Abstract
Background Nonlinear hemodynamic variables such as blood pressure and heart rate variability are abnormal in sepsis. Nitric oxide has a complex role in hemodynamic alterations in sepsis. The role of inducible nitric oxide synthase (iNOS) on nonlinear hemodynamic parameters is unknown. Hypothesis Selective inhibition of iNOS will alter the response of nonlinear hemodynamic parameters in a murine model of sepsis. Methods Radio-transmitters were implanted into the aorta of C57/BL6 wild type (n=15) and C57/BL6 NOS 2 (iNOS knockout) (n=8) mice for continuous hemodynamic monitoring. After 72 hours of recovery, baseline heart rate recordings were captured for 24 hours. Sepsis was induced by cecal ligation and puncture and continuous recordings were taken for the next 48 hours. All mice received antibiotics (ceftriaxone and clindamycin) and fluids (35mg/kg 0.9% NaCl) every 6 hours. Volatility was used as a measurement of variability. Heart rate volatility (HRV) and blood pressure volatility (BPV) measurements were compared between groups. Results At baseline the iNOS knockout mice had a higher mean systolic blood pressure (135 vs. 126 mmHg, p<0.001) and lower mean heart rate (504 vs. 534, p<0.001) compared to wild type mice. Following induction of sepsis, heart rate and blood pressure were similar between the two groups. During sepsis the iNOS knockout mice had more frequent normal HRV intervals (48.9 vs. 33.3%, p<0.001) but fewer normal BPV intervals (39.7 vs. 62.8%, p<0.001) than the wild type mice. Survival was significantly higher in the iNOS knockout mice compared to wild type mice (75 vs. 26.7%, p= 0.039). Conclusions In conclusion, selective inhibition of iNOS was associated with alterations in nonlinear hemodynamics during sepsis. Heart rate variability was improved in iNOS knockouts and correlated with improved survival. Our findings suggest a complex role of iNOS in nonlinear hemodynamics during sepsis. Heart rate variability may provide unique prognostic information in sepsis.
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