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Sevoflurane breaks down in basic environments to form a vinyl ether known as Compound A. This compound is toxic in the rat, with an LC50 of about 400 ppm after 3 h exposure and with renal damage evident between 50 and 100 ppm. There is no valid current evidence that Compound A is toxic in man, and the rat may not be an appropriate model for determination of this breakdown product's toxic potential in humans. The main factors influencing the degree of patient exposure to Compound A include fresh gas flow, sevoflurane concentrations, absorber temperature and composition, and the patient's carbon dioxide production.

We studied midlatency auditory evoked potentials (MLAEP) during general anesthesia with increasing end-expiratory concentrations of sevoflurane in 12 patients scheduled for elective gynecologic surgery. After oral premedication with 20 mg clorazepate dipotassium, anesthesia was induced with etomidate (0.2 mg/kg intravenously [IV]). Vecuronium (0.1 mg/kg) was given for neuromuscular block, and controlled ventilation with sevoflurane in 100% O2 was instituted. Auditory evoked potentials were recorded in the awake state and during anesthesia with end-expiratory steady-state concentrations of 0.5, 1.0, 1.5, and 2.0 vol% of sevoflurane on vertex (positive) and mastoids on both sides (negative). Latencies of peaks V, Na, Pa, Nb, and P1 (ms) and amplitudes of Na/Pa, Pa/Nb, and Nb/P1 (microV) were measured. In the awake state, MLAEP had high peak-to-peak amplitudes and a periodic waveform. During general anesthesia with increasing end-expiratory concentrations of sevoflurane, the latency of the brainstem response V increased slightly. In contrast, MLAEP showed marked dose-dependent, statistically significant increases in the latencies of Na, Pa, Nb, and P1 and decreases in the amplitudes of Na/Pa, Pa/Nb, and Nb/P1. Under 2 vol% of sevoflurane, MLAEPs were severely attenuated or abolished. Based on these observations, > or = 1.5 vol% sevoflurane should suppress phenomena such as auditory perceptions, intraoperative wakefulness, and awareness.

Sevoflurane is metabolized to hexa-fluoro-isopropanol and inorganic fluoride by the human liver. Its use as an anesthetic may lead to peak plasma fluoride concentrations exceeding those seen after enflurane. Although there is no nephrotoxicity after sevoflurane anesthesia in humans with normal kidneys, those with chronically impaired renal function might be at increased risk because of increased fluoride load due to prolonged elimination half-life. In this study, measures of renal function after sevoflurane anesthesia were compared to those after enflurane in patients with chronically impaired renal function. Forty-one elective surgical patients with a stable preoperative serum creatinine concentration > or = 1.5 mg/dL were randomly allocated to receive sevoflurane (n = 21) or enflurane (n = 20) at a fresh gas inflow rate of 4 L/min for maintenance of anesthesia. Serum fluoride concentrations were measured by ion-selective electrode. Renal function (creatinine, urea, sodium, osmolality) was assessed in serum and urine preoperatively and for up to 7 days postoperatively. Peak serum inorganic fluoride concentrations were significantly higher after sevoflurane than after enflurane anesthesia (25.0 +/- 2.2 vs 13.3 +/- 1.1 microM; mean +/- SEM). Laboratory measures of renal function Laboratory measures of renal function remained stable throughout the postoperative period in both groups. No patient suffered a permanent deterioration of preexisting renal insufficiency and none required dialysis. Thus, neither sevoflurane nor enflurane deteriorated postoperative renal function in these patients with preexisting renal insufficiency. There is no evidence that fluoride released by metabolism of sevoflurane metabolism worsened renal function in these patients with stable, permanent serum creatinine concentrations more than 1.5 mg/dL.(ABSTRACT TRUNCATED AT 250 WORDS)

The safe use of nitrous oxide, in particular in patients with coronary artery disease, has been questioned. This study was designed to determine whether nitrous oxide directly affects global coronary hemodynamic variables and coronary arteriolar microvessels in the absence of changes of myocardial oxygen consumption. In dogs the effects of nitrous oxide were evaluated during normotension (NT, intravenous [IV] piritramid, nitrogen/oxygen; and NT/N2O, IV piritramid, nitrous oxide/oxygen) and during hypotension (MAP 60 mm Hg) (HT, IV piritramid, halothane, nitrogen/oxygen; and HT/N2O, IV piritramid, halothane, nitrous oxide/oxygen). The diameter of coronary arteriolar microvessels (range, 20-450 microns) was assessed by intravital fluorescence microscopy. Myocardial blood flow was determined by radioactive microspheres. Systemic and coronary hemodynamics, as well as arteriolar microvessel diameters, were comparable between NT and NT/N2O. During HT, nitrous oxide (HT/N2O) affected neither systemic nor coronary hemodynamics. Moreover, there was no obvious difference in the diameters of coronary microvessels between HT and HT/N2O. In conclusion, nitrous oxide, whether at normotensive or hypotensive conditions, neither influences coronary arteriolar tone nor reduces or redistributes myocardial blood flow.

The clinical course of acute pancreatitis is strongly influenced by secondary cardiac, pulmonary and renal damage. The aim of the present study was to gather information about the compartment promoting the systemic damage. Therefore the activity of lipase, phospholipase A and plasma pro-kallikrein and the concentration of tissue kallikrein and kininogen were measured in portal venous blood, pancreatic lymph and peritoneal exudate. Anaesthetized pigs were subjected to fluid resuscitation to keep systemic haemodynamic parameters constant. The pancreas was isolated in situ. The pigs were randomly assigned to a control group (n = 9) or one of the two pancreatitis groups (n = 10 each). Pancreatitis was induced by i.a. infusion of free fatty acid (FFS) or retrograde infusion of 5% sodium taurocholate intraductally (NaT). In both pancreatitis groups the activity of lipase and phospholipase A increased. The most pronounced changes were seen in the peritoneal exudate (phospholipase A activity 40 min after induction: control 10.0 U/l, NaT 72.2 U/l). In both pancreatitis groups there was evidence for activation of the tissue kallikrein kinin system in the form of an increase in the kallikrein concentration and a decrease in the kininogen concentration. Again the changes were most pronounced in the peritoneal exudate (tissue kallikrein 40 min after induction: control 14.7 ng/ml, NaT 452 ng/ml).

