Rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART): Study protocol for a randomized controlled trial

Background: Acute respiratory distress syndrome (ARDS) is associated with high in-hospital mortality. Alveolar recruitment followed by ventilation at optimal titrated PEEP may reduce ventilator-induced lung injury and improve oxygenation in patients with ARDS, but the effects on mortality and other clinical outcomes remain unknown. This article reports the rationale, study design, and analysis plan of the Alveolar Recruitment for ARDS Trial (ART). Methods/Design: ART is a pragmatic, multicenter, randomized (concealed), controlled trial, which aims to determine if maximum stepwise alveolar recruitment associated with PEEP titration is able to increase 28-day survival in patients with ARDS compared to conventional treatment (ARDSNet strategy). We will enroll adult patients with ARDS of less than 72 h duration. The intervention group will receive an alveolar recruitment maneuver, with stepwise increases of PEEP achieving 45 cmH(2)O and peak pressure of 60 cmH2O, followed by ventilation with optimal PEEP titrated according to the static compliance of the respiratory system. In the control group, mechanical ventilation will follow a conventional protocol (ARDSNet). In both groups, we will use controlled volume mode with low tidal volumes (4 to 6 mL/kg of predicted body weight) and targeting plateau pressure <= 30 cmH2O. The primary outcome is 28-day survival, and the secondary outcomes are: length of ICU stay; length of hospital stay; pneumothorax requiring chest tube during first 7 days; barotrauma during first 7 days; mechanical ventilation-free days from days 1 to 28; ICU, in-hospital, and 6-month survival. ART is an event-guided trial planned to last until 520 events (deaths within 28 days) are observed. These events allow detection of a hazard ratio of 0.75, with 90% power and two-tailed type I error of 5%. All analysis will follow the intention-to-treat principle. Discussion: If the ART strategy with maximum recruitment and PEEP titration improves 28-day survival, this will represent a notable advance to the care of ARDS patients. Conversely, if the ART strategy is similar or inferior to the current evidence-based strategy (ARDSNet), this should also change current practice as many institutions routinely employ recruitment maneuvers and set PEEP levels according to some titration method.Hospital do Coracao (HCor) as part of the Program 'Hospitais de Excelencia a Servico do SUS (PROADI-SUS)'Brazilian Ministry of Healt

Is subdiaphragmatic aortic cross-clamping a suitable model for spinal cord ischemia/reperfusion injury study in rats? O pinçamento sub-diagragmático da aorta é um modelo adequado para o estudo da lesão medular de isquemia/reperfusão em ratos?

PURPOSE: To evaluate the efficacy of subdiaphragmatic aortic cross-clamping in an experimental model of ischemia/reperfusion injury of the spinal cord in albino rats. METHODS: Thirty-six male Wistar rats were randomized in two groups (n=18): G-1 (Sham) and G-2 (Ischemia/Reperfusion, I/R). G-2 rats were submitted to 30 min subdiafragmatic aortic cross-clamping. G-1 rats served as controls and were submitted to surgical trauma (laparotomy) without ischemia. Samples (spinal cord and arterial blood) were collected at the end of ischemic period and 10 (T-10) and 20 (T-20) min later in G-2 rats. Sham rats (G-1) samples were collected at the same time-points. Blood and tissue metabolites concentrations of pyruvate, lactate, glucose and medullary adenosine triphosphate (ATP) were assayed. RESULTS: Blood and tissue concentrations of pyruvate and glucose as well as lactate and medullary ATP were not different when comparing G1 to G2. Lactacemia was significantly elevated in G-2 compared with G-1 rats during reperfusion (T-10). CONCLUSION: Subdiaphragmatic aortic cord cross-clamping is not a suitable rat model for spinal cord ischemia/reperfusion injury study as it does not ensure changes in in vivo tissue metabolites concentrations similar to those found in tissues subjected to ischemia/reperfusion.<br>OBJETIVO: Avaliar a eficácia do pinçamento da aorta subdiafragmática no modelo experimental de isquemia/reperfusão da medula espinhal em ratos. MÉTODOS: Trinta e seis ratos Wistar, machos, foram aleatoriamente distribuídos em 2 grupos (n=18) e submetidos ao pinçamento subdiafragmático da aorta, durante 30 minutos (Grupo-2 -Isquemia/Reperfusão). Os ratos do Grupo-1 (G-1 - Sham) foram utilizados como controles e submetidos a laparotomia sem pinçamento arterial. As amostras (medula e sangue arterial) foram coletadas ao término do período de isquemia (T-0) e 10 (T-10) e 20 (T-20) minutos mais tarde e nos mesmos intervalos, no grupo G-1. As concentrações teciduais e sanguíneas de piruvato, lactato, glicose e as concentrações medulares de trifosfato de adenosina (ATP) foram determinadas por ensaios enzimáticos. RESULTADOS: As concentrações de piruvato e glicose (sangue e tecido) e de lactato e ATP (medula) não foram diferentes,comparando G-1 versus G-2. A lactacemia elevou-se significantemente no G-2, comparado ao G-1, durante a reperfusão (T-10). CONCLUSÃO: O modelo experimental de pinçamento subdiafragmático da aorta não é adequado para o estudo da lesão de isquemia/reperfusão na medula de ratos, uma vez que não proporciona alterações nas concentrações in vivo de metabólitos teciduais, por exemplo de lactato ou ATP, compatíveis com aquelas encontradas em tecidos sujeitos à isquemia/reperfusão

