Myocardial oxygen consumption during dobutamine infusion in endotoxemic pigs

PURPOSE: Dobutamine infusion is used to increase whole-body oxygen delivery in septic patients to satisfy unmet oxygen demand of hypoxic tissues. However, dobutamine infusion also increases myocardial work and myocardial oxygen consumption. Our goal was to determine the importance of this effect as a fraction of the increase in whole-body oxygen consumption, in a porcine model of septic shock. MATERIALS AND METHODS: Four hours after a 50 microg/kg infusion of Escherichia coli endotoxin (0111: B4, Sigma) in eight anesthetized pigs, whole-body oxygen delivery and myocardial oxygen delivery and consumption were calculated from blood flow and arterial and venous oxygen content measurements. We directly measured whole-body oxygen consumption by analysis of inhaled and exhaled gases using a metabolic cart. Then dobutamine 10 and 20 microg/kg/min was infused and measurements were repeated. RESULTS: Dobutamine infusion increased whole-body oxygen delivery but did not increase metabolic cart measured whole-body oxygen consumption. Dobutamine infusion of 10 and 20 microg/kg/min increased myocardial oxygen consumption by 7.0 +/- 0.6 (80 +/-10%) and 12.0 +/- 2.0 mL O2/min (142 +/- 30%), respectively (P < .01). CONCLUSIONS: In this porcine model of sepsis, dobutamine infusion significantly increases myocardial oxygen consumption. Because whole-body oxygen consumption does not change, dobutamine infusion may fail to increase and may decrease oxygen consumption by other organs.     

Enoximone in contrast to dobutamine improves hepatosplanchnic function in fluid-optimized septic shock patients

OBJECTIVE: To investigate the impact of dobutamine and enoximone on hepatosplanchnic perfusion and function in fluid-optimized septic patients. DESIGN: Prospective, randomized, double-blinded interventional study. SETTING: Intensive care unit of a university hospital. PATIENTS: Forty-eight septic shock patients were examined within 12 hrs after onset of septic shock. Patients were conventionally resuscitated, achieving an optimal pulmonary artery occlusion pressure at which the left ventricular stroke work was on the maximal plateau. Liver blood flow was estimated by venous suprahepatic catheterization using the continuous indocyanine green infusion technique. Microsomal liver function was assessed by the plasma appearance of monoethylglycinexylidide, and release of hepatic tumor necrosis factor-alpha (TNF-alpha) was measured to estimate the severity of hepatic ischemia-reperfusion syndrome. INTERVENTIONS: Patients were randomly treated with dobutamine or enoximone. Within the first 10 hrs after baseline measurements, the dosage was increased until no further increase in the left ventricular stroke work index occurred. Then, positive inotropes were kept constant throughout the study. MEASUREMENTS AND MAIN RESULTS: Measurements were performed at baseline and after 12 and 48 hrs after baseline measurements. Cardiac index, systemic oxygen delivery, systemic oxygen consumption, and liver blood flow increased significantly in both groups during treatment (p <.01) without a significant difference between groups. Fractional liver blood flow (liver blood flow/cardiac index) did not change in the enoximone group and showed a significant but only minor (median, 10%) decrease in the dobutamine group (p <.05 after 12 hrs and p <.01 after 48 hrs vs. baseline). After 12 hrs of enoximone treatment, monoethylglycinexylidide kinetics and hepatosplanchnic oxygen consumption demonstrated a significant increase (p <.05). The release of hepatic TNF-alpha after 12 hrs of dobutamine treatment was twice as high (p <.05) as during enoximone. CONCLUSION: The increase in hepatosplanchnic oxygen consumption, together with an increased lignocaine metabolism and decreased release of hepatic TNF-alpha, indicates improved hepatosplanchnic function and antiinflammatory properties after 12 hrs of enoximone treatment. Therefore, if the inflammatory response should be attenuated in high-risk patients, administration of enoximone in fluid-optimized septic shock patients may be favorable compared with dobutamine.     

Negative chronotropic effects of fentanyl attenuate beneficial effects of dobutamine on oxygen metabolism: hemodynamic and pharmacokinetic interactions.

