Nitric Oxide in Septic Shock: an experimental and clinical study

Sepsis and its sequelae are the leading cause of mortality in todays medical and surgical intensive care. The incidence of sepsis continues to increase. Mortality of septic shock ranges from 30 to 80% depending on the severity of disease and the presence of organ failure. Despite recent progress in antibiotic therapy and intensive care support mortality from septic shock has remained high over the last years. Sepsis can be defmed as the systemic response to severe infection.'" When certain micro-organisms or their toxic products invade the bloodstream, this may result in a wide variety of symptoms that are characteristic of sepsis and its sequelae (Table 1). When hypotension develops unresponsive to fluid therapy and signs of inadequate organ perfusion are present, the condition is often referred to as septic shock.s Shock develops in approximately 40 % of septic patients. The initial cardiovascular changes during hyperdynamic sepsis are characterized by massive vasodilatation with a normal to high cardiac output, low peripheral vascular resistance and severe hypotension.'" In a large number of patients the initial hypotension is unresponsive to treatment with fluid substitution or vasopressors. Umesponsive hypotension is present in 50% of patients that die of septic shock. In the first week unresponsive hypotension is the primary cause of mortality of septic patients. In the later stages of sepsis, the hyperdynamic circulatory state may turn into hypodynamic septic shock witl! failure to guarantee adequate oxygen supply to tissues and irreversible organ damage. In a retrospective study with one hundred intensive care patients with sepsis 80% of mortality in the first week was caused by severe hypotension

Effect of L-NAME, an inhibitor of nitric oxide synthesis, on cardiopulmonary function in human septic shock

STUDY OBJECTIVES: We tested the effects of continuous infusion of N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, on cardiovascular performance and pulmonary gas exchange in patients with hyperdynamic septic shock. DESIGN: Prospective clinical study. SETTING: ICU of a university hospital. PATIENTS: Eleven critically ill patients with severe refractory septic shock. INTERVENTIONS: Standard hemodynamic measurements were made and blood samples taken before, during, and after 12 h of continuous infusion of 1 mg/kg/h of L-NAME. MEASUREMENTS AND RESULTS: Continuous infusion of L-NAME increased mean arterial pressure (MAP) from 65+/-3 (SEM) to 93+/-4 mm Hg and systemic vascular resistance (SVR) from 962+/-121 to 1,563+/-173 dyne x s x cm(-5)/m2. Parallel to this, cardiac index (CI) decreased from 4.8+/-0.4 to 3.9+/-0.4 L/min/m2 and myocardial stroke volume (SV) was reduced from 43+/-3 to 34+/-3 mL/m2. Left ventricular stroke work was increased in the first hour of L-NAME infusion from 31+/-3 to 43+/-4 g x m/m2 (all p<0.01 compared with baseline). Heart rate, cardiac filling pressures, and right ventricular stroke work did not change significantly (p>0.05). L-NAME increased the ratio of arterial PO2 to the fraction of inspired O2 from 167+/-23 to 212+/-27 mm Hg (p<0.05). Venous admixture (QVA/QT) was reduced from 19.4+/-2.6% to 14.2+/-2.1% (p<0.05) and oxygen extraction ratio increased from 21.1+/-2.4% to 25.3+/-2.7% (p<0.05). Oxygen delivery (DO2) was reduced following L-NAME, whereas oxygen uptake and arterial lactate and pH were unchanged. CONCLUSIONS: Prolonged inhibition of NO synthesis with L-NAME can restore MAP and SVR in patients with severe septic shock. Myocardial SV and CI decrease, probably as a result of increased afterload, since heart rate and stroke work were not reduced. L-NAME can improve pulmonary gas exchange with a concomitant reduction in QVA/QT. L-NAME did not promote anaerobe metabolism despite a reduction in DO2

Endothelin-1 and blood pressure after inhibition of nitric oxide synthesis in human septic shock

BACKGROUND: The systemic hypotension during human sepsis has been ascribed to increased production of nitric oxide (NO). Therefore, inhibitors of NO synthesis have been used in the treatment of hypotension in patients with septic shock. In addition, NO production may inhibit the synthesis and vasoconstrictor effects of endothelin-1 (ET-1). In this study, we tested whether ET-1 contributed to the vasopressor action of the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) in patients with severe septic shock. METHODS AND RESULTS: Compared with healthy volunteers, patients with septic shock had increased plasma levels of nitrite/nitrate (37+/-5 [SEM] versus 12+/-5 mmol/L, P<0.01), the stable end products of NO metabolism, and ET-1 (45+/-7 versus 3+/-2 pg/mL, P<0.001). Plasma ET-1 concentration was not related to plasma nitrite/nitrate concentration or blood pressure. Continuous infusion of L-NAME (1 mg. kg-1. h-1 IV) for 12 hours increased mean arterial pressure by 43+/-5% and systemic vascular resistance by 64+/-10% (both P<0.01). The increase in blood pressure and systemic vascular resistance correlated positively with the level of ET-1 (both P<0. 005) but not with plasma nitrite/nitrate level. L-NAME infusion did not result in significant changes in the plasma concentrations of ET-1 or nitrite/nitrate. CONCLUSIONS: NO and ET-1 may both play a role in the cardiovascular derangements of human sepsis. Although L-NAME does not increase ET-1 concentration in patients with septic shock, the vasopressor response induced by L-NAME depends on the plasma level of ET-1. These findings may indicate that inhibitors of NO synthesis unmask a tonic pressor response of ET-1 in human septic shock

Nitric oxide causes dysfunction of coronary autoregulation in endotoxemic rats

This study tested the hypothesis that overproduction of endogenous nitric oxide (NO) during endotoxemia may modulate coronary autoregulation and myocardial reactive hyperemia. Hearts of endotoxin-pretreated rats and controls were isolated and arranged for perfusion in a Langendorff preparation. Autoregulation was studied by examining flow-pressure relations during stepwise changes in perfusion pressure. The contribution of nitric oxide was examined by perfusion with N omega-nitro-L-arginine (NNLA), an inhibitor of nitric oxide synthesis and methylene blue (MB), an inhibitor of soluble guanylate-cyclase. Endotoxin-treated hearts showed massive coronary vasodilatation and autoregulatory function was impaired at perfusion pressures from 20 to 60 mmHg. Both NNLA and MB reduced coronary flow, improved autoregulation and eliminated differences in coronary flow and autoregulation between the control and endotoxin-treated group. Vasoconstriction with vasopressin, a direct smooth muscle constrictor, could not eliminate differences in autoregulation between groups. Reactive hyperemia following coronary occlusion in endotoxin-treated hearts showed decreased duration, flow repayment and repayment ratio. In the presence of NNLA or MB, however, no significant differences in reactive hyperemic flow patterns were present. These observations suggest that massive coronary vasodilatation due to increased myocardial NO synthesis can result in autoregulatory dysfunction and altered myocardial reactive hyperemia during endotoxemi