Selective positive end-expiratory pressure and cardiac function in dogs.

Effects of general (G) versus selective (S) right (R) and left (L) positive end-expiratory pressure (PEEP) were compared during differential lung ventilation in 11 anaesthetized dogs in the supine position. GPEEP 20 cmH2O decreased cardiac output (1 min-1) from 2.9 +/- 0.2 (mean +/- SE) to 1.7 +/- 0.5 (p less than 0.05), RPEEP from 2.8 +/- 0.2 to 2.2 +/- 0.2 (p less than 0.05) while LPEEP caused no significant change in cardiac output. GPEEP increased pleural pressure more than SPEEP. Pleural pressure was asymmetric during SPEEP. Both SPEEP and GPEEP increased pericardial pressure uniformly, but the increase was less marked with SPEEP. During GPEEP 20 cmH2O transmural left ventricular end-diastolic pressure (LVEDP) decreased markedly. SPEEP caused less marked reductions in transmural LVEDP. Qualitatively similar, but less marked changes were observed with PEEP 10 cmH2O. In conclusion, cardiac output decreased less with selective PEEP than with general PEEP. This was explained by less increase in pleural and pericardial pressure, and accordingly less decrease in LV transmural filling pressure.

Ionized calcium in plasma during cardiopulmonary bypass.

The composition of the priming fluid in the heart-lung machine is of importance for the homeostasis of the patient during and after cardiopulmonary bypass. We have studied the effect of 5 different priming solutions on the degree of ionization of calcium. The primingsolutions all contained 1700 ml of a basic solution and 800 ml of one of the following solutions: CPD-plasma CPD-plasma added heparine and CaCl2 heparinized plasma 5% albumin in saline 6% dextran 70 in saline. With CPD-plasma in the priming solution, the concentration of ionized calcium dropped to very low values, followed by a normalization during the next 30 minutes, as the citrate disappeared. The addition of CaCl2 to CPD-plasma prevented the abrupt initial drop, but resulted later on in values above the normal range. Heparinized plasma, albumin, and dextran in the priming solution lead to small changes only. Bolus injections of CaCl2 during weaning from bypass resulted in substantial increases in ionized calcium, while the use of CPD-blood products lead to decreases. Citrate has great affinity to calcium ions, making strong complexes. When significant amounts of citrate are used, the level of ionized calcium cannot be predicted, but has to be measured directly. These measurements must be performed frequently.

Effect of ionized calcium on the neuromuscular blocking actions of atracurium and vecuronium in the cat.

We have determined neuromuscular blocking effects of atracurium and vecuronium at normal, high and low plasma concentrations of ionized calcium ( [Ca2+] ) in the cat. Twitch responses were measured bilaterally in the anterior tibialis muscles, using intact central innervation in one preparation. Plateaus of high and low [Ca2+] were created by infusions of calcium chloride and citrate, respectively. The interactions with changes in [Ca2+] were similar for atracurium and vecuronium, and were unaffected by central muscle innervation. The median increase in [Ca2+] from 1.21 to 1.59 mmol litre-1 shifted the dose-response curves of the drugs to the right, increasing ED50 by 7-13%, whereas the decrease to median 0.78 mmol litre-1 potentiated the drugs by a similar order. This indicates a lesser influence of [Ca2+] on the action of neuromuscular blockers than reported in a previous in vitro study. Even though the interactions were statistically significant, their moderate magnitude suggests minor clinical significance.

The effect of positive end expiratory pressure after three types of open heart surgery.

It has previously been shown that patients who have undergone mitral valve replacement (MVR) tolerate a positive end expiratory pressure (PEEP) of 1.0 kPa better than patients who have had aortic valve replacement (AVR). the difference was explained by the fact that the mitral patients had pre-existing pulmonary vascular disease. In the present study the effect of PEEP up to 2.0 kPa is investigated in three types of operations: aortocoronary bypass graft (ACBG), mitral valve replacement, and aortic valve replacement; there were five patients in each group. We found that our mitral patients tolerated PEEP better than the two other groups, and that tolerance was not correlated to a higher pulmonary vascular resistance, but rather to a higher level of pulmonary capillary wedge pressure. The influence of PEEP varies in different types of patients and the effect is still difficult to predict.

Interaction of cyclosporin and its solvent, Cremophor, with atracurium and vecuronium. Studies in the cat.