Opioids are well known to cause cardiovascular depression. The aim of the present investigation was to determine whether an interaction of opioid derivatives with catecholamines might be involved in these hemodynamic alterations. Six comatose patients were enrolled into a prospective, nonrandomized pilot trial. All patients first received a continuous i.v. infusion of dobutamine (10 microgram. kg-1. min-1) paralleled by continuous administration of midazolam (0.4 mg. kg-1. h-1); thereafter, fentanyl was added i.v. (4 microgram. kg-1. h-1). Hemodynamic parameters as well as dobutamine and endogenous catecholamines plasma levels were determined. The mean arterial blood pressure did not change significantly during the whole study period. The continuous administration of dobutamine (steady-state plasma concentrations: 217 +/- 118 ng. ml-1) increased the beta1-adrenergic receptor-mediated hemodynamic parameters such as heart rate, stroke volume index, cardiac index, and oxygen delivery index (p <.05). The concomitant administration of fentanyl decreased the heart rate-dependent hemodynamic parameters (p <.05), suggesting that fentanyl antagonizes the chronotropic effects of dobutamine. In parallel, dobutamine plasma levels increased significantly (275 +/- 165 ng. ml-1; p <.05). Noteworthy, after administration of fentanyl, oxygen delivery and consumption index returned to baseline values. Radioligand binding experiments on rat cardiac ventricular microsomes ruled out a direct interaction of fentanyl with beta-adrenergic receptors and, more importantly, a fentanyl-induced inhibition of beta-adrenergic receptor G protein coupling. Our observations suggest that fentanyl inhibits the frequency-related hemodynamic changes induced by dobutamine. The underlying mechanism is independent of beta-adrenergic receptors, but is powerful enough to abolish the salutary effect of dobutamine on oxygen delivery and consumption.     

Significance of pathologic oxygen supply dependency in critically ill patients: Comparison between measured and calculated methods

Objective Oxygen supply dependency at normal or high oxygen delivery rate has been increasingly proposed as a hallmark and a risk factor in critical illnesses. We hypothesized that as fas as an adequate oxygen delivery is provided, oxygen consumption, when determined by indirect calorimetry, is not dependent on oxygen delivery in critically ill patients whereas calculated oxygen consumption is associated with artefactual correlation of oxygen consumption and delivery. Design Oxygen delivery, oxygen consumption and their relationship were analyzed prospectively. Metabolic data gained from both measured and calculated methods were obtained simultaneously before and after volume loading. Setting The study was completed in the intensive care unit as part of the management protocol of the patients. Patients 32 consecutive patients entered the study and were divided into 3 groups according to a clinical condition known to favour oxygen supply dependency: sepsis syndrome, adult respiratory distress syndrome and acute primary liver failure. Intervention The rise in oxygen delivery was obtained by colloid infusion (oxygen flux test) performed in hemodynamically and metabolically stable patients. All were mechanically ventilated. No change in therapy was allowed during the test. Measurements and results Oxygen consumption was simultaneously evaluated by calculation (Fick Principle) and direct measurement using indirect calorimetry. Oxygen delivery was derived from the cardiac output (thermodilution) and arterial content of oxygen. Oxygen supply dependency was considered while observing an increase in oxygen delivery greater than 45 ml/min·m². Irrespective of patient's clinical diagnosis and outcome, measured oxygen uptake remained unaltered by volume infusion whereas both oxygen delivery and calculated oxygen consumption increased significantly. Arterial lactate level>2 mmol/l and measured oxygen extraction ratio>25% failed to identify oxygen supply dependency when measured data were considered. Conclusion Analysis of oxygen uptake, when measured by indirect calorimetry, failed to substantiate oxygen supply dependency in the vast majority of the critically ill patients irrespective of diagnosis and outcome. Mathematical coupling of shared variables accounted for the correlation between oxygen delivery and calculated oxygen consumption.     

Effects of epinephrine, norepinephrine, or the combination of norepinephrine and dobutamine on gastric mucosa in septic shock.

OBJECTIVES: To compare in the same patient with septic shock, respective effects of epinephrine, norepinephrine, and the combination of norepinephrine and dobutamine (5 microg/kg/min) on systemic hemodynamic parameters and gastric mucosal perfusion using gastric tonometry and laser-Doppler flowmetry techniques. DESIGN: Prospective, controlled, randomized, crossover study. SETTING: University hospital intensive care unit. PATIENTS: Twelve patients with septic shock. INTERVENTIONS: Each patient received in a random succession epinephrine, norepinephrine, and norepinephrine plus dobutamine. Dosages of epinephrine and norepinephrine were adjusted to achieve a mean arterial pressure between 70 and 80 mm Hg. A laser-Doppler probe and a tonometer were introduced into the gastric lumen. MEASUREMENTS AND MAIN RESULTS: The increase in gastric mucosal perfusion detected by laser-Doppler flowmetry was higher with epinephrine and the combination of norepinephrine and dobutamine than with norepinephrine alone (p < .05). In addition, the ratio of gastric mucosal perfusion (local oxygen delivery) to systemic oxygen delivery was increased after norepinephrine plus dobutamine as compared with norepinephrine alone and epinephrine (p< .05). Although values of intramucosal pH and gastroarterial PCO2 tended to be higher with norepinephrine plus dobutamine compared with those obtained with norepinephrine and epinephrine, differences were not statistically significant. CONCLUSIONS: For the same mean arterial pressure in patients with septic shock, our study showed that administration of epinephrine increased gastric mucosal perfusion more than norepinephrine administration alone. Addition of dobutamine (5 microg/kg/ min) to norepinephrine improved gastric mucosal perfusion. This result could be explained by a vasodilating effect of dobutamine on gastric mucosal microcirculation.     

