Interleukin-1beta alters the oxygen delivery-oxygen consumption relationship in rabbits by increasing the slope of the supply-independent line

When systemic oxygen delivery (DO2) is reduced, oxygen consumption (VO2) is maintained until a critical level is reached (DO2crit). Sepsis is thought to shift DO2crit to the right and lengthen the supply-dependent portion. We tested the effect of interleukin (IL)-1beta, which is one of the key cytokines related to sepsis, on the DO2-VO2 relationship. Fifteen rabbits were subjected to stepwise cardiac tamponade to reduce DO2 to 10% by inflating a handmade balloon placed into the pericardial sac. Seven rabbits were given 10 microg/kg of IL-1beta intravenously (IL-1beta group) prior to the graded cardiac tamponade. The remainder received saline alone (control group). The DO2-VO2 relationship was analyzed by the dual-line method. IL-1beta significantly decreased mean arterial pressure (65 +/- 11 mmHg from baseline 85 +/- 7 mmHg) without altering cardiac output. The IL-1beta group showed significantly steeper supply-independent line slopes than did the control group (0.19 +/- 0.02 vs. 0.11 +/- 0.02, respectively), which resulted in a DO2crit shift to the left (IL-1beta group, 8.7 +/- 1.7 ml/kg x min vs. control, 11.7 +/- 0.7 ml/kg x min). The IL-1beta group also showed greater PO2 and plasma lactate levels in the portal vein than did the control group. These results indicate that IL-1beta impairs systemic oxygen uptake even before VO2 becomes supply-dependent, presumably due to maldistribution of the blood flow including the splanchnic circulation.     

Effect of Ibuprofen on interleukin-1beta-induced abnormalities in hemodynamics and oxygen metabolism in rabbits

We showed previously that the administration of interleukin (IL)-1beta induces circulatory shock and impairs the oxygen consumption (VO2)/oxygen delivery (DO2) relation by increasing the slope of the supply-independent line in rabbits. We tested the effect of ibuprofen, a specific inhibitor of the development of shock in this model, on the VO2/DO2 abnormality. Eighteen rabbits were divided randomly into three groups (n = 6 each) and intravenously given 10 microg/kg of IL-1beta alone or 10 microg/kg of IL-1beta followed by 10 mg/kg of ibuprofen or saline (control). All rabbits were subjected to stepwise cardiac tamponade by inflation of a handmade balloon placed into the pericardial sac to reduce DO2. The VO2/DO2 relation was then analyzed by the dual line method. The IL-1beta group had a significantly lower mean arterial pressure than that of the other groups before cardiac tamponade, and this reduction in mean arterial pressure was suppressed completely by treatment with ibuprofen. The cardiac index did not differ between groups. The slope of the supply-independent line was increased significantly by administration of IL-1beta, and this increase was attenuated significantly by treatment with ibuprofen (IL-1beta only: y = 0.14x + 6.1, ibuprofen: y = 0.06x + 8.5, control: y = 0.01x + 9.0). We conclude that ibuprofen reversed the IL-1beta-induced shock by restoring the systemic vascular resistance to normal and thereby normalized the VO2/DO2 relation in the supply-independent range of DO2.     

Effect of blood transfusion on oxygen consumption in pediatric septic shock

Treatment plans for pediatric septic shock advocate increasing oxygen consumption (VO2). Recent studies in septic shock indicate that improving oxygen delivery (DO2) by increasing blood flow will increase VO2. We prospectively examined the effect on VO2 of improving DO2 by increasing oxygen content (CO2) with blood transfusion in eight hemodynamically stable septic shock patients. Transfusion consisted of 8 to 10 ml/kg of packed RBC over 1 to 2 h. Hemodynamic and oxygen transport measurements were obtained before and after blood transfusion. Transfusion significantly (p less than .05) increased Hgb and Hct from 10.2 +/- 0.8 g/dl and 30 +/- 2% to 13.2 +/- 1.4 g/dl and 39 +/- 4%, respectively (mean +/- SD). DO2 significantly (p less than .05) increased after transfusion (599 +/- 65 to 818 +/- 189 ml/min.m2), but VO2 did not change (166 +/- 68 to 176 +/- 74 ml/min.m2; NS). In pediatric septic shock patients, increasing CO2 by blood transfusion may not increase VO2.     

