Search

The macro- and microcirculatory effect of small-volume resuscitation with hyperosmotic-hyperoncotic solutions was analyzed in 21 anesthetized beagles subjected to standardized traumatic-hemorrhagic hypotension (laparotomy and exteriorization of the intestine; MAP 40 mmHg for 75 min). Primary resuscitation consisted of bolus infusion of 10% of the blood loss (approx. 4 ml/kg) of either hyperosmotic (7.2%) saline -HSS-, hyperoncotic (10%) dextran 60 -HDS-, or hyperosomotic-hyperoncotic saline dextran (10% dextran 60 in 7.2% saline; HHS). Within 5 min CO was restored and systemic pressure significantly increased. In the HHS-group nutritional blood flow (RBF, measured by radiolabeled microspheres phi 15 microns) in kidneys, gastric mucosa, small intestine, colon, and pancreas was completely restored, while RBF to the myocardium, brain, and skeletal muscles exceeded baseline values. Despite the identical response in central hemodynamics, RBF to gastric mucosa, intestine, pancreas, and kidneys was significantly lower in HSS-animals (P less than 0.05 vs. HHS). In contrast, in the HDS-group CO, splanchnic, myocardial, and renal blood flow remained significantly reduced (P less than 0.05 vs. HHS). Despite the normalization of cardiac output by small volumes of hypertonic solutions, 7.2% saline alone failed to fully restore RBF after protracted traumatic hemorrhage. For the concept of small-volume resuscitation, the hyperosomotic-hyperoncotic solution of 10% dextran 60 in 7.2% saline appears to be most effective to improve organ perfusion during the prehospital period of trauma patients.

Six splenectomized beagles of either sex (13.8 +/- 2.2 kg) were randomly treated either with 500 U/kg recombinant human erythropoietin (rhu-EPO) (verum group, n = 3) or an equivalent volume of the vehicle (placebo group, n = 3). Both solutions were given intravenously for 3 days. At day 4 after onset of treatment, the dogs were anesthetized and subjected to isovolemic hemodilution using 6% Dextran 60 (MW 60,000) down to a hematocrit of 0.10. During the recovery period vehicle or rhu-EPO was given every other day until the hematocrit reached control values. Every day venous blood samples were withdrawn, and the hematocrit as well as the concentrations of hemoglobin and 2,3-diphosphoglycerate were determined. In addition, the platelets and reticulocytes were counted. Treatment with rhu-EPO shortened the time of hematocrit recovery from 20 (placebo) to 11 days (p less than 0.05). The reticulocyte count peaked at day 2 (verum) versus day 5 (placebo). These findings indicate a successful stimulation of red blood cell production after extreme hemodilution in animals treated with erythropoietin. Therefore, rhu-EPO may allow to optimize blood donation programs as well as preoperative hemodilution and yield both, higher amounts of autologous blood and an accelerated reversal of dilutional anemia.

The interrelationship between systemic oxygen transport and hematocrit, has been studied under various conditions, while the influence of plasma viscosity on oxygen transport and tissue oxygenation has not entirely been explored. In experiments in dogs the plasma viscosity was increased either by isovolemic hemodilution with 6% hydroxyethyl starch (HES) 200/0.62, or 6% dextran-70, or by infusion of dextran-500 in a volume equivalent to 4% of blood volume from baseline to 3 mPa.s. Cardiac output and regional blood flow were assessed by means of radioactive labelled microspheres and local tissue oxygenation by means of pO2 multiwire surface electrodes. In normotensive healthy animals elevated plasma viscosity did neither jeopardize systemic nor regional blood flow; local tissue oxygenation of skeletal muscle remained unchanged or was even improved. We conclude that among the rheological factors influencing oxygen transport, the hematocrit plays the predominant role, while plasma viscosity is of minor importance.

