Distribution of cardiac output, oxygen consumption and lactate production in canine endotoxin shock.

Endotoxin causes shock accompanied by compensatory changes such as redistribution of cardiac output and increased oxygen extraction. We studied these effects in anaesthetised dogs (etomidate: 4 mg X kg-1 X h-1, n = 14) randomly assigned to a control (n = 6) and a shock group (endotoxin 1.5 mg X kg-1; n = 8). We measured left ventricular pressure, LVEDP and LVdP/dt (Millar microtip), mean systemic, central venous and pulmonary artery pressure (Statham P23Db), cardiac output (thermodilution), organ flow (microspheres, 15 micron, 5 labels), bloodgases (PO2, PCO2), pH and lactate. All measurements were performed before and at 60, 90, 120 and 150 min after endotoxin or saline. Sixty minutes after endotoxin mean systemic pressure, LVdP/dt and cardiac output had decreased (by 60, 50 and 35%), while heart rate had increased (by 30%). Arterial PO2 was lower after endotoxin (-29%), haematocrit and mixed venous PCO2 were higher (+16 and +38%) and arterial pH had decreased from 7.34 to 7.14. After endotoxin perfusion of heart and adrenals did not change but muscle perfusion increased (by 33% at t = 90). Endotoxin caused vasoconstriction in spleen and kidneys: the percentage of cardiac output to these organs thus decreased (by 50 and 69%). Sixty minutes after endotoxin we found vasodilatation in the hepatic arterial, pancreatic, and gastrointestinal beds. Later the percentage of cardiac output to these beds decreased. Systemic arterio-venous shunting fell (from 6.5 to 0.7%). Systemic and splanchnic oxygen extraction increased (by 66 and 71% at t = 60): oxygen consumption hardly changed; 60 min after endotoxin it tended to decrease. During shock serum lactate rose (by 167% at t = 60) before oxygen consumption fell. Myocardial oxygen consumption did not alter during shock but the tension time index decreased.

Maldistribution of heterogeneous coronary blood flow during canine endotoxin shock.

STUDY OBJECTIVE - The aim was to investigate whether heterogeneous coronary blood flow is maldistributed during endotoxin shock. DESIGN - Variables were studied before (t = 0) and at t = 90 and t = 120 min after bolus injection of saline (n = 6) or endotoxin (n = 6). SUBJECTS - 12 anaesthetised mongrel dogs, weight 20-27 kg, were used. MEASUREMENTS AND MAIN RESULTS - We studied myocardial blood flows in small tissue sections (of about 1 g in left and 2 g in right ventricle) with radioactive microspheres, together with haemodynamic variables and global myocardial metabolism. At t = 0 min in controls, regional flows per 100 g were heterogeneous and ranged from a factor 0.2 to 2.7 and 0.6 to 1.6 of mean flow per 100 g to the left and right ventricle respectively; heterogeneity was unchanged at t = 90 and t = 120 min. Between t = 0, t = 90, and t = 120 min regional flows correlated: r = 0.78(SD 0.14), n = 18, for left ventricle, and r = 0.70(0.17) for right ventricle. In the endotoxin group, cardiac output and mean arterial pressure decreased by 44(7) and 48(11)% respectively, and lactate increased by 3.2(0.6) mmol.litre-1 at t = 120 min. Global left ventricle blood flow and delivery and metabolism of O2 were unchanged; lactate extraction and external work fell. The ratio between global right ventricular O2 delivery and external work also rose. Regional blood flows ranged from a factor 0.2 to 2.7 and 0.1 to 1.8 of mean flow to left and right ventricles respectively; heterogeneity did not differ from controls and did not change with time. Flow correlations with time were reduced: 0.45(0.24) for left ventricle and 0.45(0.26) for right ventricle (both n = 18, p less than 0.005 v controls). The left ventricular endocardial to epicardial flow ratio fell; flow was redistributed to both layers. CONCLUSIONS - Heterogeneous blood flow is redistributed throughout the heart during canine endotoxin shock so that, at unchanged global blood flow and flow heterogeneity, flow decreases in some but increases in other areas. Flow maldistribution may be associated with focal ischaemia, which may be masked by a rise in O2 uptake for a given workload (contractile inefficiency) in overperfused areas, and may thereby contribute to a fall in global myocardial external work for a given O2 delivery.

