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The haemodynamic effects of an optimal dose of dobutamine (DUo) (6.7 +/- 4.2 micrograms kg-1 min-1) and the combination of this optimal dose minus 2.5 micrograms kg-1 min-1 of dobutamine (DU) plus dopamine 2.5 micrograms kg-1 min-1 (DA) were studied in a first group of 12 consecutive patients with acute myocardial infarction (AMI) and cardiac failure (CF). DUo decreased pulmonary wedge pressure from 23.5 to 16 mm Hg (P less than 0.01), systemic vascular resistance from 1 774 to 1 417 dynes s cm-5 (P less than 0.01). DUo increased cardiac output from 3.21 to 4.55 litres/min (P less than 0.01) and urinary flow (UF) from 20 to 68 ml/h (P less than 0.01). Heart rate and blood pressure did not change significantly. DUo - DU + DA significantly increased UF from 68 to 107 ml/h (P less than 0.05) while the other parameters remained unchanged with respect to DUo. The positive effect of DA on UF was confirmed in a second group of 12 consecutive patients by comparing the successive effects of DA + DUo and DUo + DU : all previously described parameters remained unchanged except UF which decreased from 107 to 65 (P less than 0.01). We conclude that in patients with CF and AMI, association of DA and DUo is useful in obtaining both inotropic and diuretic effects.

In the anesthetized dog, a low dose perfusion of endotoxin (50 ng X kg-1 X min-1) produces hemodynamic and metabolic perturbations generally similar to those clinically found in man during the hemodynamic phase of septic shock. These modifications are observed after about 30 minutes following the beginning of the perfusion. They constitute: 1) an arterial vasodilatation responsible for a hypotension without a significant modification of the cardiac output; 2) a drop in the left ventricular filling pressure; 3) a progressive metabolic acidosis; 4) a moderate arterial hypoxia that is independent of an alveolar hypoventilation. To these perturbations is added the contemporary development of a leucopenia associated with a thrombopenia. This mode of endotoxin administration seems to us to constitute a satisfactory experimental model for studying the circulatory injuries due to hyperdynamic septic shock.

Compounds with phosphodiesterase inhibitory activity stimulate myocardial contractility by increasing the intracellular cyclic AMP concentrations. They can also increase Ca2+ entry and inhibit Ca2+ sequestration by the sarcoplasmic reticulum. Xanthines produce bronchodilation with associated venous and arteriolar dilation. However, their use is limited by their positive chronotropic effect and other side effects at high plasma levels. New phosphodiesterase inhibitors have been perfected: they are more specific with little chronotropic effect. Increasing the sensitivity of the myofilaments to Ca2+, and other unclear mechanisms may be involved in the inotropic action of these drugs. These new promising active compounds are described and discussed. They augment cardiac performance and improve regional distribution of blood flow and symptoms. However, their influence on the long-term outcome of severe heart failure has yet to be determined.

In anaesthetized dogs, low dose endotoxin perfusion (250 ng kg-1 min-1 during 20 min) resulted, after a delay of 15-40 min, in a decrease of mean arterial pressure (from 127 to 106 mm Hg), a transient increase in cardiac output (from 2.2 to 2.9 L/min), a fall of systemic vascular resistance (from 60 to 41 mm Hg L-1 min-1) and an increase in heart rate (from 109 to 156/min). This haemodynamic pattern is similar to the so called "hyperdynamic" initial phase of clinical septic shock.

The aim of the present study was to determine possible effects of Escherichia coli endotoxin on peripheral vascular compliance and relate them to concomitant central hemodynamic disturbances. Endotoxin was infused at 0.25 micrograms/kg.min during 2 h in six anesthetized dogs, while six additional animals served as controls. Vascular compliance of the systemic circulation was calculated in intact animals from the changes in CVP after known changes in systemic blood volume. In control dogs, vascular compliance averaged 2.3 ml/mm Hg.kg body weight. During slow endotoxin infusion, cardiovascular effects were measurable only after a certain period of time had elapsed from the start of endotoxin insult and consisted of hypotension associated with systemic vasodilation. Systemic BP decreased gradually from 124 to 68 mm Hg while vascular compliance was finally increased by 100%, when compared to control values. This latter rise was responsible for a reduction in the cardiac preloads. Pulmonary wedge pressure and CVP were decreased from 7.1 to 3.4 and from 4.5 to 2.6 mm Hg, respectively. However, parallel to the decrease in left ventricular preload, endotoxin induced a progressive decrease in left ventricular afterload. Because of the balance in ventricular loading, cardiac output remained almost unchanged. After volume loading (dextran 30 ml/kg), cardiac output was remarkably increased from 3.28 to 6.24 L/min.m2 while peripheral vasodilation was not affected by this maneuver. It is concluded that low dose endotoxin infusion induces in dogs a hemodynamic pattern similar to human sepsis. The left ventricular loading changes are related to an enhanced systemic vascular compliance from 2.3 to 4.5 ml/mm Hg.kg. High flow shock state is encountered provided peripheral blood pooling is compensated by adequate volume replacement.