Sixteen anesthetized foxhounds were instrumented for hemodynamic measurements. The adrenolumbar vein was cannulated, and hemorrhagic hypotension (MAP = 40 mmHg for 3h) was induced by bleeding. The plasma levels of beta-endorphin (beta-END), methionine-enkephalin (M-ENK), and leucine-enkephalin (L-ENK) were determined in systemic and adrenal venous blood by specific RIA. Five dogs received an i.v. bolus of naloxone (2 mg/kg) and a subsequent naloxone infusion of 2 mg/kg per hour 1 h after onset of hypovolemia. Eleven dogs served as controls and received equivalent volumes (1 ml/kg per hour) of saline. Hemorrhage resulted in a sharp increase in plasma concentrations of all measured opioid peptides, particularly of M-ENK (26-fold) and L-ENK (24-fold) in the adrenal effluent. Systemic beta-END levels remained 3-fold increased, whereas the ENK release decreased spontaneously. Naloxone treatment inhibited the spontaneous fall of adrenal ENK release during the hypotensive phase; the ENK values remained elevated 20- to 35-fold. Reinfusion of the autologous blood resulted in a normalization of the concentrations of all peptides in both groups. These data demonstrate that hemorrhagic hypotension will cause stimulation of release of endogenous opioid peptides. The high levels of ENK in the adrenal effluent indicate that the adrenal gland is the main source of these peptides in the circulation. In addition to beta-END, the ENK have therefore to be considered as possible factors perpetuating circulatory shock.

In 16 anesthetized foxhounds a traumatic-hemorrhagic shock was performed. Following shock the dogs were randomized to treatment with autologous blood and either hydroxyethyl starch (HES, 450/0.5) or Ringer's lactate (RL). The animals were monitored for 24 h after treatment. The maintenance of normal cardiac output and left atrial pressure at pre-shock levels required 4.8 times more RL than HES. Extravascular lung water (EVLW) increased (p less than 0.01) with both treatment modalities without amelioration during the 24-hour observation period. No difference in EVLW was observed despite the higher infusion rate in the RL-group. Fluid loss into abdominal cavity, however was significantly lower (p less than 0.01) in the HES-treated animals. Albumin extravasation, on the other hand, was more pronounced (p less than 0.01) in the RL-group and, moreover, albumin redelivery by lymph was decreased (p less than 0.05). On the basis of this study, both fluid modalities appear to be equally effective in resuscitation from traumatic-hemorrhagic shock without interfering with pulmonary function and ARDS. The importance that the tissue albumin accumulation ranks for final outcome from shock, however, requires further investigation.

Experimental trauma and hemorrhage acutely reduce capillary blood flow in all organs except the heart. After reinfusion of the withdrawn blood a long-lasting increase of pulmonary bronchial blood flow and hepatic and renal blood flow is observed parallel to a rise in cardiac output. However, blood flow in the intestines, pancreas, and spleen remains significantly reduced. Particularly, renal and pulmonary bronchial blood flow is significantly higher in animals surviving for 72 hr than in animals succumbing after an average of 32 hr.

Twenty mongrel dogs are subjected to a standardized traumatic hemorrhagic shock. After reinfusion of the dogs' own blood the animals are continuously observed for the 72 hr. Deterioration of general hemodynamics and activation of intravascular coagulation is more pronounced in the nonsurviving animals. Correspondingly, histologic alterations particularly of the liver and intestine are more marked in the nonsurvivors. Increase of partial thromboplastin time and long-lasting increase of the prothrombin time (Quick) appear to be early signs of a fatal prognosis.

The left anterior descending coronary artery was variably constricted mechanically in nine dogs. Blood flow in the left anterior descending (LAD) and circumflex coronary arteries (CCA), aortic pressure and peripheral, i.e. post-stenotic coronary pressure were measured. Myocardial perfusion was determined from the clearance of radioactive xenon injected at a depth of 7 mm into the underperfused area supplied by the LAD artery. The vasoactive drug 1-(pyrrolidinyl-1-carbonyl)-methyl-4-(3,4,5-tri-methoxycinnamoyl)piperazine-maleate (cinepazide) was given at doses of 5-10 mg/kg by i.v. route. 1. Blood flow in the LAD was decreased stepwise to 50% of its initial value. There was practically no more coronary reserve. After drug injection, diastolic aortic pressure, that normally falls, was kept constant by clamping. Heart rate, perfusion pressure, post-stenotic pressure, and blood flow and resistance in the LAD showed practically no change. In the CCA, blood flow increased significantly (p less than 0.005) and flow resistance decreased (p less than 0.001). 133Xe clearance showed an increased myocardial perfusion (p less than 0.02) in the territory supplied by the LAD artery. 2. The lumen of the LAD was narrowed by 53%, i.e., coronary reserve was decreased. This constriction was followed by no haemodynamic reaction. After injection of cinepazide, mean and diastolic aortic pressure (p less than 0.02) and post-stenotic coronary pressure (p less than 0.005) decreased. Blood flow increased by 41% in the CCA and by 31% in the LAD. Coronary resistance in these vessels decreased (p less than 0.001 and 0.005, respectively). Here, too, the 133Xe clearance curve showed an increase in myocardial perfusion in the territory supplied by the LAD artery (+78%).