Skeletal muscle perfusion and metabolism during canine endotoxin shock.

Conflicting data exist in literature about the effects of endotoxin on skeletal muscle perfusion and metabolism during canine endotoxin shock. In 12 dogs we therefore studied (six control and six endotoxin treated, 1.5 mg X kg-1) under etomidate (4 mg X kg-1 X h-1) anaesthesia muscle blood flow (radioactive microspheres) in fore limb, thorax, diaphragm and hind limb (five different muscles) and skin blood flow before (t = 0) and 90 and 120 min after endotoxin. We also measured blood flow in the femoral artery and vein (electromagnetic flow transducers) and the arteriovenous differences of oxygen, lactate, glucose and FFA over the femoral vascular bed (at t = 0, 30, 90 and 120 min). Endotoxin administration caused a fall of flow in the femoral artery and vein (by 65 and 63%, respectively at t = 15). After t = 60 flow in the femoral artery and vein increased slowly but the flows were still below the preshock values at t = 20 (by 33 and 50%, respectively). Skeletal muscle and skin flow did not decrease or even increased after endotoxin but decreased in the control group. Percentage of cardiac output distributed to brachial, intercostal and hind limb muscle and skin increased after endotoxin (by 163, 167, 111 and 120%, respectively at t = 20). The five muscles of the hind limb did not respond differently to endotoxin. In spite of diminished arterial inflow, skeletal muscle perfusion was thus maintained in the hind limb, probably due to closing of shunts and redistribution of blood away from bone. Oxygen extraction but also lactate release by the femoral bed had increased during endotoxin shock. After endotoxin femoral glucose extraction was only elevated at t = 30 when arterial glucose concentration had also increased. The femoral bed produced free fatty acids (FFA) but during endotoxin shock the arteriovenous concentration difference of FFA decreased. Our data suggest that skeletal muscle flow nor oxygen consumption and glucose metabolism is affected during 2 h of canine endotoxin shock. Lactate production, however, tended to increase.

Myocardial metabolic and morphometric changes during canine endotoxin shock before and after glucose-insulin-potassium.

Glucose-insulin-potassium (GIK) improves myocardial function during endotoxin shock but the mechanism of this action is not clear. We have studied in open chest dogs the effects of GIK (n = 9) on haemodynamics, myocardial biochemistry (repeated drill biopsies; glucose-6-phosphate, G-6-P; fructose-6-phosphate, F-6-P; adenosine triphosphate, ATP; creatinine phosphate, CP; glycogen) and myocardial histomorphometry. The animals were anaesthetised (etomidate 4 mg X kg-1 X h-1) and artificially ventilated (N2O:O2 = 2:1). After endotoxin (1.5 mg X kg-1) cardiac output (CO) and mean arterial pressure (MAP) fell rapidly, with a temporary recovery followed by gradual circulatory collapse. Coronary blood flow (cbf; radioactive microspheres) decreased, but this was not significant. G-6-P tended to fall, as did ATP levels while CP levels were unaltered. Histomorphometrical analysis showed myocardial cell swelling with compression of capillaries and decreased interstitial volume. GIK infusion (50% glucose, 2 g X kg-1bw, 8 mmol KCl and 3 U insulin kg-1bw) increased CO and coronary blood flow. Glycogen and G-6-P levels did not change, while F-6-P tended to increase. ATP levels were not influenced by ATP/CP ratio decreased. Myocardial cell swelling markedly decreased; average capillary cross-sectional area, as an index of capillary compression, returned to control value. In two dogs, which died before the end of the experiment, myocardial oedema, with disturbed capillary volume and reduced interstitial volume was unaltered after GIK. The initial effects of GIK are most likely due to restoration of myocardial perfusion. Improved perfusion, and the influence of elevated serum osmolality and insulin levels on excitation-contraction coupling may help to improve myocardial function.

Metabolic vasodilatation with glucose-insulin-potassium does not change the heterogeneous distribution of coronary blood flow in the dog.

