Effects of dopamine on systemic and regional blood flow and metabolism in septic and cardiac surgery patients

Dopamine is used in the clinical setting to support cardiac output and blood pressure and to improve diuresis. Experimental studies suggest that dopamine may reduce splanchnic perfusion and redistribute blood flow locally. To assess the effects of dopamine on splanchnic perfusion, we used dopamine to increase cardiac output by 25% in nine septic patients and 11 patients after cardiac surgery. Systemic (pulmonary artery catheter) and splanchnic (hepatic vein catheter and dye dilution) hemodynamics and oxygen transport were measured at baseline and 90 min after increasing the cardiac output. Dopamine infusion [in cardiac surgery patients 4.2 (1.4-8.5) microg x kg(-1) x min(-1) (median, range) and in septic patients 4.0 (2.1-9.0) microg x kg(-1) x min(-1)] increased splanchnic blood flow in cardiac surgery patients from 0.61 (0.13) L x min(-1) x m(-2) to 0.82 (0.13) L x min(-1) x m(-2) [mean (standard deviation; SD); P = 0.018] and in septic patients from 0.91 (0.32) L x min(-1) x m(-2) to 1.12 (0.40) L x min(-1) x m(-2) (P = 0.038). Splanchnic oxygen consumption increased in cardiac surgery patients from 39 (5) mL x min(-1) x m(-2) to 46 (6) mL x min(-1) x m(-2) (P = 0.003) but decreased in septic patients from 61 (19) mL x min(-1) x m(-2) to 51 (17) L x min(-1) x m(-2) (p = 0.021). Because of the unexpected results, we compared these data post hoc with data obtained from another group of 15 septic patients with acute lung injury, where dobutamine was used to increase cardiac output in a similar design. Dobutamine in these patients [6.4 (4.2-9.5) microg x kg(-1) x min(-1)] increased splanchnic blood flow from 1.20 (0.44) L x min(-1) x m(-2) to 1.43 (0.57) L x min(-1) x m(-2) (P = 0.008), while splanchnic oxygen consumption did not change 72 (25) mL x min(-1) x m(-2) vs. 76 (22) mL x min(-1) x m(-2) (not significant)]. The reduction of splanchnic oxygen consumption by dopamine in sepsis suggests an impairment of hepatosplanchnic metabolism despite an increase in regional perfusion. The safety and indications of dopamine use in sepsis should be re-evaluated.     

N-acetylcysteine increases liver blood flow and improves liver function in septic shock patients: results of a prospective, randomized, double-blind study

OBJECTIVE: In septic shock, decreased splanchnic blood flow is reported, despite adequate systemic hemodynamics. Aacetylcysteine (NAC) was found to increase hepatosplanchnic blood flow in experimental settings. In septic shock patients, NAC improved the clearance of indocyanine green and the relationship of systemic oxygen consumption to oxygen demand. We investigated the influence of NAC on liver blood flow, hepatosplanchnic oxygen transport-related variables, and liver function during early septic shock. DESIGN: Prospective, randomized, double-blind study. SETTING: Septic shock patients admitted to an interdisciplinary surgical intensive care unit. PATIENTS: We examined 60 septic shock patients within 24 hrs after onset of sepsis. They were conventionally resuscitated with volume and inotropes and were in stable condition. A gastric tonometer was inserted into the stomach and a catheter into the hepatic vein. Microsomal liver function was assessed by using the plasma appearance of monoethylglycinexylidide (MEGX). INTERVENTIONS: Subjects randomly received either a bolus of 150 mg/kg iv NAC over 15 mins and a subsequent continuous infusion of 12.5 mg/kg/hr NAC over 90 mins (n = 30) or placebo (n = 30). MEASUREMENTS AND MAIN RESULTS: Measurements were performed before (baseline) and 60 mins after beginning the infusion (infusion). After NAC, a significant increase in absolute liver blood flow index (2.7 vs. 3.3 L/min/m2; p = .01) and cardiac index (5.0 vs. 5.7 L/min/m2; p = .02) was observed. Fractional liver blood flow index (cardiac index-related liver blood flow index) did not change. The difference between arterial and gastric mucosal carbon dioxide tension decreased (p = .05) and MEGX increased (p = .04). Liver blood flow index and MEGX correlated significantly (r(s) = .57; p < or = .01). CONCLUSIONS: After NAC treatment, hepatosplanchnic flow and function improved and may, therefore, suggest enhanced nutritive blood flow. The increase of liver blood flow index was not caused by redistribution to the hepatosplanchnic area, but by an increase of cardiac index. Because of its correlation with liver blood flow index, MEGX may be helpful in identifying patients who benefit from NAC treatment in early septic shock.     

