Inhibitory effects of diclofenac on the endotoxin shock response in relation to endothelin turnover in the pig

During sepsis vasoactive arachidonic acid metabolites of the cyclo-oxygenase pathway and the endothelium-derived vasoconstrictor endothelin-1 (ET-1) are released. The effects of cyclo-oxygenase pathway inhibition by diclofenac on the endotoxin shock response and ET-1 turnover, were investigated in five groups of pigs. In the first group (n = 7; controls) endotoxin (15μg·kg^?1·h^?1 i.v.) was infused for two hours. In a second endotoxin group (n = 7), the animals were pretreated with diclofenac (3 mg·kg^?1 i.v.). In a third group (n = 7), high-dose ET-1 was infused (20 pmol·kg^?1·min^?1 i.v.) and in a fourth group (n = 7), the ET-1 infusion was preceded by diclofenac. In a fifth group (n = 4), a low and intermediate dose of ET-1 (0.2 and 4 pmol· kg^?1·min^?1) was infused. A significant increase in ET-1-like immunoreactivity (LI) plasma levels was observed in both endotoxin groups, but in the diclofenac group the increase was comparatively delayed. Furthermore, this group showed a more stable haemodynamic course and in the biphasic increase of pulmonary vascular resistance seen in endotoxin controls, the initial peak was abolished by diclofenac. Exogenous ET-1 infusion indicated that not only locally released but possibly also circulating ET-1 could be a mediator of vascular responses to endotoxin. Indications of release from the lungs were seen during endotoxin infusion. Diclofenac had no effect on basal ET-1-LI plasma levels or on the disappearance rate from plasma of ET-1-LI and the haemodynamic changes seen on ET-1 infusion. The inhibition of cyclo-oxygenase pathway by diclofenac resulted in prevention of the initial pulmonary hypertension and a delayed increase in plasma ET-1-LI levels in porcine endotoxin shock and this latter effect is not due to an increased rate of disappearance from plasma but rather to a decreased release of ET-1.     

Endothelin-1-like immunoreactivity in human urine

By using a radioimmunoassay specific for endothelin-1 (ET-1), we studied whether ET-1-like immunoreactivity (LI) is present in human urine. Significant amounts of ET-1-LI were present in human urine, and the daily urinary excretion of ET-1-LI in 30 normal subjects was 67.6 +/- 35.5 ng/day. The mean urinary excretion of ET-1-LI determined in spot urine was 82.8 +/- 38.2 pg/mg creatinine (n = 30), while the mean plasma concentrations of ET-1-LI in the same individuals were 1.1 +/- 0.5 pg/ml. There was no significant correlation between urinary ET-1-LI excretion and its plasma levels. Reverse-phase high-pressure liquid chromatography of human urine extract revealed a major ET-1-LI component coeluting with standard ET-1. The present study demonstrates the presence of ET-1-LI excreted in human urine, although its exact source and physiological significance in renal tissues remain to be determined.     

Effect of intravenous taurine on endotoxin-induced acute lung injury in sheep.

OBJECTIVE: To find out if pretreatment with taurine would reduce the severity of endotoxin-induced acute lung injury in a large animal model. DESIGN: Randomised controlled study under licence from the Department of Health. SETTING: Department of Surgical Research, Ireland. ANIMALS: 15 male Suffolk sheep. INTERVENTIONS: Vascular catheters were placed in the femoral artery and vein and a Swan-Ganz catheter in the external jugular vein under general anaesthetic. Animals were randomized into three groups: control with measurements taken at baseline and half hourly up to 90 minutes; endotoxin, given Escherichia coli endotoxin intravenously after baseline measurements and taurine given 300 mg/kg 1 hour before endotoxin was given. MAIN OUTCOME MEASURES: Mean systemic arterial pressure, mean pulmonary arterial pressure, arterial oxygen tension (PO2), pulmonary myeloperoxidase activity, and neutrophil respiratory burst activity. RESULTS: Endotoxin induced a severe lung injury characterised by a decrease in mean systemic blood pressure and an increase in pulmonary artery pressure, hypoxia, and an increase in pulmonary myeloperoxidase activity. Pretreatment with intravenous taurine significantly reduced these haemodynamic changes. It reduced pulmonary myeloperoxidase activity and peripheral neutropenia and increased neutrophil respiratory burst activity. CONCLUSIONS: This data suggest that taurine may have a therapeutic role in preventing the lung injury seen in endotoxaemia.     