The effect of volume replacement with crystalloidal and colloidal solutions was analyzed in 40 anesthetized Foxhounds subjected to a standardized traumatic-hemorrhagic shock. Following trauma and hypotension (MAP 40 mmHg; 3.0 +/- 0.5 hr) the animals were randomized to treatment with autologous blood and hydroxyethyl starch 6% (HES 450/0.7), or human serum albumin 5% (ALB), dextran-60 6% (DX), Ringer's lactate (RL), and hyperosmolar saline 1.3% (HS), respectively. While analgesia and sedation were maintained, the hemodynamic measurements were continued for a 24-hr period. Crystalloids and colloids were found equally effective in maintaining the macrohemodynamics following resuscitation from traumatic-hemorrhagic shock. To keep central hemodynamics at pre-shock level required at least four times higher volumes of crystalloids than colloids. No specific advantage for one of the substitutes tested was found with regard to accumulation of water in the lung during the first 24 hr following shock in dogs. Extravascular lung water (thermo-dye) and organ water (gravimetry) were not different between the groups. However, fluid loss into the abdominal cavity as well as albumin extravasation into lung interstitium and abdominal cavity were more pronounced in the crystalloid-treated animals, whereas albumin redelivery by the lymph was decreased. The deterioration of tissue oxygen extractions as well as the changes in acid-base balance in both crystalloid-treated groups reflect the persistent microcirculatory inhomogeneity in spite of normal macrohemodynamics.

24 anesthetized mongrel dogs are subjected to a standardized trauma followed by a hypotonic hemorrhagic shock. Compared with the control group (n equals 8) prophylactic treatment with heparin in the second group (n equals 8) reduces the rise of pulmonary vascular resistance only insignificantly. The correction of the metabolic acidosis with Tris does not prevent a rise of PVR in third group (n equals 8).

The significance of pulmonary pressure-flow relation and its correlation to alveolar dead space and histological lesions of the lung were evaluated in ten mongrel dogs, which were subjected to standardized bone trauma and hemorrhagic hypotension at 40 mm Hg for 3h. These results were compared with those of 5 control dogs without trauma and shock. Two different pressure-flow curves were obtained by consecutive measurements of cardiac output and mean pulmonary artery pressure during stepwise arterial hemorrhage and reinfusion. In each experiment, the difference between the two curves at CO of 100 ml/kg min was obtained and represents an increase in pulmonary artery pressure (delta MPP). This increase in pulmonary artery pressure is flow-independent and, therefore, can be used as a quantitative indicator of pulmonary vasoconstriction or vascular obstruction. Severity of shock (uptake) as well as grade of early histological lesions of the lung (microthrombi, edema, hemorrhage) and increased alveolar dead space after reinfusion were associated with a more pronounced shift of the pulmonary pressure-flow curve. In severe experimental shock, therefore, a consistent pattern of pulmonary hemodynamics, lung histology, and respiratory function was demonstrated by the pulmonary pressure-flow relation. This approach permits estimation of the effects of therapeutic interventions and may be suitable for assessing postshock pulmonary impairment.

Immunohistochemical and functional studies suggest that opioid peptides are involved in blood pressure regulation. Endorphin and enkephalins contained in the brain seem to exert their effects by mediation of cardiovascular centers in the brain stem. Additional effects on blood pressure may be exhibited by circulating opioid peptides released from the pituitary and adrenal gland which may act at both central and peripheral sites. It is expected that further studies will complete our knowledge about the interaction of opioid peptides and blood pressure regulation and will result in therapeutic applications.

