Hemodynamic Assessment of Septic Mice Deficient in Inducible Nitric Oxide Synthase Demonstrates Improved Myocardial Performance
Steven M. Hollenberg, Andrew Dumasius, Mohammed Khamis, Joseph E. Parrillo, Rush Medical College, Chicago, Illinois.
Introduction: Vasodilation and myocardial depression characteristic of septic shock may result from overproduction of nitric oxide, and can lead to pressor-refractory hypotension and death. To evaluate the significance of cytokine-inducible nitric oxide synthase (iNOS) in the pathogenesis of sepsis, we measured hemodynamics in resuscitated septic wild-type (WT) and iNOS-deficient mice.
Methods: Mice were made septic by cecal ligation and puncture (controls underwent sham ligation) and were resuscitated with fluids (50 ml/kg SQ) and antibiotics (ceftriaxone and clindamycin IM) every 6 hours. Echocardiography was performed at 6 hour intervals for 48 hrs on unanesthetized, restrained mice.
Results: In controls, (n=6) mean heart rate (HR, WT 457±29, iNOS-deficient 480±53 bpm), stroke volume (SV, WT 23±3, iNOS-deficient 22±3 µL), cardiac output (CO, WT 10.4±1.2, iNOS-def 10.3±1.8 ml/min), and fractional shortening (FS, WT 0.53±0.07, iNOS-deficient 0.55±0.07) did not change significantly over 48 hours. In WT septic mice (n=9), HR and CO increased by 10-15% (from 498±37 to 542±60 bpm and 10.6±1.9 to 12.4±2.2 ml/min), peaking at 24-30 hours; SV (23±5 µL) and FS (0.54±0.07) were unchanged. In iNOS-deficient septic mice, (n=12) FS increased significantly at 24-30 hours (0.54±0.05 to 0.62±0.05, p<0.03 vs baseline and p<0.01 vs WT), with slightly larger increases in CO (10.7±2.4 to 13.3±5.4 ml/min, p=0.07) and SV (23±5 to 25±8 µL, p=0.3). End-diastolic dimension increased (3.04±0.30 vs 3.28±0.15 mm, p=0.03) and end-systolic dimension decreased (1.47±0.23 vs 1.33±0.28 mm, p=0.2).
Conclusions: iNOS-deficient septic mice had a more hyperdynamic response with increased fractional shortening in an awake, fluid-resuscitated, antibiotic-treated model that replicates the mortality and hyperdynamic state seen in clinical sepsis. This suggests that iNOS-induced NO has an important pathogenic role in producing myocardial depression in septic shock.
(ACC abstract) |