Impact of exogenous beta-adrenergic receptor stimulation on hepatosplanchnic oxygen kinetics and metabolic activity in septic shock

OBJECTIVE: To investigate the impact of exogenous beta-adrenergic receptor stimulation on splanchnic blood flow, oxygen kinetics, glucose-precursor flux, and liver metabolism in septic shock. DESIGN: Prospective trial. SETTING: University hospital intensive care unit. PATIENTS: Six patients with hyperdynamic (cardiac index >4.0 L/min/m2) septic shock, all requiring norepinephrine to maintain blood pressure >65 mm Hg. INTERVENTIONS: We compared norepinephrine and phenylephrine titrated to achieve similar systemic hemodynamics and gas exchange. Splanchnic hemodynamics, oxygen kinetics, and metabolic parameters were measured before, during, and after replacing norepinephrine with phenylephrine. MEASUREMENTS AND MAIN RESULTS: Splanchnic blood flow and oxygen kinetics were derived from the steady-state indocyanine-green clearance based on hepatic dye extraction and arterial and hepatic venous blood gases. Endogenous glucose production rate was derived from the plasma appearance rate of stable-isotope-labeled glucose using a primed-constant infusion. Splanchnic lactate, alanine (high-performance liquid chromatography) uptake, and hepatic monoethylglycinexylidide (MEGX) (fluorescence polarization immunoassay) formation rates were calculated from splanchnic blood flow and arterial-hepatic venous concentration differences. Replacing norepinephrine with phenylephrine induced no change in systemic hemodynamics or gas exchange. While splanchnic oxygen consumption and alanine uptake rate remained unaffected, splanchnic blood flow, oxygen delivery, and lactate uptake rate were significantly decreased. Glucose production rate also decreased significantly. A return to norepinephrine restored splanchnic blood flow, oxygen delivery, and lactate uptake rate to baseline values, while glucose production rate remained depressed. Hepatic MEGX formation rate was not influenced during the investigation. CONCLUSIONS: Exogenous beta-adrenergic receptor stimulation determines splanchnic blood flow, oxygen delivery, and glucose precursor flux but not splanchnic oxygen utilization in septic shock. Gluconeogenesis is not directly affiliated to hepatosplanchnic oxygen kinetics. The different response of glucose and MEGX production rates, metabolic pathways of the periportal and perivenous region, may document intrahepatic heterogeneity associated with hepatocellular metabolic compartmentation.     

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

OBJECTIVE: We 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. DESIGN: Experimental study. SETTING: Intensive care unit. SUBJECTS: Twelve septic shock patients. INTERVENTIONS: Norepinephrine 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 microg.kg-1.min-1; range, 0.18-1.1 microg.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 RESULTS: Cardiac 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). CONCLUSION: Vasopressin, 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.     

Hepato-splanchnic metabolic effects of the stable prostacyclin analogue iloprost in patients with septic shock

OBJECTIVE: To evaluate the effects of the stable prostacyclin analogue iloprost on hepato-splanchnic blood flow, oxygen exchange and metabolism in patients with septic shock. DESIGN: Prospective clinical study. SETTING: Intensive care unit in a university clinic. PATIENTS: Eleven patients with septic shock requiring norepinephrine to maintain mean arterial pressure above 70 mmHg. INTERVENTIONS: Iloprost was incrementally infused to increase cardiac index by 15%. MEASUREMENTS AND MAIN RESULTS: Splanchnic blood flow (Qspl) was measured using the steady-state indocyanine-green infusion technique and endogenous glucose production rate (EGP) using a stable isotope approach. Systemic and splanchnic oxygen consumption (VO2), the hepato-splanchnic uptake rates of the glucose precursors lactate, pyruvate, alanine and glutamine, the hepatic venous redox state and gastric mucosal-arterial PCO2 gradients were determined. After a baseline measurement, iloprost infusion was started. After 90 min all measurements were repeated and a third measurement was obtained after another 90 min following iloprost withdrawal. Qspl (baseline I: 0.82/0.75-1.08 l x min x m2; iloprost: 0.94/0.88-1.29 l x min x m2; baseline II: 0.87/0.74-1.09 l x min x m2) and splanchnic oxygen delivery (baseline I: 122/103-166 ml x min x m2; iloprost: 134/117-203 ml x min x m2; baseline II: 130/98-158 ml x min x m2) significantly increased. While systemic VO2 significantly increased (baseline I: 139/131-142 ml x min x m2; iloprost: 147/136-164 ml x min x m2; baseline II: 143/133-154 ml x min x m2) splanchnic VO2 increased in 9 of 11 patients which, however, did not reach statistical significance. EGP significantly decreased (baseline I: 23/16-26 micromol x kg x min; iloprost: 16/14-21 micromol x kg x min; baseline II: 18/12-20 micromol x kg x min), whereas all other parameters of energy metabolism remained unchanged. CONCLUSION: In patients with septic shock an iloprost-induced increase in cardiac index increased splanchnic blood flow and shifted oxygen utilization from the energy requiring de novo glucose production rate to other oxygen-demanding metabolic pathways.     

