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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The effects of sildenafil (Viagra) on hemodynamics and pulmonary
gas exchange remain uncertain. The aim of this study was to investigate what effect sildenafil had on gas exchange. A total of 24 anesthetized pigs were randomly assigned into four groups of six
animals each: Group Low received 25 mg of sildenafil, which is
equivalent to half the recommended dose for humans; group Normal received 50 mg; group High received 100 mg; and one group
served as control. Inert gas and hemodynamic measurements were
performed to define dose-dependent effects of sildenafil on cardiac and pulmonary function. Measurements were taken 30, 60, and
90 min after the administration of sildenafil via gastric tube. All
doses of sildenafil caused significant increases in intrapulmonary
shunt flow (maximum amplitude, 4.4 ± 0.3 to 11.9 ± 0.5%; mean ± SEM), which was reflected by marked decreases in PaO2. Sildenafil
elicited some significant increases in cardiac index (CI) (high dose,
142 ± 10 to 196 ± 13 ml kg
1, mean ± SEM). Mean arterial pressure was significantly depressed after the high dose of sildenafil.
Pulmonary artery pressure was decreased after high-dose sildenafil (maximum amplitude, 16 ± 1.6 to 14 ± 1.8, mean ± SEM). No
significant differences between the three treatment groups were
found. Sildenafil represents and orally active substance with phosphodiesterase V inhibitory and cardiac output-increasing actions.
PaO2 decrease after 50 and 100 mg of sildenafil was observed in
the presence of significant rises in pulmonary shunt flow and CI.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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After the introduction of the oral phosphodiesterase (PDE) V inhibitor sildenafil (Viagra), this drug has rapidly found widespread use. In the United States, sildenafil has already been prescribed more than 6 million times (representing 50 million tablets), and 130 deaths of patients who had been prescribed Viagra were reported to the U.S. Food and Drug Administration by November 1998 (1). Sildenafil inhibits PDE V, the enzyme that specifically hydrolyzes guanosine 3',5'-cyclic monophosphate (cGMP). By a complex mechanism, increased intracellular cGMP leads to the hyperpolarization of smooth-muscle membranes and subsequent vascular relaxation. Moreover, cGMP is involved in the regulation of myocardial L-type Ca2+ channel current (ICa): In guinea pig, frog, and human cardiomyocytes, cGMP can also stimulate ICa via inhibition of cGMP-inhibited cyclic adenosine monophosphate (cAMP) PDE (PDE III) (2), thus augmenting cardiac output. PDE isozyme types I, III, IV, and V are present in the human pulmonary artery (3). Hanson and coworkers have reported that cGMP exercises considerable influence on pulmonary vascular resistance (RLva), and in that there seems to be a direct correlation between the activity of PDE V and RLva (4). Pulmonary vasodilatation induces intrapulmonary right-to-left shunt flow, which in turn leads to a decrease in arterial partial pressure of oxygen (PaO2) (5, 6). Sildenafil is a selective PDE V inhibitor (7), and therefore pulmonary vascular dilatation and a subsequent increase in intrapulmonary shunt flow are likely to occur. The extent of sildenafil-associated pulmonary vasodilatation and the influence of this substance on hemodynamics remain unclear at present.
We examined the effects of sildenafil on hemodynamics and
pulmonary gas exchange, using the multiple inert gas elimination technique (MIGET) in a porcine model. Our hypothesis
was that the administration of sildenafil would result in a
dose-dependent fall in RLva, a marked increase in ventilation-
perfusion (
A/
) heterogeneity with a subsequent deterioration of pulmonary gas exchange.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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After approval by the Austrian Federal Animal Investigational Committee, a total of 24 domestic pigs of either sex, 12 to 16 wk old and weighing 38.8 ± 2 kg (mean ± standard deviation) were studied. Animals were managed according to institutional guidelines. Anesthesia was induced intramuscularly with ketamine (15 mg/kg) and maintained by continuous infusion of propofol (10 mg/ml) at a rate of 1 ml/ kg per hour. High-dose piritramide (0.8 mg/kg) was administered to achieve an adequate depth of anesthesia. This anesthetic regimen prevented adrenergic activation and non-steady-state anesthesia. Subsequently, all animals were placed in the supine position. A collid plasma expander (3% gelatin solution, 4 ml/kg per hour) was administered continuously throughout the study period. The tracheas of the animals were intubated with endotracheal tubes (7.0-mm i.d.). Lungs were ventilated in time-cycled volume-controlled mode (Servo 900 D; Siemens, Elema, Sweden) at a respiratory rate of 15 breaths/min at fraction of inspired oxygen FIO2 = 0.21. A positive end-expiratory pressure (PEEP) of 5 cm H2O was applied in all animals. The minute volume was adjusted to maintain an arterial PCO2 between 30 and 35 mm Hg. Resulting pressures were 24 ± 1.2 cm H2O peak inspiratory pressure and 10 ± 0.43 cm H2O mean inspiratory pressure, respectively. Two inspiratory holds of 20 s each were performed before all measurements to prevent nonspecific atelectasis. Body temperature was maintained between 38 and 39° C by the use of an electric heating blanket.
