Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O objetivo do presente estudo foi investigar o envolvimento do estresse oxidativo na lesão pulmonar aguda (LPA) induzida por lipopolissacarídeo (LPS) e as repercussões inflamatórias, estruturais e funcionais, através de análises bioquímicas de estresse oxidativo, prova de função pulmonar, análise histológica e RT-PCR para citocinas e fatores de transcrição pró-inflamatórios. Na primeira etapa foram utilizados camundongos machos C57BL6 foram divididos em sete grupos: Grupo controle (CTR) (50 &#956;L de solução fisiológica) administrados via intratraqueal [it], LPS 6 horas (10 &#956;L de LPS) [it], LPS 12 horas (10 &#956;L de LPS) [it], LPS 24 horas (10 &#956;L de LPS) [i], LPS 48 horas (10 &#956;L de LPS). Para verificar que as alterações observadas eram estresse oxidativo dependentes camundongos machos C57BL6 foram pré-tratados com N-acetilcisteína (NAC) 1 hora antes do estímulo com LPS e sacrifícados 24 horas depois do estímulo com LPS. Os animais foram divididos da seguinte forma: Grupo LPS 24 horas (10 &#956;L) [it], grupo NAC 40 mg/kg (gavagem) + LPS (10 &#956;L) [it] e grupo NAC 100 mg/kg (gavagem) + LPS (10 &#956;L) [it]. O sistema antioxidante enzimático protegeu o pulmão do estresse oxidativo nas primeiras 12 horas. O estresse oxidativo foi caracterizado em 24 horas e em 48 horas observou-se falência do sistema antioxidante enzimático. Parâmetros de função pulmonar se mostraram alterados nos grupo estimulados com LPS principalmente no grupo LPS. A elastância (p<0,001), resistência de via aérea periférica (&#916;P2) (p<0,001), resistência de via aérea central (&#916;P1) (p<0,001) e resistência de via aérea total (&#916;Ptot) (p<0,001) se mostraram principlamente alteradas no grupo LPS 24 horas. O pré-tratamento com NAC impediu o aumento dos parâmetros de elastância (p<0,001), resistência de via aérea periférica (&#916;P2) (p<0,001) resistência de via aérea central (&#916;P1) (p<0,05) e resistência de via aérea total (&#916;Ptot) (p<0,001) comparado com o grupo LPS 24 horas. As alterações histológicas como espessamento de septo alveolar, influxo de células inflamatórias e hemorragia mostraram-se tempo dependentes. O pré-tratamento NAC impediu as alterações observadas nos grupo estimulados com LPS. Alterações inflamatórias foram observadas no grupo estimulado com LPS como IL-6 (p<0,001), iNOS (p<0,001), COX2 (p<0,05), TNF-&#945; (p<0,001) e NF&#954;B (p<0,001) quando comparados ao grupo controle. O pré-tratamento com NAC impediu o aumento desses parâmetros como IL-6 (p<0,001), iNOS (p<0,001), COX2 (p<0,05), TNF-&#945; (p<0,05) e NF&#954;B (p<0,001) quando comparados ao grupo LPS 24 horas. Nossos resultados sugerem que o estresse oxidativo desempenha um papel importante nas respostas inflamatórios, estruturais e funcionais no modelo de LPA induzido por LPS e que essas alterações são estresse oxidativo dependentes. / The aim of this study was to investigate the involvement of oxidative stress in acute lung injury (ALI) induced by lipopolysaccharide (LPS) and inflammatory effects, structural and functional, through biochemical analysis of oxidative stress, pulmonary function test, histological and RT-PCR for cytokines and transcription factors pro-inflammatory. In the first stage were used C57BL6 male mice were divided into seven groups: control group (CTR) (50 &#956;L saline) administered via intratracheal [it], LPS 6 hours (10 &#956;L of LPS) [it], LPS 12 hours (10 &#956;L of LPS) [it], LPS 24 hours (10 &#956;L of LPS) [it], LPS 48 hours (10 &#956;L of LPS). To confirm that the observed changes were dependent on oxidative stress in C57BL6 male mice were pretreated with N-acetylcysteine (NAC) 1 hours before stimulation with LPS and sacrificed 24 hours after stimulation with LPS. The animals were divided as follows: LPS group 24 hours (10 &#956;L) [it], NAC group 40 mg / kg (gavage) + LPS (10 &#956;L) [it] NAC group and 100 mg / kg (gavage) + LPS (10 &#956;L) [it]. The enzymatic antioxidant system protected the lungs against oxidative stress in the first 12 hours. Oxidative stress was characterized in 24 hours and 48 hours there was failure of the enzymatic antioxidant system. Pulmonary function parameters were