Faculty Bibliography

We previously reported that N-acetyl-L-cysteine (NAC), an oxygen free-radical scavenger, can increase the oxygen extraction capabilities during endotoxic shock when blood flow is progressively reduced. In the present study, we investigated whether the protective effects of NAC are related to an improvement in regional blood flow following endotoxemia. Fourteen anesthetized, saline-infused and ventilated dogs were divided into two groups: 7 dogs received NAC (150 mg/kg, followed by a 20 mg/kg.h infusion), and the other 7 dogs served as a control time-matching group. Thirty minutes later all the dogs received Escherichia coli endotoxin (2 mg/kg) i.v. A saline infusion was started 30 min after endotoxin challenge to restore pulmonary artery occlusion pressure to baseline and maintain it constant. Regional blood flow was measured by ultrasonic volume flowmeter. In the control group, arterial pressure, left ventricular stroke work index and systemic vascular resistance remained lower than baseline. Mesenteric, renal and femoral arterial blood flow increased but only femoral blood flow returned to baseline levels. In the NAC group, cardiac index and left ventricular stroke work index remained higher and systemic and pulmonary vascular resistance were lower than in the control group. Blood flow in mesenteric, renal and especially femoral arteries was higher than in the control group. Fractional blood flow increased only in the femoral artery. PaO2 and PvO2 had similar courses in the two groups. A higher venous admixture was associated with a higher cardiac index and a lower pulmonary vascular resistance in the NAC group. Oxygen delivery and oxygen-uptake were higher in the NAC-treated than in the control animals throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)

PURPOSE/OBJECTIVE:The release of oxygen-free radicals has been implicated in both peripheral vascular and myocardial alterations of septic shock. N-Acetylcysteine (N-AC), a substrate for the production of glutathione, has potent antioxidant effects. As a nitrosothiol, it may also improve capillary blood flow. We studied the effects of N-AC in a dog model of endotoxic shock. METHODS:Ten pentobarbital-anesthetized, mechanically ventilated dogs were randomly assigned to receive either N-AC (150 mg/kg loading dose in 1 hour, followed by 20 mg/kg.h maintenance dose) or D5W. After the loading dose, each dog received 3 mg/kg Escherichia coli endotoxin intravenously. After 30 minutes, saline infusion was started to restore and maintain baseline filling pressures. RESULTS:The loading dose of N-AC increased DO2 significantly (from 661 +/- 54 to 914 +/- 190 mL/min, P < .05), but VO2 remained stable. After the administration of endotoxin, fluid challenge restored cardiac output to baseline, in both groups. Hemoglobin and, thus, DO2 were slightly lower in the N-AC-treated dogs, but VO2 was similar in both groups. At the end of the study, O2ER was significantly higher in the N-AC-treated dogs than in the control dogs. Blood lactate levels fell more rapidly in the N-AC dogs than in the control dogs. Blood lactate levels returned to normal in the N-AC dogs but not in the control dogs. Tumor necrosis factor (TNF) also decreased significantly in the N-AC dogs but remained elevated in the control dogs. CONCLUSION/CONCLUSIONS:These data indicate that N-AC administration in endotoxic shock is well tolerated, may increase oxygen availability to the tissues, and is associated with an attenuation of TNF release.

The relative contributions of oxygen delivery (DO2) and oxygen extraction (O2ER) to the increase in cellular oxygen uptake (VO2) after cardiopulmonary bypass were studied prospectively in 36 patients after coronary artery bypass grafting (n = 18), valve replacement (n = 17), and removal of a left atrial tumor (n = 1). VO2 was calculated from the Fick equation and DO2 from thermodilution cardiac output and arterial oxygen content. During the first 24 h after cardiac surgery, there was a strong relation between VO2 and DO2 (VO2 = 28 + 0.27 x DO2, r = 0.79, P < 0.0001) but not between VO2 and oxygen extraction. Mixed venous oxygen saturation (SVO2) was usually reduced when cardiac index was below 2.0 L.min-1.m-2. Patients with a prolonged intensive care unit course (> 24 h) had lower cardiac index and lower SVO2 than the other patients. Therefore, the progressive increase in VO2 after cardiac surgery is accomplished primarily by an increase in cardiac output and DO2. It is usually when cardiac function is compromised that O2ER increases and SVO2 decreases.

OBJECTIVES/OBJECTIVE:Severe septic shock is associated with an imbalance between oxygen demand and oxygen supply (DO2) in the presence of an impaired oxygen extraction. Vasopressors are often used to restore a minimal perfusion pressure and inotropic agents are often used to increase myocardial contractility. However, optimal adrenergic support remains controversial. The present study investigated the effects of norepinephrine and dobutamine on DO2, oxygen consumption (VO2), and oxygen extraction in a dog model of endotoxic shock. DESIGN/METHODS:Prospective, randomized, cross-over trial. SETTING/METHODS:University intensive care laboratory. SUBJECTS/METHODS:A total of 14 mongrel dogs anesthetized with pentobarbital and mechanically ventilated with air. INTERVENTIONS/METHODS:The dogs received 2 mg/kg Escherichia coli endotoxin intravenously. After 30 mins, fluid administration with 0.9% saline was started to restore baseline filling pressures. The dogs randomly received dobutamine and norepinephrine. Each agent was infused for 20 mins followed by a drug free interval of 30 mins so that each dog could serve as his own control. Results for norepinephrine were grouped as low dose (0.1 and 0.2 micrograms/kg/min) and high dose (0.5 and 1.0 micrograms/kg/min). Results for dobutamine were also grouped as low dose (5 micrograms/kg/min) and high dose (10 micrograms/kg/min). MEASUREMENTS AND MAIN RESULTS/RESULTS:Norepinephrine increased both mean arterial pressure (MAP) and cardiac output without a significant change in systemic vascular resistance. Only high-dose norepinephrine increased DO2 (from 969 +/- 62 to 1240 +/- 49 mL/min [p < .001]) and VO2 (from 176 +/- 15 to 194 +/- 14 mL/min [p < .001]). Dobutamine increased both cardiac output and MAP. Both low- and high-dose dobutamine increased DO2 (from 891 +/- 91 to 1142 +/- 99 mL/min [p < .001] and from 847 +/- 54 to 1317 +/- 75 mL/min [p < .001], respectively) and VO2 (from 172 +/- 14 to 182 +/- 15 mL/min [p < .001] and from 168 +/- 13 to 184 +/- 14 mL/min [p < .001], respectively). The increase in VO2 for a given increase in DO2 was higher with high-dose norepinephrine compared with high-dose dobutamine. When all doses were taken together, DO2 increased more with dobutamine than norepinephrine. Oxygen extraction decreased with all doses for both norepinephrine and dobutamine. CONCLUSIONS:In this endotoxic shock model, both norepinephrine and dobutamine can increase DO2 and VO2 but dobutamine caused a more consistent increase in these parameters. The decrease in oxygen extraction was relatively similar with dobutamine and norepinephrine. The present study does not support a significant beneficial effect of norepinephrine on the tissue extraction capabilities in endotoxic shock.

