Axel R. Heller

Omega-3 fatty acids improve the diagnosis-related clinical outcome.

Objective:Supplementation of clinical nutrition with omega-3 fatty acid in fish oil exerts immune-modulating and organ-protective effects, even after short-term application. The aim of this study was to evaluate dose-dependent effects of parenteral supplementation of a 10% fish oil emulsion (Omegaven, Fresenius-Kabi, Bad Homburg, Germany) on diagnosis- and organ failure–related outcome. Design:Prospective, open label, multiple-center trial. Patients and Methods:A total of 661 patients from 82 German hospitals receiving total parenteral nutrition for ≥3 days were enrolled in this study. The sample included 255 patients after major abdominal surgery, 276 with peritonitis and abdominal sepsis, 16 with nonabdominal sepsis, 59 after multiple trauma, 18 with severe head injury, and 37 with other diagnoses. The primary study end point was survival; secondary end points were length of hospital stay and use of antibiotics with respect to the primary diagnosis and the extent of organ failure. Multiple quasi-linear and logistic regression models were used for calculating diagnosis-related fish oil doses associated with best outcome. Results:The patients enrolled in this survey were (mean ± sd) 62.8 ± 16.5 yrs old, with a body mass index of 25.1 ± 4.2 and Simplified Acute Physiology Score (SAPS) II score of 32.2 ± 13.6. Length of hospital stay was 29.1 ± 18.7 days (12.5 ± 14.8 days in the intensive care unit). Total parenteral nutrition, including fish oil (mean, 0.11 g·kg−1·day−1), was administered for 8.7 ± 7.5 days and lowered hospital mortality as predicted by Simplified Acute Physiology Score II from 18.9% (95% confidence interval, 17.4–20.4%) to 12.0% (p < .001). The fish oil dose·kg−1·day−1 did correlate with beneficial outcome (intensive care unit stay, hospital stay, mortality). Fish oil had the most favorable effects on survival, infection rates, and length of stay when administered in doses between 0.1 and 0.2 g·kg−1·day−1. Lower antibiotic demand by 26% was observed when doses of 0.15–0.2 g·kg−1·day−1 were infused as compared with doses of <0.05 g·kg−1·day−1. After peritonitis and abdominal sepsis, multiple quasi-linear regression models revealed a fish oil dose for minimizing intensive care unit stay of 0.23 g·kg−1·day−1 and an inverse linear relationship between dosage and intensive care unit stay in major abdominal surgery. Conclusion:Administration of omega-3 fatty acid may reduce mortality, antibiotic use, and length of hospital stay in different diseases. Effects and effect sizes related to fish oil doses are diagnosis dependent. In view of the lack of substantial study literature concerning diagnosis-related nutritional single-substrate intervention in the critically ill, the present data can be used in formulating hypotheses and may serve as reference doses for randomized, controlled studies, which may, for instance, confirm the value of omega-3 fatty acid in the adjunctive therapy of peritonitis and abdominal sepsis.

Lipid Mediators in Inflammatory Disorders

SummaryDuring the past few decades, intensive collaborative research in the fields of chronic and acute inflammatory disorders has resulted in a better understanding of the pathophysiology and diagnosis of these diseases. Modern therapeutic approaches are still not satisfactory and shock, sepsis and multiple organ failure remain the great challenge in intensive care medicine. However, the treatment of inflammatory diseases like rheumatoid arthritis, ulcerative colitis or psoriasis also represents an unresolved problem.Many factors contribute to the complex course of inflammatory reactions. Microbiological, immunological and toxic agents can initiate the inflammatory response by activating a variety of humoral and cellular mediators. In the early phase of inflammation, excessive amounts of interleukins and lipid-mediators are released and play a crucial role in the pathogenesis of organ dysfunction. Arachidonic acid (AA), the mother substance of the pro-inflammatory eicosanoids, is released from membrane phospholipids in the course of inflammatory activation and is metabolised to prostaglandins and leukotrienes.Various strategies have been evaluated to control the excessive production of lipid mediators on different levels of biochemical pathways, such as inhibition of phospholipase A2, the trigger enzyme for release of AA, blockade of cyclooxygenase and lipoxygenase pathways and the development of receptor antagonists against platelet activating factor and leukotrienes. Some of these agents exert protective effects in different inflammatory disorders such as septic organ failure, rheumatoid arthritis or asthma, whereas others fail to do so. Encouraging results have been obtained by dietary supplementation with long chain ω-3 fatty acids like eicosapentaenoic acid (EPA). In states of inflammation, EPA is released to compete with AA for enzymatic metabolism inducing the production of less inflammatory and chemotactic derivatives.