Effects of dopamine and norepinephrine on systemic and hepatosplanchnic hemodynamics, oxygen exchange, and energy balance in vasoplegic septic patients

Dopamine is widely used to improve systemic and hepatosplanchnic hemodynamics and oxygenation during sepsis. However, some studies have suggest that norepinephrine may have beneficial effects on regional blood flow and metabolism, whereas dopamine might have deleterious effects related to redistribution of blood flow away from the intestinal mucosa or by decreasing directly the cell redox state. In 12 vasoplegic septic patients, we compared the effects of norepinephrine and dopamine on systemic and hepatosplanchnic hemodynamics, oxygenation, and energy metabolism. Catecholamines were administered in a crossover randomized order to maintain mean arterial pressure (MAP) at 80 mmHg. Hepatosplanchnic blood flow (Qspl) was determined using a continuous infusion of indocyanine green dye. Despite a similar MAP, the cardiac index was higher with dopamine than with norepinephrine (6.3 [5.3-7.3] vs. 4.3 [3.8-4.9] L.min.m) (P <0.001). Qspl was similar with both catecholamines, but the ratio of Qspl to cardiac output was significantly lower with dopamine (23.9% [17.5-33.5]) than with norepinephrine (33.5% [25.8-37]) (P <0.05). Although global O2 delivery and O2 consumption were higher with dopamine (782 [707-859] vs. 553 [512-629] mL.min.m, P <0.001 and 164 [134-192] vs. 128 [111-149] mL.min.m, P <0.001, respectively), hepatosplanchnic O2 delivery and consumption were not different. Hepatic lactate uptake was lower (0.47 [0.3-0.89] vs. 1.01 [0.69-1.34] mmol.min) (P <0.01), and hepatic venous lactate-to-pyruvate ratio was higher (15.3 [7.6-21.1] vs. 11.2 [6.6-15.1], P <0.05) with dopamine than with norepinephrine. In vasoplegic septic patients, maintaining mean arterial pressure, hepatosplanchnic hemodynamics, and oxygen exchange with dopamine requires a consequent increased cardiac output, which is responsible for an increased global oxygen demand when compared with norepinephrine. In addition, dopamine impairs the hepatic energy balance. Its position as a preferential treatment compared with norepinephrine in this context may therefore be questionable.     

Endotoxic shock alters the pharmacokinetics of lidocaine and monoethylglycinexylidide

Significant hepatic dysfunction occurs following endotoxin administration. Although the metabolism of lidocaine to one of the primary metabolites of lidocaine, monoethylglycinexylidide (MEGX), has been used as a marker of hepatic function under various conditions, it remains unknown whether these compounds can be used in vivo to evaluate hepatic function in a rat model of endotoxic shock. To study this, cytochrome P450-3A4 (CYP3A4) was determined after harvesting hepatic microsomes, hepatic blood flow was determined using radioactive microspheres, and the pharmacokinetics of lidocaine and MEGX were evaluated. Adult male Sprague-Dawley rats were divided into endotoxin (45 mg/kg, intraperitoneally; n = 28) or control (n = 32) groups. The CYP3A4 was significantly reduced after endotoxic shock. Carboxylesterase (hydrolase S) content, which was used as a control for microsomal protein, was not significantly different between groups. Total hepatic blood flow was significantly decreased (36.2 +/- 8.4 mL/min/100 g tissue vs. 120.4 +/- 10.6 mL/min/100 g tissue), which was due to the decreased portal blood flow. For the lidocaine and MEGX experiment, lidocaine (2 mg/kg) was administered followed by serial blood samples collected up to 2 h for determination of serum lidocaine and MEGX concentrations. Mean arterial pressure (MAP) was recorded throughout the experiment. The MAP was significantly lower in the endotoxin treated rats vs. control 7.5 to 8 h following endotoxin administration. Serum concentrations of lidocaine were higher in endotoxic shock versus control animals at 2 h following lidocaine administration (1.5 +/- 0.13 mg/L vs. 0.11 +/- 0.03 mg/L). Similarly, MEGX concentrations were significantly higher in endotoxic shock versus control animals (0.55 +/- 0.04 mg/L vs. 0.16 +/- 0.02, respectively) under such conditions. These data demonstrate that the elimination of lidocaine and MEGX is impaired during endotoxic shock. The elevated lidocaine and MEGX concentrations are likely to be the result of primarily reduced hepatic blood flow and secondarily due to impaired CYP450, one of which was CYP3A4. The reduced elimination of MEGX concentrations is not due to decreased hepatic metabolism of the compound via carboxylesterase. The ratio of MEGX to lidocaine concentrations, which decreased significantly following endotoxic shock, appears to be a useful measure of hepatic function during endotoxic shock where profound reductions of hepatic blood flow are observed in addition to significant reductions in CYP450. The use of only MEGX concentrations in this endotoxic shock model is not useful in evaluating liver function.     

Effects of the phosphodiesterase III inhibitors olprinone, milrinone, and amrinone on hepatosplanchnic oxygen metabolism