shown in the altered group stimulated with LPS mainly in the LPS group. Elastance (p <0,001), peripheral airway resistance (&#916;P2) (p <0,001), central airway resistance (&#916;P1) (p <0,001) and total airway resistance (&#916;Ptot) (p <0,001) if especially in the group showed altered LPS 24 hours. Pretreatment with NAC prevented the increase in elastance parameters (p <0,001), peripheral airway resistance (&#916;P2) (p <0,001) central airway resistance (&#916;P1) (p <0,05) and resistance total airway (&#916;Ptot) (p <0,001) compared with the LPS group 24 hours. Histological changes such as thickening of alveolar septa, inflammatory cells and hemorrhage proved to be time dependent. The NAC pretreatment prevented the changes observed in the group stimulated with LPS. Inflammatory changes were observed in the group stimulated with LPS and IL-6 (p <0,001), iNOS (p <0,001), COX2 (p <0,05), TNF-&#945; (p <0,001) and NF&#954;B (p <0,001) compared with the control group. Pretreatment with NAC prevented the increase of these parameters as IL-6 (p <0,001), iNOS (p <0,001), COX2 (p <0,05), TNF-&#945; (p <0,05) and NF&#954;B ( p <0,001) when compared with LPS 24 hours. Our results suggest that oxidative stress plays an important role in inflammatory responses, structural and functional model of ALI induced by LPS and that these changes are dependent oxidative stress.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / O objetivo do presente estudo foi investigar o envolvimento do estresse oxidativo na lesão pulmonar aguda (LPA) induzida por lipopolissacarídeo (LPS) e as repercussões inflamatórias, estruturais e funcionais, através de análises bioquímicas de estresse oxidativo, prova de função pulmonar, análise histológica e RT-PCR para citocinas e fatores de transcrição pró-inflamatórios. Na primeira etapa foram utilizados camundongos machos C57BL6 foram divididos em sete grupos: Grupo controle (CTR) (50 &#956;L de solução fisiológica) administrados via intratraqueal [it], LPS 6 horas (10 &#956;L de LPS) [it], LPS 12 horas (10 &#956;L de LPS) [it], LPS 24 horas (10 &#956;L de LPS) [i], LPS 48 horas (10 &#956;L de LPS). Para verificar que as alterações observadas eram estresse oxidativo dependentes camundongos machos C57BL6 foram pré-tratados com N-acetilcisteína (NAC) 1 hora antes do estímulo com LPS e sacrifícados 24 horas depois do estímulo com LPS. Os animais foram divididos da seguinte forma: Grupo LPS 24 horas (10 &#956;L) [it], grupo NAC 40 mg/kg (gavagem) + LPS (10 &#956;L) [it] e grupo NAC 100 mg/kg (gavagem) + LPS (10 &#956;L) [it]. O sistema antioxidante enzimático protegeu o pulmão do estresse oxidativo nas primeiras 12 horas. O estresse oxidativo foi caracterizado em 24 horas e em 48 horas observou-se falência do sistema antioxidante enzimático. Parâmetros de função pulmonar se mostraram alterados nos grupo estimulados com LPS principalmente no grupo LPS. A elastância (p<0,001), resistência de via aérea periférica (&#916;P2) (p<0,001), resistência de via aérea central (&#916;P1) (p<0,001) e resistência de via aérea total (&#916;Ptot) (p<0,001) se mostraram principlamente alteradas no grupo LPS 24 horas. O pré-tratamento com NAC impediu o aumento dos parâmetros de elastância (p<0,001), resistência de via aérea periférica (&#916;P2) (p<0,001) resistência de via aérea central (&#916;P1) (p<0,05) e resistência de via aérea total (&#916;Ptot) (p<0,001) comparado com o grupo LPS 24 horas. As alterações histológicas como espessamento de septo alveolar, influxo de células inflamatórias e hemorragia mostraram-se tempo dependentes. O pré-tratamento NAC impediu as alterações observadas nos grupo estimulados com LPS. Alterações inflamatórias foram observadas no grupo estimulado com LPS como IL-6 (p<0,001), iNOS (p<0,001), COX2 (p<0,05), TNF-&#945; (p<0,001) e NF&#954;B (p<0,001) quando comparados ao grupo controle. O pré-tratamento com NAC impediu o aumento desses parâmetros como IL-6 (p<0,001), iNOS (p<0,001), COX2 (p<0,05), TNF-&#945; (p<0,05) e NF&#954;B (p<0,001) quando comparados ao grupo LPS 24 horas. Nossos resultados sugerem que o estresse oxidativo desempenha um papel importante nas respostas inflamatórios, estruturais e funcionais no modelo de LPA induzido por LPS e