Enteral and supplemental parenteral nutrition enriched with omega-3 polyunsaturated fatty acids in intensive care patients - A randomized, controlled, double-blind clinical trial.

BACKGROUND & AIMS: Enteral nutrition (EN) and parenteral nutrition (PN) enriched with omega-3 polyunsaturated fatty acids (PUFA) have beneficial effects in critical illness. This study aimed to assess the combined effect of EN and supplemental PN enriched with omega-3 PUFA on blood oxygenation in intensive care unit (ICU) patients. METHODS: Single-center, prospective, randomized, controlled, double-blind, phase III trial conducted from 10/2013 to 11/2017. A total of 100 ICU patients (18-85 years, APACHE II score > 15) requiring mechanical ventilation were randomly assigned to received combined EN and PN either with omega-3 PUFA (omega-3 group) or without (control group) for up to 28 days. Primary endpoint: 'change of PaO2/FiO2 from day (D) 1 to D4'. Secondary endpoints: lung function parameters, ICU complications, length of hospital stay, days free of ICU care/ventilation/sedation/catecholamine treatment, mortality, erythrocyte fatty acid composition, inflammatory parameters. Safety parameters: standard laboratory assessment, vital signs, physical examination, SOFA score, adverse events. RESULTS: Combined EN and PN covered energy requirements to more than 80%. Blood oxygenation (ΔPaO2/FiO2 from D1 to D4: -1.3 ± 83.7, n = 42, and 13.3 ± 86.1, n = 39, in omega-3 and control group, respectively, p = 0.7795) and other lung function parameters did not differ between groups but days free of catecholamine treatment were significantly higher in the omega-3 group (~4 days, p = 0.0481). On D6, significantly more patients in the omega-3 group tolerated EN alone (51.0% vs. 29.8%, p = 0.0342). Eicosapentaenoic acid (EPA) content in erythrocytes was significantly increased in the omega-3 group at last observation compared with the control group (ΔEPA: 0.928 ± 0.808% vs. -0.024 ± 0.190%, p < 0.0001). No further significant group differences were detected. CONCLUSIONS: Enteral and supplemental PN both enriched with omega-3 PUFA did not improve lung function but allowed earlier weaning from catecholamine treatment and PN. Supplemental PN succeeded to adequately cover energy requirements in critically ill patients. TRIAL REGISTRATION: www.clinicaltrials.gov, registration number: NCT01162928.

Effect of Supplemental Enteral Fish Oil on the Development of Psychological Complications in Critically Ill Multiple-Trauma Patients: 6 Months' Follow-Up.

BACKGROUND: Posttraumatic stress disorder (PTSD) is common in intensive care unit (ICU) patients. Defic it intake of ω-3 polyuns aturated fatty ac ids (PUFAs) may be as sociated with developm ent of PTSD. METHODS: This study randomized mechanically ventilated patients suffering from multiple trauma (n = 150) into 2 groups: a study and a control group that received enteral feeding with or without fish oil. Fifty-one patients were interviewed 6 months after discharge from the ICU. Psychometric parameters of PTSD were assessed by questionnaires. The fatty acid composition of erythrocyte membranes was performed by homogenization of the cells in hexane-isopropanol. RESULTS: No differences were found in baseline characteristics between the groups. Erythrocyte membrane composition showed significantly higher concentrations of ω-3 fatty acids in the study group. Anxiety and depression symptoms were correlated with an increase in eicosapentaenoic acid (EPA) on days 4 and 8 for depression and EPA on day 4 and docosahexaenoic acid (DHA) on day 8 for anxiety. Total ω-3 content was positively correlated with anxiety and depression as well. An inverse correlation was found between DHA and EPA in the treatment group and with the total ω-3 and DHA in the control group for the Brief Illness Perceptions Questionnaire. CONCLUSION: Administration of an ω-3 PUFA-enriched diet during the ICU stay did not prevent development of PTSD in trauma patients 6 months after discharge from ICU.

Lipid metabolism in critical illness.