New approach to an ovine model of hypodynamic endotoxaemia

BACKGROUND AND OBJECTIVE: Since the moribund hypodynamic phase of septic shock has primarily been studied in small animal models, the objective of this study was to investigate the usefulness of infusing Salmonella typhosa endotoxin at incrementing doses to establish an ovine model of hypodynamic endotoxaemia. METHODS: In a prospective laboratory experiment, eight adult ewes were instrumented for a chronic study. Following a baseline measurement in the healthy state, a continuous endotoxin infusion was started with 10 ng kg(-1) min(-1) and was doubled every hour seven times. Haemodynamics, key variables of oxygen transport, and arterial lactate concentrations were determined every hour. RESULTS: In a dose-dependent manner, endotoxin infusion caused pulmonary hypertension, decreased cardiac output and mean arterial pressure, increased heart rate, and to a certain extent, systemic vascular resistance index. Following 4h of endotoxaemia, the maximum decrease in cardiac output occurred (4.8+/-0.2 vs. 7.6+/-0.3 Lmin(-1); P < 0.001). This was accompanied by tissue dysoxia, represented by decreases in oxygen delivery (797+/-20 vs. 1041+/-28 mLmin(-1)), oxygen consumption (277+/-14 vs. 396+/-15 mLmin(-1)) and oxygen extraction rate (0.35+/-0.01 vs. 0.38+/-0.01%; each P < 0.01), as well as an increase in arterial lactate concentration (1.7+/-0.1 vs. 0.7+/-0.1 mmolL(-1); P < 0.05). CONCLUSIONS: This large animal model may be helpful to study the pathophysiology responsible for cardiovascular failure, and also new therapeutic approaches relevant to management of hypodynamic circulation in the common setting of progressed systemic inflammation.     

Effects of arginine vasopressin on oxygenation and haemodynamics during one-lung ventilation in an animal model

In a case of arterial hypotension during one-lung ventilation, haemodynamic support may be required to maintain adequate mean arterial pressure. Arginine vasopressin, a potent systemic vasoconstrictor with limited effects on the pulmonary artery pressure, has not been studied in this setting. Twelve female pigs were anaesthetised and ventilated and arterial, central venous and pulmonary artery catheters were inserted. A left-sided double lumen tube was placed via tracheostomy and one-lung ventilation was initiated. The animals were in the left lateral position, with the left lung ventilated and right lung collapsed. Respiratory and haemodynamic values were recorded before and during a continuous infusion of arginine vasopressin sufficient to double the mean arterial pressure. The arginine vasopressin caused a decrease in cardiac output (3.8+/-1.1 vs. 2.7+/-0.7 l/min, P <0.001) and mixed-venous oxygen tension (39.1+/-5.8 vs. 34.4+/-5 mmHg, P=0.003). Pulmonary artery pressure was unchanged (24+/-2 vs. 24+/-3 mmHg, P=0.682). There was no effect of the arginine vasopressin on arterial oxygen tension (226+/-106 vs. 231+/-118 mmHg, P=0.745). However, there was a significant decrease in shunt fraction (28.3+/-6.2 vs. 24.3+/-7.8%, P=0.043) and a significant proportional increase in perfusion of the ventilated lung (78.8+/-9.5 vs. 85.5+/-7.9%, P=0.036). In our animal model of one-lung ventilation, doubling mean arterial pressure by infusion of arginine vasopressin significantly affected global haemodynamics, but had no influence on systemic arterial oxygen tension.     

A comparison of inhaled nitric oxide with intravenous vasodilators in the assessment of pulmonary haemodynamics prior to cardiac transplantation