OBJECTIVE: The heterogeneous distribution of coronary blood flow could represent regional differences in demand, or mismatching of regional O2 supply to demand, caused by regionally exhausted vasodilatation (anatomical/mechanical factors) or by regional arteriovenous diffusional O2 shunting. Regional coronary blood flow and global myocardial oxygenation and metabolism were measured during metabolic vasodilatation with glucose-insulin-potassium (GIK). METHODS: Variables were studied before and 30 and 60 min after start of a 30 min infusion of GIK (50% glucose, 4 ml.kg-1, 8 mM KCl, and 3 U insulin.kg-1). Regional blood flows were measured by radioactive microsphere technique and cardiac output by thermodilution. Experimental subjects were six anaesthetised mongrel dogs, weighing 20-27 kg. RESULTS: GIK increased plasma osmolarity and lactate, decreased haemoglobin, and increased cardiac output by 67(29)% and systemic O2 supply by 32(13)%, at unchanged arterial and central venous pressures and heart rate. Coronary blood flow rose by 97(50)% and left ventricular O2 supply by 56(41)%. Although regional blood flows in small tissue samples of about 1 g in the left ventricle ranged from a factor 0.31 to 1.73 of mean flow, GIK did not change flow heterogeneity and regional flows significantly correlated in time. Left ventricular O2 uptake rose by 42(40)%, while venous PO2 increased and O2 extraction decreased. Global lactate uptake increased at unchanged extraction. Changes were reversed after GIK. CONCLUSIONS: GIK transiently increases myocardial O2 uptake following a raised cardiac output, caused by a hyperosmolarity induced rise in cardiac contractility rather than by haemodilution. Although myocardial O2 supply is distributed heterogeneously, the fractional rise with GIK is almost equal among regions. At constant lactate extraction, increased venous PO2 and decreased O2 extraction do not indicate overperfusion in some regions at the cost of underperfusion in others, are probably caused by a small, direct vasodilating effect of hyperosmolarity, and argue against diffusional O2 shunting. As for global O2 supply to demand, the increase in regional O2 supply is probably well adapted to regionally increased demand during GIK, so that the heterogeneous distribution of O2 supply can be explained by regional differences in demand and not by regionally exhausted vasodilatation or O2 shunting.

Gut endotoxin restriction improves postoperative hemodynamics in the bile duct-ligated rat.

BACKGROUND: Postoperative hemodynamic disturbances in obstructive jaundice are associated with complications such as shock and renal failure. Gut-derived endotoxemia may underlie these complications. Recently, we have shown that cholestyramine treatment prevents gut-derived endotoxemia in bile duct-ligated (BDL) rats (Houdijk APJ, Boermeester MA, Wesdorp RIC, Hack CE, van Leeuwen PAM: Tumor necrosis factor unresponsiveness following surgery in bile duct-ligated rats. Am J Physiol 271: G980-G986, 1996). METHODS: The effect of cholestyramine on systemic hemodynamics and organ blood flows after a laparotomy was studied in 2 wk BDL rats using radioactive microspheres. RESULTS: Compared with sham-operated rats, postoperative BDL rats had 1) lower blood pressure (p < .05) and heart rate (p < .001) with higher cardiac output (p < .05), 2) lower splanchnic blood flow (p < .05), 3) lower renal blood flow (p < .01), and 4) higher splanchnic organ and renal-vascular resistances. Cholestyramine treatment in BDL rats prevented the postoperative decrease in blood pressure by increasing cardiac output (p < .01). In addition, cholestyramine maintained splanchnic blood flow at sham levels (p < .05). Furthermore, cholestyramine also prevented the fall in renal blood flow after surgery in BDL rats. CONCLUSION: Gut endotoxin restriction using cholestyramine treatment maintained normal blood pressure, improved splanchnic blood flow, and completely prevented the fall in renal blood flow in BDL rats. Reducing the gut load of endotoxin in patients with obstructive jaundice scheduled for abdominal surgery may prevent postoperative hemodynamic complications.

The fall of cardiac output in endotoxemic rats cannot explain all changes in organ blood flow: a comparison between endotoxin and low venous return shock.