Protocol
The animals were randomly assigned into four groups: Group Low received 25 mg of sildenafil, Group Normal received 50 mg, and Group
High received 100 mg. A control group of six animals was anesthetized according to the identical regimen as for the treatment groups
but received no sildenafil. Measurements were carried out at four
points in time. After a period of at least 60 min stabilization to establish steady state conditions, baseline measurements were taken. Sildenafil was then administered via gastric tube and further measurements
were taken 30, 60, and 90 min later. Each set of measurements included heart rate; systolic, diastolic, and mean arterial blood pressures; and central venous pressure, mean pulmonary arterial pressure
(
), and pulmonary capillary wedge pressure (Ppc,we). Respiratory
measurements were performed as described below. Inert gas as well
as arterial and mixed venous blood gas samples were taken at the same time.
Animal Instrumentation
Venous catheters were inserted percutaneously into auricular veins for inert gas infusion and continuous infusion of propofol. A no. 7F thermistor-tipped Swan-Ganz catheter (Baxter Edwards, Irvine, CA) was inserted into the right jugular vein and advanced into a main pulmonary artery by use of direct-pressure monitoring. This allowed measurement of cardiac output, pulmonary arterial pressure, and mixed venous blood sampling. The left femoral artery was cannulated for measurement of systemic pressure and arterial blood gas sampling.
Hemodynamic Measurements
Mean arterial pressure (
), central venous pressure (Pcv), , and
Ppc, we were measured with an ICU monitor (Servomed; Hellige
GmbH, Frieburg, Germany) with standard pressure transducers (model
1290A; Hewlett-Packard, Böblingen, Germany) that had been zeroed
to the level of the right atrium. Cardiac output was measured with a
Baxter-Vigilance Monitor (Edwards Critical Care Division, Irvine, CA)
and a no. 7F Swan-Ganz catheter. The mean of six determinations of
cardiac output was recorded.
Blood Gas and Metabolic Measurements
Arterial and mixed venous samples (2 ml each) were collected simultaneously and immediately analyzed for oxygen and carbon dioxide partial pressure, pH, hemoglobin concentration, and hematocrit using AVL 995 S and AVL 912 CO-Oxylite (AVL AG, Schaffhausen, Switzerland). All values were corrected to body temperature.
Inert Gas Measurements
A/ distributions were determined using the MIGET as previously described (8, 9). A mixture of six inert gases, including sulfur hexafluoride,
ethane, cyclopropane, halothane, diethyl ether, and acetone dissolved in
saline, was infused via an auricular vein at a rate of 3 ml/kg per hour.
This infusion was started at least 1 h before the first set of measurements. Blood samples, 10 ml, were collected in duplicate into heparinized glass syringes from the pulmonary artery and the left femoral artery. Mixed expired gas samples of 30 ml were collected from a specially
designed heated mixing chamber into preheated gas-tight glass syringes. All samples were kept at a temperature of 39 ° C and then analyzed. Gas
extraction was performed as described by Wagner and coworkers (9).
Concentrations of inert gases were measured by gas chromatography (HP-5890, Series II; Hewlett-Packard). A/ distributions were determined from inert gas data by use of the 50-compartment model of Wagner and colleagues (8) and Evans and Wagner (10). Inert gas shunt flow
(S/T), log standard deviation of (log SD), log standard deviation
of A (log SDA), mean A/ ratios of A and distributions, and ratio of dead space to tidal volume (VD/VT) were calculated from this 50-compartment model. Distributions of A and are presented as follows: (1) blood flow to unventilated lung units, shunt flow (A/ < 0.005); (2) blood flow to poorly ventilated lung units (low A/, > 0.005 through 0.1); (3) blood flow to normally ventilated lung units (normal
A/, > 0.1 through 10); (4) ventilation of poorly perfused lung units
(high A/, > 10 through 100); and (5) ventilation of unperfused lung
units, alveolar dead space (A,D/) > 100).