Reversal of Central Nervous System and Cardiac Toxicity After Local Anesthetic Intoxication by Lipid Emulsion Injection

A 91-yr-old man (57 kg, 156 cm, ASA III) received an infraclavicular brachial plexus block for surgery of bursitis of the olecranon. Twenty minutes after infraclavicular injection of 30 mL of mepivacaine 1% (Scandicain) and 5 min after supplementation of 10 mL of prilocaine 1% (Xylonest) using an axillary approach, the patient complained of agitation and dizziness and became unresponsive to verbal commands. In addition, supraventricular extrasystole with bigeminy occurred. Local anesthetic toxicity was suspected and a dose of 200 mL of a 20% lipid emulsion was infused. Symptoms of central nervous system and cardiac toxicity disappeared within 5 and 15 min after the first lipid injection, respectively. Plasma concentrations of local anesthetics were determined before, 20, and 40 min after lipid infusion and were 4.08, 2.30, and 1.73 microg/mL for mepivacaine and 0.92, 0.35, and 0.24 microg/mL for prilocaine. These concentrations are below previously reported thresholds of toxicity above 5 microg/mL for both local anesthetics. Signs of toxicity resolved and the patient underwent the scheduled surgical procedure uneventfully under brachial plexus blockade.

Omega-3 fatty acids improve liver and pancreas function in postoperative cancer patients.

Epidemiologic studies have indicated that high intake of saturated fat and/or animal fat increases the risk of colon and breast cancer. Omega‐3 PUFAs in fish oil (FO) can inhibit the growth of human cancer cells in vitro and in vivo. These effects are related to the uptake of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) into the cellular substrate pool and their competitive metabolism with arachidonic acid (AA) at the cyclooxygenase and 5‐lipoxygenase levels. The metabolites of EPA and DHA have less inflammatory and immunosuppressant potency than the substances derived from AA. Based on previous experimental data, we hypothesized that FO supplementation after major abdominal cancer surgery would improve hepatic and pancreatic function. Ours was a prospective, randomized, double‐blinded clinical trial on 44 patients undergoing elective major abdominal surgery, randomly assigned to receive total parenteral nutrition (TPN) supplemented with either soybean oil (SO 1.0 g/kg body weight daily, n = 20) for 5 days or a combination of FO and SO (FO 0.2 + SO 0.8 g/kg body weight daily, n = 24). Compared to pure SO supplementation in the postoperative period, FO significantly reduced ASAT [0.8 ± 0.1 vs. 0.5 ± 0.1 mmol/(l · sec)], ALAT [0.9 ± 0.1 vs. 0.6 ± 0.1 mmol/(l · sec)], bilirubin (16.1 ± 5.3 vs. 6.9 ± 0.6 mmol/l), LDH (7.7 ± 0.4 vs. 6.7 ± 0.4 mmol/(l · sec) and lipase (0.6 ± 0.1 vs. 0.4 ± 0.1 μmol/(l · sec) in the postoperative course. Moreover, patients with increased risk of sepsis (IL‐6/IL‐10 ratio >8) showed a tendency to shorter ICU stay (18 hr) under omega‐3 PUFA treatment. Weight loss as encountered after the SO emulsion of 1.1 ± 2.2 kg was absent in the FO group. After major abdominal tumor surgery, FO supplementation improved liver and pancreas function, which might have contributed to the faster recovery of patients.

