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

Clinical studies to investigate pharmacokinetics of antimicrobial agents in critically ill patients

__Abstract__ The intensive care unit (ICU) is an essential part of the surgical department, providing an environment for surveillance and treatment of the critically ill. Patients are admitted either with a life threatening condition due to a critical illness or they need observation and support after major surgery. In the Netherlands, approximately 60.000 patients are admitted to an adult ICU annually, which is 4% of total number of hospital admissions (Prismant 2002, Utrecht). Infections are common in surgical ICU patients. An incidence of up to 40% of all admissions has been reported. Infections are a major indication for admission as in patients with generalised peritonitis or respiratory insufficiency due to a postoperative pneumonia. Furthermore, patients admitted for extensive trauma or after major surgery are susceptible to infectious complications. The host defences of the surgical patient are compromised by both extrinsic and intrinsic factors. Normal barriers are breached by surgical incisions and by intravascular lines, wound drains, urinary catheters and endotracheal tubes. The integrity of the gastrointestinal epithelium is compromised by lack of enteral nutrition and periods of hypoperfusion, promoting bacterial translocation. The protective indigenous microbial flora is changed by the use of broad-spectrum antibiotics. Furthermore, multiple alterations in the systemic immunity are seen. Natural downregulatory mechanisms for the inflammatory response exist, probably to limit autoimmune damage. Iatrogenic immune suppression is applied frequently following organ transplantation or with corticosteroids in pulmonary dysfunction. At last, there are preexistent diseases associated with impaired host defences, including cirrhosis, renal failure, malignancy and diabetes