que essas alterações são estresse oxidativo dependentes. / The aim of this study was to investigate the involvement of oxidative stress in acute lung injury (ALI) induced by lipopolysaccharide (LPS) and inflammatory effects, structural and functional, through biochemical analysis of oxidative stress, pulmonary function test, histological and RT-PCR for cytokines and transcription factors pro-inflammatory. In the first stage were used C57BL6 male mice were divided into seven groups: control group (CTR) (50 &#956;L saline) administered via intratracheal [it], LPS 6 hours (10 &#956;L of LPS) [it], LPS 12 hours (10 &#956;L of LPS) [it], LPS 24 hours (10 &#956;L of LPS) [it], LPS 48 hours (10 &#956;L of LPS). To confirm that the observed changes were dependent on oxidative stress in C57BL6 male mice were pretreated with N-acetylcysteine (NAC) 1 hours before stimulation with LPS and sacrificed 24 hours after stimulation with LPS. The animals were divided as follows: LPS group 24 hours (10 &#956;L) [it], NAC group 40 mg / kg (gavage) + LPS (10 &#956;L) [it] NAC group and 100 mg / kg (gavage) + LPS (10 &#956;L) [it]. The enzymatic antioxidant system protected the lungs against oxidative stress in the first 12 hours. Oxidative stress was characterized in 24 hours and 48 hours there was failure of the enzymatic antioxidant system. Pulmonary function parameters were shown in the altered group stimulated with LPS mainly in the LPS group. Elastance (p <0,001), peripheral airway resistance (&#916;P2) (p <0,001), central airway resistance (&#916;P1) (p <0,001) and total airway resistance (&#916;Ptot) (p <0,001) if especially in the group showed altered LPS 24 hours. Pretreatment with NAC prevented the increase in elastance parameters (p <0,001), peripheral airway resistance (&#916;P2) (p <0,001) central airway resistance (&#916;P1) (p <0,05) and resistance total airway (&#916;Ptot) (p <0,001) compared with the LPS group 24 hours. Histological changes such as thickening of alveolar septa, inflammatory cells and hemorrhage proved to be time dependent. The NAC pretreatment prevented the changes observed in the group stimulated with LPS. Inflammatory changes were observed in the group stimulated with LPS and IL-6 (p <0,001), iNOS (p <0,001), COX2 (p <0,05), TNF-&#945; (p <0,001) and NF&#954;B (p <0,001) compared with the control group. Pretreatment with NAC prevented the increase of these parameters as IL-6 (p <0,001), iNOS (p <0,001), COX2 (p <0,05), TNF-&#945; (p <0,05) and NF&#954;B ( p <0,001) when compared with LPS 24 hours. Our results suggest that oxidative stress plays an important role in inflammatory responses, structural and functional model of ALI induced by LPS and that these changes are dependent oxidative stress.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / In this study we aimed to validate a model of acute lung injury (ALI) induced by surgical muscle trauma, which attempts to reproduce the conditions of a skeletal muscle trauma that occurs in humans and, therefore, to provide a better understanding of this disease and its treatmentsâ alternatives. In the first step we evaluated the effect of the experimental model. Thirty-six male Wistar rats with average weight of 250g, were divided into 6 groups. In the first step we evaluated the effect of the experimental model. Saline Group (n = 6): animals received 2 ml of saline (i.v) at the same times of the Saline and trauma group; Saline and Trauma Group (n = 6): animals received saline 30 minutes before the induction of muscle trauma and again at 6 and 12 hours after the trauma; Dexamethasone Group (n = 6): animals received 2 doses of dexamethasone 2 mg / kg (i.p) at the same times of Dexamethasone and Trauma Group; Dexamethasone and Trauma Group (n = 6): animals received 2 doses, 2 hours before the occurrence of trauma and 10 hours after the trauma - this group was used as positive control. Surgical procedures were performed under anesthesia of tribromethanol 2.5% (1 ml/100g body weight). The induced trauma surgery was performed in the thigh of the animal and every muscle was detached from the knee to the hip joint. After 24 h of injury, the lungs were retreated to evaluate myeloperoxidase (MPO), glutathione (GSH), neutrophil