During endotoxin shock mean arterial pressure (MAP) and cardiac output (CO) fall, and the latter is redistributed. To evaluate whether these changes are solely caused by the low output, or are also based on endotoxin itself, we compared regional hemodynamic changes during endotoxemia with those in a nonendotoxemic state of decreased CO in anesthetized rats. In group E (n = 10) endotoxin Escherichia coli O127:B8 (8 mg.kg-1) was infused from t = 0 till t = 60 min. In group B (n = 10) the same decrease of CO and MAP was obtained as in group E by inflating a balloon in the inferior caval vein, distal to the renal veins, from t = 0 till t = 60 min. We measured MAP, CO (thermodilution), central venous pressure, heart rate, organ blood flow, and redistribution of CO (microspheres), arterial lactate and glucose, and hematocrit. MAP and CO decreased (p < .05) in both groups (by 30 and 50%, respectively at t = 60). Heart rate, hematocrit, arterial lactate, and arterial glucose were significantly higher (p < .05) in group E (by 17, 12, 180, and 55%, respectively). Blood flow to most organs had similarly decreased in both groups. The decreased intestinal blood flow lead to macroscopic damage only in group E. Blood flows (absolute or as percentage of CO) to heart, hepatic artery, and diaphragm, however, had significantly increased in group E while blood flows to skin, skeletal muscle, and stomach had decreased more in group E. Except for the heart these differences could be explained by increased work load (detoxification: liver; hyperventilation: diaphragm, muscle) and thus to a more pronounced redistribution at the expense of skin and muscle blood flow. Regional hemodynamic changes during endotoxemia thus could largely be attributed to decrease of CO and redistribution of the circulating blood volume. In the heart, endotoxin seemed to exert effects independent of the hypodynamic state. This was also true for the intestinal damage and the rise in hematocrit and arterial lactate.

Laparotomy and renal function during endotoxin shock in rats.

Despite the wide use of laparotomy to study kidney function, the possible influence of this procedure on systemic and renal parameters in septic rats is unknown. We studied this in anesthetized Wistar rats with and without endotoxin shock (1 h Escherichia coli O 127.B8: 8 mg.kg-1 infusion). We also compared clearance of creatinine and inulin to measure glomerular filtration rate (GFR). Laparotomy attenuated the endotoxin-induced decrease in cardiac output and abolished the increase in systemic and renal vascular resistance, while renal plasma flow was maintained. Better perfusion in other organs as well was indicated by a more gradual increase in arterial lactate concentration and less intestinal damage. By contrast, GFR decreased considerably during endotoxemia, irrespective of laparotomy. This change in GFR could be reliably assessed using creatinine clearance. The ratio of creatinine-to-inulin clearance averaged between .5 and .75. Renal ATP content did not change and the endotoxin-induced increase in the number of granulocytes lodged in glomeruli was not affected by laparotomy. In conclusion, our study indicates that laparotomy significantly influences the vascular effects caused by endotoxin. Laparotomy also revealed an effect of endotoxin on GFR, independent of renal blood flow.

Gram-negative shock in rats depends on the presence of capsulated bacteria and is modified by laparotomy.

To develop a hyperdynamic sepsis model in rats, four Escherichia coli strains were used, which differed in the presence or absence of a capsule or K antigen (K1 and K-, respectively) and/or in O serogroup (O9 and O18). Of the two clinical isolates, O9K- did not survive in rat serum, whereas O18K1 and two isogenic laboratory strains (O18K1 and O18K-) were able to resist serum bacteriolysis. Pentobarbital-anesthetized rats (n = 21) received an intravenous bolus of 10(9) bacteria. In contrast to the two noncapsulated strains, both capsulated strains induced hyperdynamic shock; arterial lactate rose from a mean value of .91 to 3.09 mmol.L-1, systemic vascular resistance dropped from 1.15 to .78 mmHg.min.mL-1, and cardiac output transiently increased from 98 to 115 mL.min-1; renal plasma flow remained at 3-4 mL.min-1, whereas glomerular filtration rate decreased from 1.3 to .7 mL.min-1. Laparotomy, which is often performed to study kidney function, completely abolished the hyperdynamic condition, while glomerular filtration rate was still decreased. We conclude that in rats, in contrast to humans, capsulated bacteria are required to induce a hyperdynamic septic shock; the hyperdynamic characteristics of the shock do not occur in animals subjected to a laparotomy.

Paradoxical changes in organ blood flow after arginase infusion in the non-stressed rat.