Dopexamine attenuates flow motion in ileal mucosal arterioles in normotensive sepsis

OBJECTIVES: Injury to the small intestine is thought to play a crucial role in the development and propagation of sepsis. Cellular hypoxia, caused by hypoperfusion, may result in increased mucosal permeability, thus allowing the translocation of bacteria and endotoxin to the circulation. The purpose of this study was to assess the effect of the synthetic catecholamine, dopexamine, on the mucosal microcirculation of the septic rat ileum. DESIGN: Randomized, crossover study. SETTING: Teaching hospital animal laboratory. SUBJECTS: Sprague-Dawley male rats. INTERVENTIONS: Sepsis was induced by cecal ligation and perforation in 11 male Sprague-Dawley rats. Six sham animals were also studied. At 24 hrs, rats were anaesthetized, intubated, ventilated, and prepared for intravital microscopy of the mucosal surface of the ileum. Dopexamine (8 microg/kg/min) and saline were infused intravenously into each rat using a randomized crossover design. MEASUREMENTS AND MAIN RESULTS: Observations were videotaped for later analysis of arteriolar flow patterns, red cell velocity, arteriolar diameter, and intercapillary area. All values are expressed as mean +/- SEM. The main effect of dopexamine infusion in the sepsis group was the attenuation of the rhythmic blood flow patterns (flow motion) observed during saline infusion. In each subject, dopexamine decreased the absolute number of arterioles exhibiting flow motion by 35.93+/-6.81% (p<.001, paired t-test). Dopexamine decreased the amount of time red cell flow was stopped in marginal and central arterioles by 11.83+/-2.49% (p<.001, paired t-test). Dopexamine did not alter significantly the diameter of the marginal arterioles, the intercapillary area, or the red cell velocity compared with saline in the sepsis group. The sham group displayed marked microvascular differences compared with the sepsis group with respect to arteriolar diameter (13.32+/-0.05 vs. 9.46+/-0.24 mm, p<.001), intercapillary area (975.93+/-60.60 vs. 1256.03+/-43.88 mm2, p<.05 ), red cell velocity (611.40+/-38.77 vs. 289.15+/-36.45, p<.001), and blood flow patterns (% displaying flow motion, 15.89+/-6.09 vs. 58.22+/-9.63, p<.01; % time stopped flow, 1.96+/-0.89 vs. 20.21+/-3.92, p<.005). CONCLUSIONS: These results indicate that dopexamine increased overall blood flow and possibly oxygen delivery to the mucosa by altering patterns of blood flow within the villi. The observation that the diameter of the marginal arterioles is not affected by dopexamine indicates that dopexamine influences the mucosal microcirculation at the level of higher order arterioles. We conclude that sepsis results in abnormal microvascular villus blood flow and that dopexamine can partially restore these changes towards normal.     

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 titrated arginine vasopressin on hemodynamic variables and oxygen transport in healthy and endotoxemic sheep

