of the predominant surfactant PL classes occur, both in ARDS triggered by nonpulmonary events and PNEU. The marked reduction of palmitic acid in the PC fraction may be related to changes in surfactant function under these conditions.

Omega-3 fatty acid-based lipid infusion in patients with chronic plaque psoriasis: results of a double-blind, randomized, placebo-controlled, multicenter trial.

BACKGROUND: Profound changes in the metabolism of eicosanoids with increased concentrations of free arachidonic acid (AA) and its proinflammatory metabolites have been observed in psoriatic lesions. Free eicosapentaenoic acid (EPA) may compete with liberated AA and result in an antiinflammatory effect. OBJECTIVE: Our purpose was to assess the efficacy and safety of intravenously administered fish-oil-derived lipid emulsion on chronic plaque-type psoriasis. METHODS: A double-blind, randomized, parallel group study was performed in eight European centers. Eighty-three patients hospitalized for chronic plaque-type psoriasis with a severity score of at least 15 according to the Psoriasis Area and Severity Index (PASI) participated in a 14-day trial. They were randomly allocated to receive daily infusions with either a omega-3 fatty acid-based lipid emulsion (Omegavenous; 200 ml/day with 4.2 gm of both EPA and docosahexaenoic acid (DHA); 43 patients) or a conventional omega-6-lipid emulsion (Lipovenous; EPA+DHA < 0.1 gm/100 ml; 40 patients). The groups were well matched with respect to demographic data and psoriasis-specific medical history. Efficacy of therapy was evaluated by changes in PASI, in an overall assessment of psoriasis by the investigator, and a self-assessment by the patient. In one center neutrophil 4- versus 5-series leukotriene (LT) generation and platelet 2- versus 3- thromboxane generation were investigated and plasma-free fatty acids were determined. RESULTS: The total PASI score decreased by 11.2 +/- 9.8 in the omega-3 group and by 7.5 +/- 8.8 in the omega-6 group (p = 0.048). In addition, the omega-3 group was superior to the omega-6 group with respect to change in severity of psoriasis per body area, change in overall erythema, overall scaling and overall infiltration, as well as change in overall assessment by the investigator and self-assessment by the patient. Response (defined as decrease in total PASI of at least 50% between admission and last value) was seen in 16 of 43 patients (37%) receiving the omega-3 emulsion and 9 of 40 patients (23%) receiving omega-6 fatty acid-based lipid emulsion. No serious side effects were observed. Within the first few days of omega-3 lipid administration, but not in the omega-6 supplemented patients, a manifold increase in plasma-free EPA concentration, neutrophil leukotriene B5 and platelet thromboxane B3 generation occurred. CONCLUSION: Intravenous omega-3-fatty acid administration is effective in the treatment of chronic plaque-type psoriasis. This effect may be related to changes in inflammatory eicosanoid generation.

Clinical use of lipids to control inflammatory disease.

Selective dietary supplementation with lipids has long been used to influence the course of chronic inflammatory diseases. This review describes new aspects of the molecular mechanism of lipids to modulate leukocyte activity and highlights some recent clinical studies on therapeutic lipid administration. New promising advances in parenteral application of lipids as well as the impact on acute inflammatory disorders are discussed.

Ultrasonic nebulization for efficient delivery of surfactant in a model of acute lung injury. Impact on gas exchange.

We investigated the effect of ultrasonic nebulization versus instillation of exogenous surfactant on gas exchange abnormalities provoked by detergent inhalation in perfused rabbit lungs. Ventilation-perfusion (VA/Q) distribution was assessed by the multiple inert gas elimination technique. For nebulization of natural bovine surfactant (Alveofact), an ultrasonic device was placed in line with the inspiratory gas flow tubing, manufacturing particles with a mass median aerodynamic diameter of approximately 4.5 microM and high aerosol concentration. In vitro studies demonstrated biochemical and biophysical integrity of postnebulization surfactant. Lung aerosol deposition was monitored by a laser-photometric technique. In lungs with sham inhalation of saline, tracheal instillation of surfactant (approximately 11 mg/kg body weight, infused over 50 min) provoked substantial VA/Q mismatch and limited shunt flow, whereas lung surfactant deposition by ultrasonic nebulization (approximately 7 to 9 mg/kg body weight; nebulization time, 50 min) did not interfere with physiologic gas exchange. Tween 20 inhalation provoked severe VA/Q mismatch with predominant shunt-flow (approximately 21%). This was not reversed by "rescue" application of instilled surfactant, but largely reversed by nebulized surfactant (shunt reduced to 5.5%; p < 0.01). Analysis of postaerosol lavage fluid demonstrated partial reconstitution of surface activity by nebulized surfactant. We conclude that ultrasonic nebulization may be employed for efficient delivery of functionally intact natural surfactant to the distal bronchoalveolar space. This approach effects rapid improvement of gas exchange in a model of acute homogeneous lung injury.