Arginine (ARG) is the precursor of nitric oxide (NO), a potent vasodilator. Arginase (ASE) is released following hepatocellular damage, resulting in low plasma ARG levels. The effect of ASE infusion on hemodynamics was studied. Rats received a 20 min ASE or saline infusion, and systemic hemodynamics and organ blood flow were studied, at 30 and 270 min, using radiolabeled microspheres. Compared with control, ASE resulted (30 min) in 1) undetectable ARG levels; 2) higher mean arterial pressure and total peripheral resistance (both p < .05); 3) higher blood flow to the heart, kidneys, stomach, small intestine (all p < .05), and spleen (p < .001); and 4) lower vascular resistance in the heart, kidneys, stomach, and small intestine (all p < .05) and in the spleen (p < .005). At 270 min, ASE rats had similar organ blood flow and higher nitrate levels in urine and plasma (both p < .05) compared with control. We conclude that ASE reduces ARG levels with simultaneous increase in mean arterial pressure and total peripheral resistance. Higher nitrate production, suggesting higher NO formation in the presence of low ARG plasma levels, is paradoxical but could explain the higher blood flow in some organs. The increased total peripheral resistance during higher nitrate formation suggests regional differences in dependency of NO production on plasma ARG levels.

Reduced arginine plasma levels are the drive for arginine production by the kidney in the rat.

In bile duct ligated rats, arginase (ASE) release from damaged hepatocytes results in low arginine (ARG) levels despite maximal renal ARG production. Plasma ARG levels were restored by reducing gut-derived endotoxemia that lowered circulating ASE activity although maintaining increased renal production. From this it was not clear if the higher renal ARG production was induced by the low grade endotoxemia or the low arginine plasma levels. The separate and combined influence of both factors on ARG metabolism was studied in the rat. Male Wistar rats received either bovine liver ASE, to lower ARG levels, or saline (SAL). Following the ASE or SAL infusion, rats were randomized to receive a low dose endotoxin (LPS) or SAL infusion. In ASE/SAL- and ASE/LPS-treated rats, ARG levels were lower compared with SAL/SAL (p<.005) and SAL/LPS (p<.005). The increased ARG production by the kidneys and gut proved to be independent of LPS but related to reduced ARG plasma levels (both p<.05 when compared with SAL/SAL and SAL/LPS). Metabolism of related amino acids was not explanatory. The study concluded that a low grade endotoxemia did not influence the metabolism of ARG by the gut, kidney, and liver. Reductions in ARG plasma by ASE treatment, irrespective a low dose endotoxin, were the drive for ARG production by the gut and the kidney.

Soluble glucan protects against endotoxin shock in the rat: the role of the scavenger receptor.

Soluble carboxymethyl-b-1,3-glucan (CMG), a possible ligand for scavenger receptors, has macrophage-activating action but lacks the granulomatose inflammatory side effect: it is a promising immunomodulator that may mitigate the severity of sepsis. This motivated us to study in rats the effect of CMG (25 mg/kg), injected into the tail vein at 48 and 24 h prior to the administration of 5 mg/kg Escherichia coli 0127.B8 endotoxin on survival, hemodynamic condition, and, in vitro, on the chemiluminescence of PMNs and macrophages, and on macrophagal tumor necrosis factor (TNF) production. Acetylated low density lipoprotein (AcLDL) clearance in vivo and in vitro binding to macrophages was used to study scavenger receptor function. In the nonpretreated group 9 of 10 rats died during the first 24 h after endotoxin, but all CMG-pretreated rats survived. CMG-pretreatment prevented severe decreases in cardiac output and blood pressure after endotoxin. Chemiluminescence of macrophages and PMNs from CMG-pretreated rats was about two times less (p < .05) than that from nonpretreated ones; the endotoxin induced TNF production by macrophages also decreased. Pretreatment with CMG increased, but coinjection of CMG and AcLDL decreased the AcLDL clearance, while coinjection of endotoxin and AcLDL decreased the survival rate. In vitro AcLDL uptake by macrophages decreased after coinjection with CMG. Our results thus showed that CMG was protective in rat endotoxin shock, which seemed partly connected with enhancement of endotoxin clearance through scavenger receptors and to decreased TNF production.

The liver is an important organ in the metabolism of asymmetrical dimethylarginine (ADMA).