Pulmonary embolism can produce severe cardiopulmonary dysfunction characterized by pulmonary artery hypertension, right ventricular failure, and hypoxemia. The search for the source of a pulmonary embolus, by exploration of the veins of the lower limbs and the inferior vena cava should be systematically carried out in all cases of pulmonary embolus which are not immediately life-threatening to the patient. The treatment of deep vein thrombosis associated with pulmonary embolism with thrombolytic agents has been proposed and utilized for approximately 20 years. Although superior results have been claimed with thrombolytic agents, the use of this type of treatment remains limited to massive or sub-massive pulmonary embolism. Fibrinolytic agents with high specificity for fibrin in the thrombi and little systemic activation of the fibrinolytic system have been developed and tested in preliminary clinical trials of patients with acute pulmonary embolism. The largest published experience available has been with recombinant tissue plasminogen activator (rtPA). The acylated streptokinase-plasminogen complex (APSAC) and pro-urokinase also gave promising results. All these agents were accompanied by unexpectedly high incidence of systemic activation of the fibrinolytic system and by hemorrhagic complications with frequencies similar to those that follows the use of first generation products (urokinase and streptokinase). Hence, their superior clinical efficacy must be clearly proven before they are substituted for a more widely available and less expensive drug, such as streptokinase.

The effects of histamine on systemic and pulmonary hemodynamics of dogs were studied in six intact animals. Histamine infusion resulted in an almost immediate, precipitous fall in blood pressure (BP), pulmonary capillary wedge pressure (PCWP), and right atrial pressure (RA) as well as an increase in heart rate. Partial recovery occurred about 5 minutes after infusion was stopped. Cardiac output did not change significantly. Consequently, the calculated peripheral resistance decreased afterwards. Hepatic portal pressure rose significantly after 2 minutes of histamine infusion with partial recovery in about 5 minutes. Suprahepatic venous pressure did not change significantly. Although pulmonary arterial pressure did not necessarily rise, total pulmonary vascular resistance increased in every dog. If the absolute level in pulmonary arterial resistance remained greater (Ra 105 mm Hg/liter-1 min X kg-1) than the level of venous resistance (Rv 70 mm Hg/liter-1 min X kg-1), the relative increase in venous resistance (100%) was higher than the increase in Ra (35%). On the other hand, effective capillary pulmonary pressure remained unchanged. Central blood volume and extravascular lung water increased upon histamine infusion and returned rapidly to baseline when histamine infusion was stopped. No significant changes occurred in either effective pulmonary compliance and arterial blood gas values. Our data lead us to conclude that histamine's major action occurs in the venous pulmonary segments; pulmonary and splanchnic blood pooling is responsible for a fall in cardiac preload; and an increase in extravascular lung water and central blood volume with unchanged effective pulmonary pressure might be explained by an increase in microvascular surface area.

Two-dimensional echocardiography provides adequate spatial orientation and anatomic definition. Eighteen consecutive patients undergoing myocardial biopsy had concomitant two-dimensional echocardiography during 22 biopsies of five to six samples each. The transducer was placed at the apex and in the subcostal area and four-chamber views were used. The bioptome was seen entering the right atrium and crossing the tricuspid valve to the right ventricle. The catheter was then manipulated under two-dimensional echocardiography and the tip's position was strictly adapted, using two different classic views before sampling. The success rate in visualizing the forceps and in defining the site of sampling was 100 percent, and no complication was noted. Radiation exposure was largely reduced. Two-dimensional echocardiography to guide endomyocardial biopsy may reduce the risk of perforation by a better anatomic definition of the sampling site. It permits sampling from different ventricular sites or from the same site during serial procedures for monitoring evolution or treatment.

We tested the early effects of endotoxin on both the permeability of capillary membranes and microvascular pressure. One group of dogs (n = 8) were fluid loaded (30 ml/kg dextran-40) after having been subjected to a 2-h Escherichia coli endotoxin infusion (0.25 micrograms/kg X min). A second control group of animals (n = 6) was submitted to a similar (25 ml/kg) volume loading over an equivalent 30-min period. We estimated extravascular lung water (EVLW), calculated the effective pulmonary capillary pressure, and determined the alveolar-capillary filtration coefficient (Kf) after volume loading. Only the septic animals consistently showed elevated EVLW values consistent with pulmonary edema. The results showed, however, that the Kf calculated for the dogs that received endotoxin was no different from that of control group (Kf = 0.005 ml/kg X min X mm Hg). Instead, endotoxin constricted the pulmonary veins which led to a considerable rise in microvascular hydrostatic pressure above the level at which the lungs could not resist edema formation. We conclude that acute pulmonary edema that follows endotoxin insult and subsequent therapeutic volume replacement is due to an increased filtration force instead of an alteration in the microvascular permeability.