PURPOSE OF REVIEW: This article describes recent findings regarding lipid metabolism in critical illness as well as in lipid therapy. RECENT FINDINGS: In critical illness, in the presence of a decrease in lipid absorption, adipose tissue lipolysis raises triglyceride levels. High-density lipoprotein and low-density lipoprotein are decreased because of impairment of lecithin-cholesterol acyltransferase, mainly in sepsis. In septic patients, lipid profile may be a predictor of survival. Nonsurvivors have lower levels of high-density lipoprotein and low-density lipoprotein. In metabolomic studies, most of the changes from baseline in septic patients were related to lipid metabolism. Lysophosphatidylcholine was also significantly lower in nonsurviving septic patients. SUMMARY: Lipid profile results are too often neglected by the clinician despite increasing knowledge in the modifications related to septic state as well as the importance of these values in the prognosis of the critically ill. Lipid administration (enterally or parenterally) should be guided by better knowledge of the lipid metabolism of the patient.

Pathways of polyunsaturated fatty acid utilization: implications for brain function in neuropsychiatric health and disease.

Essential polyunsaturated fatty acids (PUFAs) have profound effects on brain development and function. Abnormalities of PUFA status have been implicated in neuropsychiatric diseases such as major depression, bipolar disorder, schizophrenia, Alzheimer's disease, and attention deficit hyperactivity disorder. Pathophysiologic mechanisms could involve not only suboptimal PUFA intake, but also metabolic and genetic abnormalities, defective hepatic metabolism, and problems with diffusion and transport. This article provides an overview of physiologic factors regulating PUFA utilization, highlighting their relevance to neuropsychiatric disease.

BBS4 directly affects proliferation and differentiation of adipocytes.

BBS4 is one of several proteins whose defects cause Bardet-Biedl syndrome (BBS), a multi-systemic disorder, manifesting with marked obesity. BBS4 polymorphisms have been associated with common non-syndromic morbid obesity. BBS4 obesity molecular mechanisms, and the role of the BBS4 gene in adipocyte differentiation and function are not entirely known. We now show that Bbs4 plays a direct and essential role in proliferation and adipogenesis: silencing of Bbs4 in 3T3F442A preadipocytes induced accelerated cell division and aberrant differentiation, evident through morphologic studies (light, scanning and transmission electron microscopy), metabolic analyses (fat accumulation, fatty acid profile and lipolysis) and adipogenic markers transcripts (Cebpα, Pparγ, aP2, ADRP, Perilipin). Throughout adipogenesis and when challenged with fat load, Bbs4 silenced cells accumulate significantly more triglycerides than control adipocytes, albeit in smaller (yet greater in number) droplets containing modified fatty acid profiles. Thus, greater fat accumulation in the silenced cells is a consequence of both a higher rate of adipocyte proliferation and of aberrant differentiation leading to augmented aberrant accumulation of fat per cell. Our findings suggest that the BBS obesity might be partly due to a direct role of BBS4 in physiological and pathophysiological mechanisms that underlie adipose tissue formation relevant to obesity.

Arachidonic acid-containing phosphatidylcholine species are increased in selected brain regions of a depressive animal model: implications for pathophysiology.

The Flinders Sensitive Line (FSL) rat is a genetic animal model of depression. Following recent findings that the brain fatty acid composition of FSL is characterised by increased arachidonic acid (AA), we used electrospray tandem mass spectrometry and (1)H-NMR to examine lipid species in different brain areas. Cholesterol and sphingolipids were increased in the hypothalamus of the FSL rats. Furthermore, arachidonic acid-containing phosphatidylcholine (AA-PC) species were elevated with PC16:0/20:4, PC18:1/20:4 and PC18:0/20:4 (p<0.003) increased in the hypothalamus and striatum. In contrast, there was a decrease in some docosahexaenoic acid (DHA)-containing species, specifically PC18:1/22:6 (p<0.003) in the striatum and PE18:1/22:6 (p<0.004) in the prefrontal cortex. Since no significant differences were observed in the erythrocyte fatty acid concentrations, dietary or environmental causes for these observations are unlikely. The increase in AA-PC species which in this animal model may be associated with altered neuropathy target esterase activity, an enzyme involved in membrane PC homeostasis, may contribute to the depressive phenotype of the FSL rats.

Docosahexaenoic acid and arachidonic acid are fundamental supplements for the induction of neuronal differentiation.