BACKGROUND AND AIMS: Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthase enzymes, whereas symmetrical dimethylarginine (SDMA) competes with arginine transport. Although both dimethylarginines may be important regulators of the arginine-NO pathway, their metabolism is largely unknown. Both dimethylarginines are removed from the body by urinary excretion. However, ADMA is also subject to enzymatic degradation by the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which is highly expressed in the liver. To elucidate the role of the liver in the metabolism of ADMA, we aimed to investigate dimethylarginine handling of the liver in detail. METHODS: Ten male Wistar rats were used for this study. Blood flow was measured using radiolabeled microspheres according to the reference sample method. Concentrations of dimethylarginines were measured by HPLC. The combination of arteriovenous concentration difference and organ blood flow allowed calculation of net organ fluxes and fractional extraction rates. RESULTS: Both the liver (0.89+/-0.11) and the kidney (0.68+/-0.06) showed a high net uptake (nmol/100 g body weight (BW)/min) of ADMA, whereas a significant net uptake of SDMA was only observed in the kidney (0.34+/-0.04). For the liver, fractional extraction rates were 29.5% +/-3.0 for ADMA and 0.0%+/-3.7 for SDMA. Fractional extraction rates of ADMA and SDMA for the kidney were 36.0%+/-2.7 and 31.6%+/-3.8, respectively. CONCLUSIONS: The liver plays an important role in the metabolism of ADMA by taking up large amounts of ADMA from the systemic circulation.

Organ blood flow and distribution of cardiac output in dopexamine- or dobutamine-treated endotoxemic rats.

Endotoxemia causes a decrease of blood flow to most organs. If this could be prevented, chances of survival might improve. In endotoxemic rats, we studied the effect of a therapeutic infusion of dopexamine (dopaminergic, beta 2-adrenergic) on blood flow and percentage of the cardiac output distributed to heart, brain, hepatic artery, stomach, intestines, spleen, pancreas, kidneys, adrenals, diaphragm, skeletal muscle, and skin. Dopexamine action was compared with that of dobutamine (beta 1-adrenergic). Endotoxin shock was induced in 28 rats with infusion of 8 mg/kg Escherichia coli O127:B8 endotoxin from 0 to 60 minutes; the rats were then divided into 3 groups, which received from 60 to 135 minutes of an infusion of saline (ES; n = 10), dopexamine hydrochloride (DX, 3 x 10(-8) mol/kg.min; n = 10) or dobutamine (DB, 10(-7) mol/kg.min; n = 8). A fourth group served as time-matched controls (C, saline from 0 to 135 minutes; n = 8). In the untreated endotexemic rats, cardiac output decreased and organ blood flow decreased except in the diaphragm, heart, and brain; the percentage of the cardiac output to those organs increased. Dopexamine and dobutamine similarly improved cardiac output in endotoxemic rats. All organs benefitted to the same extent from the increased cardiac output. Therapeutic infusion of dopexamine during endotoxemia did not favor flow to any particular organ; redistribution of cardiac output changed little after administration of dopexamine, and its effects were not significantly different from those of dobutamine.

Influence of fluid resuscitation on renal function in bacteremic and endotoxemic rats.

PURPOSE: Fluid resuscitation, which is the most important primary therapy in sepsis, is not always able to prevent acute renal failure. In this study, we investigated in two different rat models of distributive shock whether fluid resuscitation would increase renal plasma flow (RPF) and subsequently glomerular filtration rate (GFR). MATERIALS AND METHODS: In pentobarbital anesthetized wistar rats Haemaccel (Behring Pharma, Hoechst, the Netherlands) infusion (1.2 mL/100 g/h for 3 hours) was started immediately during either bacteremia (bolus of living Escherichia coli bacteria, 10(9) or endotoxemia (1 hour infusion of E. coli endotoxin, 8 mg/kg), as well as in time-matched healthy controls. RESULTS: After 3 hours, this treatment had increased RPF (clearance of 131I-hippurate) above normal in control (+67%) and bacteremic rats (+75%), whereas in endotoxemic animals, the significantly decreased RPF was normalized. On the other hand, in bacteremic animals, the lowered GFR (clearance of creatinine; x44%) was normalized, whereas in endotoxemic animals GFR remained depressed (x30%). The lack of improvement in GFR during endotoxemia was also indicated by a profound fall in urine flow, which by contrast steadily increased in control and bacteremic rats owing to volume loading. In both shocked groups, the decreased renal oxygen delivery was normalized, but the higher renal oxygen consumption than expected on the basis of the work needed for sodium reabsorption was not influenced by Haemaccel treatment, despite the fact that it caused this work load to rise in bacteremic but not in endotoxemic rats. In both shock models, renal cortical adenosine triphosphate content did not differ from healthy controls and was not influenced by volume loading. CONCLUSIONS: In conclusion, our study suggests that a decrease in GFR caused by live bacteria in the circulation may benefit from fluid resuscitation, while during endotoxemia this therapy could not prevent acute renal failure.