The object of this investigation was to compare the effects of volatile anesthetics and of hemorrhage at comparable arterial blood pressures on splanchnic blood flow (radioactive microspheres) and tissue oxygenation of the liver and pancreas (surface PO2 [PSO2] electrodes). In contrast to earlier studies, we did not use identical minimum alveolar anesthetic concentration multiples as a reference to compare volatile anesthetics; rather, we used the splanchnic perfusion pressure. Under general anesthesia (intravenous chloralose) and controlled ventilation, 12 Sprague-Dawley rats underwent laparotomy to allow access to abdominal organs. Mean arterial pressure was decreased from 84 +/- 3 mm Hg (mean +/- SEM) at control to 50 mm Hg by 1.0 +/- 0.1 vol% halothane, 2.2 +/- 0.2 vol% enflurane, and 2.3 +/- 0.1 vol% isoflurane in a randomized sequence. For hemorrhagic hypotension, blood was withdrawn gradually until a mean arterial pressure of 50 mm Hg was attained. Volatile anesthetics and hemorrhage reduced cardiac output, and hepatic arterial, portal venous, and total hepatic blood flows by comparable degrees. Mean hepatic PSO2 decreased significantly from 30.7 +/- 2.6 mm Hg at control to 17.4 +/- 2 and 17.5 +/- 2 mm Hg during enflurane and isoflurane (each P less than 0.05) anesthesia, respectively. The decrease to 11.5 +/- 2.5 mm Hg was more pronounced during halothane anesthesia. Hemorrhagic hypotension was associated with the lowest hepatic PSO2 (3.4 +/- 1.3 mm Hg) and the highest number of hypoxic (0-5 mm Hg 86%) and anoxic PSO2 values (0 mm Hg 46%). Pancreatic blood flow and oxygenation remained unchanged from control during halothane and enflurane administration, whereas isoflurane increased both variables. Hemorrhagic hypotension slightly reduced pancreatic flow (-8%) but significantly decreased PSO2 from 58 +/- 5 mm Hg at control to 36 +/- 3 mm Hg, with 7% of all measured values in the hypoxic range. Thus, volatile anesthetics preserved pancreatic but not hepatic blood flow and tissue oxygenation in this rat model. Despite comparable effects on perfusion, the PSO2 of the liver and pancreas was the least during hemorrhagic hypotension compared to that with the anesthetics. Because the volative anesthetic-induced hypotension has such a different effect on splanchnic tissue oxygenation compared with hemorrhagic-induced hypotension, the authors conclude that the method of inducing hypotension may have different effects on oxygenation of various tissues.

Background: Propanidid, an ultra-short-acting i.v. anaesthetic agent, was widely used in the 1960s. Reports of anaphylactoid reactions in patients associated with release of histamine following administration of the drug, however, led to withdrawal of this useful anaesthetic. Since the adverse side effects of the former solution could be attributed to the solvent cremophor, attempts have recently been made to produce a propanidid solution without addition of the solvent. We report on comparative investigations employing a new liposomal solution (B. Braun, Melsungen, FRG) and the conventional cremophor preparation with regard to anaesthetic properties, haemodynamic side effects, and electroencephalographic effects (EEG)., Methods: Sprague-Dawley rats (n = 46) were implanted with venous and arterial lines and epidural EEG electrodes during chloral-hydrate anaesthesia. The following day, arterial blood pressure (ABP), heart rate (HR), and EEG were monitored in awake animals and then after induction of anaesthesia by a bolus of the respective propanidid preparation, followed by an infusion period of 15 min in six different experimental groups. Animals of groups L-60, L-90, L-120, or C-60, C-90, or C-120 groups received 60, 90, or 120 mg.100 g-1.h-1 of the liposomal (L) or cremophor (C) preparation. During anaesthesia, the corneal reflex and nociception to tail-clamping were also tested. At termination of the infusion, blood samples were drawn for determination of plasma propanidid concentrations., Results: Both preparations were similarly effective in induction and maintenance of anaesthesia in a dose-dependent manner; both similarly lowered ABP and HR. The corneal reflex and nociceptive responses to tail clamping were also comparably suppressed. However, whereas the liposomal preparation was well tolerated at higher dose levels, the cremophor preparation caused considerable dose-dependent mortality of 11%, 86%, and 86% in animals in groups C-60, C-90, and C-120, respectively. Both preparations were found to induce a burst-suppression pattern in the EEG associated with clonic seizures, with a lower incidence with the liposomal preparation (22% and 50% in groups L-90 and L-120) as compared to the cremophor preparation (100% and 89% in groups C-90 and C-120). A remarkable variability in propanidid plasma concentrations was found at the end of the infusion period, although no differences were observed between both preparations. Discontinuation of infusion of propanidid resulted in rapid awakening (less than 5 min), irrespective of whether the liposomal or conventional preparation was employed., Conclusion: The present findings demonstrate largely identical anaesthetic potencies of a new liposomal solution as compared to the conventional cremophor preparation of propanidid. The liposomal preparation, however, was superior as far as tolerance and incidence of clonic seizures was concerned. The present findings should prompt further studies on the suitability of liposomal propanidid as a short-acting anaesthetic agent in patients.