OBJECTIVE: To determine the effects of titrated arginine vasopressin (AVP) alone or in combination with norepinephrine (NE) on hemodynamics and oxygen transport in healthy and endotoxemic sheep. DESIGN: Prospective controlled trial. SETTING: University research laboratory. SUBJECTS: Six adult ewes. INTERVENTIONS: Healthy sheep received AVP as a titrated infusion, initiated with 0.6 units/hr and increased by 0.6 units/hr every 15 mins, either until mean arterial pressure was increased by 20 mm Hg vs. baseline or a maximum of 3.6 units/hr was administered. After 90 mins, AVP infusion was continued with the investigated dosage, and NE (0.2 microg x kg(-1) x min(-1)) was also infused for 90 mins. After a 24-hr period of recovery, endotoxemia was induced and maintained (Salmonella typhosa endotoxin, 10 ng x kg(-1) x min(-1)) in the same sheep for the next 19 hrs. After 16 hrs of endotoxemia, AVP and NE were administered as described previously. MEASUREMENTS AND MAIN RESULTS: Hemodynamics were obtained at baseline, every 15 mins during the titration period, and 60 and 90 mins after additional NE infusion. Variables of oxygen transport were calculated before and after the titration period. In healthy and endotoxemic sheep, AVP reduced heart rate and cardiac index (p <.001) and compromised oxygen delivery (p <.001) and oxygen consumption (healthy sheep, p =.003; endotoxemic sheep, p <.001). Vasopressin infusion did not alter mean pulmonary arterial pressure but increased pulmonary vascular resistance index in both groups (p <.001). Additional infusion of NE further augmented mean arterial pressure and increased cardiac index during endotoxemia (p <.001). This was accompanied by an increase in oxygen delivery and consumption (p <.05 each). CONCLUSIONS: During ovine endotoxemia, AVP decreased cardiac index, compromised oxygen delivery, and increased pulmonary vascular resistance index. These side effects may limit its use as a sole vasopressor during sepsis. Potentially, a simultaneous infusion of AVP and NE could represent a useful therapeutic option.     

Seasonal variation in the epidemiology of sepsis

OBJECTIVE: We sought to investigate seasonal and regional variability in the epidemiology of sepsis and to identify underlying associations based on geography and seasonal viral infections. Understanding seasonal or regional variations may improve knowledge of sepsis epidemiology and pathophysiology and could affect healthcare planning and resource allocation. DESIGN: Retrospective cohort study using the National Hospital Discharge Survey to identify cases of sepsis, severe sepsis, influenza, and viral pneumonia using ICD-9-CM codes. Incidence rates are reported as mean cases frequencies per season per 100,000 as calculated by normalization to the 2000 U.S. Census. SETTING: Acute-care nonfederal U.S. hospitals. PATIENTS: Patients hospitalized between 1979 and 2003 in acute-care nonfederal U.S. hospitals with a diagnosis of sepsis or viral respiratory infection. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The seasonal incidence rate of sepsis increased 16.5% from a low of 41.7 in the fall to a high of 48.6 cases per 100,000 in the winter (p<.05). Similarly, seasonal rates for severe sepsis statistically increased 17.7% from fall to winter at 13.0 and 15.3 cases per 100,000, respectively. The greatest change in sepsis incidence occurred with respiratory sources, increasing 40% during the winter compared with the fall (p<.05). Seasonal variations in viral respiratory infections paralleled changes in sepsis incidence but did not fully account for the changes. The greatest seasonal change in sepsis rates occurred in the Northeast (+30%). Sepsis case-fatality rates were 13% greater in the winter compared with the summer (p<.05) despite similar severity of illness. CONCLUSIONS: The incidence and mortality of sepsis and severe sepsis are seasonal and consistently highest during the winter, predominantly related to respiratory sepsis. Seasonal changes in sepsis incidence vary according to geographic region. The mechanisms underlying these differences require further investigation.     

Effects of propofol, etomidate, and pentobarbital on critical oxygen delivery

OBJECTIVE: To test the hypothesis that propofol, etomidate, and pentobarbital increase critical oxygen delivery in a dose-dependent manner during progressive hemorrhage. DESIGN: Prospective, randomized laboratory investigation. SETTING: University laboratory. SUBJECTS: A total of 40 anesthetized, paralyzed, and mechanically ventilated dogs weighing 29.2+/-4.6 kg. INTERVENTIONS: Dogs were randomly assigned to be anesthetized with propofol (n = 13), etomidate (n = 13), or pentobarbital (n = 14) at either low or high dosages. At 30 mins after splenectomy, the dogs underwent progressive hemorrhage by successive withdrawals of 3-5 mL/kg arterial blood. MEASUREMENTS AND MAIN RESULTS: At each step of hemorrhage, oxygen consumption and oxygen delivery were determined. Oxygen consumption was obtained from expired gas analysis, and oxygen delivery was determined from thermodilution cardiac output and calculated arterial oxygen content. In each animal, critical oxygen delivery and critical oxygen consumption were obtained from a plot of oxygen consumption vs. oxygen delivery as the point of intersection of the two best-fit regression lines determined by a least sum of squares method. Critical oxygen extraction was obtained by dividing critical oxygen consumption by critical oxygen delivery. In the three groups, animals receiving the higher anesthetic infusion had a significantly higher critical oxygen delivery (propofol: 10.5+/-0.8 vs. 13.9+/-2.5 mL/min/m2, p < .05; etomidate: 10.1+/-0.7 vs. 13.4+/-3.0 mL/min/m2, p < .05; pentobarbital: 7.8+/-1.0 vs. 12.3+/-2.5 mL/min/m2, p < .01) attributable to a lower critical oxygen extraction ratio (propofol: 41.1+/-6.4% vs. 54.2+/-2.5%, p < .01; etomidate: 42.7+/-10.2% vs. 60.6+/-7.1%, p < .01; pentobarbital: 42.2+/-7.2% vs. 64.3+/-8.8%, p < .01). CONCLUSIONS: This study indicates that propofol, etomidate, and pentobarbital increased critical oxygen delivery in a dose-dependent manner. This effect was mainly related to a decrease in tissue oxygen extraction capabilities.     