One-lung Ventilation with High Tidal Volumes and Zero Positive End-expiratory Pressure Is Injurious in the Isolated Rabbit Lung Model

We tested the hypothesis that one-lung ventilation (OLV) with high tidal volumes (Vt) and zero positive end-expiratory pressure (PEEP) may lead to ventilator-induced lung injury. In an isolated, perfused rabbit lung model, Vt and PEEP were set to avoid lung collapse and overdistension in both lungs, resulting in a straight pressure-time (P-vs-t) curve during constant flow. Animals were randomized to (a) nonprotective OLV (left lung) (n = 6), with Vt values as high as before randomization and zero PEEP; (b) protective OLV (left lung) (n = 6), with 50% reduction of Vt and maintenance of PEEP as before randomization; and (c) control group (n = 6), with ventilation of two lungs as before randomization. The nonprotective OLV was associated with significantly smaller degrees of collapse and overdistension in the ventilated lung (P < 0.001). Peak inspiratory pressure values were higher in the nonprotective OLV group (P < 0.001) and increased progressively throughout the observation period (P < 0.01). The mean pulmonary artery pressure and lung weight gain values, as well as the concentration of thromboxane B2, were comparatively higher in the nonprotective OLV group (P < 0.05). A ventilatory strategy with Vt values as high as those used in the clinical setting and zero PEEP leads to ventilator-induced lung injury in this model of OLV, but this can be minimized with Vt and PEEP values set to avoid lung overdistension and collapse.

N-acetylcysteine reduces respiratory burst but augments neutrophil phagocytosis in intensive care unit patients.

ObjectiveThe antioxidant N-acetylcysteine (NAC) has been shown to attenuate septic tissue injury. To evaluate whether NAC affects host defense mechanisms in critically ill patients, thus predisposing to increased risk of infection, the current study focuses on neutrophil phagocytotic and burst activity after treatment with NAC. DesignProspective, randomized, clinical trial. SettingTwelve-bed operative intensive care unit in a university hospital. PatientsThirty patients diagnosed with sepsis/systemic inflammatory response syndrome, or multiple trauma. InterventionsPatients were randomly assigned to receive either NAC (n = 15) for 4 days in increasing dosages (day 1: 6 g; day 2: 12 g; days 3 and 4: 18 g) or a mucolytic basis dosage of NAC (3 × 300 mg/day [control]; n = 15), respectively. Measurements and Main Results Blood samples were taken before NAC high-dose infusion (day 1), after increasing doses of NAC (days 3 and 5) and 4 days after the last high-dose treatment (day 8). Neutrophil oxidative burst activity after stimulation with Escherichia coli and polymorphonuclear phagocytosis were determined in a flow cytometric assay. Baseline values of polymorphonuclear functions were comparable in both groups. NAC high-dose treatment resulted in a significantly improved phagocytosis activity compared with control patients. In contrast to this, polymorphonuclear burst activity was significantly reduced in the NAC high-dose treated group on day 3. ConclusionThese findings suggest that infusion of NAC in high doses affects granulocyte functions in critically ill patients. Antimicrobial host defense requires the effective sequence of cell adhesion, phagocytosis, and bactericidal respiratory burst. The enhanced phagocytotic activity might be a compensatory mechanism in states of impaired respiratory burst to maintain tissue sterility. For certain mechanisms of disease, the effects observed might be favorable (e.g., ischemia/reperfusion, endothelial cell activation), for others (infection) this might be detrimental.

Anticancer Actions of Omega-3 Fatty Acids - Current State and Future Perspectives

Omega-3 fatty acids (omega3-FA) were shown to attenuate growth and induce apoptosis in a variety of human cancer cell lines derived from colonic, pancreatic, prostate, and breast cancer. In addition, recent findings indicate that omega3-FA act synergistically with chemotherapeutic agents and may also be used to enhance tumour radiosensitivity. The mechanisms underlying the anti-tumour effects of omega3-FA are complex. Incorporation of omega3-FA in biological membranes alters the profile of lipid mediators generated during inflammatory reactions. Furthermore, omega3-FA act as ligands of nuclear peroxisome proliferator-activated receptors that attenuate transcription of NF-kappaB-dependent genes. Thereby, the cyclooxygenase-2/prostaglandin E(2)-dependent production of pro-angiogenic vascular endothelial growth factor and levels of anti-apoptotic bcl-2 and bcl-X(L) are decreased. Eicosanoid-independent pro-apoptotic pathways include enhanced lipid peroxidation, modulation of mitochondrial calcium homeostasis and enhanced production of reactive oxygen species as well as activation of p53. This review article will give a comprehensive overview over the pleiotropic actions of omega3-FA and will discuss the potential of omega3-FA and derivatives like conjugated eicosapentaenoic acid as important nutritional adjuvant therapeutics in the management of various human cancer diseases and the impact of nutritional omega-3 FA on cancer prevention.