An experimental model was established for fluorescence video microscopy of coronary microvessels. Nineteen dogs were anesthetized with a narcotic. Catheters were placed for hemodynamic monitoring and sampling of arterial and coronary venous blood. Myocardial perfusion was measured with radioactive microspheres. Following thoracotomy, movements of the myocardial surface area under investigation were restricted by a specially designed heart holder. Plasma was stained with FITC labelled dextran. Diameters were determined in arteriolar and venular microvessels greater than or equal to 20 microns. Measurements were performed during baseline conditions, i.e. only the basic anesthetic drug was applied, and during coronary vasodilation by continuous infusion of adenosine in a randomized sequence. Mean arterial pressure was reduced from 85 +/- 2 mmHg during baseline to 59 +/- 1 mmHg by infusion of 16.9 +/- 2.2 mg.kg-1.h-1 adenosine. Adenosine increased left ventricular blood flow by 253%, left ventricular oxygen demand remained unchanged. A total of 495 arteriolar and 170 venular diameters were measured during baseline condition and during adenosine infusion. Arteriolar diameters increased in all vessel segments between 20 and 600 microns, however, arterioles below a critical size of 100 microns had a greater dilating capacity than larger arterioles. Maximal decrease of segmental resistance occurred in 20-40 microns arterioles and amounted to 74%, which is less than the 82% decrease of total coronary resistance. Venular diameter changes, too, were more pronounced in smaller vessels.

We investigated the effects of clinically administered volatile anesthetics and of adenosine on the microvasculature of the in situ beating canine heart. Thirteen dogs were studied during general anesthesia with an opioid (piritramide), which was infused throughout the experiments. Measurements were obtained in each animal at control (piritramide only) and during hypotension (mean arterial pressure 60 mmHg) induced by halothane, enflurane, isoflurane, and adenosine. Using epiillumination and fluorescence microscopy, 354 arterial microvessels with diameters from 20 to 450 microns were examined through all experimental periods. Hypotension by halothane, enflurane, isoflurane, and adenosine reduced coronary vascular resistance by 13%, 23%, 40%, and 85%, respectively. Coronary venous PO2 was unchanged from control with halothane (+/- 0%) and enflurane (+7%) and significantly increased with isoflurane (+16%) and adenosine (+65%). Left ventricular blood flow decreased significantly during halothane (-35%) and enflurane (-23%); was unchanged from control during isoflurane (-9%); but significantly increased during adenosine (+397%). Coronary arterial and arteriolar diameters increased with all hypotensive agents. Vasodilation was least with halothane, intermediate with enflurane and isoflurane, and most pronounced with adenosine. Diameters increased considerably more in vessels with initial diameters below 100 microns as opposed to larger vessels. Calculation of microvascular segmental resistances revealed that the maximum conductance changes during volatile anesthetics were located in the vessel segments visualized by microscopy, i.e., in vessels larger than 20 microns. However, this was not the case with adenosine. We conclude that volatile anesthetics induce coronary vasodilation by preferentially acting on vessels with diameters from 20 microns to approximately 200 microns, whereas adenosine, in addition, has a pronounced impact on the small precapillary arterioles.

The authors studied the effects of sevoflurane and isoflurane on systemic hemodynamics and regional blood flow distribution (microsphere technique) in 15 rats during general anesthesia with intravenous chloralose and controlled ventilation. Inhaled anesthetics were applied to reduce mean arterial blood pressure (MAP) to 70 mm Hg (1.66 vol% sevoflurane and 0.96 vol% isoflurane) and 50 mm Hg (MAP 50; 3.95 vol% sevoflurane and 2.43 vol% isoflurane). Control recordings were obtained with intravenous chloralose only. At a MAP of 70 mm Hg, both anesthetics reduced heart rate, cardiac output, and systemic vascular resistance to a similar degree. Isoflurane decreased systemic vascular resistance markedly at a MAP of 50 mm Hg and thereby maintained cardiac output at higher levels than sevoflurane. The left ventricular rate-pressure product decreased comparably with both anesthetics. Cerebral blood flow increased dose-dependently with both inhaled anesthetics but to a greater degree with isoflurane. Total hepatic blood flow remained unchanged from control at a MAP of 70 mm Hg but decreased at a MAP of 50 mm Hg. This was due to reductions of hepatic arterial and portal venous tributaries. Renal blood flow was reduced with only the high concentrations of the anesthetics. Myocardial blood flow was reduced at all concentrations of volatile anesthetic; however, the decrease was less with isoflurane. This would indicate a more pronounced coronary vasodilation by isoflurane as the rate-pressure product, as a measure of the actual left ventricular oxygen demand, decreased by comparable degrees with both anesthetics. Our results indicate that sevoflurane and isoflurane (each approximately 0.7 MAC) have no dissimilar systemic and regional hemodynamic effects at a MAP of 70 mm Hg in this animal model. At higher concentrations (approximately 1.7 MAC), cerebral blood flow was more with isoflurane than with sevoflurane and was associated with a more pronounced vasodilation in the myocardium.