OBJECTIVE: Elevated pulmonary vascular resistance and transpulmonary gradient are predictors of increased perioperative mortality in patients undergoing orthotopic heart transplantation. Sodium nitroprusside and prostacyclin PGI2 are routinely used to assess the reversibility of pulmonary vascular resistance and transpulmonary gradient in heart transplant candidates, but their use is limited by their systemic vasodilatory effect. The aim of this study was to evaluate the systemic and pulmonary haemodynamic effects of low concentration (10 and 20 parts per million) inhaled nitric oxide in patients with severe heart failure with elevated transpulmonary gradient and pulmonary vascular resistance undergoing assessment for cardiac transplantation, and to compare the haemodynamic effects of inhaled nitric oxide with those of sodium nitroprusside and prostacyclin PGI2. METHOD: In 10 consecutive patients with elevated transpulmonary gradient (16+/-2 mm Hg) and pulmonary vascular resistance (3.6 +/-0.3 Wood units (WU)) nitric oxide (10 and 20 parts per million in 23% inspired oxygen (O2) via a tight fitting facemask) and increasing doses of intravenous sodium nitroprusside and prostacyclin were administered in a random, single-blinded fashion. RESULTS: Inhalation of nitric oxide (10 ppm) reduced the transpulmonary gradient (-7+/-2 mm Hg; P<0.01) and pulmonary vascular resistance (-1.8+/-0.4 WU; P<0.001) but did not affect the systemic vascular resistance (-0.3+/-1 WU) or mean systemic arterial pressure (-1.3 5 mm Hg). Sodium nitroprusside and prostacyclin reduced the transpulmonary gradient (-4.5+/-2 mm Hg; P<0.01 and -3.6+/-2 mm Hg; P<0.05), pulmonary vascular resistance (-1.5+/-0.4 WU; P<0.001 and -1.3+/-0.4 WU; P<0.01), systemic vascular resistance (-7+/-2 WU; P<0.01 and -7.2+/-2 WU; P<0.01) and mean systemic arterial pressure (-15+/-5 mm Hg; P<0.01 and -18+/-4 mm Hg; P<0.01). CONCLUSION: Low-concentration inhaled nitric oxide is as effective as sodium nitroprusside and prostacyclin in reducing transpulmonary gradient and pulmonary vascular resistance, and is highly pulmonary vasoselective.     

Dopamine stabilizes milrinone-induced changes in heart rate and arterial pressure during anaesthesia with isoflurane

BACKGROUND AND OBJECTIVE: Phosphodiesterase-III inhibitors and dobutamine effectively improve cardiac function in patients with cardiac failure, but they are limited by possible hypotensive effects. We tested the hypothesis that dopamine contributes to stabilizing milrinone-induced haemodynamic changes. METHODS: Nine patients undergoing major surgery were anaesthetized using nitrous oxide and oxygen supplemented with isoflurane 1-2%. After baseline haemodynamics were recorded, milrinone (25 or 50 microg kg(-1)) was administered over 10min, followed by a continuous infusion (0.5 microg kg(-1) min(-1). The second set of haemodynamic values was measured 50 min after beginning the continuous infusion of milrinone. Dopamine (4 microg kg(-1) min(-1)) was then administered with milrinone. RESULTS: Milrinone significantly increased the heart rate from 81 +/- 8 to 102 +/- 16beats min(-1), but it decreased the mean arterial pressure from 83 +/- 10 to 66 +/- 10 mmHg and systemic vascular resistance (P < 0.05 for each). The pulmonary capillary wedge pressure, cardiac index and pulmonary vascular resistance did not change significantly. The addition of dopamine to the milrinone infusion significantly decreased the heart rate (94 +/- 12 beats min(-1)) and increased the mean arterial pressure (82 +/- 11 mmHg). Dopamine and milrinone, but not milrinone alone, significantly increased the cardiac index and the rate-pressure product. CONCLUSIONS: The combination regimen of milrinone and dopamine improved cardiac function, and changes in heart rate and mean arterial pressure induced by milrinone were attenuated by dopamine. The results suggest that a combination regimen of milrinone and dopamine rather than milrinone alone should be used to maintain arterial pressure.     

Continuous Venovenous Hemofiltration Improves Arterial Oxygenation in Endotoxin-induced Lung Injury in Pigs

Background: Hypoxemia is common in septic acute lung failure. Therapy is mainly supportive, and most trials using specific inhibitors of key inflammatory mediators (i.e., tumor necrosis factor [alpha], interleukin 1) have failed to prove beneficial. The authors investigated if a nonspecific blood purification technique, using zero-balanced high-volume continuous venovenous hemofiltration (CVVH), might improve arterial oxygenation in a fluid-resuscitated porcine model of endotoxin-induced acute lung injury.

Methods: Piglets of both sexes weighing 25-30 kg were anesthetized and mechanically ventilated. After baseline measurements, animals received an intravenous infusion of 0.5 mg/kg endotoxin (Escherichia coli lipopolysaccharide). One hour after endotoxin, animals were randomly assigned to either treatment with CVVH (endotoxin + hemofiltration, n = 6) or spontaneous course (endotoxin, n = 6). At 4 h after randomization, animals were killed. Hemofiltration was performed from femoral vein to femoral vein using a standard circuit with an EF60 polysulphone hemofilter.