infiltration, congestion, edema, necrosis and hemorrhage. In plasma only GSH was measured. It was observed that the muscle trauma was shown to induce ALI by promoting a significant reduction in GSH (8.53  1.22 versus 18.87  7.35 p <0.01) and a significant increasing activity of MPO (23.96  4.86 versus 24.50  7.45 p <0.001), neutrophil infiltration (71.00 versus 19.64  28.50  7.63 p <0.001), degree of congestion, edema, necrosis and hemorrhage (p <0.01), when compared with Saline Group without trauma. In Dexamethasone and Trauma Group, when compared to Saline and Trauma Group, Dexamethasone, by being an inhibitor of inflammatory gene, was able to modulate the inflammatory response in almost all parameters. Subsequently we evaluated the effect of L-alanyl-glutamine (L-Ala-Gln) on acute lung injury induced by muscle trauma surgery. 24 h after trauma it was made a comparison between the group treated with L-Ala-Gln and trauma (n = 6) and the saline and trauma group, and it was found that L-Ala-Gln promoted a statistically significant reduction in neutrophil infiltration ( 19.64  71.00 versus 28.50  7.63 p <0.001), in MPO activity (23.96  4.86 versus 12.90  2.01, p <0.001) and a significant increase in concentration of GSH (36.79  7.31 versus 8.53  1.22 p <0.001) in the lung. In histopathological evaluation it was also observed a significant decrease (p <0.01) in the degree of edema, hemorrhage and necrosis in lung tissue of the evaluated groups above. The possible mechanism to justify the observed effects could be that glutamine enhanced glutathione levels, the energy substrate for immune cells, and, additionally, increased the expression of heat shock proteins (HSP) and, as such, prevented the infiltration of neutrophils in tissues. These results suggest that the Ala-Gln treatment has the potential to reduce the inflammatory reaction that was installed in lungs after skeletal muscle trauma. / Nesse estudo procurou-se validar um modelo de lesÃo aguda pulmonar (LAP) induzida por um trauma muscular cirÃrgico que tenta reproduzir as condiÃÃes de um trauma muscular esquelÃtico que ocorre em seres humanos e com isso proporcionar um melhor entendimento da doenÃa e das suas alternativas de tratamento. Na primeira etapa foi avaliado o efeito do modelo experimental. Trinta e seis ratos machos Wistar, com peso mÃdio de 250g, foram distribuÃdos em 6 grupos. Grupo Salina (n=6): os animais receberam apenas 2 ml de salina (i.v.) nos mesmos tempos do grupo salina e trauma; Grupo Salina e trauma (n=6): os animais receberam salina 30 minutos antes do trauma muscular e novamente Ãs 6 e 12 horas depois do trauma. Grupo Dexametasona (n=6): os animais receberam 2 doses de Dexametasona 2mg/kg i.p. nos mesmos tempos do grupo Dexametasona e trauma; Grupo Dexametasona e trauma (n=6): os animais receberam 2 doses, 2 horas antes da ocorrÃncia do trauma e 10 horas depois do trauma, esse grupo foi utilizado como controle positivo. Os procedimentos cirÃrgicos foram realizados sob anestesia tribromethanol 2,5% (1 ml/100g de peso do animal). A operaÃÃo de induÃÃo do trauma foi realizada na coxa do animal e toda musculatura foi descolada desde o joelho atà a articulaÃÃo do quadril. ApÃs 24 h do trauma, retiraram-se os pulmÃes para avaliar mieloperoxidase (MPO), glutationa (GSH), infiltraÃÃo neutrofÃlica, congestÃo, edema, necrose e hemorragia. No plasma foi dosado apenas GSH. Observou-se que o trauma muscular mostrou ser capaz de induzir LAP por promover uma reduÃÃo significante GSH (8,53  1,22 versus 18,87  7,35 p <0,01), aumento significante na atividade de MPO (23,96  4,86 versus 24,50  7,45 p<0,001), do infiltrado neutrofÃlico (71,00 versus 19,64  28,50  7,63 p <0.001), no grau de congestÃo, edema, necrose, hemorragia (p<0,01), quando comparamos com grupo salina sem trauma. No grupo Dexametasona e trauma quando comparado ao grupo salina e trauma, a Dexametasona um inibidor do gene inflamatÃrio, foi capaz de modular a resposta inflamatÃria em quase todos os parÃmetros avaliados. Posteriormente avaliou-se o efeito da L-alanil-glutamina (L-Ala-Gln) sobre a lesÃo aguda pulmonar induzida por trauma muscular cirÃrgico. 