Inhalational anesthetics produce differential effects on hepatic blood flow and oxygenation that may impact hepatocellular function and drug clearance. In this investigation, the effects of sevoflurane on hepatic blood flow and oxygenation were compared with those of enflurane, halothane, and isoflurane in ten chronically instrumented greyhound dogs. Each dog randomly received enflurane, halothane, isoflurane, and sevoflurane, each at 1.0, 1.5, and 2.0 MAC concentrations. Mean arterial blood pressure and cardiac output decreased in a dose-dependent fashion during all four anesthetics studied. Heart rate increased compared to control during enflurane, isoflurane, and sevoflurane anesthesia and did not change during halothane anesthesia. Hepatic arterial blood flow and portal venous blood flow were measured by chronically implanted electromagnetic flow probes. Hepatic O2 delivery and consumption were calculated after hepatic arterial, portal venous, and hepatic venous blood gas analysis. Hepatic arterial blood flow was maintained with sevoflurane and isoflurane. Halothane and enflurane reduced hepatic arterial blood flow during all anesthetic levels compared to control (P less than 0.05), with marked reductions occurring with 1.5 and 2.0 MAC halothane concomitant with an increase in hepatic arterial vascular resistance. Portal venous blood flow was reduced with isoflurane and sevoflurane at 1.5 and 2.0 MAC. A somewhat greater reduction in portal venous blood flow occurred during 2.0 MAC sevoflurane (P less than 0.05 compared to control and 1.0 MAC values for sevoflurane). Enflurane reduced portal venous blood flow at 1.0, 1.5, and 2.0 MAC compared to control. Halothane produced the greatest reduction in portal venous blood flow (P less than 0.05 compared to sevoflurane).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of reactions. The treatment of reactions to protamine is still symptomatic. Hypotension resulting from systemic vasodilation (anaphylactoid reaction) is treated by volume infusion, and alpha-stimulating catecholamines may be necessary. The combination of increased right ventricular afterload and systemic hypotension (anaphylactic/anaphylactoid reaction) requires primarily the improvement of coronary perfusion pressure and, thus, of O2 delivery to the right ventricular myocardium. To this end, catecholamines with alpha-stimulating action should be administered. Nitroglycerin is indicated when pulmonary hypertension persists in the presence of essentially normal systemic pressure. In the acute situation, steroids and antihistamines have no beneficial effect. Prevention of protamine reactions. For prevention of systemic hypotension by vasodilatation, protamine should be infused very slowly and not during hypovolemia. General prophylaxis using H1/H2 antagonists is not justified. Reliable preoperative identification of patients who would suffer an anaphylactic/anaphylactoid reaction to protamine, for example by skin tests or by measuring specific anti-protamine IgE or IgG antibodies, is not possible. This prevents individual prophylaxis in risk patients. In view of the low incidence of severe protamine reactions and the lack of better alternatives to the heparin/protamine regimen, general prevention is not indicated. For patients who are potentially at risk (insulin-dependent diabetics, prior protamine exposure), the side-effects of preventive measures must be weighed against their benefits. Only known sensitivity to protamine justifies certain preventive actions. In vascular surgery prostacyclin can be used instead of heparin/protamine or can be withheld (fading out of heparin action). Administration of steroids and/or antihistamines should be avoided. In cardiac surgery the use of hexadimethrine (if available) or total avoidance of protamine is paramount. Corticosteroids may be considered. Aortic administration of protamine and anticoagulation with ancrod are not recommended. The most promising compounds for rpharmacologic prevention of anaphylactic/anaphylactoid reactions in the future are thromboxane receptor antagonists.

Protamine is a strongly alkaline polypeptide with a molecular weight of about 4500. Protamine solutions contain paraben compounds as antimicrobial agents. Rapid neutralization of heparin by protamine may cause an anaphylactoid reaction characterized by a non-immunogenic histamine release and by unknown mediators mechanisms. This response is associated with systemic peripheral vasodilation resulting in slight to moderate hypotension. Weak negative inotropic effects by mechanisms different from the reduction of ionized calcium concentrations may also contribute to systemic hypotension. Apart from these mostly slight reactions, severe reactions may occur with life-threatening systemic hypotension, bronchospasm and, in rare cases, death. They are caused by anaphylactic/anaphylactoid reactions resulting in catastrophic pulmonary vasoconstriction which induces right and eventually global ventricular failure. Sensitization to protamine (anaphylactic) and anaphylactoid reactions are the underlying mechanisms. The majority of anaphylactic/anaphylactoid reactions are associated with complement activation and the release of anaphylatoxins C3a and C5a. These activate the cyclo-oxygenase pathway of the arachidonic acid metabolism in yet unidentified cells, probably within the lung. As a result, thromboxane and prostaglandins are released. Thromboxane is the pivotal mediator responsible for the pulmonary vasoconstriction and, presumably, also for the bronchospasm during protamine reactions. The pronounced activation of polymorphonuclear leukocytes and the decrease in platelet counts may reflect a mere epiphenomenon. The degree of right ventricular afterload increase at which systemic hypotension requiring immediate therapy would occur depends mainly on the contractile state of the heart. Potential risk patients for severe protamine reactions are depot insulin-dependent diabetics and patients with prior exposure to protamine.

An experimental model of edematous pancreatitis in pigs was established and measurement of pancreatic macro- and microcirculatory parameters and determinations of pancreatic enzymes (lipase, phospholipase A) and vasoactive mediators (prostanoids, kallikrein, kininogen) were performed. During general anesthesia the pancreas was isolated in situ. Pancreatic microcirculatory parameters were measured using videofluorescence microscopy after iv administration of FITC-Dextran. In hourly collected samples lipase and phospholipase A activities were determined enzymatically, concentrations of kallikrein, kininogen, and selected prostanoids were measured by radioimmunoassay. Two experimental groups were studied: (1) control (n = 9); (2) edematous pancreatitis induced by injection of oleic acid into the pancreatic artery (free fatty acid, ffa; n = 10). The animals were followed up for 6 hr. Systemic hemodynamic parameters remained constant in both groups. In the pancreatitis group pancreatic blood flow and O2-consumption decreased significantly (-55 and -49%), while pancreatic vascular resistance increased significantly (+50%). During baseline conditions 41% of all capillaries were perfused. In the pancreatitis group there were both areas with persistent stasis as well as areas with continuous perfusion. However, in the latter areas the portion of perfused capillaries decreased significantly to 27%. In the control group the portion of perfused capillaries remained constant. Liberation of lipase and phospholipase A especially into lymph and ascites fluid was measured during pancreatitis. Furthermore, considerable releases of kallikrein into lymph (+50%) and ascites (+800%) and a marked consumption of kininogen in lymph (+90%) and in ascites fluid (+80%) were measured. Activation of the arachidonic acid cascade and a significant release of prostacyclin and thromboxane A2 into pancreatic venous blood and lymph was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Severe pulmonary hypertension after protamine neutralization of heparin is an infrequent but life-threatening event following cardiopulmonary bypass. The effect of left ventricular infusion of protamine on pulmonary hypertension as well as a possible role of platelet-activating factor (PAF) or histamine in the heparin-protamine reaction was investigated in 30 pigs in four different groups during general anesthesia. Group 1 animals received 250 IU/kg heparin, followed by 100 mg protamine intravenously after 15 min. In group 2 protamine was infused into the left ventricle. Group 3 animals received the histamine H1- and H2-antagonists clemastine and ranitidine 5 min before protamine infusion. In group 4 the PAF receptor blocker WEB 2086 was given 5 min before protamine. Platelet-activating factor was measured by a bioassay in serum samples of group 1 and group 4 animals. In all four groups protamine caused severe pulmonary hypertension, thromboxane A2 release, and a transient decrease in leukocyte counts. No PAF release was detected after protamine infusion. Neither left ventricular infusion of protamine nor histamine or PAF antagonists prevented or attenuated the reactions after protamine infusion. The authors conclude that left ventricular infusion of protamine provides no protection from pulmonary hypertension, and that histamine and PAF are not involved in the acute pulmonary vasoconstriction after protamine neutralization of heparin.