Repercussões da L-alanil-glutamina sobre as concentrações de lactato e lactato desidrogenase (LDH) em pacientes com isquemia crítica dos membros inferiores submetidos a revascularização distal Repercussions of l-alanyl-glutamine upon the concentrations of lactate and lactate dehydrogenase (LDH) in patients with critical ischemia of lower limbs subjected to distal revascularization

OBJETIVO: Investigar efeitos da L-alanil-glutamina nas concentrações musculares de lactato, e nas concentrações sanguíneas de LDH, em pacientes com isquemia crítica dos membros inferiores submetidos à revascularização distal. MÉTODOS: Dezesseis adultos (12-homens/4-mulheres) foram distribuídos em 2 grupos (1-controle/2-estudo). Três horas após injeção endovenosa de 250 ml de L-alanil-glutamina a 20% adicionados a 750 ml de soro fisiológico (Grupo 2), ou 1000 ml de solução salina (Grupo 1), iniciava-se a revascularização, sob raquianestesia. Amostras musculares e de sangue (arterial/venoso) foram coletadas no início do procedimento (TI), no final (TF), e 10 e 20 minutos após isquemia (T1/T2). RESULTADOS: Observou-se redução significante (p<0,05) da concentração de lactato no tecido muscular sadio dos pacientes tratados com L-alanil-glutamina, em comparação ao grupo controle, em todos os tempos estudados. Houve redução significante nas concentrações de LDH no sangue venoso dos pacientes tratados, em todos os tempos (TIV/TFV/T1V/T2V), e no sangue arterial durante a reperfusão (T1A/T2A). CONCLUSÕES: Queda na concentração de lactato no músculo, e redução nas concentrações arteriais e venosas de LDH, em pacientes recipientes de L-alanil-glutamina, sugere maior utilização de piruvato para produção de energia no ciclo de Krebs do que sua conversão para lactato, com prevalência da glicólise aeróbica.<br>PURPOSE: Investigate the repercussions of L-alanyl-glutamine in muscular tissue concentrations of lactate, and venous and arterial blood concentrations of LDH, in patients with critical ischemia of the lower limbs submitted to distal revascularization. METHODS: Sixteen adults (12 male/4 female) were distributed in 2 groups (1-Control/2-Experiment). Three hours after the intravenous injection of 250 ml of a 20% solution of L-alanyl-glutamine added to 750 ml of saline solution (Group 2); or 1000 ml of saline solution (Group 1), distal bypass was carried out under spinal anesthesia. Muscle and blood samples (arterial/venous) were collected at the beginning of the surgical procedure (TI), at the end (TF), and 10 and 20 minutes after re-establishment of blood flow. RESULTS: Significant reduction (p<0,05) of lactate concentration was observed in healthy muscle tissue in L-alanyl-glutamine treated patients in comparison to control group, at all times studied. There was a significant reduction (p <0,05) in venous concentrations of LDH in treated patients at all times studied (TI/TFV/T1V/T2V); and in arterial blood during reperfusion (T1A/T2A). CONCLUSIONS: 1. Decreased lactate concentrations in healthy skeletal muscle in patients treated with L-alanyl-glutamine suggests greater utilization of pyruvate for energy production than its conversion to lactate in Krebs cycle boosting aerobic glycolysis. 2. - Drop in venous blood concentrations of LDH in treated patients with L-alanyl-glutamine at all times during ischemia, and 10 and 20 minutes after reperfusion, also suggests augmented utilization of pyruvate for energy production via aerobic glycolysis

