Abstract 77: Nitric Oxide in Sepsis: Friend or Foe? Hemodynamics in a Murine Model
Introduction: Overproduction of NO by inducible nitric oxide synthase (iNOS) in sepsis has been implicated in vascular relaxation associated with hypotension and in myocardial depression, but whether this response is adaptive or pathogenic has not yet been fully addressed. We investigated the effect of NO on cardiac function in septic mice.
Methods: 20 C57Bl/6 (WT), 16 iNOS-deficient mice (iNOSKO), and 4 eNOS-deficient mice (eNOSKO) were studied. Mice were made septic by cecal ligation and puncture (CLP); controls underwent sham ligation. After CLP animals were given antibiotics (ceftriaxone 30mg/kg and clindamycin 25mg/kg IM q6hr) and aggressive fluid resuscitation: 35mL/kg after surgery and then q6hr SQ. Animals were anesthetized briefly with isoflurane and cardiac performance was assessed every 3 hrs for 36 hr, then every 12 hr by echocardiography with a 30Mhz scan-head. Stroke Volume (SV, μL) was assessed by Doppler, Fractional Shortening (FS%) by short axis M-mode, and Cardiac Output (CO, mL/min) was calculated as SV*HR.
Results: Even with aggressive fluid resuscitation, CO was reduced at 6 hr (from 26±3 to 18±5 mL/min (WT), 26±3 to 18±6 mL/min (iNOSKO), and 23±6 to 7±2 mL/min (eNOSKO), p<0.05 vs baseline and sham control). In WT and iNOSKO, CO increased at 12 hr and normalized by 24 hr (25±8 WT, 22±10 iNOSKO) due to a reduction in SV (from 58±7 to 38±4 μL with recovery to 51±13 μL (WT), 57±6 to 38±8 μL with recovery to 50±13 μL (iNOSKO) with no significant change in heart rate. In eNOSKO mice, SV and CO remained low (32±10 μL and 10±4 mL/min at 24 hr). FS, however, was higher at 24 hr in iNOSKO, (48±11% vs WT 35±11, eNOSKO 26±4, p<0.001). LV end-diastolic diameter was decreased in both iNOSKO and eNOSKO (3.2±0.5 mm and 3.2±0.3 mm vs 3.8±0.3 mm, p<0.01).
Conclusions: Early and aggressive fluid resuscitation is mandatory to restore a normodynamic state in sepsis. Increased FS in iNOS-deficient mice suggests that NO may be a myocardial depressant in sepsis, but this may serve to match metabolic demand to supply. In sepsis, capillary leakage decreases filling pressure, so the LV must fill at a lower pressure to maintain SV. Decreased diastolic dimensions in NOS knockouts suggests that lusitropic effects of eNOS are important in the hemodynamic response to sepsis.