Measurements of pancreatic micro- and macrocirculation were performed to evaluate the pancreatitis-induced changes. Pigs were anesthetized and ventilated mechanically. Hypotension induced side-effects were avoided by adequate volume replacement. After laparatomy, splenectomy and gastroectomy the animals were enterotomized. Systemic hemodynamic parameters were monitored as well as pancreatic blood flow (Q), which was measured electromagnetically, and arterial and portal-venous blood gases. Pancreatic microcirculatory parameters were observed using fluorescence-videomicroscopy after i.v. administration of FITC dextran 150 and FITC labeled autologous erythrocytes. The pigs were randomly assigned to a control (n = 9) and a pancreatitis group (n = 10), the later being induced by the retrograde infusion of sodium-taurocholate. Systemic and pancreatic macrohemodynamic parameters remained constant in both groups, except for avdO2 and O2-consumption (O2-c) decreasing significantly in the pancreatitis group. At baseline 42% of all capillaries were perfused in both groups. In pancreatitis we detected focal areas with persistent stasis and areas which were continuously perfused. In these areas the portion of capillaries perfused by erythrocytes increased significantly to 67%. This was accompanied by an extravasation of FITC dextran. The finding of an unchanged Q beside reduced O2-c and avdO2 during pancreatitis is explained by the changes in pancreatic microcirculation. Focal stasis was observed beside areas showing typical signs of an acute inflammation: increased macromolecular permeability and capillary recruitment, e.g. oedema and hyperaemia.

Arterial hypoxemia decreased epicardial tissue PO2, measured by means of a multiwire surface electrode, as well as coronary venous PO2 and myocardial lactate extraction. Left ventricular blood flow increased, O2 delivery, O2 demand and O2 consumption of the left ventricle remained unchanged. Thus, epicardial and coronary venous PO2 indicated decreased capillary and interstitial PO2 rather than cellular hypoxia. A linear relation between mean epicardial PO2 and coronary venous PO2 proves both parameters equally effective in reflecting changes in myocardial tissue oxygenation. However, PO2 distribution curves provide additional information and epicardial PO2 is superior in models with regional changes of myocardial oxygenation.

This study has quantitated the effects of topically-applied leukotriene C4 (LTC4) upon vessel diameters, red blood cell velocities and vascular permeability to macromolecules in an animal model, namely, the dorsal skin-fold preparation of Syrian golden hamsters. Furthermore, we studied the efficacy of the leukotriene receptor blocking agent FPL 55712 in this preparation in order to establish a model for testing antiinflammatory compounds possibly involved in the lipoxygenase cascade.

An experimental study was performed to evaluate the effects of positive end-expiratory pressure (PEEP) on central hemodynamics and on regional blood flow (RBF) using the radioactive microsphere (MS) method. Ten dogs with intact lungs and 10 dogs with oleic acid-induced pulmonary edema were ventilated with PEEP 10 and PEEP 20 (cmH2O). PEEP significantly reduced cardiac output (CO) by 25% at PEEP 10 and 40--50% at PEEP 20 despite volume expansion with dextran 60. RV afterload rose markedly due to a significant increase of pulmonary vascular resistance. PEEP tended to redistribute CO in favor of brain, heart and adrenals, at the expense of stomach, pancreas and thyroid glands. Hepatic artery flow was moderately reduced; renal RBF was seriously affected only when PEEP caused an extreme low-output state. RBF to the RV remained essentially unchanged, whereas RBF to the LV decreased, roughly paralleling the respective ventricular work. Nevertheless, the RV may suffer from underperfusion during PEEP, since its tension-time-index rises; this may indicate increased oxygen needs exceeding actual oxygen delivery.

The signal characteristics of 14 shockwave-treated and 14 solid control tumors were studied before and after injection of Gd-DTPA in an animal model. T1-weighted images of shockwave-treated tumors documented no significant signal intensity increase after contrast media injection in comparison with the untreated control tumors. The reduction of perfusion in shockwave-treated tumors can be documented in vivo by the signal intensity changes of the tumors after contrast media injection.

Products of the arachidonate cascade are known to be released from pulmonary tissue in normal and abnormal states, contributing to the regulation of pulmonary vascular resistance. To what extent hypoxic pulmonary vasoconstriction is affected by prostaglandin imbalances is still controversial. To evaluate PG and TX release, we measured plasma levels of TXA2, PGI2, PGF2a, and 13,14-dihydro-15-keto-PGF2a in healthy pigs undergoing normobaric hypoxic ventilation. Plasma levels of TXA2, PGI2, and PGF2a did not change during 10 minutes of hypoxia, whereas 13,14-dihydro-15-keto-PGF2a, the stable metabolite of PGF2a, was significantly elevated after 2, 5 and 10 minutes. Hemodynamic parameters showed an increase in heart rate and pulmonary vascular resistance. Our results suggest that alveolar hypoxia releases PGF2a from lung tissue, being rapidly metabolized to 13,14-dihydro-15-keto-PGF2a and that prostaglandins, at least in part, contribute to hypoxic pulmonary vasoconstriction.