Using Art to Help Understand the Imagery of Irritable Bowel Syndrome and Its Response to Hypnotherapy

A medical artist asked 109 patients if they had an image of their IBS pre- and posthypnotherapy, making precise watercolor paintings of any images described. Results were related to treatment outcome, symptoms, anxiety, depression, and absorption (hypnotizability); 49% of patients had an image, and a wide variety were recorded and painted. Imagery was significantly associated with gender (p < .05), anxiety (p < .05), noncolonic symptomatology (p < .05), and absorption (p = .001); 57.8% of responders compared with 35.5% of nonresponders to hypnotherapy had an image of their disease (p < .05) before treatment, and color images were associated with better outcomes (p = .05) than monochrome ones. All images changed in responders, often becoming more nonspecific in nature. Inquiring about IBS imagery helps to identify potential responders and nonresponders to hypnotherapy and may also provide insights into how patients think about their illness.     

Effect of intraoperative dobutamine on splanchnic tissue perfusion and outcome after Whipple surgery

Purpose

Splanchnic hypoperfusion during abdominal surgery contributes to postoperative gut sepsis and mortality. Dobutamine is an inotrope with vasodilator properties that improve hepatosplanchnic perfusion. The aim of this study was to examine the effect of intraoperative dobutamine infusion during Whipple surgery on splanchnic perfusion, hemodynamic, and overall postoperative outcome.

Methods

Sixty patients were randomly allocated to receive intraoperatively (3 μg/kg per minute or 5 μg/kg per minute) doses of dobutamine or saline. Baseline measurements included hemodynamic parameters, gastric tonometric parameters, and arterial and mixed venous gases. These patients had a follow-up for development for in-hospital morbidity and mortality.

Results

Intraoperative use of dobutamine increased oxygen-derived parameters as evidenced by increased mixed venous oxygen saturation. Tonometered gastric mucosal pH, a surrogate for splanchnic perfusion, increased in patients who received intraoperative dobutamine. Patients in the dobutamine groups demonstrated significant higher heart rates, premature ventricular contraction arrhythmias, and electrocardiographic signs of ischemia. Mean arterial blood pressure demonstrated no significant difference among groups. The overall incidence of postoperative complications was higher in control group 70 % vs 20% to 40% in dobutamine groups.

Conclusion

Intraoperative use of dobutamine improved global oxygen delivery, splanchnic perfusion, and postoperative outcome after Whipple surgery. These findings may be of clinical importance when the therapeutic goal is to improve gut perfusion.     

Jejunal luminal nitric oxide during severe hypovolemia and sepsis in anesthetized pigs

OBJECTIVE: Lowered gut blood perfusion and the associated intestinal mucosal barrier dysfunction is considered important in the pathophysiology leading to critical illness. Intestinal mucosal nitric oxide formation has been attributed a key role in the regulation of epithelial permeability and other properties of the intestinal mucosal barrier. This study was performed to delineate intestinal mucosal NO formation during hypovolemia or sepsis, both of which are associated with intestinal hypoperfusion. MATERIALS AND METHODS: Seventeen pigs were subjected to 2 h of severe hypovolemia (bleeding induced) or sepsis (systemic infusion of live Escherichia coli) or no treatment (controls). Jejunal mucosal NO production was monitored by a tonometer. Mesenteric blood flow was measured as portal venous blood flow by an ultrasonic transit time flowmeter probe, and oxygen delivery and consumption were calculated from regional blood samples. RESULTS: Intestinal perfusion and oxygen delivery were reduced by the same order of magnitude in both groups. Jejunal mucosal NO production and oxygen consumption decreased markedly in the hypovolemia group but remained stable in the group subjected to septic shock. CONCLUSIONS: These data suggest that blood loss inhibits jejunal mucosal NO production as part of a general downregulation of nonvital organs. Sepsis represents a more complex stress condition with activation/maintenance of host defense mechanisms as reflected by maintained jejunal mucosal NO production despite reduced gut blood perfusion.     