Omega-3 lipid infusion in a heart allotransplant model. Shift in fatty acid and lipid mediator profiles and prolongation of transplant survival.

BACKGROUND: omega-3 Fatty acids may have a major impact on immune responses involved in heart transplant rejection. We compared the effects of posttransplant intravenous supplementation with omega-3-rich versus omega-6-rich lipid emulsions on graft survival, plasma fatty acid profiles, and levels of arachidonic acid versus eicosapentaenoic acid-derived lipid mediators. METHODS AND RESULTS: Inbred PVG and Wistar-Kyoto rats were used as donors and recipients, respectively, in a model of heterotopic heart transplantation. Animals received 9 g/kg body wt per day of either fish oil-derived (n = 8) or soybean oil-derived fat (n = 7) in the form of a continuously infused lipid emulsion; controls were sham-infused with saline (n = 8). Graft rejection was assessed by loss of activity of the transplant. The fish oil-derived preparation but not that originating from soybean oil caused an increase in total and free plasma fatty acids. Substantial quantities of eicosapentaenoic acid and docosahexaenoic acid appeared in the free fatty acid fraction, surpassing those of arachidonic acid. Ex vivo stimulation of neutrophils with the Ca2+ ionophore A23187 demonstrated an increase in 5-series leukotriene (LT) generation in animals undergoing omega-3 lipid infusion (LTB5, omega-oxidation products of LTB5, LTA5 secretion), with 5-series/4-series LT ratios ranging between 0.08 and 0.36. Ratios of TX B3/B2 liberated from ex vivo stimulated platelets even approached 1:1 in omega-3 supplemented rats. Graft survival was 7.6 +/- 0.3 (mean +/- SEM) days in saline-infused, 10.4 +/- 0.7 in omega-6 lipid-infused, and 12.9 +/- 0.4 in omega-3 lipid-infused animals. CONCLUSIONS: Posttransplant intravenous alimentation with fish oil-derived lipid emulsions prolongs heart transplant survival in excess to omega-6 lipids. Profound changes in fatty acid profiles and lipid mediator generation may underlie this finding.

Lesion of dentatothalamic pathways in severe post-traumatic tremor.

The present study investigates evidence of dentatothalamic pathway lesions in nineteen patients with severe kinetic post-traumatic tremor respectively by magnetic resonance imaging (MRI). Kinetic tremor is thought to be characteristic of lesions of the cerebellar outflow. While this hypothesis is supported by experimental data, neuropathological and neuroradiological findings have been limited. The appendicular tremors were unilateral in 13 patients and bilateral in 6, accounting for 25 instances of tremor. The tremor developed after severe head trauma in 18 patients. These patients had evidence of diffuse axonal injury on MRI. Postural and kinetic tremor was present in all patients, and was accompanied by tremor also present at rest in 14 instances. Multiplanar MRI studies were performed on a high-field MRI system operating at 2.0 T in 13 patients and on intermediate-field strength MRI systems in 6 patients according to a standardized protocol. To detect small deposits of hemosiderin after post-traumatic lesions, the protocol included a heavily T2-weighted spin-echo pulse sequence. Lesions of the dentatothalamic pathways were found in 22 instances. The lesions were classified into different types of according to their distribution. A lesion of the dentate nucleus ipsilateral to the tremor (type 1) was found in one instance (4%), lesions involving the ipsilateral predecussational dentatothalamic pathway (type II and III) were found in 14 instances (56%), and lesions involving the contralateral post-decussational course (type IV) in 7 instances (28%). One patient with a mild head trauma had a lesion of the contralateral thalamus. The lesions appeared as hypointense, hyperintense or mixed. Two of three patients with a parkinsonian-like rest tremor had type IV lesions involving the substantia nigra. The nosological concepts of tremors are discussed. 'Midbrain' tremor may have distinct pathoanatomical lesion sites.

Microsurgery of deep-seated cavernous angiomas: report of 26 cases.

The authors review 26 patients with deep-seated cavernous angiomas which were removed by microsurgery. Ten of the angiomas were located in the insula and basal ganglia, 2 in the thalamus, 5 in the midbrain, 8 in the pons, and 1 in the brachium pontis. The patients were among 73 consecutive cases operated on between August 1983 and December 1989 for symptomatic cavernous angiomas in various locations. In 11 cases total excision of the cavernoma was achieved without producing additional neurological deficits. Postoperative neurological recovery was delayed in 7 patients. In the remaining 8, the complicated postoperative course was caused by bleeding from residual parts of the malformation or damage to long-tract pathways in two cases, respectively, vascular injury during dissection in three cases, and paradoxical air embolism in one case. In order to achieve a satisfactory surgical result, it is stressed that particular attention has to be paid to the operative approach, to careful dissection and complete removal of the malformation, to perforating arteries, and to anomalous venous drainage.

