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Abstract

30.1 ml/kg vs. OB 17 ml/kg, p<0.01) was lower in the OB group. In both groups, the drip rates were significantly lower in patients who failed versus those who did not. Conclusions: This study questions the efficacy of non-weight vasopressor dosing. Adequately dosing obese patients may result in faster obtainment of goal MAP and decreased use of secondary agents. Randomized trials are needed to validate these results and examine adverse event rates.Learning Objectives: AMP-activated protein kinase (AMPK) is a crucial regulator of energy homeostasis, which controls disposal of mitochondria by autophagy and mitochondrial biogenesis by activation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α). We hypothesized that genetic deficiency in α1 subunit of AMPK exacerbates organ injury in sepsis by impairing energy homeostasis. Methods: C57BL/6 AMPKα1-/-(KO), +/-(HT), and +/+ (WT) 2-3 mo old male mice were subjected to sepsis by cecal ligation and puncture (CLP). Organs were harvested at 18 hr after CLP for biochemical assays. Results: At Western blot analysis, AMPKα1 and pAMPKα1 in the heart and liver were undetectable in KO and decreased in HT. Since AMPK can indirectly activate SIRT1, which in turn activates PGC1α, we assessed SIRT1 and PGC1α. At baseline, SIRT1 expression in the heart was significantly lower in KO than in WT. After CLP, however, SIRT1 expression in KO increased to the level higher than WT. Notably, there was no significant difference in PGC1α expression between KO and WT after CLP. Next, tissue ATP level (nmol/mg dry weight) was measured in the liver. It was lower at baseline in KO (1.4 ± 0.1) and HT (1.5 ± 0.3) than WT (2.9 ± 0.1, P<0.05). In sepsis, ATP level decreased in all groups, but more severely in KO (0.4 ± 0.1) than WT (1.2 ± 0.2, P<0.05). We further assessed autophagosome formation by following the LC3B-I to LC3B-II conversion in the heart and liver. Interestingly the conversion increased dramatically from baseline after CLP in KO and HT despite their lower baseline conversion levels than WT. Finally, we examined the degree of organ injury in the lung and liver. MPO activity (U/100mg tissue) in the lung increased after CLP in all three groups, but more greatly in KO (394 ± 74), than HT (249 ± 63, P<0.05) and WT (44 ± 12, P<0.05). Similar increase in MPO activity was also observed in the liver of KO mice. Conclusions: AMPKα1 deficiency impaired energy production and exacerbated organ injury in sepsis, which could be due to impaired anti-inflammatory effect of AMPK rather than impaired AMPK-dependent metabolic pathways.