Interactions between Sandimmun (formulated as cyclosporin (CyA) in Cremophor and ethanol) and atracurium or vecuronium were investigated in anaesthetized cats. During stable 50% blockade and with a constant rate of infusion of the neuromuscular blocking drugs, Sandimmun 0.8 mg kg-1 or an equivalent amount of its solvent moiety was injected over 5 min. Sandimmun potentiated the blockade induced by vecuronium (median infusion rate 110 micrograms kg-1 h-1) from 50.7% before injection to maximum 95.2% 17.3 min after injection (median values), whereas the median blockade in cats receiving atracurium (median 250 micrograms kg-1 h-1) increased from 51.3% to 72.4% after 32.9 min. At 45 min after the injection the median blockades were 93.1% and 69.8%, respectively. In cats receiving vecuronium (median 104 micrograms kg-1 h-1) the solvent produced an increase in effect of from 51.1% to maximum 78.0% blockade after 5.4 min and 61.5% after 45 min (median values). Interaction with solvent was negligible in cats receiving atracurium. We attribute the effect of the solvent to the Cremophor component. The mechanism of the interaction related to the cyclosporin is unknown.

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. III. Nicardipine and isoflurane.

To assess the interaction between isoflurane and the new calcium channel blocker, nicardipine, mongrel dogs were chronically instrumented to allow the following measurements: aortic, left ventricular and left atrial pressures; heart rate; cardiac output; and carotid, coronary, and renal blood flows. The hemodynamic effects of intravenous nicardipine 5, 10, 30, and 50 micrograms/kg were measured in awake dogs and during 1.6 and 3.0 per cent (end-tidal) isoflurane anesthesia. Nicardipine induced a dose-dependent fall in mean arterial pressure in both awake dogs and during 1.6 and 3.0 per cent isoflurane anesthesia. Heart rate and cardiac output were increased in proportion to the nicardipine dose in the awake dogs and, to a lesser degree, in the dogs anesthetized with 1.6 per cent isoflurane, but did not change during 3.0 per cent isoflurane anesthesia. Left atrial pressure was unchanged by nicardipine in awake dogs and during anesthesia. Left ventricular maximum rate of tension development (dP/dt) increased in awake dogs and decreased during anesthesia. Coronary blood flow increased dose dependently without anesthesia, and, to a smaller degree, during anesthesia. Nicardipine increased carotid blood flow without anesthesia, whereas it was unchanged during anesthesia. Renal blood flow was unchanged in awake dogs and decreased during anesthesia. The authors conclude that nicardipine is a potent vasodilator that minimally affects cardiac function and regional blood flow in the presence of isoflurane. The interactions between nicardipine and isoflurane are mainly the result of the isoflurane-induced inhibition of the reflex tachycardia elicited by nicardipine.

Hemodynamic interactions when combining verapamil, acute changes in extracellular ionized calcium concentration and enflurane, halothane or isoflurane in chronically instrumented dogs.

To assess the hemodynamic interactions when combining verapamil, acute changes in extracellular ionized calcium concentration [Ca2+] and enflurane (2.5%), halothane (1.2%) or isoflurane (1.6%), seven dogs were chronically instrumented to measure heart rate (HR), aortic, left atrial and left ventricular (LV) pressures, and cardiac output (CO). [Ca2+] was lowered 0.35 mmol.l-1 by citrate infusion and then increased 0.35 mmol.l-1 above control level by CaCl2 infusions. Verapamil was infused at 3 micrograms.kg-1 x min-1 (loading dose 200 (awake), 150 (isoflurane) or 100 (enflurane and halothane) micrograms.kg-1), giving mean verapamil concentrations around 75 (range of means: 66-84 ng.ml-1). Verapamil produced mostly minor changes in the cardiovascular effects of changing [Ca2+] in both awake and anesthetized dogs, indicating mostly additive effects. Verapamil induced a decrease in HR at high [Ca2+] and abolished an increase in mean aortic pressure at both low and high [Ca2+] awake. Verapamil exaggerated the decrease in CO and stroke volume (SV) induced by low [Ca2+] during enflurane anesthesia and abolished the increase in CO induced by low [Ca2+] and exaggerated the increase in SV and LV dP/dtmax induced by high [Ca2+] during halothane anesthesia.

Cardiovascular effects of acute changes in extracellular ionized calcium concentration induced by citrate and CaCl2 infusions in chronically instrumented dogs, conscious and during enflurane, halothane, and isoflurane anesthesia.