Effect of dobutamine on oxygen consumption and fluid and protein losses after endotoxemia

OBJECTIVE: To determine the effect of a dobutamine infusion on the relationship between oxygen consumption (VO2) and oxygen delivery (DO2) after endotoxin administration, as well as the rate of fluid and protein loss from permeability-injured tissue. METHODS: Unanesthetized adult sheep with lung and soft-tissue lymph fistulas were given 5 micrograms/kg Escherichia coli endotoxin alone, or E. coli endotoxin plus a continuous infusion of dobutamine (10 to 15 micrograms/kg.min) beginning at 3 hrs. Lymph flow reflected the vascular permeability and surface area perfused. Data were compared with dobutamine alone and with controls. Filling pressures were maintained at baseline. RESULTS: Dobutamine alone produced a 75% increase in DO2, a transient 10 +/- 4% increase in VO2, but no increase in lung or soft-tissue lymph flow. Beginning at 3 hrs after endotoxin alone, a significant increase in protein-rich lung and soft-tissue lymph flow was noted, but only a transient 14 +/- 5% increase in VO2. Plasma proteins were slightly decreased. With the addition of dobutamine at 3 hrs postendotoxin, DO2 increased by greater than 50% for the 3-hr infusion period, while VO2 increased for a 30-min period by 25 +/- 8%, which was not different than endotoxin alone. Lung and soft-tissue lymph flow did not increase further, but plasma proteins did decrease significantly compared with controls and with endotoxin alone. CONCLUSION: Increasing DO2 with dobutamine postendotoxin does not increase the surface area perfused or the edema process, at least in lung and soft tissue. Therefore, no microvessels in these tissues are reopened with dobutamine when normal filling pressures are present. Dobutamine administration does not increase VO2 more than the increase seen with endotoxin alone.     

Effects of dopamine and epinephrine infusions on renal hemodynamics in severe malaria and severe sepsis

OBJECTIVE: To describe and compare the effects of dopamine and epinephrine in various doses on renal hemodynamics and oxygen transport in patients with severe malaria and severe sepsis. DESIGN: Prospective, controlled, crossover trial. SETTING: The intensive care unit of an infectious diseases hospital in Viet Nam. PATIENTS: Fourteen patients with severe falciparum malaria and five with severe sepsis. INTERVENTIONS: In an open, crossover design, we observed the effects on renal and systemic hemodynamics and oxygen transport of separate stepped infusions of epinephrine and dopamine. We measured renal blood flow (RBF) and cardiac output by the thermodilution method using fluoroscopically guided catheters. Creatinine clearance at each time point was calculated from the renal plasma flow and the renal arteriovenous difference in plasma creatinine. MEASUREMENTS AND MAIN RESULTS: Dopamine at a "renal" dose (2.5 microg/kg/min) was associated with a mean (95% confidence interval) fractional increase in the absolute renal blood flow index (RBFI) of 37% (13% to 61%) and in RBF as a fraction of cardiac output (RBF/CO) of 35% (10% to 59%; p = .007 and p = .014, respectively). The consequent 39% (14% to 64%) increase in renal oxygen supply (p = .002) was accompanied by a 32% (20% to 44%) decrease in the renal oxygen extraction ratio (p = .0003), leading to no net change in renal oxygen consumption. At higher doses (10 microg/kg/min), both RBF and RBF/CO were not significantly different from baseline values and decreased further as the dose was reduced again. There was no obvious explanation for this hysteresis. There was no change in renal oxygen consumption throughout the study. Because lactic acidosis developed, epinephrine was only given to eight of the 19 patients, and the full stepped epinephrine infusion was given to four patients. Epinephrine infusion was associated, both in absolute terms and when compared with dopamine, with a significant increase in renal vascular resistance (p = .0008 and .0005, respectively), a decrease in RBF/CO (p = .002 and .03), and a compensatory increase in the renal oxygen extraction ratio (p = .005 and .0001). RBFI and renal oxygen consumption remained constant throughout the epinephrine infusion profile. Neither epinephrine nor dopamine significantly affected creatinine clearance or urine output. Twelve patients (63%) were in established renal failure (plasma creatinine, >3 mg/dL) at the time of the study, although the presence or absence of renal failure did not significantly influence the effects of the study drugs. However, overall, the presence of renal failure was associated with a lower mean renal oxygen consumption, a lower mean renal oxygen consumption as a fraction of systemic oxygen consumption, and a higher mean renal vascular resistance. CONCLUSION: Although dopamine increased and epinephrine decreased fractional renal blood flow, there was no evidence that either drug produced either a beneficial or a deleterious effect on renal oxygen metabolism or function at any of the doses investigated.     