Eleven mongrel dogs were observed for 72 h following a standardized traumatic hemorrhagic shock. The decrease of plasma albumin concentration and blood 125-I-albumin activity with a concomitant increase in lung I-albumin content is possibly caused by capillary leakage. A rise in the extravascular lung water content was measured by a gravimetric postmortem method. An in vivo double indicator technique, however, failed to document these findings.

Leukotriene C4 (LTC4) underwent rapid elimination from the circulating blood and was extensively converted to LTD4 within the vascular space of the guinea pig. To mimic the elimination and metabolism of endogenous LTC4 generated during anaphylaxis, 14,15-3H-labeled LTC4 was infused intravenously over a period of 15 min, leading to a recovery in bile of 85% of the infused LT radioactivity within 2 h. Corresponding to the tracer studies, LTD4 and, to a lesser extent, LTC4 were the predominant endogenous cysteinyl LTs in guinea pig bile. The biliary production rate of endogenous LTD4 increased from 0.3 +/- 0.1 to 6.2 +/- 1.8 pmol x min-1 x kg-1 (p less than 0.001) during anaphylactic shock induced by intravenous injection of OVA (0.2 mg/kg) into sensitized guinea pigs. A novel LT biosynthesis inhibitor (MK-886; 10 mg/kg, i.v., 15 min before antigen challenge) suppressed the antigen-induced cysteinyl LT production by greater than 92% (p less than 0.001). This inhibition of systemic LTC4 formation was associated with a complete protection against lethal anaphylactic shock in animals pretreated in addition with the H1 receptor antagonist pyrilamine. Pretreatment with either the inhibitor of LT synthesis or the histamine receptor antagonist reduced the lethality during anaphylactic shock from 100 to 60 and 78%, respectively. In artificially ventilated, pyrilamine-pretreated animals, the antigen-induced decrease in dynamic lung compliance and the rise in hematocrit were significantly reduced (p less than 0.05) by pretreatment with the inhibitor of LT synthesis. Dexamethasone at high doses (10 mg/kg, i.p., once daily for 7 d, or in a single dose of 10 mg/kg, i.v., 3.5 h before challenge) had no inhibitory effect on LT generation during anaphylaxis in vivo. However, in resident peritoneal macrophages, harvested from these dexamethasone-treated sensitized guinea pigs and stimulated with zymosan, both cysteinyl LT and 6-keto-PGF1 alpha formation were strongly suppressed. These studies indicate an important role of cysteinyl LTs in systemic anaphylaxis in vivo and demonstrate the blockade of anaphylactic LT generation by a novel inhibitor of LT biosynthesis (MK-886) but not by dexamethasone.

Twenty-six anesthesized mongrel dogs were subjected to a standardized traumatic hemorrhagic shock. Compared with the control group prophylactic treatment with high doses of methylprednisolone reduced functional and histologic alterations of the lung. Methylprednisolone in combination with heparin pretreatment prevents microthrombi but produces more alveolar bleeding.

The influence of coronary stenosis on resting blood flow (201Tl-uptake) and myocardial flow reserve (bicycle ergometry) is studied in 18 patients with coronary disease. Severe coronary stenosis of 75--90% caused a reduced 201Tl-uptake both at rest and peak exercise. In contrast to this group patients with a 50--60% stenosis have a normal scintigram at rest but focal defects of 201Tl-uptake at peak exercise. Results are compared with experimental data obtained after acute coronary constriction and simultaneous coronary dilatation (myocardial flow reserve, MFR) in 12 dogs. 60% coronary constriction causes a 37% decrease of poststenotic MFR measured with tracer microspheres. Changes of transmural flow distribution (endo/epi ratio) are minor in the left ventricular free wall but significant in the poststenotic septum (endo/epi = .84). It is concluded that even a moderate coronary stenosis of 60% not affecting resting blood flow becomes "critical" under conditions of high flow velocities.