Results: Endotoxin challenge induced arterial hypoxemia, an increase in peak inspiratory pressure, pulmonary hypertension, and systemic hypotension. Treatment with CVVH did not improve systemic or pulmonary hemodynamics. However, arterial oxygenation was increased in endotoxin-challenged animals at 5 h after completion of endotoxin infusion, as compared with animals not receiving CVVH (arterial oxygen tension, 268 +/- 33 vs. 176 +/- 67 mmHg, respectively, P < 0.01). In addition, treatment with CVVH attenuated the endotoxin-induced increase in peak inspiratory pressure and increased lung compliance.     

ET-1 infusion increases systemic vascular resistance and depresses cardiac output in patients with chronic hypoxaemia and pulmonary hypertension.

The pulmonary vascular effects of the endothelium-derived peptide endothelin (ET) vary depending on the existing vascular tone, modes of administration and species studied; ET can cause both pulmonary vasodilatation and vasoconstriction. Increased plasma levels of ET have been reported in hypoxic pulmonary hypertension, although it is unclear whether ET is a mediator or a marker of hypoxia-induced increase in pulmonary vascular resistance (PVR). In our study, the plasma levels of ET-1 and the functional effects of ET-1 infusion in patients (n = 4) with chronic hypoxaemia and elevated PVR were evaluated. At rest, the arterial and venous ET-1-levels (13 +/- 2 and 12 +/- 1 fmol/ml, respectively) were significantly higher than those detected in venous plasma of an age-matched healthy control group (7 +/- 1 fmol/ml). Consecutive 10 min infusions of ET-1 at 1, 5, 10 and 15 ng/kg/min into the pulmonary artery decreased cardiac output (by 32%) and stroke volume (by 33%) and increased the systemic vascular resistance (by 62%) and arteriovenous oxygen difference (by 83%) at the highest dose. No deleterious effect was observed in the pulmonary circulation. The present study therefore suggests that intra-pulmonarily administered ET does not attenuate the increased PVR associated with chronic hypoxaemia.     

Influence of fructose-1,6-diphosphate on endotoxin-induced lung injuries in sheep

BACKGROUND: Fructose-1,6-diphosphate (FDP) is reported to have a salutary effect in endotoxin shock and sepsis. This investigation describes the effect of FDP on pulmonary and systemic hemodynamics, lung lymph protein clearance, and leukocyte count in sheep infused with Escherichia coli endotoxin. MATERIALS AND METHODS: Anesthetized sheep (n = 18), some of which underwent thoracotomy to cannulate lymphatic nodes, were used in this study. After stabilization, all sheep received E. coli endotoxin, 5 microg/kg i.v. infusion over 30 min. Concomitant with the endotoxin infusion, half of the animals were randomly selected to receive an i.v. bolus of FDP (10%), 50 mg/kg, followed by a continuous infusion of 5 mg.kg(-1).min(-1) for 4 h; the rest were treated in the same manner with glucose (10%) in 0.9% NaCl. RESULTS: Pulmonary artery pressure (PAP) and resistance in the glucose group increased from 20.8 +/- 1.6 to 36.7 +/- 3.2 mmHg (P < 0.007) and from 531 +/- 114 to 1137 +/- 80 dyn.s(-1).cm(-5), respectively (P < 0.005). Despite an increase during endotoxin infusion, these parameters in the FDP group returned to control values. There were no differences in left ventricular pressures, cardiac output, heart rate, and arterial oxygen tension between the groups. In the glucose group, lymph protein clearance was higher (P < 0.01) and blood leukocyte count was lower (P < 0.02). The wet/dry lung weight ratio (g/g) for the glucose group was 5.57 +/- 0.04 and for the FDP-treated group 4.76 +/- 0.06 (P < 0.0005). CONCLUSION: FDP treatment attenuated significantly the characteristic pulmonary hypertension, lung lymph protein clearance, and pulmonary vascular leakage seen in sheep infused with endotoxin.     

Characterization of the pulmonary arterial response to endothelin-1 and bosentan in neonatal pigs