Epidemiology of sepsis in Victoria, Australia

OBJECTIVE: To determine the clinical and epidemiologic characteristics of patients with sepsis admitted to hospitals in Victoria, Australia, including the incidence of sepsis and severe sepsis, utilization of intensive care unit (ICU) resources, and hospital mortality. DESIGN: A population-based hospital morbidity database generated from hospital discharge coding. SETTING: State of Victoria, Australia (population, 4.5 million), the 4-yr period from July 1, 1999, to June 30, 2003. PATIENTS: A total of 3,122,515 overnight hospitalizations. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The overall hospital incidence of sepsis was 1.1%, with a mortality of 18.4%. Of septic patients, 23.8% received some care in an ICU. For these patients, hospital mortality was 28.9%. Severe sepsis, defined by sepsis and at least one organ dysfunction, occurred in 39% of sepsis patients and was accompanied by a hospital mortality of 31.1%. Fifty percent of patients with severe sepsis received at least some care in an ICU. CONCLUSIONS: Australian state hospital administrative data reveal epidemiologic features of sepsis and severe sepsis that are strikingly similar to those recently reported from comparable populations in North American and Europe. This suggests that lessons learned in this area may be directly applicable internationally.     

Lipoprotein metabolism in patients with severe sepsis

OBJECTIVE: Lipoproteins have been implicated to play a role in innate immunity. Changes in lipoprotein levels have been reported in a variety of inflammatory disorders. Not much is known about lipoprotein metabolism in patients with severe sepsis. We conducted an ancillary study in a multiple-center phase III sepsis trial to investigate the dynamics of plasma lipoproteins in patients with severe sepsis. DESIGN: Prospective analysis in patients meeting criteria for severe sepsis as part of a multiple-center sepsis study (KyberSept) with antithrombin III (Kybernin P). SETTING: University hospital intensive care unit. PATIENTS: Seventeen patients were included in the study. INTERVENTIONS: Randomized patients received a loading dose of 6000 IU of antithrombin III (Kybernin P) or placebo followed by a 96-hr continuous infusion of 250 IU/hr antithrombin III (Kybernin P) or placebo. In each patient, serial blood samples for total cholesterol, lipoprotein cholesterol, triglycerides, apolipoprotein A-1, apolipoprotein B, and C-reactive protein determination as well as clinical data were collected over 28 days. MEASUREMENTS AND MAIN RESULTS: Plasma cholesterol levels rapidly decreased from 2.67 +/- 2.02 mmol/L on day 0 to a nadir of 1.41 +/- 0.70 mmol/L on day 3, followed by a slow increase to 4.18 +/- 1.94 mmol/L on day 28. High-density lipoprotein (HDL) cholesterol concentrations decreased rapidly from 0.84 +/- 0.92 mmol/L to a nadir of 0.42 +/- 0.35 mmol/L on day 3, to show a slow increase during the following 4 wks to 0.84 +/- 0.42 mmol/L. The low-density lipoprotein (LDL) cholesterol concentrations were already low (0.94 +/- 0.81 mmol/L) at study entry, to show a progressive increase to subnormal values (2.01 +/- 0.94 mmol/L) at 4 wks. Nadir and recovery lipoprotein concentrations were significantly different (paired Student's t-test, p <.05). A significant correlation was found between HDL cholesterol and apolipoprotein A-1 (r =.714, p <.05) and between LDL cholesterol and apolipoprotein B (r =.733, p <.05). There was no statistical difference in lipoprotein concentrations either between survivors and nonsurvivors or between patients receiving antithrombin III or placebo.Serum amyloid A was a major apoprotein (45%) in HDL at the start of the sepsis and was slowly replaced by apolipoprotein A-1 during recovery. A positive correlation was found between plasma C-reactive protein concentrations and serum amyloid A concentrations in HDL (r =.684, p <.05). No other relevant correlations were found between inflammatory and lipoprotein parameters. CONCLUSIONS: In patients with severe sepsis, lipoprotein concentrations rapidly change and can be reduced to 50% of recovery concentrations. The pattern of early rapid decline is found primarily in the HDL and a slow recovery in both HDL and LDL fractions. The correlation between apolipoprotein and lipoprotein cholesterol concentrations suggests a decline in lipoprotein particles. During severe sepsis, HDL is shifted to acute phase HDL, which is enriched in serum amyloid A and depleted of cholesterol and apolipoprotein A-1. Lipoprotein concentrations are unable to discriminate between survivors and nonsurvivors.     