An experimental study was performed on 10 dogs to evaluate the effect of positive end-expiratory pressure ventilation (PEEP) on hemodynamics and regional blood flow (RBF). The following conclusions can be drawn from the results of this study: 1) PEEP leads to a significant reduction of cardiac output (CO). 2) Total blood flow to the preportal splanchnic organs, and consequently the portal venous flow, decreases in proportion to the reduction of CO. Within the splanchnic area, there is a redistribution of RBF in favour of the small and large intestines, at the expense of stomach and pancreas. 3) The arterial blood flow to the liver is only moderately affected. 4) The observed changes of RBF may in part contribute to the complications of the splanchnic organs occurring in PEEP-ventilated patients. 5) PEEP should be used only when strictly indicated; close monitoring of organ function appears mandatory in these patients.

The pancreatic release of arachidonic acid metabolites was studied in a porcine model of acute pancreatitis. In situ isolation of the pancreatic gland enabled selective collection of pancreatic venous blood, pancreatic lymph, and ascites fluid. Three experimental groups were studied: 1) control (n = 9); 2) hemorrhagic pancreatitis induced by injection of 5% bile salt (sodium taurocholate) into the pancreatic duct (n = 10); and 3) edematous pancreatitis induced by injection of free fatty acid (FFA) into the pancreatic artery (n = 10). Determinations of cyclooxygenase metabolites were performed by radioimmunoassay; lipoxygenase metabolites (LTC4, LTD4) were measured by radioimmunoassay after purification by high-performance liquid chromatography. Prostaglandin (PG)F1 alpha, thromboxane B2, and PGF2 alpha concentrations were almost doubled in the lymph of the FFA group during pancreatitis, as were PGF1 alpha levels in pancreatic venous blood. However, concentrations of cyclooxygenase metabolites remained unchanged in the control group and in the bile salt group. Concentrations of LTC4 and LTD4 in lymph and ascites fluid of both pancreatitis groups increased from about 50 pg/ml to a mean level of 600 pg/ml at 6 h. Leukotriene concentrations in the control group were consistently below 50 pg/ml. The results of this study indicate that above all LTC4 and LTD4 are released from the organ and that these arachidonic acid metabolites may be also involved in the events following acute pancreatitis contributing to the systemic effects of the disease.

Protamine neutralization of heparin is often associated with severe hemodynamic side-effects, including pulmonary hypertension and systemic hypotension. Because prostanoids may be involved, the authors studied the role of arachidonic acid metabolites, especially thromboxane A2, in this process. During anesthesia with enflurane and fentanyl, four groups of pigs were studied: Group 1 (n = 10) received heparin (250 IU/kg), followed by protamine (100 mg) after 15 minutes to neutralize the heparin. The same protocol was used in group 2 (n = 11), except that the thromboxane A2 receptor antagonist BM 13.177 (10 mg/kg) was infused 5 minutes before the protamine. The protocol for group 1 was also used for group 3 (n = 7) except that these animals were pretreated with indomethacin (10 mg/kg). Animals in group 4 (n = 10) were given protamine only (100 mg). Pulmonary artery pressure and pulmonary vascular resistance increased significantly in group 1 after protamine neutralization of heparin. This was accompanied by significant increases in plasma concentrations of the cyclooxygenase products thromboxane B2, 6-keto-prostaglandin F1 alpha, and prostaglandin F2 alpha. Cyclooxygenase products increased to comparable degrees in group 2, but without hemodynamic effects. Leukocyte counts decreased comparably in both groups. Hemodynamic reactions, as well as changes in plasma prostanoid levels were absent in group 3, and group 4, but leukocyte counts were less affected in animals that received protamine alone. The results indicate that the hemodynamic side-effects of protamine are mediated by prostanoids and that thromboxane A2 release is the pivotal step, because side effects were effectively prevented by pretreatment with a thromboxane receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to investigate the effects of the anesthetics enflurane and isoflurane and of the coronary vasodilator dipyridamole on myocardial oxygen balance and myocardial tissue oxygen tensions. The studies were performed in 24 open-chest dogs during basal anesthesia with a narcotic. Myocardial blood flow (MBF) was measured using radioactive microspheres, myocardial surface tissue PO2 by means of a platinum multiwire surface electrode. One control group and three experimental groups were studied: enflurane (1.1 vol%), isoflurane (0.7 vol%, both end-tidal concentrations), and dipyridamole (0.4 mg/kg). Mean arterial pressure significantly decreased to an average of 70 mm Hg in all three experimental groups. Although MBF was unchanged during enflurane (-18%) and isoflurane (+20%), it increased during dipyridamole (+304% p less than 0.05 vs baseline and control, enflurane, and isoflurane groups). Myocardial oxygen consumption decreased significantly during enflurane and isoflurane but remained unchanged during dipyridamole. Thus, the ratio between myocardial oxygen delivery and consumption increased 6% with enflurane (p less than 0.05 vs baseline), 47% with isoflurane (p less than 0.05 vs baseline and control group) and 280% with dipyridamole (p less than 0.05 vs baseline and control, enflurane, and isoflurane groups). Coronary venous PO2 remained unchanged during enflurane but increased significantly during isoflurane and dipyridamole. Left ventricular surface tissue PO2 was unchanged in enflurane and isoflurane animals and decreased slightly, yet significantly, during dipyridamole. All variables remained unchanged in the control group. Thus, isoflurane and dipyridamole interfered with MBF autoregulation and increased myocardial oxygen delivery out of proportion to myocardial demands.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of 0.7, 1.4 or 2.1 vol % isoflurane on hepatic blood flow and hepatic tissue oxygenation was studied in 12 dogs under basal anaesthesia with i.v. piritramid. Blood flow was measured by the microsphere method (phi = 15 micron). Tissue pO2 was determined by a platinum multiwire electrode and by measuring hepatic venous pO2. Isoflurane effected a marked fall in arterial blood pressure in these surgically not stimulated animals. However, cardiac output fell only moderately due to a considerable reduction in systemic vascular resistance. Both local tissue pO2 and venous pO2 were decreased with isoflurane. A potentially hazardous reduction in hepatic tissue pO2 was found predominantly with high isoflurane concentrations. The decrease in hepatic tissue pO2 results from disadvantageous effects on hepatic O2-balance: total hepatic blood flow decreases, whereas splanchnic O2 consumption increases. The lower blood flow is due to a reduction of portal blood flow whereas arterial perfusion remains unchanged. The increase in splanchnic O2 consumption possibly results from an elevated O2 consumption of the liver. Further studies have to clarify whether the disadvantageous effects of high isoflurane concentrations fail to appear when pain-induced stimulation of the sympathico-adrenergic system counteracts the fall in arterial blood pressure.