OBJECTIVE: To measure the hepatic venous oxygen saturation in patients after cardiac surgery and to compare the effects of olprinone (OLP), a newly synthesized phosphodiesterase III inhibitor, with those of milrinone (MIL) and amrinone (AMR) on hepatosplanchnic oxygen dynamics. Phosphodiesterase III inhibitors are used to improve the hemodynamic state after cardiac surgery. However, the effect of these agents on the hepatosplanchnic circulation has not been investigated thoroughly. DESIGN: Prospective, randomized study. SETTING: University hospital intensive care unit (ICU). PATIENTS: Twenty-nine patients undergoing elective cardiac surgery. MEASUREMENTS AND MAIN RESULTS: In each patient, a 7.5-Fr oximeter catheter was placed in the hepatic vein via the right femoral vein. Catheterization was completed before admission to the ICU, and the study was performed 8 to 24 hrs after surgery, after obtaining stable systemic hemodynamics in the ICU. The patients were assigned randomly to three groups, and they received one of three drugs for 2 hrs (OLP group, 0.3 microg/kg/min of OLP; MIL group, 0.5 microg/kg/min of MIL; AMR group, 10 microg/kg/min of AMR). The authors did not change the patient's hemodynamic interventions, including catecholamines and vasodilators, throughout the study period. Arterial and hepatic venous blood gas data and hemodynamic data (via a pulmonary artery catheter) were obtained before and after drug infusion. Using these data, the authors calculated systemic oxygen delivery and consumption, the systemic oxygen extraction ratio and the hepatosplanchnic oxygen extraction ratio, and the change in hepatosplanchnic blood flow using Fick's equation. Although the increases in cardiac index were not significantly different among the three groups, hepatic venous oxygen saturation increased significantly only in the OLP group (from 47.1% +/-2.6% to 57.0% +/- 1.5% in the OLP group, from 48.4% +/- 2.3% to 50.9% +/- 2.6% in the MIL group, and from 49.8% +/- 3.6% to 50.8% + +/-.7% in the AMR group). The calculated hepatosplanchnic blood flow change was significantly larger in the OLP group than in the other groups (30.1% +/- 5.7% in the OLP group, 9.3% +/- 5.1% in the MIL group, and 2.6% +/- 6.5% in the AMR group). CONCLUSIONS: These results suggest that OLP enhances hepatosplanchnic blood flow and thus may be beneficial in protecting the hepatosplanchnic organs after cardiac surgery.     

Hepatic and splanchnic oxygen consumption during acute hypoxemic hypoxia in anesthetized pigs

OBJECTIVE: To compare the hepatosplanchnic oxygen consumption (VO2) with the hepatic and splanchnic VO2 and to calculate the critical oxygen delivery (DO2crit) below which VO2 decreases in the hepatic, splanchnic, and hepatosplanchnic regions in a model of hypoxemic hypoxia. DESIGN: Prospective animal study. SETTING: University research laboratory. SUBJECTS: Anesthetized and ventilated pigs (n = 7). INTERVENTIONS: The right carotid artery was cannulated to measure mean arterial pressure. A pulmonary artery catheter was inserted to measure mean pulmonary arterial pressure and cardiac output. After a midline abdominal incision, two flow probes were positioned around the portal vein and the hepatic artery to measure portal vein blood flow and hepatic artery blood flow. Oxygen and lactate contents in the carotid artery, the portal vein, and the hepatic vein were measured in blood samples obtained from the appropriate catheters. MEASUREMENTS AND MAIN RESULTS: After a 2-hr stabilization period, hemodynamic and biological variables were recorded during acute hypoxemic hypoxia (FIO2 = 0.5, 0.4, 0.3, 0.21, 0.15, 0.10, and 0.07). VO2, DO2, and DO2crit were determined in the hepatic, splanchnic, and hepatosplanchnic regions. The hepatosplanchnic VO2 was 48 +/- 5 mL/min at high FIO2 (40% for the liver and 60% for the splanchnic organs) and decreased below FIO2 of 0.15. Lactate uptake in the whole hepatosplanchnic region remained steady at FIO2 values of 0.5 to 0.15 and then switched to a lactate release at low FIO2. However, the splanchnic region released lactate, whereas lactate was taken up by the liver. DO2crit in the hepatic, splanchnic, and hepatosplanchnic regions was 24 +/- 3, 38 +/- 2, and 49 +/- 4 mL/min, but the systemic DO2crit, below which regional VO2 became oxygen supply dependent, did not differ in the liver, splanchnic, and hepatosplanchnic regions. CONCLUSIONS: The variables of oxygenation and lactate flux measured in the hepatosplanchnic region summarize the metabolic changes of various organs that may vary in different ways during hypoxemic hypoxia.     

The hepatosplanchnic contribution to hyperlactatemia in endotoxic shock: effects of tissue ischemia

We investigated the role of the hepatosplanchnic region in the hyperlactatemia observed during endotoxic shock. The study included 18 dogs anesthetized with pentobarbital and mechanically ventilated. After baseline measurements, including gut lactate production (GLP), liver lactate uptake (LLU), liver lactate extraction (LLE), and hepatosplanchnic lactate production (HSLP), each dog received 2 mg/kg of E. coli endotoxin. After a second set of measurements, cardiac tamponade was induced in 12 dogs (EDTX + Tamp) by repeated injections of normal saline into the pericardial sac to progressively reduce cardiac output and hepatic blood flow. The six remaining dogs served as septic controls (EDTX). From a net lactate consumer before endotoxin infusion, the gut became a lactate producer after the endotoxin infusion, with GLP increasing from -11.4 +/- 27.0 to 32.9 +/- 38.2 x 10(-3) mEq/min (P < 0.05). LLU increased from 48.1 +/- 26.2 to 86.6 +/- 45.2 x 10(-3) mEq/min (P < 0.05), so that LLE and HSLP did not change. In the EDTX + Tamp group, LLE became negative, and HSLP became positive only when hepatic oxygen delivery reached its critical value during cardiac tamponade. In the EDTX group, LLE remained positive and HSLP negative. In endotoxic shock, GLP is increased, but the liver can metabolize this additional load of lactate, so that the hepatosplanchnic area is not a major source of lactate unless the liver becomes profoundly hypoxic.     