BACKGROUND: This study determined the pulmonary vascular responses to intravenous (IV) administration of endothelin-1 (ET-1) before and after an IV bolus of bosentan (Ro 47-0203), an endothelin receptor antagonist, in anesthetized open-chest 48-hour-old and 2-week-old Yorkshire pigs. METHODS: Eighteen 48-hour-old and 25 2-week-old pigs were randomly allocated to receive either (1) 400 ng x kg(-1) x min(-1) of ET-1 or (2) 5 mg/kg or 10 mg/kg of Ro 47-0203 followed by 400 ng x kg(-1) x min(-1) of ET-1 over a 10-minute interval. Pulmonary vascular resistance (PVR, dyne sec/cm(-5)), elastic modulus (E(Yo), dyne/cm2), and characteristic impedance (Zo) were determined (+/- SEM). RESULTS: In 48-hour-old pigs, ET-1 decreased pulmonary artery pressure (PAP, dyne/cm2; 21,317 +/- 1,833 versus 17,757 +/- 1,823; p = 0.003). In 2-week-old pigs, ET-1 elevated PAP (19,009 +/- 1,834 versus 21,935 +/- 2,104; p = 0.003) and PVR (1,624 +/- 254 versus 2,302 +/- 416; p = 0.001), whereas bosentan abolished the ET-1 induced pulmonary and systemic vasoconstriction. Neither agent altered E(Y) or Z(o). CONCLUSIONS: ET-1 caused a pulmonary depressor response in 48-hour-old pigs and a constrictor response in 2-week-old pigs, whereas bosentan inhibited the ET-1 induced pulmonary arteriolar vasoconstriction in 2-week-old pigs. The response to ET-1 changes from dilation in 48-hour-old pigs (neonates) to constriction in 2-week-old pigs (infants) suggests a maturational dependent alteration in ET receptors during the first 2 weeks of life. These data suggest that bosentan may have potential clinical application in the treatment of newborn pulmonary hypertensive episodes as it ablated ET-1 induced pulmonary vasoconstriction, while maintaining systemic pressure.     

Sublethal endotoxin administration evokes super-resistance to systemic hypoxia in rats

BACKGROUND: Systemic hypoxia following surgical injury modulates cytokine and catecholamine responses. Endotoxin tolerance develops after pretreatment of animals with sublethal endotoxin doses and is characterized by a reduced inflammatory cytokine response to subsequent endotoxin challenges. The administration of endotoxin also attenuates ischemic injury of rat myocardial tissue following hypoxia, a phenomenon described as cross-tolerance. The objectives of this study were: 1) to determine whether endotoxin evokes a cross-tolerance to systemic hypoxia in rats; and 2) to estimate circulatory and pulmonary performance in rats with systemic hypoxia after endotoxin pretreatment. METHODS: Seventy-two hours before the experiment, Wistar rats were given an intraperitoneal injection of endotoxin at a dose of 10 microg/kg. Polyethylene catheters were inserted into the femoral vein for infusion, and into the femoral artery for blood sampling and blood pressure monitoring. Systemic hypoxia was achieved by continuous inhalation of a modified gas mixture (9% oxygen+ 91% N2) for 4 hours. Plasma TNF-alpha and IL-6 were measured by ELISA, and norepinephrine (NE) by HPLC. RESULTS: The hypoxic rats that were pretreated with saline showed a significant decrease in mean arterial blood and base excess, as compared with the normoxic rats. Endotoxin pretreatment prevented the drop in mean arterial pressure during hypoxia and reduced the decrease in base excess. Hypoxic conditions markedly stimulated TNF-alpha and IL-6 release and increased NE levels, compared to the normoxic rats. Pretreatment with endotoxin suppressed the hypoxia-induced cytokine production as well as attenuating the increase in NE levels CONCLUSIONS: In this rat hypoxia model, endotoxin pretreatment ameliorated the hypoxia-induced inflammatory response as well as suppressing the effects on arterial oxygenation, anaerobic metabolism and NE stimulation.     

Effect of ONO1714, a Specific Inducible Nitric Oxide Synthase Inhibitor, on Lung Lymph Filtration and Gas Exchange during Endotoxemia in Unanesthetized Sheep

Background: The effect of nitric oxide synthase inhibitor on acute lung injury remains controversial. The current study was designed to examine effects of a newly synthesized and selective inducible nitric oxide synthase inhibitor, ONO1714, on endotoxin-induced lung injury in unanesthetized sheep.

Methods: Thirteen unanesthetized sheep chronically instrumented with a lung lymph fistula and vascular catheters for monitoring were prepared. Animals were randomly allocated into two experimental groups. In experiment 1, sheep (n = 6) were infused only with endotoxin (1 [mu]g/kg) for 30 min. In experiment 2, sheep (n = 7) were pretreated with ONO1714 (0.1 mg/kg) before 30 min of endotoxin administration, and the endotoxin was infused in the same manner as in experiment 1. Mean pulmonary arterial pressure, left atrial pressure, systemic arterial pressure, and lung lymph flow were measured. Observation was continued over 5 h after endotoxin administration.