Blood flow to and oxygen consumption of the splanchnic organs were determined together with hepatic surface oxygen tensions in 18 mongrel dogs anesthetized with the long-acting narcotic piritramid. Twelve animals also received 0.7 Vol% and 1.4 Vol% isoflurane; six time-related controls received piritramid only. Surgical preparation consisted of a left thoracotomy for inserting a catheter into the left atrium for microsphere injections and for gaining access to the hepatic surface through an incision in the diaphragm. Parameters in the animals receiving isoflurane were recorded at three stages: stage 1--piritramid anesthesia after surgical preparation; stage 2-60 min after addition of 0.7 Vol% (end-expiratory) isoflurane; stage 3-60 min after addition of 1.4 Vol% (end-expiratory) isoflurane. Hepatic surface oxygen tension was determined at each stage using an eight-channel oxygen sensitive electrode. Mean arterial pressure and cardiac output decreased during both stages with isoflurane; hepatic arterial inflow remained constant. Portal blood flow and, hence, total hepatic inflow decreased significantly. An unchanged splanchnic O2 consumption induced lower hepatic venous pO2 values: 40 +/- 1 mmHg at control, 35 +/- 2 mmHg, and 31 +/- 2 mmHg (mean +/- SEM; both P less than 0.05) during isoflurane. A concomitant decrease of hepatic surface pO2 values indicated an altered tissue oxygenation. The percentage of hepatic surface pO2 values in the lowest pO2 range (0-5 mmHg) increased significantly from 8.4 to 20.3% during 1.4 Vol% isoflurane; the percentage of values of 0 mmHg increased from 2.4 to 9.8% during 1.4 Vol.%. No changes of these parameters were detected in the control animals during the 3-h observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

Left ventricular contractility (Vmax), myocardial blood flow (MBF), and oxygen consumption (O2C) were determined together with systemic hemodynamic parameters in a total of 21 mongrel dogs. Baseline recordings were obtained under basal anesthetic conditions with a narcotic (piritramid, IV). In the control group (n = 7), recordings were obtained during a three-hour observation period with infusion of piritramid. In experimental groups measurements were repeated with equi-anesthetic concentrations of isoflurane (0.7 and 1.4 vol%; n = 8) and enflurane (1.1 and 2.2 vol%; n = 6). Dose-dependent reductions of arterial pressure, cardiac output (CO) and peripheral vascular resistance were observed with isoflurane and enflurane. CO at the higher anesthetic level was depressed significantly more with enflurane. This difference was obviously due to a more severe depression of myocardial contractility with enflurane; Vmax was decreased by 18% and 26% with enflurane, but only by 10% and 17% with isoflurane (P less than 0.01). MBF and the fraction of CO received by the heart were increased above their baseline values with both concentrations of isoflurane. In contrast, the fraction of CO remained constant with enflurane while MBF decreased. O2C was reduced due to decreases of afterload and left ventricular contractility. The reduction was greater with enflurane than with isoflurane. All parameters remained unchanged in the control group. The results of this study indicate that the most striking difference in the actions of isoflurane and enflurane on cardiac parameters is on myocardial vascular resistance; MBF is increased with isoflurane, but is decreased with enflurane although myocardial perfusion pressure is reduced by almost identical amounts.(ABSTRACT TRUNCATED AT 250 WORDS)

A review of the myocardial effects of the volatile anesthetics halothane (HAL), enflurane (ENF) and isoflurane (ISO) is presented. In the first part the effects on cardiac rhythm, myocardial contractility and oxygen supply are discussed. In the second part the pathophysiology of myocardial ischemia during anesthesia and surgery is summarized. Finally the role of inhalation anesthetics in inducing or preventing myocardial ischemia is considered, with special regard to the "coronary steal" phenomenon.

The effects of a pyridoxalated polyhaemoglobin (SFH-PLP)n-solution on haemodynamics were investigated in a model of partial (hct = 12%) and total blood exchange (hct less than 1%) in 7 dogs. Partial blood exchange resulted in a slight increase in right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) and in a marked decrease in heart rate (HR). Cardiac output (CO) did not increase as would be expected from haemodilution. After total blood exchange, arterial pressure, HR, RAP, PCWP and CO were unchanged compared to the pre-exchange values during the 90 minutes of observation. However, pronounced pulmonary vasoconstriction was observed in 4 dogs. The beneficial effects on haemodynamics are due to the long intravascular persistance of the polymerized haemoglobin molecules (plasma half-disappearance time = 36 hours) and the addition of albumin supplying a sufficient colloid-osmotic pressure of the solution. These characteristics and the good oxygen unloading capacity of the pyridoxalated polyhaemoglobin resulted in longterm survival of three dogs. These results demonstrate a better haemodynamic efficacy of the (SFH-PLP)n-solution compared to previous investigations with unmodified haemoglobin solutions. However, there are still many problems, which have to be clarified prior to its clinical application.