Blood transfusion and oxygen consumption in surgical sepsis

OBJECTIVE: To evaluate the use of serum lactic acid values to predict flow-dependent increases in oxygen consumption (VO2) in response to increasing oxygen delivery (DO2) after blood transfusion in surgical sepsis. DESIGN: Prospective study. SETTING: Tertiary care, trauma center. PATIENTS: Twenty-one patients, postsurgical or posttrauma, judged septic by defined criteria. INTERVENTIONS: Serum lactic acid concentrations, DO2, and VO2 were measured before and after transfusion therapy. MEASUREMENTS AND MAIN RESULTS: Overall, the DO2 increased from 532 +/- 146 to 634 +/- 225 (SD) mL/min.m2 (p less than .001), and the VO2 increased from 145 +/- 39 to 160 +/- 56 mL/min.m2 (p = .02). These changes occurred with an Hgb increase from 9.3 +/- 1.1 to 10.7 +/- 1.5 g/dL (p less than .001). The patients were grouped by their pretransfusion serum lactic acid values. In those patients with normal (less than 1.6 mmol/dL) serum lactic acid (n = 10), DO2 increased from 560 +/- 113 to 676 +/- 178 mL/min.m2 (p less than .02), and VO2 increased from 150 +/- 25 to 183 +/- 46 mL/min.m2 (p less than .02). However, in the increased serum lactic acid group (n = 17), VO2 was not significantly changed after transfusion (143 +/- 46 to 146 +/- 58 mL/min.m2) despite increased DO2 (515 +/- 163 to 609 +/- 251 mL/min.m2, p less than .01). CONCLUSIONS: Blood transfusion can be used to augment DO2 and VO2 in septic surgical patients. Increased serum lactic acid values do not predict patients who will respond. The absence of lactic acidosis should not be used in this patient population to justify withholding blood transfusions to improve flow-dependent VO2. Patients who have increased lactate concentrations may have a peripheral oxygen utilization defect that prevents improvement in VO2 with increasing DO2.     

Whole body oxygen consumption and critical oxygen delivery in response to prolonged and severe carbon monoxide poisoning

BACKGROUND: Carbon monoxide (CO) poisoning remains the leading cause of death by poisoning in the world. One of the major proposed mechanisms for CO toxicity is the binding of CO to cytochrome oxidase and interference with cellular oxygen utilization but evidence for this is inconclusive. AIM OF STUDY: This study examined the effects of prolonged CO exposure on the dynamics of whole body oxygen consumption (VO(2)) and oxygen delivery (DO(2)) in an attempt to observe if CO exposure results in a defect of oxygen utilization defect as determined by a reduction in VO(2) during the course of poisoning prior to reaching the point where VO(2) is directly dependent on DO(2). This critical level of DO(2) (DO(2)crit) produced by CO poisoning was compared to historical values produced by other insults, which decrease global body DO(2). METHODS: Five small dogs were ventilated for 2 h with 0.25% CO and room air followed by 0.5% CO until death. Cardiac index (Q), DO(2), VO(2), oxygen extraction ratio (OER), and systemic lactate were measured every 15 min until death. RESULTS: Carboxyhemoglobin (COHb) levels increased linearly over 2.5 h to values above 80% until death. VO(2) remained constant and not significantly different from baseline below a COHb of 80%. At COHb levels above 80%, VO(2) precipitously dropped. Similarly lactate levels were not significantly elevated from baseline until VO(2) dropped. DO(2) decreased by 78% (from 23+/-6 ml/kg/min to 5+/-4 ml/kg/min) over time despite an increase in Q by 58% until levels of COHb were above 80%. OER increased from 19+/-5% to 50+/-11% until death. The calculated DO(2)crit was 10.7+/-4 ml/min/kg, which is not significantly different from values ranging from 7 to 13 ml/min/kg reported in the literature due to other insults, which reduce DO(2). CONCLUSION: In this canine model of prolonged CO exposure, no gradual reduction in VO(2) or increase in systemic lactate prior to reaching DO(2)crit was noted. In addition, CO exposure does not appear to change the DO(2)crit. The combination of these findings does not support the theory that CO produces a whole body intracellular defect in oxygen utilization.     