Surface properties and sensitivity to protein-inhibition of a recombinant apoprotein C-based phospholipid mixture in vitro--comparison to natural surfactant.

Surfactant alterations due to protein leakage are implicated in the pathogenesis of the adult respiratory distress syndrome. In the present study, surface properties of a palmitic acid containing phospholipid mixture (DPPC: PG: PA/68.5:22.5:9) supplemented with 2% recombinant human surfactant apoprotein C (PLM-Crec) were compared to those of the lipids alone (PLM) and to those of calf lung surfactant extract (CLSE). Experiments were performed in a Wilhelmy balance and in a pulsating bubble surfactometer. Adsorption facilities and dynamic surface tension-lowering properties of the surfactants alone, their sensitivity to the inhibitory effect of fibrinogen (fbg), and their capacity to restore surface properties of fbg-inhibited CLSE were investigated. PLM revealed limited surface activity, was very sensitive to inhibition by fbg and had moderate effect on the surface properties of fbg-inhibited CLSE. In contrast, PLM-Crec and CLSE revealed similar excellent adsorption kinetics and dynamic surface tension lowering properties. Higher percentage of SP-C within the synthetic mixture (up to 10%) or additional admixture of human purified or recombinant SP-A (up to 10%) did not further improve these surface properties. However, PLM-Crec was markedly more sensitive to inactivation by fbg than CLSE. The surface activity of fbg-inhibited CLSE was fully restored by additional admixture of CLSE or PLM-Crec in both the Wilhelmy and the bubble system, with slight superiority of the natural surfactant extract. We conclude that the surface properties of PLM-Crec are clearly superior to those of the apoprotein-free lipid mixture and are similar to those of the natural surfactant extract CLSE. PLM-Crec is markedly more sensitive to inhibition by fibrinogen than CLSE, but possesses nearly equivalent efficacy in restoring the surface properties of fbg-inhibited CLSE as compared to the natural material.

Serum alpha-tocopherol levels after high-dose enteral vitamin E administration in patients with acute respiratory failure.

Serum levels of tocopherols were measured in 5 healthy volunteers and in 14 patients with acute respiratory failure before and after onset of high-dose enteral vitamin E administration. The initial alpha-tocopherol levels did not differ between both groups (12.1 +/- 2.7 micrograms/ml in the volunteers and 11.3 +/- 3.5 micrograms/ml in the patients; mean +/- SD). After oral administration of 1 g d,l-alpha-tocopherylacetate per day the serum levels more than doubled within 1 day and reached a plateau between 22 and 30 micrograms/ml after 3 days in the volunteers. In contrast, application of even 3 g vitamin E/day by gastric tube in the patients with respiratory failure caused only a delayed increase of the serum levels with values nearly doubling after 5-10 days (6 patients), or there was no increase at all (8 patients). Serum alpha-tocopherol did not rise in patients without accompanying highmolecular weight formula diet and in patients with prolonged hemodynamic insufficiency and metabolic acidosis. The age of the patients, the fact of severe blood losses, hemodialysis and hemofiltration and the final outcome of death or survival appeared to be without influence on the response to enteral vitamin application. Neither in the volunteers nor in the patients with acute respiratory failure were there any detectable amounts of beta-, gamma- or delta-tocopherol or of alpha-tocopherolquinone or alpha-tocotrienol.

[Molecular basis for the pathogenicity of S. aureus alpha-toxins]. / Molekulare Grundlage für die Pathogenität des S.aureus-alpha-Toxins.

Staphylococcal alpha-toxin is produced by most strains of S. aureus and is considered a major pathogenic factor of these bacteria. The toxin is produced as a water-soluble molecule of MW 34000. Binding to a membrane target is accompanied by the formation of ring-structured hexamers with outer and inner diameters of 10 and 2-3 nm, respectively. The toxin rings carry lipid-binding surfaces that allow for insertion into and firm embedment within the membrane. Small transmembrane channels are thus generated that can induce a variety of pathological cellular changes. Large doses of toxin will generally cause cell lysis and death. However, sub-cytolytic toxin doses can also elicit major pathophysiological reactions. When introduced into the circulation of an isolated and perfused rabbit lung, the toxin causes steep rises in the pulmonary artery pressure, and lung edema results as a consequence of increases in vascular permeability occurring in parallel. These processes are the result of the activation of the arachidonic acid cascade by alpha-toxin in the lung. Studies using cultured endothelial cells as targets subsequently led to a hypothesis that would explain how membrane channel formation by a toxin could be linked to the observed arachidonic acid cascade activation. In essence, we propose that the toxin pores serve as non-physiological calcium channels, and that calcium influx triggers the observed reactions. It is probable that many other pathophysiological processes including inflammatory tissue reactions derive from such secondary effects of toxin action.(ABSTRACT TRUNCATED AT 250 WORDS)