Nitric oxide in experimental sepsis

University dissertation from Department of Anaesthesiology and Intensive Care, University Hospital, S-221 85 LUND, Sweden

Abstract: Nitric oxide (NO) is important in the control of blood pressure and organ perfusion. In septic shock, NO produced by inducible NO-synthase (NOS) has been claimed to mediate pathological vasodilation and cell injury, while NO produced by constitutive NOS may be protective in counteracting hypoperfusion and organ injury. This thesis comprises studies on the effects of inhaled NO on pulmonary function in a porcine model of unresuscitated Gram-negative septic shock and acute lung injury (ALI). In this model and in normal pigs, we also investigated the effects of non-selective NOS inhibition on global and regional haemodynamics and oxygen extraction. NO inhalation: Inhaled NO (57 and 60 ppm) selectively attenuated pulmonary vasoconstriction without direct effects on the systemic circulation. Early NO inhalation preserved gas exchange by reducing venous admixture and alveolar dead space, but had no effects on respiratory mechanics. The effects on pulmonary haemodynamics and gas exchange were repeatable. Inhaled NO may mitigate endotoxic lung injury by reducing leukocyte sequestration in the pulmonary microvasculature. NOS inhibition: In both normal and endotoxic pigs, the pulmonary vasculature was more sensitive to the vasoconstricting effects of NOS inhibition than the systemic. In normal pigs, this pulmonary vasoconstriction was enhanced by prior stimulation with acetylcholine. The enhancement may be related to an associated release of a vasoconstricting prostanoid. In endotoxic shock, NOS inhibition caused several animals, with extreme pulmonary hypertension, to die before the end of the observation time. In spite of the fatal overall effects, hepatic perfusion was unharmed by NOS inhibition. The capacity to increase oxygen extraction, in response to the decrease in oxygen delivery, was preserved. In hypodynamic shock, compensatory mechanisms other than NO may be more important in the regulation of hepatic blood flow.

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