The renal and neurohumoral effects of the addition of low-dose dopamine in septic critically ill patients

OBJECTIVES: Dopamine exerts a complicated action on the cardiovascular-renal and neurohumoral systems. We evaluated the effects of the addition of different doses of dopamine on top of treatment with norepinephrine on the haemodynamics, renal function and neurohormones of septic shock patients. DESIGN: Open, uncontrolled, dose-finding study. SUBJECTS: Dopamine was administered, after fluid resuscitation, to septic shock patients who were more than 2 h haemodynamically and pulmonary stable with the use of a constant dose norepinephrine. Patients with a serum creatinine above 180 micromol x l were excluded. METHODS: Dopamine doses of 0, 2, 4, 6 and 0 microg x kg(-1) x min(-1) were given consecutively for 1 h each. Neurohormones were measured hourly after baseline levels had been taken. Systemic haemodynamics were measured using a pulmonary artery (PA) catheter every 30 min, whereas urine collections were examined every hour during the study period. RESULTS AND STATISTICAL ANALYSES: Eight patients (mean age 46 +/- 13 years, M/F 3/5) were included. The median norepinephrine dose at the start of the study was 0.29 microg x kg(-1) x min(-1) (range 0.07-0.48 microg x kg(-1) x min(-1)). Cardiac output (CO) rose during the dopamine infusion for all doses from 7.9 +/- 1.74 l/min to a maximum of 10.1 +/- 1.71 l/min, achieved at the 4 microg x kg(-1) x min(-1) dopamine dose, whereas systemic vascular rate (SVR) decreased slightly for all doses. Heart rate remained unchanged during the 2 microg x kg(-1) x min(-1) dose of dopamine but increased for the 4 and 6 microg x kg(-1) x min(-1) doses from 108 +/- 17 to a maximum of 124 +/- 24 beats/min. Filling pressures remained unchanged whereas the mean arterial blood pressure increased (from 83 +/- 7 to 93 +/- 11 mmHg). Plasma renin activity (PRA) was relatively high (but remained unchanged) as were aldosterone levels. Sodium excretion and diuresis increased for all doses, accompanied by an increase of fractional sodium excretion at the 4 and 6 microg x kg(-1) x min(-1) doses of dopamine. Creatinine clearances remained unchanged. All changed values returned to baseline values after cessation of the dopamine administration. CONCLUSION: During norepinephrine infusion, increasing doses of dopamine from 2 to 6 microg x kg(-1) x min(-1) augments CO, diuresis and sodium excretion in patients treated for septic shock, without changes in creatinine clearance. Higher doses of dopamine (4 and 6 microg x kg(-1) x min(-1)) also induce an increase in heart rate. PRA, aldosterone and norepinephrine levels remain unchanged during dopamine infusion.     

Different dosages of dobutamine in septic shock patients: determining oxygen consumption with a metabolic monitor integrated in a ventilator

OBJECTIVE: Oxygen consumption (VO2) obtained from respiratory gases by indirect calorimetry (VO2,IC) with a metabolic monitor integrated in a ventilator were to be compared to VO2 obtained by the Fick principle (VO2,Fick) in septic patients following an increase in oxygen delivery (DO2) induced by positive inotropic support. DESIGN: Prospective clinical study. SETTING: University Hospital, Surgical Intensive Care Unit (ICU). PATIENTS: Thirty patients suffering from sepsis. INTERVENTIONS: DO2 was increased by dobutamine infusion, starting with an initial dosage of 5 microg x kg x min, increased to a maximum of 10 microg x kg x min. MEASUREMENTS AND MAIN RESULTS: Dobutamine infusion induced a dosage-related increase in DO2 (from 577 +/- 192 to 752 +/- 202 ml x min x m2, p < 0.01), which was associated with a statistically significant increase in VO2,IC (from 173 +/- 30 to 188 +/- 28 ml x min x m2, p < 0.01) and in VO2,Fick (from 140 +/- 25 to 156 +/- 24 ml x min x m2, p < 0.01). The comparison between VO2,IC and VO2,Fick revealed differences (bias and precision--33 +/- 32 ml x min x m2). CONCLUSIONS: With a metabolic monitor integrated in a ventilator it was possible to carry out continuous monitoring of calorimetric data under clinical conditions. In contrast to previous studies using indirect calorimetry, this study showed a moderate correlation between VO2 and DO2 in septic patients using either method. The clinical relevance of this finding requires further investigation. Different factors (e. g. injectant temperature, pulmonary VO2) produced substantial differences between VO2,IC and VO2,Fick as previously shown.     

