Donald L. Bredle

Epinephrine impairs splanchnic perfusion in septic shock

OBJECTIVE To assess the effects of epinephrine on splanchnic perfusion and splanchnic oxygen uptake in patients with septic shock. DESIGN Prospective, controlled trial. SETTING University hospital intensive care unit (ICU). PATIENTS Eight patients with septic shock, according to the criteria of the 1992 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference, requiring treatment with vasopressors. INTERVENTIONS We compared in crossover design a 2-hr infusion of epinephrine with dobutamine plus norepinephrine in eight ICU patients with septic shock. Systemic and splanchnic hemodynamics and oxygen transport were measured before and during treatment with epinephrine. MEASUREMENTS AND MAIN RESULTS There was essentially no effect of epinephrine on the global parameters, except for increased lactate concentrations. There were marked effects on the regional variables; epinephrine caused lower splanchnic flow and oxygen uptake, lower mucosal pH, and higher hepatic vein lactate. CONCLUSION We conclude that undesirable splanchnic effects on patients in whom that region is particularly fragile should be considered when using epinephrine for septic shock treatment.

High-dose vasopressin is not superior to norepinephrine in septic shock.

ObjectiveWe examined the effects of arginine vasopressin, when substituted for norepinephrine as a vasopressor in septic shock, on global and hepatosplanchnic hemodynamic and oxygen transport variables. DesignExperimental study. SettingIntensive care unit. SubjectsTwelve septic shock patients. InterventionsNorepinephrine was replaced by vasopressin in a dose sufficient to keep mean arterial blood pressure constant. Blood flow, oxygen delivery, and oxygen consumption of the hepatosplanchnic region (calculated by a hepatic venous catheter technique using the Fick principle during continuous infusion of indocyanine green), global hemodynamics (by thermodilution), and gastric regional Pco2 gap (by air tonometry) were calculated during infusion of norepinephrine (mean, 0.56 &mgr;g·kg−1·min−1; range, 0.18–1.1 &mgr;g·kg−1·min−1) and again 2 hrs after replacement by vasopressin (mean, 0.47 IU/min; range, 0.06–1.8 IU/min). Measurements and Main ResultsCardiac index decreased significantly from 3.8 ± 1.3 to 3.0 ± 1.1 L·min−1·m−2, heart rate decreased from 96 ± 14 to 80 ± 16 min−1 (p < .01), and global oxygen uptake decreased from 248 ± 67 to 218 ± 75 mL/min (p < .05). Absolute splanchnic blood flow tended to increase, although not significantly, whereas fractional splanchnic blood flow increased from 10.8 ± 7.6 to 25.9 ± 16.6% of cardiac output (p < .05). Gastric regional Pco2 gap increased from 17.5 ± 26.6 to 36.5 ± 26.6 mm Hg (p < .01). ConclusionVasopressin, in doses sufficient to replace the vasopressor norepinephrine, had mixed effects in septic shock patients. Hepatosplanchnic blood flow was preserved during substantial reduction in cardiac output. An increased gastric Pco2 gap suggests that the gut blood flow could have been redistributed to the disadvantage of the mucosa. Based on these limited data, it does not appear beneficial to directly replace norepinephrine with vasopressin in septic shock.