Results: ONO1714 did not cause any pulmonary hemodynamic changes at baseline or exert any influences on transient pulmonary hypertension and increased pulmonary vascular resistance during endotoxemia. However, inducible nitric oxide synthase inhibition with ONO1714 significantly reduced lung lymph filtration and improved abnormal oxygenation during endotoxemia. In addition, increased nitrate-nitrite in plasma and lung lymph in response to endotoxin was prevented by treatment with ONO1714.     

Reactive Oxygen Species Scavengers Attenuate Endotoxin-induced Impairment of Hypoxic Pulmonary Vasoconstriction in Mice

Background: Sepsis and endotoxemia attenuate hypoxic pulmonary vasoconstriction (HPV), thereby impairing systemic oxygenation. Reactive oxygen species (ROS) are implicated in the pathogenesis of sepsis-induced lung injury. The authors investigated whether treatment with scavengers of ROS prevents impairment of HPV in mice challenged with endotoxin.

Methods: The pulmonary vasoconstrictor response to left mainstem bronchus occlusion (LMBO) was studied in anesthetized mice 22 h after an intraperitoneal challenge with saline solution or 10 mg/kg Escherichia coli endotoxin. In some mice, challenge with saline solution or endotoxin was followed after 1 h with intraperitoneal or intratracheal administration of the ROS scavengers N-acetylcysteine or EUK-8. Myeloperoxidase activity and nitric oxide synthase-2 gene expression were measured in lung tissues.

Results: The LMBO increased left pulmonary vascular resistance by 106 +/- 24% in saline-challenged control mice but by only 23 +/- 12% (P < 0.05) in endotoxin-challenged mice. Intraperitoneal administration of N-acetylcysteine or EUK-8 1 h after endotoxin challenge attenuated the endotoxin-induced impairment of HPV (58 +/- 6% and 68 +/- 10%, respectively; both P < 0.05 vs. endotoxin-challenged mice). Intratracheal administration of ROS scavengers 1 h after endotoxin challenge was equally effective but required lower doses than systemic treatment. Administration of the ROS scavengers 22 h after endotoxin challenge did not restore HPV.     

Effect of ONO1714, a specific inducible nitric oxide synthase inhibitor, on lung lymph filtration and gas exchange during endotoxemia in unanesthetized sheep

BACKGROUND: The effect of nitric oxide synthase inhibitor on acute lung injury remains controversial. The current study was designed to examine effects of a newly synthesized and selective inducible nitric oxide synthase inhibitor, ONO1714, on endotoxin-induced lung injury in unanesthetized sheep. METHODS: Thirteen unanesthetized sheep chronically instrumented with a lung lymph fistula and vascular catheters for monitoring were prepared. Animals were randomly allocated into two experimental groups. In experiment 1, sheep (n = 6) were infused only with endotoxin (1 microg/kg) for 30 min. In experiment 2, sheep (n = 7) were pretreated with ONO1714 (0.1 mg/kg) before 30 min of endotoxin administration, and the endotoxin was infused in the same manner as in experiment 1. Mean pulmonary arterial pressure, left atrial pressure, systemic arterial pressure, and lung lymph flow were measured. Observation was continued over 5 h after endotoxin administration. RESULTS: ONO1714 did not cause any pulmonary hemodynamic changes at baseline or exert any influences on transient pulmonary hypertension and increased pulmonary vascular resistance during endotoxemia. However, inducible nitric oxide synthase inhibition with ONO1714 significantly reduced lung lymph filtration and improved abnormal oxygenation during endotoxemia. In addition, increased nitrate-nitrite in plasma and lung lymph in response to endotoxin was prevented by treatment with ONO1714. CONCLUSIONS: These findings suggest that nitric oxide release by the inducible nitric oxide synthase pathway partially contributes to the increased permeability of pulmonary edema and decreased oxygenation during endotoxemia in sheep.     

Haemodynamic and renal effects of endothelin receptor antagonism in patients with chronic kidney disease.