Prevention of systemic hyperlactatemia during splanchnic ischemia

Arterial blood lactate increases as a result of poor tissue perfusion. In splanchnic hypoperfusion, increased hepatic lactate uptake may delay increases in arterial blood lactate. We hypothesized that during isolated reduction of mesenteric blood flow, maintaining systemic blood volume and flow by fluid resuscitation may prevent systemic hyperlactatemia and therefore mask splanchnic ischemia. In a randomized study, 7 pigs were subjected to 4 h of splanchnic hypoperfusion by reducing the superior mesenteric artery blood flow to 4 +/- 0.8 mL/kg min [mean +/- standard deviation (SD)]. Seven pigs served as controls. Fluid was administered in order to keep the pulmonary artery occlusion pressure at 5 to 8 mm Hg. Cardiac output, portal vein, superior mesenteric, and hepatic arterial blood flow were measured every 30 min. Arterial, mixed venous, hepatic, portal, and mesenteric venous blood lactate, and jejunal mucosal pCO2 were measured at baseline and thereafter at 30-min intervals. The initial decrease in portal venous blood flow in the ischemic animals was subsequently counterbalanced by increasing hepatic arterial blood flow from 2 +/- 1 mL x kg(-1) x min(-1) at baseline to 11 +/- 4 mL x kg(-1) x min(-1) [after 4 h of ischemia; mean +/- standard deviation (SD), P = 0.02]. Jejunal mucosal- and mesenteric vein-arterial pCO2 gradients increased in the ischemic group from 11 +/- 8 mm Hg to 73 +/- 5 mm Hg (P = 0.02), and from 10 +/- 4 mm Hg to 44 +/- 8 mm Hg, respectively (P = 0.02). Mesenteric and portal venous lactate increased in the ischemic animals from 1.1 +/- 0.3 mmol/L to 4.2 +/- 1.0 mmol/L (P = 0.02), and from 1.0 +/- 0.2 mmol/L to 1.6 +/- 0.3 mmol/L, respectively (P = 0,03). While mesenteric lactate production and hepatic lactate uptake increased in parallel in the ischemic animals from 5 +/- 6 micromol x kg(-1) x min(-1) to 14 +/- 5 micromol x kg(-1) x min(-1) (P = 0.04), and from 14 +/- 7 micromol x kg(-1) x min(-1) to 24 +/- 6 micromol x kg(-1) x min(-1), respectively (P = 0.02), hepatic venous and arterial lactate, and apparent splanchnic lactate uptake and extraction did not change. We conclude that the hepatic lactate uptake increases in response to hepatic lactate influx. Systemic hyperlactatemia and increased hepatic venous lactate concentrations are late consequences of mesenteric hypoperfusion if hypovolemia is prevented. The net exchange of lactate across the splanchnic region does not reflect hepato-portal lactate kinetics in this animal model of intestinal hypoperfusion.     

Splanchnic perfusion during hemodialysis: evidence for marginal tissue perfusion.

OBJECTIVE: Splanchnic perfusion may be compromised during hemodialysis because of hypovolemia, inflammatory response, and blood flow redistribution. The aim of this study was to assess the response of splanchnic blood flow and oxygen transport to hemodialysis. DESIGN: A prospective clinical study. SETTING: A mixed medical-surgical intensive care unit in a university hospital. PATIENTS: Nine patients with acute renal failure. INTERVENTIONS: A 4-hr period of hemodialysis. MEASUREMENTS AND MAIN RESULTS: Systemic (via a pulmonary artery catheter), hepatosplanchnic, and femoral (via dye dilution) blood flow and gastric mucosal Pco2 were measured before, during, and 2 hrs after hemodialysis. During hemodialysis, despite unchanged arterial blood pressure, cardiac output and stroke volume decreased from 3.0 +/- 1.0 L/m2/min (mean +/- sd) to 2.3 +/- 0.7 L/m2/min (p =.02), and from 38 +/- 16 mL/m2/min to 28 +/- 12 mL/m2/min (p =.01), respectively. Splanchnic but not femoral blood flow decreased from 0.9 +/- 0.3 L/m2/min to 0.7 +/- 0.2 L/m2/min (p =.02). The blood flows returned to baseline values after dialysis without need for therapeutic interventions. Gastric mucosal-arterial Pco2 gradients were high before dialysis (35 +/- 23 torr [4.6 +/- 3.1 kPa]) and did not change. Renin but not atrial natriuretic peptide concentration increased during hemodialysis from 13 +/- 13 microg/L to 35 +/- 40 microg/L and decreased afterward to baseline values (13 +/- 13 microg/L; p =.01). Whereas interleukin 6 tended to decrease, tumor necrosis factor alpha increased during hemodialysis from 74 +/- 24 pg/mL to 86 +/- 31 pg/mL and continued to increase after hemodialysis to 108 +/- 66 pg/mL (p =.022). CONCLUSION: Hemodialysis and fluid removal in normotensive patients with acute renal failure may result in a reduction of systemic and splanchnic blood flow that is undetectable using traditional clinical signs. In contrast to what is observed in hypovolemia, the changes in regional blood flow are rapidly reversible after hemodialysis.     