Cardiorespiratory and metabolic effects of dopamine and dobutamine infusions in dogs

The effects of iv dobutamine and dopamine infusions were studied at six incremental doses (range 5 to 160 micrograms/kg.min) in two groups of five dogs. Dobutamine decreased the systemic vascular resistance (SVR), without significant changes in mean arterial pressure (MAP), or pulmonary vascular resistance (PVR). Dopamine increased MAP, SVR, and PVR, except for a decrease at 10 micrograms/kg.min. Both drugs produced dose-related increases in cardiac output and venous admixture; however, with dopamine the dose-response curve reached a plateau at doses greater than 40 micrograms/kg.min. While the oxygen consumption (VO2) increased progressively in both groups, the oxygen availability ratio (DO2/VO2) and arteriovenous oxygen content difference (CaO2 - CvO2) were maintained mainly by increased cardiac output in the dobutamine group and hemoglobin concentration in the dopamine group. Thirty minutes after termination of drug infusions, the DO2/VO2 dropped, and CaO2 - CvO2 increased significantly in both groups. These changes were mainly due to sustained high VO2; however, in the dopamine group, a larger imbalance resulted from further decreases in cardiac output to levels below the control value.     

Increased systemic oxygen consumption offsets improved oxygen delivery during dobutamine infusion in newborn lambs

OBJECTIVE: To determine: 1) if dobutamine elicited a thermogenic response during postnatal development; and 2) if this response impacted on the balance between systemic O(2) delivery (DO(2)) and O(2) consumption (VO(2)), and involved one or a combination of adrenoceptor subtypes. DESIGN: Prospective non-randomized unblinded study. SETTING: University research laboratory. Subjects: Thirty-five Border-Leicester cross lambs used in a main study performed at 1-2 days (n=7), 7-10 days (n=7), and 6-8 weeks (n=8), and in a adrenoceptor blockade substudy performed at 1-2 days (n=13). INTERVENTIONS: Lambs were instrumented under anaesthesia and dobutamine was infused at incremental rates of 1-40 microg/kg per minute. In separate subgroups of 1-2 day-old lambs, dobutamine was infused after selective or combined alpha1, beta 1, and beta 2-adrenoceptor blockade. MEASUREMENTS: Cardiac output, aortic and pulmonary arterial blood gases, and body temperature were measured. DO(2) and VO(2) were calculated. MAIN RESULTS: Dobutamine increased DO(2) similarly at all three ages. Dobutamine also increased VO(2) in the absence of muscle shivering, but the average rise in 1-2 day-old lambs was sevenfold to 12-fold greater (P<0.001) than in 7-10 day-old and 6-8 week-old animals, was associated with an increase in systemic O(2) extraction, and accounted for approximately 90% of the rise in DO(2). Body temperature rose by 1.3+/-0.5 degrees C in 1-2 day-old animals (P<0.001), but was unchanged in 7-10 day-old or 6-8 week-old lambs. In 1-2 day-old lambs, rises in DO(2), VO(2), and body temperature induced by dobutamine were not affected by selective alpha1, beta1 or beta2 adrenoceptor blockade, but were markedly attenuated by combined adrenoceptor blockade. CONCLUSIONS: A substantial rise in VO(2) which accompanied a pronounced thermogenic effect of dobutamine in newborn lambs utilized most of the associated increase in DO(2) and appeared to be dependent on activation of multiple adrenoceptor subtypes.     