To study the cardiovascular effects of low blood ionized calcium ion concentrations [Ca2+] induced by citrate infusion followed by high [Ca2+], induced by CaCl2 infusion awake and during enflurane (2.5% ET), halothane (1.2% ET), and isoflurane (1.6% ET) anesthesia, dogs were chronically instrumented to measure heart rate, aortic, left atrial, and left ventricular (LV) blood pressures, and cardiac output. In conscious dogs low [Ca2+] (decreased 0.35 mM); increased heart rate (HR) and mean aortic pressure (MAP) and decreased stroke volume (SV) and LV dP/dtmax. Low [Ca2+] increased HR during all three anesthetics and decreased LV dP/dtmax except during isoflurane anesthesia. Low [Ca2+] produced more hemodynamic depression during enflurane anesthesia than during anesthesia with halothane or isoflurane increasing left atrial pressure and decreasing MAP and SV. The differences seen were partially related to decreased systemic vascular resistance during halothane and isoflurane anesthesia. In conscious dogs following high [Ca2+] (increased 0.37 mM); only MAP and LV dP/dtmax increased. LVdP/dtmax was also increased by high [Ca2+] during all three anesthetics without a change in MAP. Cardiac output increased during halothane and isoflurane anesthesia but was unchanged during enflurane. It would appear that the hemodynamic sensitivity for the effects of changing [Ca2+] was enflurane greater than halothane greater than isoflurane greater than awake. The results suggest that the effects of changes in [Ca2+] induced by citrate and CaCl2 infusion are modified by the three volatile anesthetics.

Comparative effects of halothane, enflurane, and isoflurane at equihypotensive doses on cardiac performance and coronary and renal blood flows in chronically instrumented dogs.

In order to compare equihypotensive effects of the three available volatile anesthetics, halothane, enflurane, and isoflurane, dogs were chronically instrumented for measurement of: arterial, left ventricular, and left atrial blood pressures; rate of rise of left ventricular blood pressure; myocardial wall thickening (pulsed Doppler); cardiac output (pulmonary artery electromagnetic flow meter); and coronary and renal blood flows (pulsed Doppler flow meters). All three anesthetics were administered on different days in random order to each dog (n = 10) at doses necessary to decrease mean arterial pressure to 70 and 45 mmHg and two intermediate arterial blood pressures. Changes in cardiac function and regional blood flows were compared to the awake resting state and between anesthetics using analysis of variance and paired t tests. All three anesthetics produced increases in heart rate and decreases in left ventricular dP/dt, myocardial thickening fraction, and stroke volume with the hypotension. The decreases in cardiac performance were similar among the anesthetics except at the high dose (mean arterial pressure = 45 mmHg). During this profound hypotension, cardiac performance was better maintained during isoflurane anesthesia and most depressed by enflurane anesthesia. Coronary and renal blood flows were well preserved with all three anesthetics even at mean arterial pressures of 45 mmHg. Our results suggest that isoflurane may be more beneficial than halothane or enflurane for producing profound intentional hypotension (less than 50 mmHg mean arterial pressure), although extrapolation from animal experiments to the clinical situation should be used with caution.

Cardiovascular effects of acute changes in extracellular ionized calcium concentration induced by citrate and CaCl2 infusions in conscious, chronically instrumented dogs and their interactions with ganglionic blockade.

To assess the hemodynamic effects of acute changes in extracellular ionized calcium concentration, [Ca2+], seven dogs were chronically instrumented to measure heart rate, aortic, left atrial, and left ventricular (LV) pressures, cardiac output, and coronary and renal blood flows. [Ca2+] was lowered 0.35 mmol.l-1 by citrate infusion and then increased 0.35 mmol.l-1 above control level by CaCl2 infusions. This protocol was performed in the conscious dogs with and without ganglionic blockade (chlorisondamine 2 mg.kg-1). LV dP/dtmax decreased at low [Ca2+] and increased at high [Ca2+] during all conditions. The other hemodynamic variables measured were only slightly changed by changing [Ca2+] without ganglionic blockade and surprisingly even less with ganglionic blockade. Therefore, the lesser hemodynamic effects induced by acute changes in [Ca2+] in the conscious compared with anesthetized dogs cannot be explained by the depressant effects of the anesthetics upon the autonomic nervous system. We have suggested that the binding of Mg2+ to citrate may be of importance for the minor hemodynamic effects in the conscious dogs.

Effects of inhalational anesthetics on verapamil pharmacokinetics in dogs.