24 h apÃs o trauma comparou-se o grupo tratado com L-Ala-Gln e trauma (n=6) com o grupo salina e trauma e verificou-se que a L-Ala-Gln promoveu uma reduÃÃo estatisticamente significante na infiltraÃÃo neutrofÃlica (71,00 versus 19,64  28,50  7,63 p <0.001), na atividade de MPO (23,96  4,86 versus 12,90  2,01, p <0,001), e um aumento significante na concentraÃÃo de GSH (36,79  7,31 versus 8,53  1,22 p <0,001) no pulmÃo. Na avaliaÃÃo histopatolÃgica tambÃm foi observada uma reduÃÃo significante (p< 0,01) no grau de edema, hemorragia e necrose no tecido pulmonar nos grupos acima avaliados. Os possÃveis mecanismos para justificar os efeitos da L-Ala-Gln em modular a resposta inflamatÃria no pulmÃo deve-se ao fato da glutamina ser precursora de glutationa, funciona como substrato energÃtico para cÃlulas do sistema imune, aumenta as expressÃes de proteÃnas de choque tÃrmico (HSP) e impede a infiltraÃÃo neutrofÃlica. Esses resultados sugerem que o tratamento com L-Ala-Gln tem potencial para reduzir o processo inflamatÃrio agudo no pulmÃo induzido por trauma muscular esquelÃtico cirÃrgico.

Inhaled drug delivery is currently the gold standard for treating many respiratory diseases. However, improved treatments are needed for lung diseases like Cystic Fibrosis (CF) and Acute Respiratory Distress Syndrome (ARDS), where mucus or fluid build-up in the lung limits ventilation and, thus, delivery of inhaled drugs. Delivery is most needed in the diseased or damaged regions of the lung, but if an area is not ventilated, inhaled drug will simply not reach it. To overcome this, this research proposes delivering drugs to the lungs within a perfluorocarbon (PFC) liquid. The lungs will be filled with a reverse emulsion containing a disperse phase of aqueous drugs within the bulk PFC and then ventilated. The PFC functions as both a respiratory medium, providing gas exchange, and as a delivery vehicle, providing a more uniform deposition of drugs. After treatment, the highly volatile PFCs are exhaled, returning the patient to normal respiration. This technique improves upon current therapies as follows. First, drugs are delivered directly to where they are needed, yielding higher concentrations in the lung and lower systemic concentrations. Second, PFCs are ideal for washing out lung exudate and mucus. The low surface tension and high density of PFC allows it to easily penetrate plugged or collapsed alveoli, detach infected mucus from the airway walls, and force these fluids to the top of the lungs where they can then be removed via suction. Mucus and exudate removal should allow drugs to penetrate previously plugged airways during emulsion delivery and subsequent treatment with inhaled therapies. Thus, drug delivery via emulsion would be used as a pre-treatment to enhance inhaled or systemic drug therapy. Third, PFC’s anti-inflammatory properties help return to normal lung function. This research examines two applications of this technology: delivery of antibiotics to combat respiratory infections (antibacterial perfluorocarbon ventilation, APV) or delivery of growth factors to enhance alveolar repair (perfluorocarbon emulsions for alveolar repair, PEAR). This work represents an in-depth analysis of the emulsions used during APV and PEAR. Initial efforts evaluated emulsion efficacy under in vitro setting that better simulated lung in vivo antibiotic delivery. The subsequent studies utilized an in vivo rat model of bacterial respiratory infection to validate the effects of emulsion on pharmacokinetics and to assess APVs potential treatment benefits. Lastly, in vitro methods of cellular response assessed the utility of delivering growth factors in PEAR. Significant advancements were made in optimizing the emulsion as a viable means of pulmonary drug delivery. Final efforts resulted in a promising emulsion formulation that overcame the quick transport of tobramycin away from the lung and successfully reduced pulmonary bacterial load in vivo. In vitro applications of PEAR showed the emulsions posed a significant barrier to the availability and, thus, the biological effect of lysophosphatidic acid growth factors. Further in vivo work is required to improve APV’s efficacy over conventional treatments and to determine PEAR’s feasibility and efficacy in promoting lung repair.