Epinephrine versus dopamine to treat shock in hypoxic newborn pigs resuscitated with 100% oxygen

Shock and tissue hypoperfusion are common after asphyxia. We compared systemic and regional hemodynamic effects of epinephrine and dopamine in the treatment of shock and hypotension in asphyxiated newborn piglets resuscitated with 100% oxygen. Twenty-four piglets (1-3 days old; weight, 1.4-2.6 kg) were acutely instrumented to measure cardiac index (CI), carotid, mesenteric and renal arterial blood flows, and mean systemic (SAPs) and pulmonary arterial pressures (PAPs). Piglets had normocapnic alveolar hypoxia (F(IO2)=0.08-0.10) for 50 min and reoxygenated with F(IO2)=1.0 for 1 h then F(IO2)=0.21 for 3.5 h. After 2 h reoxygenation, either dopamine (2 microg kg(-1) min(-1)) or epinephrine (0.2 microg kg(-1) min(-1)) was given for 30 min in a blinded randomized manner, which was then increased to maintain SAP (within 10% of baseline, pressure-driven dose) for 2 h. Hypoxia caused hypotension (SAP, 44%+/-3% of baseline), cardiogenic shock (CI, 41%+/-4%), and metabolic acidosis (mean pH, 7.04-7.09). Upon reoxygenation, hemodynamic parameters immediately recovered but gradually deteriorated during 2 h with SAP at 45+/-1 mmHg, CI at 74+/-9% of baseline, and pH 7.32+/-0.03. Low doses of either drug had no significant systemic and renal hemodynamic response. Epinephrine (0.3-1.5 microg kg(-1) min(-1)) for 2 h increased SAP and CI (with higher stroke volume) and decreased pulmonary vascular resistance (with reduced PAP-SAP ratio), whereas the responses with dopamine (10-25 microg kg(-1) min(-1)) were modest. Low-dose epinephrine improved mesenteric and carotid arterial flows, whereas the pressure-driven doses of epinephrine and dopamine increased carotid and mesenteric arterial flows, respectively. To treat shock in asphyxiated newborn piglets resuscitated with 100% oxygen, epinephrine exhibits an inotropic action compared with dopamine, whereas both catecholamines can increase carotid and mesenteric perfusion.     

Systemic and regional hemodynamic effects of high-dose epinephrine infusion in hypoxic piglets resuscitated with 100% oxygen

Shock and poor regional perfusion are common in asphyxiated neonates. We compared the systemic and regional hemodynamic effects of high-dose epinephrine (E) with those of dopamine combined with low-dose epinephrine (DE) infusions in a neonatal model of hypoxia-reoxygenation. Neonatal piglets (1-3 days, 1.5-2.5 kg) were acutely instrumented to continuously monitor systemic arterial pressure (SAP), pulmonary artery pressure, cardiac index (CI), and blood flows at the left common carotid, superior mesenteric, and renal arteries. Either epinephrine (1 microg.kg(-1).min(-1)) or dopamine (10 microg.kg(-1).min(-1)) and epinephrine (0.2 microg.kg(-1).min(-1)) were given for 2 h in hypoxic piglets resuscitated with 100% oxygen (n = 8 per group) in a randomized blinded fashion. Control piglets received hypoxia and reoxygenation but no catecholamine infusion (n = 7). Alveolar hypoxia (PaO2, 33-37 mmHg) caused reduced CI (89-92 vs. 171-186 mL.kg(-1).min(-1) of baseline, P < 0.05), hypotension (SAP, 28-32 mmHg) with pH 7.05 to 7.10, and decreased regional flows. Upon reoxygenation, CI and SAP improved but gradually deteriorated to 131 to 136 mL.kg(-1).min(-1) and 41 to 49 mmHg at 2 h of reoxygenation, respectively. E and DE administration similarly improved CI (167 +/- 60 and 166 +/- 55 vs. 121 +/- 35 mL.kg(-1).min(-1) of controls) and SAP (53 +/- 7 and 56 +/- 10 vs. 39 +/- 8 mmHg of controls), respectively, and the pulmonary vascular resistance (vs. controls, all P < 0.05). Heart rate and pulmonary artery pressure were not different between groups. Systemic oxygen delivery and consumption were increased in E- and DE-treated groups with no difference in extraction ratio between groups. There were no differences in regional blood flows and oxygen delivery between groups. After hyperlactatemia with hypoxia, plasma lactate levels decreased with no difference between groups. Epinephrine given as the sole agent is as effective as dopamine and low-dose epinephrine combined in treating shock and hypotension that follow the resuscitation of hypoxic neonatal piglets, with no reduction in regional perfusion.     

