INFLUENCE OF N-ACETYLCYSTEINE ON INDIRECT INDICATORS OF TISSUE OXYGENATION IN SEPTIC SHOCK PATIENTS - RESULTS FROM A PROSPECTIVE, RANDOMIZED, DOUBLE-BLIND-STUDY

Objectives: Deactivation of endothelium-derived relaxing factor due to an increased oxygen radical load during sepsis may contribute to an i mpairment in microcirculatory blood flow. We investigated whether trea tment with the sulfhydryl donor and oxygen radical scavenger, N-acetyl cysteine, would improve whole-body oxygen consumption (Vo(2)), gastric intramucosal pH, and veno-arterial CO2 gradient (veno-arterial PCO2) during septic shock. Design: Prospective, randomized, double-blind stu dy conducted over 2 yrs. Setting: Septic shock patients admitted to th e intensive care unit. Patients: Fifty-eight patients requiring hemody namic monitoring (radial and pulmonary artery catheters) due to septic shock, were included in this study. All patients were examined within 72 hrs after the onset of sepsis. They were optimally resuscitated by conventional means with volume and inotropic agents, and exhibited st able clinical conditions (hemodynamic values, body temperature, hemogl obin, FIO2). Interventions: A gastric tonometer was inserted to measur e the gastric intramucosal pH. Subjects randomly received either 150 m g/kg of intravenous N-acetylcysteine or placebo over a 15-min period, then a continuous infusion of 12.5 mg/hr of N-acetylcysteine or placeb o over similar to 90 mins. Measurements: Infusion measurements were be gun 60 mins after the beginning of infusion and lasted similar to 30 m ins. The infusion was then discontinued and 2 hrs later the final meas urements were taken. Main Results: Basic patient characteristics (age, sex, Acute Physiology and Chronic Health Evaluation [APACHE] II score s, Multiple Organ Failure scores) did not differ significantly, nor di d pre- and 2-hr postinfusion measurements differ between any of the gr oups. Thirteen (45%) patients responded (i.e., showed an increase in V o(2) >10%, reaching a mean of 19%) to the N-acetylcysteine infusion. T he N-acetylcysteine responders also showed an increase in gastric intr amucosal pH, a decrease in veno-arterial PCO2, an increase in oxygen d elivery, cardiac index, stroke index, and left ventricular stroke work index, as well as a significant decrease in systemic vascular resista nce in comparison to baseline. The N-acetylcysteine nonresponders, as well as the patients in the placebo group, did not show any significan t changes in any of these variables. The N-acetylcysteine responders h ad a higher survival rate (69%) than the nonresponders (19%) and were studied earlier after onset of sepsis (37 hrs) than the nonresponders (61 hrs). The only significant difference between the entire N-acetylc ysteine group (which included responders plus nonresponders) and the p lacebo group was an increased 30, in the entire N-acetylcysteine group during infusion measurements. Conclusions: N-acetylcysteine provided a transient improvement in tissue oxygenation in about half of the sep tic shock patients, as indicated by an increase in Vo(2) and gastric i ntramucosal pH and a decrease in veno-arterial PCO2. The higher surviv al rate in the N-acetylcysteine responders and the fact that half of t he patients receiving N-acetylcysteine did not respond, suggests that, in some patients, sepsis irreversibly damages the microvasculature to the extent that N-acetylcysteine has no effect. If analyzed by intent ion to treat, the N-acetylcysteine did not produce effects that were s ignificantly different from the placebo. Whether the N-acetylcysteine challenge was merely diagnostic or whether N-acetylcysteine can be eff ective in the treatment of sepsis deserves further investigation.