Efeitos metabólicos da glutamina em ratos submetidos à queimadura por água fervente (escaldadura) Metabolic effects of glutamine in rats subjected to scald burn

OBJETIVO: Investigar os efeitos metabólicos da L-glutamina (Gln) em ratos anestesiados submetidos à queimadura por água fervente. MÉTODOS: Foram estudados vinte e quatro ratos Wistar machos, anestesiados, submetidos a queimaduras da pele dorsal após exposição à água quente (100ºC) durante 10 segundos (30% de superfície corporal). Os ratos foram randomizados para receber, por gavagem, 2ml de água (G-1) ou igual volume de solução de Gln (0,5g/peso/dia) (G-2). Amostras de tecido (pele sadia e queimada, músculo e fígado) e sangue foram coletadas 24h (D1) e 48h (D2) pós-trauma para análise enzimática. RESULTADOS: A oferta de Gln induziu aumento significante nas concentrações de glicose na pele saudável em animais do G-2 no D2, e na pele queimada em G-2/D1. As concentrações de lactato também aumentaram significantemente em G-2/D1 no músculo (11,29 ± 1,25 mmol/g contra 7,43 ± 0,93 mmol/g - p<0,05) e no G-2/D2 no fígado (7,68 ± 1,49 mmol/g contra 3,27 ±0,67 mmol/g p<0,01), e em pele sadia (5,30 ± 0,42 mmol/g contra 3,57 ± 0,38 mmol/g - p<0,05). As concentrações de piruvato diminuíram significantemente no grupo G-2/D1 (músculo e fígado) e aumentaram na pele sadia no grupo G-2/D2. As concentrações de ATP diminuíram significantemente no músculo em G-2 nos tempos D1 e D2. CONCLUSÕES: A oferta de Gln sinaliza para utilização de piruvato para glicólise preponderantemente anaeróbica no músculo. O aumento nas concentrações de lactato tecidual pode vir a ser decorrente da oferta exógena de Gln, que transformada em glutamato, leva à ativação do ciclo malato-aspartato com conseqüente favorecimento da glicólise anaeróbica. A oferta de Gln induz a possível aumento na captação de glicose tanto por pele sadia quando na pele queimada. Houve falha de desenvolvimento da hipercetonemia adaptativa ao jejum em ambos os grupos. A oferta exógena de Gln parece não induzir alteração na ureagênese.<br>PURPOSE: Investigate the metabolic effects of L- glutamine (Gln) in rats subjected to scald burn. METHODS: Twenty-four anesthetized male Wistar rats were submitted to scald burn of dorsal skin secondary to exposure to hot water (100ºC) for 10 sec (30% of body surface). Eighteen and 42h later rats were randomized to receive (by gavage) 2ml of water (G-1) or equal volume (0,5g/Kg weight/day) of Gln solution (G-2). Tissue and blood samples were collected at the end of 24h (D1) and 48h (D2) post burn for enzymatic analysis. RESULTS: Glucose concentrations were significantly increased in healthy skin in G-2/D2 and in burned skin in G-2/D1. Lactate concentrations were significantly increased in G-2/D1 in muscle (11,29 ± 1,25 mmol/g versus 7,43 ± 0,93 mmol/g - p<0.05) and in G-2/D2 subgroups in liver (7,68 ± 1,49 mmol/g versus 3,27 ±0,67 mmol/g - p<0.01) and healthy skin (5,30 ± 0,42 mmol/g versus 3,57 ± 0,38 mmol/g - p<0.05). Pyruvate concentrations were significantly decreased in G-2/D1 subgroups in muscle and liver and increased in healthy skin in G-2/D2 subgroups. ATP concentrations were significantly decreased in muscle in G-2/D1 and G-2/D2. CONCLUSIONS: The offer of Gln signals for preponderance of pyruvate use for anaerobic glycolysis in muscle. Increase in tissue lactate concentrations may be due to exogenous offer of Gln, that once transformed in glutamate leads to the activation of malate-aspartate shuttle with consequent enhancing of anaerobic glycolysis. Offer of Gln induces possible increase in glucose uptake both in healthy and burned skin. There was a development flaw of the fast adapting hyperketonemia in both groups. Exogenous offer of Gln seems not to induce alteration in urea genesis