We reported earlier in a guinea pig model that exposure of 2-chloroethyl ethyl sulfide (CEES), a mustard gas analog, causes lung injury associated with the activation of tumor necrosis factor alpha (TNF-α), mitogen activated protein kinases (MAPK) signaling, and activator protein-1 (AP-1) transcription factor. Our earlier studies also revealed that antioxidant liposomes can be used as antidotes. Proinflammatory cytokines IL-1, IL-6, and TNF-α, either alone or in combination, can induce the activation of another group of transcription factors, namely SAF-1 (serum accelerator factor-1)/MAZ (Myc-associated zinc finger protein). Phosphorylation of SAF-1 via MAPK markedly increases its DNA-binding and transactivational potential. The objective of the present study was to investigate whether CEES exposure causes activation of IL-1β, IL-6, and SAF-1/MAZ and whether these effects can be prevented by antioxidant liposomes. A single dose (200 μL) of the antioxidant liposome mixture was administered intratracheally after 5 min of exposure of CEES (0.5 mg/kg). The animals were sacrificed either 1 h or 30 days after CEES exposure. CEES exposure caused an upregulation of proinflammatory cytokines IL-6 and IL-1β in the lung along with an increase in the activation of transcription factor SAF-1/MAZ. The antioxidant liposomes treatment significantly blocked the CEES-induced activation of IL-6, IL-1β, and SAF-1/MAZ. This might suggest that antioxidant liposomes might offer a potential therapeutic strategy against inflammatory diseases associated with activation of these bioactive molecules.

The purpose of this study was to develop antioxidant liposomes as an antidote for mustard gas-induced lung injury in a guinea pig model. Five liposomes (LIP-1, LIP-2, LIP-3, LIP-4, and LIP-5) were tested with differing levels of phospholipid, cholesterol, phosphatidic acid, tocopherol (α, γ, δ), N-acetylcysteine (NAC), and glutathione (GSH). A single dose (200 μL) of liposome was administered intratracheally 5 min or 1 h after exposure to 2-chloroethyl ethyl sulfide (CEES). The animals were sacrificed either 2 h after exposure (for lung injury study) or 30 days after exposure (for histology study). The liposomes offered 9%-76% protection against lung injury. The maximum protection was with LIP-2 (71.5% protection) and LIP-4 (75.4%) when administered 5 min after CEES exposure. Delaying the liposome administration 1 h after CEES exposure decreased the efficacy. Both liposomes contained 11 mM α-tocopherol, 11 mM γ-tocopherol, and 75 mM NAC. However, LIP-2 contained additionally 5mM δ-tocopherol. Overall, LIP-2 and LIP-4 offered significant protection by controlling the recruitment of neutrophils, eosinophils, and the accumulation of septal and perivascular fibrin and collagen. However, LIP-2 showed better protection than LIP-4 against the accumulation of red blood cells in the bronchi, alveolar space, arterioles and veins, and fibrin and collagen deposition in the alveolar space. The antifibrotic effect of the liposomes, particularly LIP-2, was further evident by a decreased level of lipid peroxidation and hydroxyproline in the lung. Thus, antioxidant liposomes containing both NAC and vitamin E are an effective antidote against CEES-induced lung injury.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20250号 / 医博第4209号 / 新制||医||1020(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊達 洋至, 教授 戸口田 淳也, 教授 開 祐司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Enteral nutrition (EN) is often delayed in critically ill patients despite strong evidence to support that early enteral nutrition feeding is beneficial in this population. Adverse outcomes in critically ill patients in which nutrition is delayed include a longer length of stay and time on the ventilator, and a higher incidence of pneumonia and hospital mortality. The purpose of this literature review was to evaluate the current evidence regarding trophic enteral feeds in mechanically ventilated adult patients with acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) and associated clinical outcomes. A retrospective literature review was performed to identify articles published on the topic of trophic feeds in mechanically ventilated adult patients with ALI/ARDS, with a focus on associated clinical outcomes. The studies included in this literature review indicated that the dose and timing of enteral nutrition in critically ill patients with ARDS/ALI had an effect on clinical outcomes. It is possible that additional variables such as the level of organ dysfunction and varying definitions for trophic enteral nutrition also influenced clinical outcomes. The United States (U.S.) and Canadian guidelines for nutrition supportrecommend either trophic or full EN for patients with ARDS/ALI on the basis that these two feeding strategies have similar patient outcomes over the first week of hospitalization. After reviewing the literature, we conclude that caution is warranted when following this recommendation. Regressions suggest full calorie enteral nutrition administered early in the course of critical illness significantly increased the odds of mortality, whereas full calorie enteral nutrition administered later reduced the odds of mortality.

No description available.

No description available.