N-acetylcysteine decreases lactate signal intensities in liver tissue and improves liver function in septic shock patients, as shown by magnetic resonance spectroscopy: extended case report

Background

N-acetylcysteine (NAC) has been shown to improve splanchnic blood flow in experimental studies. This report evaluates the effects of NAC on liver perfusion and lactate signal intensities in the liver tissue of septic shock patients using proton magnetic resonance imaging and spectroscopy. Furthermore, the monoethylglycinexylidide (MEGX) test was used to investigate hepatic function.

Methods

Five septic shock patients received 150 mg/kg body weight NAC as an intravenous bolus injection over 15 min. Lidocaine was injected both prior to and following NAC administration in order to determine MEGX formation. Measurements (hemodynamics, oxygen transport-related variables, blood samples for lactate, liver-related markers) were performed 1 hour before and 1 hour after NAC injection. In addition to the proton magnetic resonance imaging patients received two proton magnetic resonance spectra, one prior to and one 30 min subsequent to the onset of the NAC infusion at a 1.5 Tesla clinical scanner, for measurement of liver perfusion and liver lactate signal intensity.

Main findings

Following NAC infusion, the lactate signal intensity in the liver tissue showed a median decrease of 89% (11–99%), there was a median increase in liver perfusion of 41% (-14 to 559%), and the MEGX serum concentration increased three times (1.52–5.91).

Conclusions

A decrease in the lactate signal intensity in the liver tissue and an increase in the MEGX serum concentration and in liver perfusion might indicate improved liver function as a result of NAC administration. Patients with compromised hepatosplanchnic function, such as patients with septic shock due to peritonitis, may therefore benefit from NAC therapy.     

Gastric-arterial PCO2 gradient does not reflect systemic and splanchnic hemodynamics or oxygen transport after cardiac surgery

Gastric mucosal-arterial PCO2 gradient (P(g-a)CO2) is used to assess splanchnic perfusion and oxygenation. We evaluated whether P(g-a)CO2 reflects whole body (Q) and splanchnic (Qsp) blood flow, oxygen delivery (DO2) and consumption (VO2) after coronary artery by pass graft (CABG) operation. Thirty patients received dobutamine or dopexamine to increase cardiac index, 15 patients enalapril or sodium nitroprusside to lower blood pressure, and 30 patients were controls. We measured Q, Qsp (hepatic vein catheter and indocyanine green), and gastric mucosal PCO2 (nasogastric tonometer) before and after interventions. Multiple linear regression model showed that none of the changes in Q, Qsp, and splanchnic or systemic DO2 and VO2 significantly explained changes in P(g-a)CO2 (deltaP(g-a)CO2). All independent variables together explained only 7% of deltaP(g-a)CO2. Increased splanchnic blood flow (0.65 +/- .19 vs. 0.94 +/- .31 L/min/m2, P < 0.001) and increased splanchnic DO2 (101 +/- 28 vs. 143 +/- 42 mL/min/m2, P < 0.001) during catecholamine infusions were associated with increased P(g-a)CO2 (8 +/- 8 vs. 11 +/- 7 mmHg, P = 0.003). P(g-a)CO2 does not reflect whole body or splanchnic blood flow, DO2 or VO2 after CABG operations. The physiology of P(g-a)CO2 is complex and therefore it is difficult for clinicians to interpret changes in gastric mucosal-arterial PCO2 gradient in individual patients after cardiac surgery.     

Differential effect of chronic renal failure on the pharmacokinetics of lidocaine in patients receiving and not receiving hemodialysis

BACKGROUND AND OBJECTIVES: The effect of chronic renal failure (CRF) on the pharmacokinetics of lidocaine, a drug cleared almost exclusively by hepatic metabolism, has thus far only been evaluated in patients undergoing regular hemodialysis. This study had 2 objectives: (1) to investigate the effect of CRF on the pharmacokinetics of lidocaine in both patients undergoing hemodialysis and patients not undergoing hemodialysis and (2) to test the effects of plasma from the patients examined and of lidocaine metabolites possibly accumulated in vivo on lidocaine biotransformation in vitro. METHODS: In a clinical investigation we studied the kinetics of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), after intravenous injection of 1 mg/kg lidocaine in 15 healthy volunteers (creatinine clearance [CL(cr)] >80 mL/min x 1.73 m(-2)), 10 subjects with moderate renal insufficiency (CL(cr) between 30 and 60 mL/min x 1.73 m(-2)), 10 subjects with severe renal insufficiency (CL(cr) <30 mL/min x 1.73 m(-2)), and 10 functionally anephric patients undergoing long-term hemodialysis. In experiments in vitro we determined the effects of plasma and GX on the formation rate of the primary lidocaine metabolite, MEGX, by use of human liver microsomes. RESULTS: In patients not undergoing hemodialysis, lidocaine kinetic parameters were altered in proportion to the degree of renal function impairment, but only in patients with severe renal insufficiency were differences statistically significant: clearance was about half that of control subjects (mean +/- SD, 6.01 +/- 2.54 mL/min x kg versus 11.87 +/- 2.97 mL/min x kg; P < .001), and half-life was approximately doubled (4.55 +/- 1.71 hours versus 2.24 +/- 0.55 hours, P < .001). No such alterations were observed in patients undergoing regular hemodialysis, whose values were similar to those of the control group. The steady-state volume of distribution and MEGX levels were independent of renal function, whereas GX levels were more than double those of control subjects (P < .05) in all CRF groups. No inhibitory effect of plasma was observed, for any of the subjects examined, on lidocaine biotransformation in vitro. GX was found to be a competitive inhibitor, but its apparent inhibition constant value (52 +/- 6 micromol/L) was 2 orders of magnitude higher than its concentrations in vivo. CONCLUSIONS: Our in vivo findings have both clinical and methodologic implications: (1) Lidocaine dose adjustment may be required in patients with severe renal insufficiency who are not receiving hemodialysis. (2) Results of studies evaluating the effect of CRF on metabolic drug disposition are not of general validity, unless both patients undergoing hemodialysis and patients not undergoing hemodialysis have been examined. Our in vitro observations exclude that impairment of lidocaine disposition is the result of direct inhibition of metabolizing enzymes by accumulated metabolites or uremic toxins. Alternative mechanisms, suggested by the results of recent in vitro studies, are discussed.     