Cell replacement therapy is being investigated for the treatment of neurodegenerative disorders. Adult autologous bone marrow-derived mesenchymal stem cells (MSCs) have been induced to differentiate into neuron-like cells harboring a variety of neuronal markers and transcription factors. Neural tissue characteristically contains high proportions of docosahexaenoic acid (DHA) and arachidonic acid (AA). In this study, evaluation of the fatty acid profile of differentiated neuron-like cells revealed a very low level of DHA, similar to that in MSCs but different from typical neurons. Supplementation of the medium with DHA alone resulted in increased levels of DHA but concomitant low levels of AA. However, supplementation with both DHA and AA yielded a fatty acid profile resembling that of neural tissue. It also resulted in enhanced outgrowth of neurite-like processes, hallmarks of neuronal differentiation. These findings demonstrate the essentiality of DHA and AA supplementation in the process of induced neuronal differentiation and have important implications for the development of cell replacement strategies of neural repair.

Red cell membrane omega-3 fatty acids are decreased in nondepressed patients with social anxiety disorder.

The "phospholipid hypothesis" attributes a pathophysiologic role to the polyunsaturated fatty acid (PUFA) composition of phospholipids in depression. The aim of the present study was to determine whether the hypothesis is relevant to social anxiety disorder (SAD). The study sample consisted of 27 untreated, nondepressed patients with SAD (DSM-IV) and 22 controls. Severity of SAD was assessed with the Liebowitz Social Anxiety Scale (LSAS). Erythrocyte PUFA concentrations were measured by gas-liquid chromatography. Concentrations of most n-3 PUFAs were lower in the patients: 18:3n-3 by 32% (p < 0.002), 20:3n-3 by 34%, 20:5n-3 by 36% (all p < 0.001) and 22:6n-3 by 18% (p = 0.002). No significant differences were observed in other fatty acids. Significant inverse correlations were obtained between levels of n-3 PUFAs and LSAS scores. In conclusion, the phospholipid hypothesis may apply to SAD, thereby opening new therapeutic options. The robust relationship between low erythrocyte n-3 PUFA concentrations and SAD justifies exploration of relevant neuropathophysiological mechanisms.

Increased arachidonic acid concentration in the brain of Flinders Sensitive Line rats, an animal model of depression.

Depression may be associated with impaired membrane PUFA composition, especially decreased n-3 PUFA. This assumption has not been tested at the level of brain tissue. Moreover, most studies were confounded by dietary variability. We examined the FA composition of selected brain areas in an animal model of depression, the Flinders Sensitive Line (FSL) rat, and compared the findings with those in controls fed identical diets. In all brain regions studied, the concentration of arachidonic acid (AA) was significantly higher in the FSL rats: in the hypothalamus by 21%, in the nucleus accumbens by 24%, in the prefrontal cortex by 31%, and in the striatum by 23%. No significant differences were observed for n-3 PUFA or for the saturated and monounsaturated FAs. Our results confirm the existence of altered brain PUFA composition in an animal model of depression. The finding of increased AA, an n-6 PUFA, rather than decreased n-3 PUFA, emphasizes the importance of both PUFA families in the pathophysiological processes underlying depression. The FSL rat is a useful tool for further elucidation of the FA disturbances in depression.

Docosahexaenoic acid abundance in the brain: a biodevice to combat oxidative stress.

Docosahexaenoic acid (DHA) (22:6) is a polyunsaturated fatty acid of the n - 3 series which is believed to be a molecular target for lipid peroxides (LPO) formation. Its ubiquitous nature in the nervous tissue renders it particularly vulnerable to oxidative stress, which is high in brain during normal activity because of high oxygen consumption and generation of reactive oxygen species (ROS). Under steady state conditions potentially harmful ROS and LPO are maintained at low levels due to a strong antioxidant defense mechanism, which involves several enzymes and low molecular weight reducing compounds. The present review emphasizes a paradox: a discrepancy between the expected high oxidability of the DHA molecule due to its high degree of unsaturation and certain experimental results which would indicate no change or even decreased lipid peroxidation when brain tissue is supplied or enriched with DHA. The following is a critical review of the experimental data relating DHA levels in the brain to lipid peroxidation and oxidative damage there. A neuroprotective role for DHA, possibly in association with the vinyl ether (VE) linkage of plasmalogens (pPLs) in combating free radicals is proposed.