Effects of maximizing oxygen delivery on morbidity and mortality in high-risk surgical patients

OBJECTIVE: To evaluate the effects of maximizing the oxygen delivery on morbidity and mortality in patients >60 yrs of age and/or with chronic diseases of vital organs who underwent major elective surgery. DESIGN: Prospective, randomized, controlled trial. SETTING: A 24-bed general intensive care unit of a teaching hospital. PATIENTS: Thirty-seven high-risk patients who underwent major surgery. INTERVENTIONS: The hemodynamic and oxygen transport variables and outcomes in 18 patients (control group) treated to maintain normal values of oxygen delivery were compared with 19 patients (protocol group) treated to maintain "supranormal" values. Therapy in both groups consisted of volume expansion and, when necessary, dobutamine to reach target values, during the surgery and 24 hrs postoperatively. MEASUREMENTS AND MAIN RESULTS: We interrupted the study because of a significant difference in the 60-day mortality rate. The mortality rate in the control group was significantly higher when compared with the protocol group (9/18 [50%] vs. 3/19 [15.7%], p < .05). The prevalence of clinical and infectious complications was higher in the control group than in the protocol group (67% and 31% respectively; relative risk, 0.47; 95% confidence interval, 0.226-0.991; p < .05) and there was a trend toward more severe organ dysfunction in nonachievers patients (17/24 [71%] vs. 6/13 [46%], relative risk, 0.65; 95% confidence interval, 0.343-1.237; NS). CONCLUSION: Older patients with existing cardiorespiratory illness undergoing major surgery have a reduced morbidity and mortality when dobutamine is used to maximize oxygen transport.     

Administration of human inter-alpha-inhibitors maintains hemodynamic stability and improves survival during sepsis

OBJECTIVES: The major forms of human inter-alpha-inhibitor proteins circulating in the plasma are inter-alpha-inhibitor (IalphaI, containing one light peptide chain called bikunin and two heavy chains) and pre-alpha-inhibitor (PalphaI, containing one light and one heavy chain). Although it has been reported that a decrease in IalphaI/PalphaI is correlated with an increased mortality rate in septic patients, it remains unknown whether administration of IalphaI/PalphaI early after the onset of sepsis has any beneficial effects on the cardiovascular response and outcome of the septic animal. The aim of this study, therefore, was to determine whether IalphaI and PalphaI have any salutary effects on the depressed cardiovascular function, liver damage, and mortality rate after polymicrobial sepsis. DESIGN: Prospective, controlled, randomized animal study. SETTING: A university research laboratory. SUBJECTS: Male adult rats were subjected to polymicrobial sepsis by cecal ligation and puncture or sham operation followed by the administration of normal saline (i.e., resuscitation). MEASUREMENTS AND MAIN RESULTS: At 1 hr after cecal ligation and puncture, human IalphaI/PalphaI at a dose of 30 mg/kg body weight or vehicle (normal saline, 1 mL/rat) were infused intravenously over a period of 30 mins. At 20 hrs after cecal ligation and puncture (i.e., the late, hypodynamic stage of sepsis), cardiac output was measured by using a dye dilution technique, and blood samples were collected for assessing oxygen content. Oxygen delivery, consumption, and extraction ratio were determined. Plasma concentrations of liver enzymes alanine aminotransferase and aspartate aminotransferase as well as lactate and tumor necrosis factor-alpha also were measured. In additional animals, the necrotic cecum was excised at 20 hrs after cecal ligation and puncture with or without IalphaI/PalphaI treatment, and survival was monitored for 10 days thereafter. The results indicate that administration of human IalphaI/PalphaI early after the onset of sepsis maintained cardiac output and systemic oxygen delivery, whereas it increased oxygen consumption and extraction at 20 hrs after cecal ligation and puncture. The elevated concentrations of alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor-alpha, and lactate were attenuated by IalphaI/PalphaI treatment. In addition, administration of human IalphaI/PalphaI improved the survival rate from 30% to 89% in septic animals at day 10 after cecal ligation and puncture and cecal excision. CONCLUSION: Human IalphaI/PalphaI appears to be a useful agent for maintaining hemodynamic stability and improving survival during the progression of polymicrobial sepsis.