Effects of alpha - and beta -adrenergic stimulation on hepatosplanchnic perfusion and oxygen extraction in endotoxic shock

OBJECTIVE: To examine the effects of adrenergic stimulation on hepatosplanchnic perfusion, oxygen extraction, and tumor necrosis factor-alpha production during endotoxic shock. DESIGN: In vivo, prospective, randomized, controlled, repeated-measures, experimental study. SETTING: Experimental physiology laboratory in a university teaching hospital. SUBJECTS: Twenty-one anesthetized and mechanically ventilated dogs. INTERVENTIONS: An intrapericardial catheter was positioned. Catheters for blood sampling were inserted into the right femoral artery, hepatic vein, portal vein, and pulmonary artery. Ultrasonic flow probes were placed around the portal vein, the hepatic artery, the mesenteric artery, the left renal artery, and the left femoral artery. Animals received 2 mg/kg of Escherichia coli endotoxin, followed by fluid resuscitation. Seven dogs received intravenous isoproterenol (0.1 microg/kg x min(-1)), seven received phenylephrine (1 microg/kg x min(-1)), and seven served as controls. Thirty minutes later, cardiac tamponade was introduced to study organ perfusion and tissue oxygen extraction capabilities. MAIN RESULTS: The isoproterenol group had a higher cardiac index and stroke index and lower systemic vascular resistance than the other groups. The phenylephrine group had a higher arterial pressure but a lower cardiac index than the isoproterenol group. The isoproterenol group had a higher hepatic artery blood flow than the other groups and a higher portal and mesenteric flow than the control group. Liver and gut mucosal blood flow was greater in the isoproterenol than in the phenylephrine group. The isoproterenol group had a lower global critical oxygen delivery than the other groups (8.8 +/- 1.3 vs. 13.1 +/- 2.0 (control) and 11.8 +/- 3.3 mL/kg x min(-1) (phenylephrine); both p < .05) and a higher liver critical oxygen extraction ratio than the control group. Isoproterenol tended to attenuate, but phenylephrine significantly increased, blood tumor necrosis factor levels. CONCLUSIONS: During endotoxic shock, beta-stimulation can improve hepatosplanchnic perfusion and enhance tissue oxygen extraction capabilities, whereas alpha-stimulation does not. In addition, alpha-adrenergic stimulation can increase tumor necrosis factor levels.     

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.     

Effects of dopamine,norepinephrine, and epinephrine on the splanchnic circulation in septic shock: which is best?

OBJECTIVE: To assess the effects of different doses of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in patients with septic shock. DESIGN: Prospective, randomized, open-label study. SETTING: A 31-bed, medicosurgical intensive care unit of a university hospital. PATIENTS: Convenience sample of 20 patients with septic shock, separated into two groups according to whether (moderate shock group, n = 10) or not (severe shock, n = 10) dopamine alone was able maintain mean arterial pressure >65 mm Hg. INTERVENTIONS: Dopamine was progressively withdrawn and replaced successively by norepinephrine and then epinephrine (the order of the two agents was randomly determined) to maintain mean arterial pressure constant (moderate shock) or to increase mean arterial pressure above 65 mm Hg (severe shock). MEASUREMENTS AND MAIN RESULTS: Systemic circulation (pulmonary artery catheter) and splanchnic circulation (indocyanine green dilution and hepatic vein catheter) and gastric mucosal Pco(2) (gas tonometry) were measured during dopamine (moderate shock only), norepinephrine, and epinephrine administration (both groups). Data were analyzed with nonparametric tests and are presented as median [percentiles 25-75]. In moderate shock, cardiac index was similar to dopamine and norepinephrine (3.1 [2.7-3.8] vs. 2.9 [2.7-4.1] L/min.m2, p = nonsignificant) but greater with epinephrine (4.1 [3.5-4.4] p <.01 vs. dopamine and norepinephrine). Splanchnic blood flow was similar with the three agents (732 [413-1483] vs. 746 [470-1401] vs. 653 [476-1832] mL/min.m, p = nonsignificant). The gradient between mixed-venous and hepatic venous oxygen saturations was lower with dopamine than with norepinephrine and epinephrine, but the Pco(2) gap was similar with the three agents. In severe shock, cardiac index was higher, but splanchnic blood flow was lower, with epinephrine than with norepinephrine (4.6 [3.7-5.3] vs. 3.4 [3.0-4.1] L/min.m2, p <.01 and 860 [684-1334] vs. 977 [806-1802] mL/min.m2, p <.05, respectively). Epinephrine increased the mixed-venous and hepatic venous oxygen saturation gradient but did not alter Pco(2) gap. CONCLUSIONS: Dopamine and norepinephrine have similar hemodynamic effects, but epinephrine can impair splanchnic circulation in severe septic shock.     