The validity of myocardial surface tissue PO2 (PtO2) as a reliable indicator of transmural myocardial tissue oxygenation was studied in six anaesthetised, open chest pigs. Epicardial surface PtO2 was correlated with other variables of myocardial tissue oxygenation such as regional blood flow, coronary venous PO2, O2 saturation, PCO2 and regional myocardial lactate extraction. The study design was based on an experimental model in which the effects of a pacing induced tachycardia on tissue oxygenation of ischaemic and normally supplied myocardium were measured. Two platinum multiwire surface electrodes were placed on the epicardium, on the areas supplied by the left anterior descending coronary artery (LAD) and the left circumflex coronary artery (CX). The LAD was constricted to reduce mean surface PtO2 in the LAD area to about 50% of its baseline value. This did not affect surface PtO2 in the CX area. The reduction of surface PtO2 in the LAD area was associated with decreases in coronary venous PO2 and O2 saturation and with increases in coronary venous lactate and PCO2. Subendocardial regional blood flow and the subendocardial to subepicardial flow ratio were significantly lower than in the CX area. Increasing the heart rate by pacing (+45 beats.min-1) led to an increased degree of ischaemia as shown by fall in surface PtO2 in the LAD area to values around zero kPa, by marked increase in coronary venous lactate and PCO2, by reduction in total (-10%) and subendocardial (-40%) LAD flow and by deterioration of the subendocardial to subepicardial flow ratio. The increased degree of ischaemia was not accompanied by an increase in O2 extraction. The marked decrease in surface PtO2 occurred in spite of a slight increase in the subepicardial regional blood flow (+10%); thus the increase in O2 delivery was not sufficient to meet the increase in O2 demand. Total flow was increased by 27% in the CX area without changes in the subendocardial to subepicardial flow ratio and in the surface PtO2 values. When pacing was stopped, surface values of PtO2 in the LAD area returned to prepacing values, as did lactate extraction and coronary venous PCO2. Clear and close relationships with surface PtO2 were found for regional lactate extraction, coronary venous PCO2 and the normalised subendocardial RBF. Poor or no correlations were found for the normalised subepicardial regional blood flow, the coronary venous O2 saturation and the absolute values of subendocardial and subepicardial regional blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)

Thermal injury causes directly a liberation of inositolphosphates, diacylglycerols, free arachidonic acid, and lyso PAF from eukaryotic cells. From lyso PAF derivates PAF, from free arachidonic acid are derivating PG, LT, and TX. These "soluble mediators" are stimulating inflammatory cell populations in a feedback mechanism: the stimulus activates the inflammatory cells to produce the same soluble mediators (Fig.1). The arising soluble mediators are the take off for the inflammation cascade causing as later step the activation of kinin, clotting, and complement systems. The pure biochemical lesions at the onset results in the clinical manifestation of oedema, increased dermal temperature, and pains. The possibilities for prevention and allevation of early pain, due to the acute burn, lie in the inhibition of the spreading out of inflammatory mediators (Bauer 1987a) (Fig.2).

The hypothesis that adverse effects observed when heparin is antagonized by protamine are mediated by metabolites of the arachidonic acid cascade was tested during general anesthesia (enflurane, fentanyl) in 16 pigs classified into two groups. In the first group (n = 9), effects of intravenously administered protamine on systemic hemodynamics, blood/gas tensions, and arterial and mixed-venous prostanoid levels were studied. The second group (n = 7) was pretreated with indomethacin 10 mg/kg, and the same measurements were made. All pigs received heparin 150 units/kg. When protamine 1.1 +/- 0.1 mg/kg was administered over 3 minutes, marked hemodynamic alterations were observed in group 1: pulmonary artery pressure and pulmonary vascular resistance increased, and left ventricular end-diastolic and systemic arterial pressures decreased. Arterial and mixed-venous PO2 values deteriorated in all pigs in group 1 at the end of protamine infusion. These alterations were accompanied by significantly elevated prostanoid levels in arterial and mixed-venous plasma samples: Thromboxane A2, prostaglandin F2 alpha, KH2-PGF2 alpha (a metabolite of prostaglandin F2 alpha), and prostacyclin were maximally elevated at completion of protamine and remained significantly above control values at 5 minutes but were not significantly different from control after 10 minutes. Blocking the cyclooxygenase cascade by pretreatment of the pigs with indomethacin (group 2) prevented hemodynamic and blood gas alterations. It is concluded that in pigs the detrimental side effects associated with the use of protamine to reverse heparin are mediated by metabolites of the cyclooxygenase cascade.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors investigated the effects of isoflurane on blood flow and tissue oxygen pressures of a collateral-dependent myocardium. Seventeen dogs divided into two groups were studied 3-4 weeks after implantation of ameroid coronary artery constrictors to completely occlude the proximal part of the left anterior descending artery. Experiments were performed during anesthesia with an opiate that was infused intravenously throughout the experiments. In Group 1 (n = 9), measurements were obtained during control and during isoflurane- (1.6-2.2 vol%) induced hypotension (mean arterial pressure, 60 mmHg). In Group 2 (n = 8), the identical protocol was applied, but norepinephrine was infused to maintain normotension. Dipyridamole effects were studied in five animals of Group 2 after a second control period at least 1 h after discontinuation of isoflurane. Isoflurane-induced hypotension caused reductions of blood flow and surface tissue oxygen pressures in the collateral flow-dependent area. Vasodilation in the normal left ventricular areas was demonstrated by an unchanged blood flow despite a reduced oxygen consumption and by a significantly increased coronary sinus hemoglobin oxygen saturation. When arterial pressure was maintained at its control level by norepinephrine, tissue oxygen pressures remained constant and collateral as well as normal area flow increased significantly during isoflurane. Coronary vascular resistance was lower during administration of isoflurane and norepinephrine compared with that during isoflurane induced hypotension, suggesting a significant contribution of tissue oxygen demand in regulation of coronary vascular resistance. At comparable levels of arterial pressure and left ventricular oxygen consumption, normal zone blood flow was significantly higher during dipyridamole than during isoflurane and norepinephrine. Thus, isoflurane-induced hypotension decreased blood flow and tissue oxygen pressures of collateral flow-dependent myocardial areas. However, neither isoflurane nor dipyridamole caused such alterations when arterial pressure was normal.