Six dogs were chronically instrumented in order to collect aortic blood samples and record mean arterial pressure, cardiac output and heart rate. Each animal received verapamil 200 micrograms X kg-1 by 10-min intravenous infusions on four occasions in random sequence: awake, and during halothane 1.2%, enflurane 2.5%, and isoflurane 1.6% anesthesia. Rate of initial distribution of verapamil was reduced during anesthetic exposure. Verapamil intercompartmental clearance from the central compartment to the peripheral compartment was decreased during exposure to halothane and isoflurane, and tended to decrease during enflurane exposure as well. Verapamil terminal volume of distribution at steady-state was reduced by halothane, enflurane, and isoflurane exposure as compared with awake: 65 +/- 10, 80 +/- 9, and 93 +/- 191, respectively, versus 132 +/- 121 (mean +/- SEM; P less than 0.05). Verapamil total clearance was also reduced by halothane, enflurane, and isoflurane as compared with awake: 37 +/- 4, 39 +/- 2 and 41 +/- 31 X h-1, respectively, versus 64 +/- 71 X h-1 (P less than 0.05). Verapamil administered to awake animals resulted in a decrease from baseline in mean arterial pressure; 95 +/- 8 mmHg versus 108 +/- 4 mmHg (P less than 0.05): and an increase in cardiac output; 2.60 +/- 0.33 1 X min-1 versus 1.93 +/- 0.22 1 X min-1 (P less than 0.05). During halothane, enflurane, and isoflurane anesthesia, verapamil administration resulted in a similar decrease in mean arterial pressure; however cardiac output decreased, in contrast to the increase noted in awake animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. I. Verapamil and halothane.

In order to assess the interaction between halothane and verapamil on the cardiovascular system, mongrel dogs were instrumented so that the following measurements could be made awake and under the influence of the drugs: aortic, left ventricular, and left atrial blood pressures; myocardial segment length shortening; heart rate and rhythm; and coronary, carotid, and renal blood flows. The effect of two infusion doses of verapamil (3 micrograms X kg-1 X min-1 and 6 micrograms X kg-1 X min-1 after 200 micrograms X kg-1 bolus) were examined awake. On a different day in the same dogs, two concentrations of halothane (1.2-low and 2.4-high % end-tidal) and the effect of the two infusion doses of verapamil during low and high halothane were studied. Thirty minutes of either infusion dose of verapamil produced only heart rate and electrocardiographic P-R interval increases in conscious dogs. Halothane produced dose-related decreases in mean aortic pressure, left ventricular maximum rate of tension development (dP/dt), and segment length shortening and increases in heart rate and left atrial pressure. Carotid blood flow was increased by low halothane concentrations and returned to control with high halothane concentrations. There were no significant changes in coronary or renal blood flow produced by halothane. Verapamil infusion during low halothane concentration produced minimal effects. However, both the 3 and 6 micrograms X kg-1 X min-1 verapamil doses further depressed hearts already depressed by the high concentrations of halothane and decreased renal and carotid blood flows.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. II. Verapamil, enflurane, and isoflurane.

The effects of enflurane and isoflurane on the cardiovascular system and cellular calcium kinetics are somewhat different. Consequently, the interaction with the calcium channel blocking drug, verapamil, may also differ. In order to compare the anesthetics, the authors studied the effects of two infusion doses of verapamil (which produced plasma levels of 90 and 180 ng X ml-1) on cardiovascular dynamics and regional blood flow in awake dogs. On two other days, in the same dogs, the effects of approximately 1.1 and 2 MAC enflurane and isoflurane were first studied and then the same verapamil dose regimens while the same anesthetic concentrations were maintained. Verapamil produced only increases in heart rate and the P-R interval in the awake animal. The high dose of both anesthetics markedly decreased mean aortic pressure and left ventricular rate of tension development (dP/dt), and increased heart rate. However, only enflurane also decreased myocardial segment length shortening and increased left atrial pressure. Neither anesthetic alone affected coronary or renal blood flow, while both increased carotid blood flow at the low dose. Verapamil infusion during 1.2 MAC enflurane was more depressant than during 1.2 MAC isoflurane, but the combination of verapamil with 2 MAC concentration of both anesthetics was equally depressant. Both doses of both anesthetics increased plasma verapamil levels compared with the same verapamil dosing regimen awake. When these results are compared with those previously reported for halothane, the effects of verapamil during all three anesthetics are more similar than different.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. V. Role of pharmacokinetics and the autonomic nervous system in the interactions between verapamil and inhalational anesthetics.