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 endotheliumderived relaxing factor due to an increased oxygen radical load during sepsis may contribute to an impairment in microcirculatory blood flow. We investigated whether treatment with the sulfhydryl donor and oxygen radical scavenger, N‐acetylcysteine, would improve wholebody oxygen consumption (&OV0312;o2), gastric intramucosal pH, and veno‐arterial CO2 gradient (veno‐arterial Pco2) during septic shock. Design: Prospective, randomized, doubleblind study conducted over 2 yrs. Setting: Septic shock patients admitted to the intensive care unit. Patients: Fifty‐eight patients requiring hemodynamic 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 stable clinical conditions (hemodynamic values, body temperature, hemoglobin, Fio2). Interventions: A gastric tonometer was inserted to measure the gastric intramucosal pH. Subjects randomly received either 150 mg/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 placebo over ˜90 mins. Measurements: Infusion measurements were begun 60 mins after the beginning of infusion and lasted ˜30 mins. The infusion was then discontinued and 2 hrs later the final measurements were taken. Main Results: Basic patient characteristics (age, sex, Acute Physiology and Chronic Health Evaluation [APACHE] II scores, Multiple Organ Failure scores) did not differ significantly, nor did pre‐ and 2‐hr postinfusion measurements differ between any of the groups. Thirteen (45%) patients responded (i.e., showed an increase in &OV0312;o2 >10%, reaching a mean of 19%) to the N‐acetylcysteine infusion. The N‐acetylcysteine responders also showed an increase in gastric intramucosal pH, a decrease in veno‐arterial Pco2, an increase in oxygen delivery, cardiac index, stroke index, and left ventricular stroke work index, as well as a significant decrease in systemic vascular resistance in comparison to baseline. The N‐acetylcysteine nonresponders, as well as the patients in the placebo group, did not show any significant changes in any of these variables. The N‐acetylcysteine responders had 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‐acetylcysteine group (which included responders plus nonresponders) and the placebo group was an increased &OV0312;o2 in the entire N‐acetylcysteine group during infusion measurements. Conclusions: N‐acetylcysteine provided a transient improvement in tissue oxygenation in about half of the septic shock patients, as indicated by an increase in &OV0312;o2 and gastric intramucosal pH and a decrease in veno‐arterial Pco2. The higher survival rate in the N‐acetylcysteine responders and the fact that half of the 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 intention to treat, the N‐acetylcysteine did not produce effects that were significantly different from the placebo. Whether the N‐acetylcysteine challenge was merely diagnostic or whether N‐acetylcysteine can be effective in the treatment of sepsis deserves further investigation. (Crit Care Med 1994; 22:1738–1746)

Dopexamine increases splanchnic blood flow but decreases gastric mucosal pH in severe septic patients treated with dobutamine

OBJECTIVE To assess the effects of dopexamine on splanchnic blood flow and splanchnic oxygen uptake in septic patients. DESIGN A prospective, controlled trial. SETTING A ten-bed intensive care unit (ICU) in a university hospital. PATIENTS Twelve patients with severe sepsis (according to the criteria of the 1992 American College of Chest Physicians/Society of Critical Care Medicine consensus conference) being stabilized by volume loading and treated to an elevated oxygen delivery by dobutamine infusion. INTERVENTIONS Infusion of increasing dosages of dopexamine (0.5, 1.0, 2.0, and 4.0 microg/kg/min). MEASUREMENTS AND MAIN RESULTS Systemic and splanchnic hemodynamic and oxygen transport parameters as well as gastric mucosal pH (pHi) were measured. A hepatic venous catheter technique with indocyanine green dye dilution was used to determine splanchnic blood flow. Dopexamine increased global and splanchnic oxygen delivery without affecting oxygen consumption (VO2). Splanchnic blood flow increased proportionally to cardiac output, indicating that there was no selective effect of dopexamine on the splanchnic flow. Dopexamine decreased pHi in a dose-dependent fashion in all 12 patients. CONCLUSIONS In hemodynamically stable, hyperdynamic septic patients being treated with dobutamine, dopexamine has no selective effect on splanchnic blood flow. In fact, a decreased pHi suggests a harmful effect on gastric mucosal perfusion.