In this pilot study, murine monoclonal anti-TNF antibody (2 mg/kg) was administered to ten patients within 24 h of septic shock which persisted after initial resuscitation with intravenous fluids and adrenergic agents. This treatment resulted in a reduction in heart rate (from 122 +/- 10 to 113 +/- 10 beats per minute at 4 h, p less than 0.01) associated with an increase in LVSWI (from 26.5 +/- 5.6 to 31.5 +/- 10.5 g.m2 at 2 h, p less than 0.05), indicating in the absence of change in cardiac filling pressures, an improvement in ventricular function. Arterial oxygenation improved concurrently in six patients. These changes, however, appeared transient. The improvement in cardiac function following anti-TNF antibody administration in patients is in keeping with recent experimental studies indicating the role of TNF in the myocardial depression characterizing septic shock.

Recent reports have shown that venous hypercarbia, resulting in a widening of the veno-arterial difference in PCO2 (dPCO2), is related to systemic hypoperfusion in various forms of low-flow state. Although septic shock usually is a hyperdynamic state, other factors can influence the CO2 production and elimination, and thus dPCO2 in septic shock This study examined the dPCO2 and acid-base balance together with cardiac output measurements and oxygen-derived variables in 64 adult patients with documented septic shock. For a total of 191 observations, a significant exponential relation between dPCO2 and CO was found. At time of first measurement, 15 patients had an increased dPCO2 (above 6 mm Hg) and a higher mixed venous PCO2 (PvCO2) (47.2 +/- 10.0 vs 35.9 +/- 7.3 mm Hg, p less than 0.001). These patients had a lower cardiac index (2.9 +/- 1.3 vs 3.8 +/- 2.0 L/min.m2, p less than 0.01), a higher oxygen extraction ratio, but a similar VO2 than patients with normal dPCO2. The higher dPCO2 could also be related to an impaired CO2 elimination as indicated by a higher PaCO2 and a lower PaO2/FIO2 in these patients. Nonsurvivors had a significantly higher dPCO2 than survivors (5.9 +/- 3.4 vs 4.4 +/- 2.3 mm Hg, p less than 0.05) in the presence of similar cardiac output. The higher dPCO2 in these patients was probably related to the higher blood lactate levels (7.7 +/- 5.3 mmol/L vs 4.5 +/- 2.8 mmol/L, p less than 0.01) and the more severe pulmonary impairment (SaO2 90 +/- 8 percent vs 95 +/- 4 percent, p less than 0.001). Arteriovenous oxygen content difference (dAVO2) and VO2 were similar in survivors and nonsurvivors. In conclusion, dPCO2 patients with septic shock is related principally to cardiac output but apparently also to the degree of pulmonary impairment. Although dPCO2 is larger in nonsurvivors, its prognostic value is modest.

Recent reports have shown that oxygen delivery (Do2) and oxygen uptake (Vo2) could be related to outcome of critically ill patients. In this study, we examined measurements of cardiac output, oxygen-derived variables, and blood lactate levels in 48 patients with documented septic shock. There were 27 survivors and 21 nonsurvivors from the shock episode. For all 174 observations, there was a significant linear relationship between Vo2 and Do2 (Vo2 = 79 + 0.17 x Do2, r = 0.64, p less than 0.001). There were no significant differences in Do2 between survivors and nonsurvivors at the onset of septic shock (mean +/- SD, 540 +/- 219 vs 484 +/- 222 ml/min.m2, NS) or in the final phase of septic shock (506 +/- 163 vs 443 +/- 187 ml/min.m2, NS). Also, no significant differences were found in Vo2 and oxygen extraction between survivors and nonsurvivors. However, survivors had significantly lower blood lactate levels both initially (5.1 +/- 2.7 vs 8.2 +/- 5.4 mmol/L, p less than 0.05) and in the final phase of septic shock (2.6 +/- 1.9 vs 7.7 +/- 5.6 mmol/L, p less than 0.001). Only the survivors had a significant decrease in blood lactate levels during the course of septic shock (p less than 0.001). We conclude that the oxygen-derived variables, Do2 and Vo2, cannot be used as prognostic indicators in human septic shock. In contrast, blood lactate levels are closely related to ultimate survival from septic shock. Furthermore, decreases in blood lactate levels during the course of septic shock could indicate a favorable outcome. Therefore, blood lactate levels can serve as a reliable clinical guide to therapy.