Fifteen mongrel dogs are subjected to a standardized traumatic hemorrhagic shock. Plasma albumin, measured by J-125-albumin distribution, decreases to 58% of its original level after trauma and hemorrhage. Lung albumin content increases to 53% of the blood level. Lung water content is studied in vivo using the double indicator technique, post mortem by gravimetric methods. None of these methods shows an augmentation of lung water. The massive albumin loss occurs, particularly in the lungs, due to capillary leakage. The constant pulmonary water content can possibly be explained by early artificial respiration and by the fact that in contrast to clinical situations no infusion therapy was performed.

The distribution of myocardial blood flow (MBF) was evaluated in pressure-induced LV hypertrophy of foxhounds. At the early stage of developing hypertrophy, i.e., 3 months after aortic banding (+ 53% LV weight) resting MBF and flow reserve were not significantly different from control hearts. One year after banding (+94% LV weight) myocardial flow reserve had clearly decreased. Acute coronary stenosis of 60 and 70% cross-sectional area resulted in a moderate fall of flow reserve in controls and hearts with early hypertrophy. In hearts with extensive hypertrophy the drop of poststenotic MBF was considerably greater affecting preferentially the subendocardium. The data suggest that myocardial blood flow was impaired before any signs of heart failure were observed. Furthermore a decrease of MBF may not be confined to forms of hypertrophy induced by renal and idiopathic hypertension.

26 mongrel dogs are subjected to a standardized bone trauma followed by a hypotonic hemorrhagic shock. Compared with a control and heparin group prophylactic treatment with Dipyridamol and Acetylsalicylic Acid decreases pulmonary vascular resistance significantly. After an initial period of hyperocagulability secondary fibrinolysis develops. The decrease of the fibrinogen level and the fall of total platelet count after trauma and hemorrhage can partly be prevented by the application of heparin, likewise the development of pulmonary microthrombosis. Histological examination shows a markedly diminished pulmonary microthrombosis.

A severe shock is produced in 18 mongrel dogs by standardized bone trauma and haemorrhagic shock. Impairment of microcirculation is demonstrated by acidosis, reduced oxygen uptake and disseminated intravascular coagulation (DIC). Further, a specific increase in pulmonary vascular resistance--independent of the reduction in blood flow--is evoked, concomitantly with the occurrence of microthrombi, oedema and haemorrhage in lung tissue. Pretreatment with heparin inhibits disseminated intravascular coagulation and reduces impairment of microcirculation and the consecutive damage of intestinal organs. However increase of pulmonary vascular resistance is unchanged and pulmonary haemorrhage is pronounced. Therefore heparin pretreatment enhances pulmonary histologic impairment after trauma and haemorrhagic shock.

The effects of experimentally induced, severe coronary artery stenosis on regional changes in myocardial blood supply, cardiac function, and metabolism were studied in 14 dogs. The anterior interventricular branch of the left coronary artery (LAD) was constricted such that arterial inflow was reduced by 80%. Nine dogs were given enflurane in a concentration of 2.2 vol.% (1 MAC) in air, and five animals received no enflurane (controls). Regional myocardial blood supply was measured by the tracer microspheres technique, using 8-micron microspheres labelled with five different radioisotopes. Regional cardiac function (end-diastolic length of the muscle fibres = EDL; segmental shortening during systole = delta L) was estimated with the aid of two ultrasonic crystals which were placed in the subendocardial layer of the myocardium supplied by the LAD. Regional myocardial metabolism (oxygen consumption; lactate extraction) was evaluated from arterial and coronary venous blood samples. The latter were collected selectively from the region supplied by the LAD via the great cardiac vein. The results showed that, during severe coronary artery stenosis comparable to clinical conditions, apart from the known actions on systemic haemodynamics and contractility, enflurane had beneficial effects on regional myocardial variables. This was indicated by reduced regional contraction, measured as EDL and delta L; unchanged subendocardial blood flow without any redistribution; and improved lactate extraction in the ischaemic region.

The authors report on the action of a new drug, 1-(pyrrolidinyl-1-carbonyl)-methyl-4-(3,4,5-trimethoxycinnamoyl)-piperazine-maleate (cinepazide), on the heart and systemic and coronary circulation. At doses of 1--3 mg/kg i.v. (n=6), systemic blood pressure decreased by 4%, and heart rate increased reflexly by 8%...