Decreased supply-dependent oxygen consumption in the skeletal muscle of the spontaneously hypertensive rat during acute hypoxia

The purpose of this study was to correlate microvascular oxygen delivery (DO2) and consumption (VO2) in the skeletal muscle of spontaneously hypertensive rats (SHRs) and Wistar Kyoto rats (WKY) with hemodynamics during acute hypoxia. We expected greater abnormalities in central and microvascular hemodynamics during hypoxic induced shock in the SHR compared with the WKY due to microvascular rarefaction. The inspired oxygen fraction (FiO2) was lowered from 0.21 to 0.15, 0.1, 0.08, and 0.05 in anesthetized, mechanically ventilated rats. Lactate and base deficit values were similar for both groups at 0.21 and 0.15 FiO2, but higher in SHR at lower FiO2. Baseline aortic blood flow (SHR, 56.2+/-4.0 mL min; WKY, 61.8+/-5.3 mL min) and systemic DO2 (SHR, 9.02+/-0.82 mL min; WKY, 9.32+/-0.54 mL min) increased similarly when FiO2 was lowered to 0.15. Further reductions in FiO2 caused lower aortic flow and systemic DO2 in the SHR than WKY at 0.08 and 0.05 FiO2. Spinotrapezius blood flow increased from baseline (SHR, 24.8+/-1.8 nL s; WKY, 22.7+/-2.1 nL s) in both groups when FiO2 was reduced to 0.15; further reductions in FiO2 decreased blood flow in both groups, with lower values in the SHR group at 0.1 and 0.08 FiO2. The SHR group demonstrated higher venous oxygen saturation at low values of FiO2 compared with WKY. This reduced oxygen extraction in SHR resulted in a lower supply-dependent VO2 at low values of spinotrapezius DO2, perhaps attributed to arteriolar thickening and rarefaction seen in chronic hypertension.     

Changes in whole body and tissue oxygen consumption during recovery from hypothermia: effect of amino acid infusion

OBJECTIVE: To study the effects of amino acids on whole body and peripheral energy metabolism during recovery from post-operative hypothermia. DESIGN: Clinical study using three randomly assigned patient groups. SETTING: ICU of a university hospital. PATIENTS: Nineteen elective coronary bypass operation patients. INTERVENTIONS: Postoperatively, either glucose alone, glucose and a conventional amino acid solution, or glucose and a branch-chain amino acid enriched solution was infused. After ICU arrival (period 1) both conventional amino acid solution and branch-chain amino acid enriched solution groups received 0.15 g/kg-day of nitrogen as a conventional amino acid mixture (20% branch-chain amino acids). After rewarming (period 2), both groups received 0.18 g of nitrogen/kg-day for 2 hrs (branch-chain amino acid content 20% in the conventional amino acid solution and 35% in the branch-chain amino acid enriched solution), and for the following 2 hrs (period 3), 0.22 g of nitrogen/kg-day (branch-chain amino acid content 20% in the conventional amino acid solution and 50% in the branch-chain amino acid enriched solution). MEASUREMENTS AND MAIN RESULTS: Whole body oxygen consumption (VO2) increased during period 1 and continued to increase during period 2 (baseline, 133 +/- 20 mL/min.m2; period 1, 152 +/- 12 mL/min.m2; period 2, 158 +/- 21 mL/min.m2; period 3, 153 +/- 15 mL/min.m2; p less than .05, period 1 vs. baseline). VO2 in the leg increased during period 1 but remained constant thereafter (baseline, 16 +/- 8 mL/min.m2; period 1, 26 +/- 14 mL/min.m2; period 2, 23 +/- 6 mL/min.m2; period 3, 24 +/- 10 mL/min.m2; p less than .05, period 1 vs. baseline). Amino acid infusions had no thermogenic effect. A two-phase redistribution of VO2 and leg VO2 suggested increased visceral VO2 after rewarming. CONCLUSION: The amino acid infusions had no effect on the leg uptake of glucose, ketone bodies, and pyruvate and the leg release of lactate, free fatty acids, and triglycerides, which remained constant during the study.     

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

BACKGROUND AND METHODS: This study was designed to test whether dopexamine, a dopaminergic and beta 2-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 micrograms/kg.min. Data were analyzed between and within groups by split-plot analysis of variance with significance of identified differences tested post hoc by Duncan's 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. RESULTS: In 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. CONCLUSIONS: Dopexamine provided hemodynamic support for endotoxic dogs, thereby increasing total DO2 and VO2, while not altering oxygen extraction in the muscle.     