Short-term effects of phenylephrine on systemic and regional hemodynamics in patients with septic shock: a crossover pilot study

Clinical studies evaluating the use of phenylephrine in septic shock are lacking. The present study was designed as a prospective, crossover pilot study to compare the effects of norepinephrine (NE) and phenylephrine on systemic and regional hemodynamics in patients with catecholamine-dependent septic shock. In 15 septic shock patients, NE (0.82 +/- 0.689 microg x kg(-1) x min(-1)) was replaced with phenylephrine (4.39 +/- 5.23 microg x kg(-1) x min(-1)) titrated to maintain MAP between 65 and 75 mmHg. After 8 h of phenylephrine infusion treatment was switched back to NE. Data from right heart catheterization, acid-base balance, thermo-dye dilution catheter, gastric tonometry, and renal function were obtained before, during, and after replacing NE with phenylephrine. Variables of systemic hemodynamics, global oxygen transport, and acid-base balance remained unchanged after replacing NE with phenylephrine except for a significant decrease in heart rate (phenylephrine, 89 +/- 18 vs. NE, 93 +/- 18 bpm; P < 0.05). However, plasma disappearance rate (phenylephrine, 13.5 +/- 7.1 vs. NE, 16.4 +/- 8.7% x min(-1)) and clearance of indocyanine green (phenylephrine, 330 +/- 197 vs. NE, 380 +/- 227 mL x min(-1) x m(-2)), as well as creatinine clearance (phenylephrine, 81.3 +/- 78.4 vs. NE, 94.3 +/- 93.5 mL x min(-1)) were significantly decreased by phenylephrine infusion (each P < 0.05). In addition, phenylephrine increased arterial lactate concentrations as compared with NE infusion (1.7 +/- 1.0 vs. 1.4 +/- 1.1 mM; P < 0.05). After switching back to NE, all variables returned to values obtained before phenylephrine infusion except creatinine clearance and gastric tonometry values. Our results suggest that for the same MAP, phenylephrine causes a more pronounced hepatosplanchnic vasoconstriction as compared with NE.     

Increased hepatosplanchnic inflammation precedes the development of organ dysfunction after elective high-risk surgery

This study investigated the relationship of the hepatosplanchnic production and uptake of inflammatory mediators, hepatosplanchnic perfusion, and outcome during major abdominal surgery to evaluate the hypothesis that regional production of inflammatory mediators precedes the development of hepatic dysfunction. This retrospective analysis of data and blood samples collected during a randomized controlled clinical trial included high-risk surgical patients undergoing major abdominal surgery in a 24-bed university-afilliated intensive care unit. Patients were divided into a subgroup that developed hepatic dysfunction (HD+) postoperatively and a subgroup without hepatic dysfunction (HD-). Hepatic vein and arterial plasma levels of IL-6, IL-8, s-E-selectin, s-ICAM-1, and the TNF-receptors 55 and 75 were measured, and the flux was calculated by multiplying the difference in hepatic vein minus arterial levels of the mediators by the hepatosplanchnic flow. Systemic (thermodilution) and total hepatosplanchnic blood flow (using indocyanine green [ICG]-dilution method) and gastric intramucosal pH (pHi) were assessed preoperatively, 4, 24, and 36 h postoperatively. Of a total of 26 patients, 6 patients developed hepatic dysfunction after their abdominal surgery (mean 6 days postoperatively). The number of sepsis-related deaths and postoperative days on the ventilator were significantly higher in this group. A higher production of IL-8, TNF-receptor-75 and 55 in the hepatosplanchnic area in the HD+ subgroups was found, which preceded the development of organ dysfunction (P = 0.04, P = 0.02, and P = 0.02, respectively). Moreover, the uptake of s-ICAM-1 was significantly increased in this subgroup. Furthermore, total hepatosplanchnic blood flow was significantly higher and pHi was significantly lower in the HD+ group, whereas global hemodynamic data were similar in the two subgroups. In conclusion, the development of postoperative organ dysfunction is preceded by an increased regional inflammatory response, indicated by an increased soluble TNF-receptor shedding and IL-8 production from the hepatosplanchnic area together with an increased uptake of s-ICAM-1. Moreover, an increased total hepatosplanchnic blood flow with intramucosal acidosis was associated with this regional inflammatory response.