The effects of endotoxin on pulmonary hemodynamics were studied in seven intact dogs. The distribution of pulmonary vascular resistance was estimated by the effective pulmonary capillary pressure, which was derived from the pressure transient recorded while the pulmonary artery catheter was rapidly wedged. After the injection of endotoxin, cardiac output and aortic pressure consistently fell. Pulmonary artery occlusion (wedge) pressure also decreased, but not significantly. Although pulmonary artery pressure did not necessarily rise, total pulmonary vascular resistance increased in every dog. The absolute increase in pulmonary artery resistance was greater (142 mm Hg/L X min/kg); than in venous resistance (111 mm Hg/L X min/kg); however, the relative increase in venous resistance was higher (410% for venous resistance vs. 220% for pulmonary artery resistance). As a result of venoconstriction, there was a consistent increase in effective pulmonary capillary pressure (from 2.5 to 6.3 mm Hg). Our data indicate that the pulmonary vascular response to endotoxin injection is characterized by constriction of both pulmonary arteries and pulmonary veins. The capillary wedge pressure did not reflect the pulmonary microvascular pressure, since it varied in the opposite direction to the effective capillary pressure.

The aim of the present study was to determine possible direct adverse effects of a 2-hour Escherichia coli endotoxin infusion (50 ng kg-1 min-1) on myocardial oxidative carbohydrate metabolism. The experiments were performed in intact dogs to assay glucose and lactate cardiac uptake and relate them to oxygen consumption (MVO2), CO2 production, and myocardial hemodynamics. Coronary sinus blood flow (CSBF) was measured by thermodilution, and the arteriovenous differences in glucose, lactate, pyruvate, O2, and CO2 were determined by blood samples obtained simultaneously from the carotid artery and sinus coronary. The adequacy of CSBF in meeting cardiac oxygen needs was evaluated by calculating the percentage of anaerobic metabolic rate (% AMR). During endotoxin infusion, CSBF was significantly lowered by 33% while mean aortic blood pressure was decreased by 43%. Cardiac index exhibited a minimal reduction of 14%. Mean arterial blood glucose decreased 30% and arterial lactate increased 100%. Despite the progressively developing hypoglycemia, cardiac glucose uptake increased 140%. Although MVO2 was reduced to 70% of control value, lactate uptake increased 50%. Throughout the experimental period, the % AMR remained negative. Under endotoxin infusion, up to 78% of the cardiac CO2 production was derived from carbohydrate utilization, as compared to 40% prior to endotoxin infusion. Our findings suggest the absence of any toxic action by an endotoxin-sustained infusion on cardiac oxidative metabolism.

AR-L 115 BS is a new active noncatecholamine, non glycoside phenyl-imidazo-pyridine derivative inotropic agent. It has a strong inotropic effect in experimental animals. Its effectiveness and associated adverse effects were tested in 23 patients with severe heart failure (NYHA class III to IV). Intravenous administration of AR-L 115 BS at 1.4 mg/min for 6 hours in 11 patients increased cardiac index from 2.07 +/- 0.13 to 2.99 +/- 0.203 l/min/m2 (p less than 0.005) while pulmonary wedge pressure decreased from 23 +/- 2 to 13 +/- 2 mm Hg (p less than 0.005). Systemic vascular resistance fell from 1759 +/- 137 to 1263 +/- 71 dynes.sec. cm-5 (p less than 0.005). Heart rate and blood pressure remained unchanged. Following oral administration (450 mg) in 12 other patients, cardiac performance was similarly improved. Hemodynamic changes were apparent as early as 60 min after administration, and the duration of action ranged from 5 to 7 hours. No serious arrhythmias or side effects occurred. It could therefore be useful in the management of congestive heart failure.

Arterial tissue has been analysed by 31P-, 13C-, 23Na- and 1H-NMR spectroscopy. Rabbit thoracic aortas were mounted on a system with perfusate circulation and studied in basal conditions. Phosphorus spectra remained stable for hours and showed low levels of phosphocreatine (PCr) compared to skeletal, cardiac or even to nonvascular smooth muscle. Significant levels of sugar-phosphates (SP), phosphodiesters (PDE) were detected, as well as occasionnally a peak in the diphosphodiester region. Experiments with phosphate-free perfusate demonstrated a very low level of intracellular inorganic phosphate. As expected from previous data, free ADP levels in tonic arterial tissue were found much higher than in any other muscle. Addition of norepinephrine into the perfusate induced transient decrease in ATP and PCr levels, associated with an increased production of phosphorylated intermediates. At the early stage of renovascular hypertension, aortic energetic pattern was characterized by an increased ADP/ATP ratio. Natural abundant 13C spectra were recorded from dog aortic fragments and showed mainly resonances attributed to fatty components. After addition of a shift-reagent, dysprosium tripolyphosphate, 23Na-NMR allowed separation of intra- and extracellular Na of perfused rabbits aortas. Proton NMR of lyophilized aortic fragments revealed several peaks originating from biologically relevant molecules, lactate, creatine, taurine... These preliminary data demonstrate the feasability of multinuclear NMR spectroscopy of vascular tissue and are suggestive of the potential of the method when it will be combined with monitoring of functional parameters.