Lung fluid dynamics and supply dependency of oxygen uptake during experimental endotoxic shock and volume resuscitation

BACKGROUND AND METHODS: We studied the effect of volume resuscitation on lung fluid balance and systemic oxygen extraction during septic shock in eight anesthetized dogs. Sepsis was induced using a 2-hr continuous infusion of Escherichia coli endotoxin at 0.25 micrograms/min.kg. Relationships between oxygen uptake (VO2) and oxygen supply (DO2) were performed acutely during stepwise controlled decrements in cardiac output by progressive inflation of an intracardiac balloon. At each stage, DO2 and corresponding VO2 were measured independently and the individual critical DO2 level was referred to as the point below which the relationship held. The slope of such a constructed relationship was defined as the maximal oxygen extraction ratio. Lung fluid balance was assessed by measurements of extravascular lung water. All values were studied at baseline, after endotoxin insult, and after reversing hypotension by a 10% dextran infusion. RESULTS: Endotoxin infusion led to a shock state that associated hypotension (from 135 to 63 mm Hg) with increases in blood lactate (from 0.53 to 3.9 mmol/L). The mean critical DO2 and maximal oxygen extraction ratio were significantly altered from 7.9 to 17.8 mL/min.kg and from 0.81 to 0.38, respectively. After reversing hypotension by 28 mL/kg colloid infusion, the critical DO2 (11.4 mL/min.kg) and maximal oxygen extraction ratio (0.48) were significantly improved. However, restoration of normal values required a state of fluid overload by further dextran infusion (8 mL/kg). At the end of the fluid challenge, extravascular lung water significantly increased from 6.4 to 17.4 mL/kg. CONCLUSIONS: These data suggest that volume loading may reverse endotoxin-induced peripheral perfusion abnormalities. However, substantial pulmonary edema may occur, possibly jeopardizing the beneficial effects of fluid expansion.     

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.     

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.     

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.     

Effects of dobutamine on hepato-splanchnic hemodynamics in an experimental model of hyperdynamic endotoxic shock

Dobutamine infusion has been proposed to increase splanchnic blood flow in septic conditions, but its' effects on liver blood flow and metabolism have not been well defined. We investigated the effects of dobutamine on liver blood flow, metabolism, and pathology in a canine hyperdynamic endotoxic shock model. Twenty-one dogs were anesthetized and paralyzed. After the administration of 2 mg/kg endotoxin, normal saline was infused to restore the pulmonary artery-occluded pressure to 10 mmHg. The dogs were then randomized to receive fluids either alone (n = 7) or combined with a dobutamine infusion at a rate of 5 (n = 7) or 10 microg/kg per min (n = 7). After initial fluid resuscitation, cardiac index (CI) increased from 152+/-48 to 386+/-97 mL/kg per min (P < 0.01) and then slightly decreased with time in the control group, but further increased to 458+/-54 mL/kg per min (P< 0.05) and remained elevated in the group treated with 5 microg/kg per min of dobutamine. Portal vein and hepatic arterial blood flows followed a similar course and increased with fluid resuscitation. Both decreased with time in the control group, but further increased in the dobutamine-treated animals. Liver oxygen delivery (DO2liv) increased with fluids from 2.2+/-2.4 to 3.8+/-1.9 mL/kg per min (P < 0.01) and further increased in the dobutamine-treated animals to 4.1+/-1.2 mL/kg per min. This was associated with an increase in liver oxygen uptake from 1.6+/-1.6 to 2.9+/-1.1 mL/kg per min with fluid resuscitation and a further increase to 4.3+/-1.5 mL/kg per min with dobutamine administration. Lactate consumption and hepatic vein oxygen saturation increased with initial fluid resuscitation and then decreased with time in the control group, but not in the dobutamine-treated animals. Increasing the dose of dobutamine to 10 microg/kg per min did not alter this response. At the end of the experiment, liver tissue samples were obtained for microscopic studies. The histological lesions seen in the control group were unaffected by dobutamine. In conclusion, dobutamine increases liver blood flow and metabolism, but does not affect microscopic findings in this hyperdynamic endotoxic shock model.