Total plasma antioxidant capacity is not always decreased in sepsis

OBJECTIVE To compare total plasma antioxidant capacity and selected individual antioxidants in patients with varying degrees of severity of sepsis. DESIGN A prospective, observational, consecutive case study. SETTING A 16-bed intensive care unit (ICU) in a university teaching hospital. INTERVENTIONS None. PATIENTS Forty-six healthy controls, ten ICU patients, nine patients with systemic inflammatory response syndrome (SIRS), 11 septic patients, and 14 septic shock patients. Plasma was obtained in healthy patients scheduled for minor surgery immediately before anesthesia and in ICU patients within 24 hrs of admittance to the unit or diagnosis of SIRS, sepsis, or septic shock. MEASUREMENTS AND MAIN RESULTS Using the total peroxyl radical trapping method, we found plasma antioxidant capacity to be lower in septic patients but higher in septic shock patients, as compared with controls. Bilirubin was the greatest contributor to the increase with shock, followed by uric acid. Neopterin also correlated with the peroxyl radical trapping antioxidant parameter values. CONCLUSION Although total plasma antioxidant capacity is decreased from normal levels in septic patients, an increase in some oxidants contributes to an increased total antioxidant capacity in septic shock patients.

Hypertonic saline in stabilized hyperdynamic sepsis.

Hypertonic saline with or without colloidal solution has been successfully used for treating hemorrhagic shock in animal experiments and clinical studies. Due to its various effects at systemic, organ, and microcirculatory levels, the substance appears to be a promising candidate for improving tissue oxygenation in sepsis. We therefore investigated the hypothesis that infusion of hypertonic saline would further improve O2 delivery, O2 extraction, and O2 uptake in hyperdynamic septic shock patients already stabilized by adequate volume and catecholamine infusion. Twenty-one patients received 2–4 mL/kg body weight of hypertonic saline in hydroxyethyl starch within 15 min. This hypertonic saline infusion caused a rapid significant increase in O2 delivery by 14% but only a marginal increase in O2 consumption (7% by cardiovascular Fick [p < .05], 4% by respiratory gases [n.s.]). Hypertonic saline increased the already elevated cardiac output by 24%. The pulmonary capillary wedge pressure increased from 14 ± 3 to 23 ± 3 mmHg and pulmonary shunt fraction increased 15%, but arterial PO2 did not fall. Except for the increase in pulmonary capillary wedge pressure, none of the cardiovascular changes lasted longer than 60 min. Plasma sodium levels increased from 138 ± 25 to 163 ± 38 mmol/L and normalized within 24 h. In these hyperdynamic septic patients, hypertonic saline infusion produced a transient increase in circulation, but no evidence of a substantial increase in O2 consumption. Either there was no significant O2 debt due to the already elevated O2 delivery levels at baseline (700 mL/min/m2) or the global O2 measurements we used were not able to detect discrete regional hypoxia.

Systemic and muscle oxygen uptake/delivery after dopexamine infusion in endotoxic dogs.

Background and MethodsThis study was designed to test whether dopexamine, a dopaminergic and β2-adrenergic agonist, would a) increase systemic oxygen delivery (Do2) in endotoxic dogs, and b) interfere with the ability of resting skeletal muscle to extract oxygen. There were three treatment groups (n = 6 in each group): control, endotoxin alone (E) 4 mg/ kg iv, and endotoxin + dopexamine (E + D) 12 μg/kg-min. Data were analyzed between and within groups by split-plot analysis of variance with significance of identified differences tested post hoc by Duncans multiple range test. Donor RBC and dextran were used after endotoxin to maintain adequate perfusion pressures, with Hct kept near 40%. Blood flow to left hindlimb muscles was decreased in controlled steps of 15 min each after stabilization. ResultsIn E group, cardiac output (Qt), mean arterial pressure (MAP), systemic Do2, and oxygen uptake (Vo2) decreased despite blood volume expansion. In E + D group with similar volume expansion, dopexamine maintained Qt, systemic Do2, and Vo2 near the control levels, although MAP and systemic vascular resistance were reduced. In comparison with control subjects, endotoxin increased critical Do2 in the isolated limb muscles from 4.6 to 7. mL/kg-min and decreased critical oxygen extraction from 81% to 68%. The pressure/flow relationship in the limb became flattened, indicating loss of vascular reactivity. In the E + D group, there was no further change in the pressure/flow curve nor in the critical oxygen extraction level. ConclusionsDopexamine provided hemodynamic support for endotoxic dogs, thereby increasing total DO2 and VO2, while not altering oxygen extraction in the muscle. (Crit Care Med 1991: 19:198)