BACKGROUND: Endothelin-1 (ET-1) has been implicated in the pathophysiology of chronic kidney disease (CKD) and ET receptor blockade has shown renoprotective effects in animals. We examined the haemodynamic and renal effects of an ET receptor antagonist, TAK-044, in patients with CKD. METHODS: Seven patients with CKD (mean arterial pressure 103 mmHg; mean plasma creatinine 3.5 mg/dl) received three 15 min intravenous infusions, each separated by at least 7 days, of either placebo or TAK-044 (100 or 750 mg) in a randomized, double blind crossover study. Systemic and renal haemodynamics, and plasma immunoreactive ET-1, big ET-1 and C-terminal fragment concentrations, were determined before and after the infusions of placebo and drugs. RESULTS: Compared with placebo, TAK-044 reduced mean arterial pressure (MAP) (100 mg: 7.4 +/- 1.9 mmHg, 750 mg: 8.4 +/- 2.3 mmHg, P < 0.01) and systemic vascular resistance index (100 mg: 650 +/- 140 dyne.s.cm(-5).m(-2), 750 mg: 829 +/- 141 dyne.s.cm(-5).m(-2), P < 0.01) at both doses. TAK-044 increased cardiac index and heart rate to a similar degree at both doses. With regards to renal haemodynamics, TAK-044 had no significant effect on the glomerular filtration rate at either dose but tended to increase renal plasma flow (100 mg: 9.6 +/- 5.0 ml/min, 750 mg: 25.3 +/- 19.5 ml/min) and decreased the effective filtration fraction (100 mg: 3.6 +/- 1.1%, 750 mg: 4.7 +/- 1.7%, P < 0.01), in a dose-dependent manner. TAK-044 had no significant effect on sodium or lithium clearance, or on fractional excretion of sodium and lithium. Plasma ET-1 concentrations rose more than two-fold after 750 mg TAK-044 while big ET-1 and C-terminal fragment concentrations were unchanged. CONCLUSIONS: These findings suggest an important role for ET-1 in controlling systemic and renal haemodynamics in patients with CKD. The antihypertensive and potentially renoprotective actions of ET receptor antagonists shown in this study may prove useful in slowing the progression of CKD. Clinical trials are now needed to address these key questions for CKD.     

Decreases in myocardial glucose and increases in pyruvate but not ischaemia are observed during porcine endotoxaemia

Background: Myocardial dysfunction occurs commonly in septic shock. It is not known whether this is due to local ischaemia and metabolic disturbances. Our hypothesis was that endotoxaemic myocardial dysfunction may be associated with interstitial ischaemic and metabolic changes, measured using interstitial microdialysis (MD).
Methods: Eighteen pigs were randomized to control ( n =6) or endotoxin infusion ( n =12). MD catheters were inserted into the myocardium for measurement of interstitial glucose, pyruvate and lactate concentrations. Plasma glucose and lactate concentrations and systemic haemodynamic parameters were measured simultaneously.
Results: Compared with the control group, the endotoxaemic animals had significantly decreased left ventricular stroke work and venous oxygen saturation (SvO2), and increased mean pulmonary artery pressure and plasma lactate. In the endotoxaemic group, decreases in interstitial glucose were observed, occurring simultaneously with increases in interstitial pruvate. Interstitial lactate : pyruvate ratios decreased with time in all animals.
Conclusions: Despite severe systemic and pulmonary haemodynamic changes, interstitial MD measurements revealed no evidence of anaerobic metabolism in the myocardium of endotoxaemic pigs. There were, however, changes in glucose and pyruvate concentrations, suggesting local energy metabolic disturbances.     

Reactive oxygen species scavengers attenuate endotoxin-induced impairment of hypoxic pulmonary vasoconstriction in mice

BACKGROUND: Sepsis and endotoxemia attenuate hypoxic pulmonary vasoconstriction (HPV), thereby impairing systemic oxygenation. Reactive oxygen species (ROS) are implicated in the pathogenesis of sepsis-induced lung injury. The authors investigated whether treatment with scavengers of ROS prevents impairment of HPV in mice challenged with endotoxin. METHODS: The pulmonary vasoconstrictor response to left mainstem bronchus occlusion (LMBO) was studied in anesthetized mice 22 h after an intraperitoneal challenge with saline solution or 10 mg/kg Escherichia coli endotoxin. In some mice, challenge with saline solution or endotoxin was followed after 1 h with intraperitoneal or intratracheal administration of the ROS scavengers N-acetylcysteine or EUK-8. Myeloperoxidase activity and nitric oxide synthase-2 gene expression were measured in lung tissues. RESULTS: The LMBO increased left pulmonary vascular resistance by 106 +/- 24% in saline-challenged control mice but by only 23 +/- 12% (P < 0.05) in endotoxin-challenged mice. Intraperitoneal administration of N-acetylcysteine or EUK-8 1 h after endotoxin challenge attenuated the endotoxin-induced impairment of HPV (58 +/- 6% and 68 +/- 10%, respectively; both P< 0.05 endotoxin-challenged mice). Intratracheal administration of ROS scavengers 1 h after endotoxin challenge was equally effective but required lower doses than systemic treatment. Administration of the ROS scavengers 22 h after endotoxin challenge did not restore HPV. CONCLUSIONS: Administration of N-acetylcysteine or EUK-8 1 h after endotoxin challenge in mice prevented the impairment of HPV after LMBO. Early therapy with ROS scavengers, either systemically or by inhalation, may provide a means to preserve HPV in sepsis-associated acute lung injury.     