To assess the role of both pharmacokinetics and the autonomic nervous system in the interaction between inhalational anesthetics and verapamil, dogs were chronically instrumented to measure heart rate, PR interval, dP/dt, cardiac output, and aortic blood pressure. In a first group of seven dogs, studied awake and during halothane (1.2%), enflurane (2.5%), and isoflurane anesthesia (1.6%), verapamil was infused for 30 min in doses calculated to obtain similar plasma concentrations (83 +/- 10, 82 +/- 6, 81 +/- 10, and 77 +/- 9 ng.ml-1, respectively). For the latter purpose, the infusion dose was 3 and 2 micrograms.kg-1.min-1 awake and during anesthesia, respectively, preceded by a loading dose of 200, 150, and 100 micrograms.kg-1, awake, during isoflurane, and halothane and enflurane, respectively. In awake dogs, verapamil induced an increase in heart rate (24 +/- 5 bpm) and PR interval (35 +/- 9 msec) and a decrease in mean arterial pressure (-5 +/- 2 mmHg) and dP/dt (-494 +/- 116 mmHg/s). Although plasma concentrations were similar in awake and in anesthetized dogs, the only statistically significant changes induced by verapamil were an increase in heart rate and a decrease in dP/dt during halothane and enflurane, while left atrial pressure increased only with enflurane. In a second group of six dogs, verapamil pharmacokinetics were determined in the presence and absence of a ganglionic blocking drug (chlorisondamine, 2 mg.kg-1 iv). Blockade of ganglionic transmission resulted in a decrease in both initial volume of distribution and total clearance of verapamil--changes similar to those previously reported with inhalational anesthetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of isoflurane on hemodynamic properties and disposition of nicardipine.

Nicardipine properties (30 micrograms/kg i.v.) were studied in a group of eight dogs awake and anesthetized with isoflurane 1.6% end-tidal. Awake, nicardipine produced a decrease in mean arterial pressure (-12 +/- 2 mm Hg) associated with an increase in cardiac output (1.63 +/- 0.2 liters/min), heart rate (75 +/- 9 beats/min), dP/dt (741 +/- 202 mm Hg/sec) and carotid (41 +/- 11 ml/min) and coronary blood flows (39 +/- 6 ml/min). During isoflurane, responses to nicardipine injections were less pronounced except for mean arterial pressure (-19 +/- 2 mm Hg) and reversed for dP/dt (-290 +/- 63 mm Hg/sec). In a second group of six conscious dogs, nicardipine (30 micrograms/kg i.v.) injected after ganglionic blockade (chlorisondamine, 2 mg/kg i.v.) elicited changes similar to those recorded during isoflurane anesthesia, data that demonstrated the importance of isoflurane-induced baroreflex blockade as a mechanism of the pharmacodynamic interactions between nicardipine and isoflurane. Isoflurane reduced nicardipine initial volume of distribution (11.6 +/- 1.2 vs. 8.9 +/- 0.8 liters), total clearance (28.5 +/- 2.9 vs. 19.2 +/- 2.1 liters/hr) and volume of distribution at steady state (50.0 +/- 11.3 vs. 29.2 +/- 3.7 liters, P less than .05). Nicardipine-induced hemodynamic changes were linearly correlated with the drug concentrations in plasma. In the presence of isoflurane, the slopes of these relationships were reduced for all hemodynamic variables except for mean arterial pressure, for which the slope was more pronounced, and dP/dt, for which the slope was reversed. In conclusion, isoflurane alters the drug plasma concentration-effect relationship of nicardipine as a result of both pharmacokinetic and pharmacodynamic interactions.

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. IV. Chronically administered oral verapamil and halothane, enflurane, and isoflurane.

Dogs were chronically instrumented to measure aortic and left atrial blood pressures, left ventricular maximal rate of tension development (dP/dt), cardiac output, and carotid, coronary and renal blood flows. Measurements were taken with the animals awake and during steady-state low and high concentrations of halothane (1.2%, 2.4%), enflurane (2.4%, 4.0%), and isoflurane (1.6%, 3.0%) with and without at least 2 weeks of oral verapamil, 120 mg, three times per day. Plasma verapamil levels varied widely, with means of 500-700 ng X ml-1 in awake animals and lower (300-400 ng X ml-1) at the time of hemodynamic measurements during anesthesia. Chronic oral verapamil in awake dogs produced predominantly tachycardia. The hemodynamic effects of low-dose halothane and isoflurane before and after oral verapamil were unchanged except for decreased renal blood flow after oral verapamil and no coronary vasodilation nor tachycardia. However, left atrial pressure was increased and cardiac output and coronary blood flow were decreased by low concentrations of enflurane with oral verapamil compared to without. The combination of oral verapamil with low (clinical) doses of enflurane was more depressant to the cardiovascular system of healthy dogs than was the combination of verapamil and halothane or isoflurane.