Prognostic factors and evaluation of a clinical score for predicting survival after resection of colorectal liver metastases.

Background: Patient outcome after resection of colorectal liver metastases can be predicted by various prognostic factors.

Comparison of the American Society of Anesthesiologists Physical Status classification with the Charlson score as predictors of survival after radical prostatectomy

OBJECTIVES To compare the American Society of Anesthesiologists Physical Status (ASA) classification with the Charlson score in the radical prostatectomy setting. The ASA classification is a widely accepted way to evaluate perioperative risk. At present, the Charlson score is probably the most frequently used comorbidity measure to predict long-term survival after radical prostatectomy. METHODS A total of 444 consecutive patients were enrolled in this study. The ASA classification was obtained from the anesthesia chart, and the Charlson score was assigned based on conditions noted during the preoperative cardiopulmonary risk assessment or mentioned on the discharge document. Kaplan-Meier time-event curves and Mantel-Haenszel hazard ratios were estimated for comorbid (noncancer) and overall survival. RESULTS After a mean follow-up of 5.9 years, both classifications were able to predict comorbid and overall survival in dose-response patterns. The ASA classification was superior in terms of a clearer discrimination of the survival curves (lower P values, higher hazard ratios). Both classifications identified a high-risk group (ASA 3 and Charlson score 2 or more), but only the ASA classification sufficiently defined a low-risk group (ASA 1). CONCLUSIONS In experienced hands, the ASA classification is a promising tool to improve the classification of prognostic comorbidity in the radical prostatectomy setting and may be used as an alternative to the Charlson score.

Pressure support ventilation and biphasic positive airway pressure improve oxygenation by redistribution of pulmonary blood flow.

BACKGROUND:Spontaneous breathing (SB) activity may improve gas exchange during mechanical ventilation mainly by the recruitment of previously collapsed regions. Pressure support ventilation (PSV) and biphasic positive airway pressure (BIPAP) are frequently used modes of SB, but little is known about the mechanisms of improvement of lung function during these modes of assisted mechanical ventilation. We evaluated the mechanisms behind the improvement of gas exchange with PSV and BIPAP. METHODS:Five pigs (25–29.3 kg) were mechanically ventilated in supine position, and acute lung injury (ALI) was induced by surfactant depletion. After stabilization, BIPAP was initiated with lower continuous positive airway pressure equal to 5 cm H2O and the higher continuous positive airway pressure titrated to achieve a tidal volume between 6 and 8 mL/kg. The depth of anesthesia was reduced, and when SB represented ≥20% of total minute ventilation, PSV and BIPAP + SB were each performed for 1 h (random sequence). Whole chest helical computed tomography was performed during end-expiratory pauses and functional variables were obtained. Pulmonary blood flow (PBF) was marked with IV administered fluorescent microspheres, and spatial cluster analysis was used to determine the effects of each ventilatory mode on the distribution of PBF. RESULTS:ALI led to impairment of lung function and increase of poorly and nonaerated areas in dependent lung regions (P < 0.05). PSV and BIPAP + SB similarly improved oxygenation and reduced venous admixture compared with controlled mechanical ventilation (P < 0.05). Despite that, a significant increase of nonaerated areas in dependent regions with a concomitant decrease of normally aerated areas was observed during SB. In five of six lung clusters, redistribution of PBF from dependent to nondependent, better aerated lung regions were observed during PSV and BIPAP + SB. CONCLUSIONS:In this model of ALI, the improvements of oxygenation and venous admixture obtained during assisted mechanical ventilation with PSV and BIPAP + SB were explained by the redistribution of PBF toward nondependent lung regions rather than recruitment of dependent zones.