Dopexamine reverses the vasopressin-associated impairment in tissue oxygen supply but decreases systemic blood pressure in ovine endotoxemia

Since arginine vasopressin (AVP) may reduce cardiac output and, in proportion, oxygen delivery, we studied the efficacy of dopexamine (DPX) as an adjunct to AVP infusion. After 1 h of continuous AVP infusion (0.04 U/min) in healthy sheep (n = 7), DPX was additionally administered in incremental doses (1, 5, and 10 microg. kg(-1). min(-1); each dose for 30 min). After a 24-h period of recovery, endotoxin was continuously infused in the same sheep to induce and maintain a hypotensive/hyperdynamic circulation. After 16 h of endotoxemia, AVP and DPX were given as described previously. AVP infusion increased systemic vascular resistance index and decreased cardiac index in both healthy and endotoxemic conditions (P < 0.001 each). This was accompanied by an augmented pulmonary vascular resistance index in endotoxemia (159 +/- 13 dynes. cm(-5). m(-2) versus 202 +/- 16 dynes. cm(-5). m(-2)) and a decrease in oxygen delivery index (health: 842 +/- 66 mL. min(-2). m(-2) versus 475 +/- 38 mL. min(-2). m(-2); endotoxemia: 1073 +/- 49 mL. min(-2). m(-2) versus 613 +/- 44 mL. min(-2). m(-2)) and mixed venous oxygen content (health: 63% +/- 2% versus 47% +/- 2%; endotoxemia: 68% +/- 2% versus 51% +/- 3%; P < 0.001 each). Small doses of DPX (1 and 5 microg. kg(-1). min(-1)) improved not only the AVP-associated depressions in cardiac index, oxygen delivery index, and mixed venous oxygen content, but also the pulmonary vasopressive effect in both groups. While large-dose DPX (10 microg. kg(-1). min(-1)) also reduced mean pulmonary arterial pressure in endotoxemia (27 +/- 1 mm Hg versus 23 +/- 1 mm Hg; P < 0.05 versus baseline), mean arterial blood pressure decreased (105 +/- 4 mm Hg versus 80 +/- 3 mm Hg) and heart rate increased (84 +/- 4 bpm versus 136 +/- 9 bpm; P < 0.001 versus AVP alone), thereby limiting its therapeutic use.     

Continuous venovenous hemofiltration improves arterial oxygenation in endotoxin-induced lung injury in pigs

BACKGROUND: Hypoxemia is common in septic acute lung failure. Therapy is mainly supportive, and most trials using specific inhibitors of key inflammatory mediators (ie., tumor necrosis factor alpha, interleukin 1) have failed to prove beneficial. The authors investigated if a nonspecific blood purification technique, using zero-balanced high-volume continuous venovenous hemofiltration (CWH), might improve arterial oxygenation in a fluid-resuscitated porcine model of endotoxin-induced acute lung injury. METHODS: Piglets of both sexes weighing 25-30 kg were anesthetized and mechanically ventilated. After baseline measurements, animals received an intravenous infusion of 0.5 mg/kg endotoxin (Escherichia coli lipopolysaccharide). One hour after endotoxin, animals were randomly assigned to either treatment with CWH (endotoxin + hemofiltration, n = 6) or spontaneous course (endotoxin, n = 6). At 4 h after randomization, animals were killed. Hemofiltration was performed from femoral vein to femoral vein using a standard circuit with an EF60 polysulphone hemofilter. RESULTS: Endotoxin challenge induced arterial hypoxemia, an increase in peak inspiratory pressure, pulmonary hypertension, and systemic hypotension. Treatment with CWH did not improve systemic or pulmonary hemodynamics. However, arterial oxygenation was increased in endotoxin-challenged animals at 5 h after completion of endotoxin infusion, as compared with animals not receiving CVVH (arterialoxygen tension, 268+/-33 vs. 176+/-67 mm/Hg, respectively, P < 0.01). In addition, treatment with CWH attenuated the endotoxin-induced increase in peak inspiratory pressure and increased lung compliance. CONCLUSION: These results suggest that nonspecific blood purification with high-volume CWH improves arterial oxygenation and lung function in endotoxin-induced acute lung injury in pigs, independent of improved hemodynamics, fluid removal, or body temperature.