Effects of endotoxin on tone and pressure-responsiveness of preglomerular juxtamedullary vessels.

Endotoxin might affect renal vasoreactivity, but in vivo this is difficult to assess (systemic influences). Therefore, we used the in vitro blood-perfused juxtamedullary nephron preparation to study early changes in preglomerular vascular reactivity induced by exposure to endotoxin. Pressure-evoked vasomotor responses were determined videometrically by measuring steady-state inside vessel diameters at a perfusion pressure of 60 or 120 mmHg. Intraluminal application of endotoxin (primary contact with endothelium) for 120 min elicited an early (within 30 min) and sustained approximately 25% vasoconstriction from arcuate artery to the distal portions of the afferent arterioles; autoregulatory responses, indicated by pressure-induced vasoconstriction, were unchanged. When topically applied, endotoxin (primary contact with smooth muscle cells) had no vasomotor effects. Significant constrictions, and increases in autoregulatory responses were obtained when the preparation was taken from kidneys from endotoxin-treated rats. Endotoxin had no effect on efferent arteriolar dimensions. Such preferential preglomerular early vasoconstriction is consistent with the early increase in renal resistance and parallel decrease in renal blood flow and glomerular filtration observed during endotoxin shock in vivo. Our results support the concept of local, endothelium-mediated effects of endotoxin on renal vessels.

Comparison of two types of nonbarbiturate anesthetics during endotoxemia in dogs.

In dogs anesthetized with etomidate (n = 8) or droperidol-methadone-atropine (n = 5), we measured before (t = 0) and after (t = 90 min) endotoxin (1.5 mg X kg-1 IV as a bolus) systemic and pulmonary blood pressures, cardiac output and its distribution (microspheres), blood gases, blood glucose, and lactate. The effects of endotoxin depended little on the type of anesthetic. The differences between the two groups were quantitative rather than qualitative. The influence of the type of anesthesia during endotoxin shock studies should thus not be overestimated.

Blood flow and plasma extravasation in skeletal muscle during endotoxemia. A study in rats.

Apparently skeletal muscle is little affected during endotoxemia. We therefore studied in anesthetized rats the effects of endotoxin on blood flow and extravasation of plasma in skeletal muscle of different regions (thorax, abdomen, foreleg, hind limb) and whether or not extravasation, if present, is related to hypoperfusion. Endotoxemia was induced by infusion of E. coli endotoxin (10 mg/kg) from t = 0 to t = 60 min (E-group: n = 8); control rats received saline (C-group: n = 8). One femoral artery (C:n = 6, E: n = 6) was ligated to cause muscle hypoperfusion in that limb. Experiments ended at t = 120 min. Cardiac output and blood flow were measured at t = 0 and 120 (radioactive microspheres); extravasation was measured with a double isotope technique: 125I-HSA as plasma and 51Cr-labeled red cells as intravascular marker (injected at t = -50 and t = -40 min, respectively). Cardiac output decreased and lactate levels increased markedly during endotoxemia, but muscle blood flow was not affected: percentage of cardiac output to muscles increased in all regions (by 50-100%, p less than 0.05). Femoral artery ligation caused a 33% decreased in muscle blood flow at t = 0; at t = 120 the reduction was 88% in the E-, but only 15% in the C-group. Extravasation of 125I-HSA (from t = 0 to t = 120, as percentage of the total integrated plasma supply over 2-hr) increased during endotoxemia for abdominal, thoracic and foreleg muscles by 178, 148 and 133%, respectively (p less than 0.05). In the non-ligated hind limb endotoxin had no significant effect on extravasation; hypoperfusion alone caused a 300% increase (p less than 0.05%) and the combined effect was a 400% increase (p less than 0.05) in extravasation. Our results show that during endotoxemia muscle blood flow hardly decreases, and that plasma extravasation is only substantial when muscle blood flow is also severely impaired.