The residual sum of squares was used as an indicator of fit of the
experimental data to this 50-compartment model (6). After obtaining
the A/ distribution, each set of data was examined for possible pulmonary oxygen diffusion limitation, as inert gas exchange is unaffected by this. Mixed Pa O2 was calculated from compartmental end-capillary values and compared with the measured value.
Respiratory Measurements
Airway pressures, expiratory tidal volume, expiratory minute volume, and respiratory rate values were recorded by the built-in detectors of the ventilator.
Statistical Analyses
The data were examined by two-factor analysis of variance for repeated measurements. Significant post hoc differences were further analyzed by the Newman-Keuls test; p values less than 0.05 in intergroup comparison were considered significant. Results are expressed as means ± standard error of the mean (SEM).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemodynamic Measurements
Results are shown in Table 1. The administration of low, normal, and high doses of sildenafil resulted in significant increases in cardiac index (CI) and stroke volume index (SVI).
The greatest extent of these changes was observed 90 min after drug application via gastric tube. The changes in heart rate
did not reach significance. CI rose 30, 60, and 90 min after all
doses of sildenafil (p < 0.01). SVI was significantly augmented
in all measurements after drug application. was depressed
60 and 90 min after high-dose sildenafil relative to the control
group. Trends toward an increase in were observed in the
control group as well as in the low- and normal-dose groups.
However, these differences were insignificant. Central venous
pressure (Pcv) and RLva did not undergo significant change in
comparison with control. was depressed 30 and 60 min after low-dose sildenafil and in all measurements postbaseline after high-dose sildenafil.
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Inert Gas Measurements
Normal-, low-, and high-dose sildenafil significantly increased
blood flow to units with a A/ ratio or zero (intrapulmonary shunt); significant reductions in blood flow to units with a normal A/ ratio were hence found in all groups (Figure 1). The
amount of blood flow to units with a low A/ ratio did not
change significantly (Figure 1). Alveolar dead space ventilation (A/ > 100) remained unchanged in all four groups (Table 2). Log SDA as well as mean A/ of A did not change
significantly in any of the four groups (Table 2). Mean A/ of
and log SD decreases reflected the redistribution of blood
flow as described earlier, although these changes were not significant. No measured-predicted PaO2 difference could be detected in comparing treatment groups with control. An indication of acceptable quality of theA/ distribution is a residual
sum of squares (RSS) of 5.3 or less in half the experimental
runs (50th percentile) or 10.6 or smaller in 90% of the experimental runs (90th percentile) (6). In our experiment, 88.9% of
the RSS was less than 5.3 and 100% was less than 10.6.
|
p < 0.01 in
comparison with control. BL = baseline. (B) Low
|
Blood Gas Data
Arterial blood gas data and calculations are presented in Table 3, and mixed venous blood gas data are presented in Table 4. Pa O2 was significantly decreased 30, 60, and 90 min after administration of normal- and high-dose sildenafil in comparison with control, but not after 25 mg. Alveolar-arterial oxygen pressure difference [P(A-a)O2], oxygen delivery, and uptake were increased in all animals treated with sildenafil in comparison with control. There were no significant changes in arterial and mixed venous partial pressures of carbon dioxide, mixed venous partial pressure of oxygen, or in arterial pH (pHa) and mixed venous pH (pHv).
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Respiratory Measurements
Mean airway pressure was 10 cm H2O (mean), and peak airway pressure was 24 cm H2O (mean). No significant differences could be observed. Respiratory system compliance remained stable in all animals.
Dose Dependency
No significant differences between the three treatment groups could be detected in any of the parameters measured. However, there was a trend for normal- and high-dose sildenafil to cause the greatest extent of change with respect to the depression of PaO2 and hemodynamic stimulation (Tables 1 and 2).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The main findings of our study were that 50 and 100 mg of
sildenafil depressed PaO2 and that all applied doses of sildenafil stimulated hemodynamics in anesthetized, ventilated pigs.
Increased perfusion of a lung with unchanged ventilation may
have caused this inadequate gas exchange. In the presence of
the cardiac depressant effects of propofol (11), all doses of
sildenafil elicited significant increases in CI (p < 0.01). We
propose two possible explanations for the CI-increasing action
of sildenafil. On the one hand, sildenafil might possess considerable affinity for PDEs V and III. On the other hand, an intracellular cGMP-dependent inhibition of PDE III resulting in
increased myocardial cAMP (2, 12) and consequently in increased cardiac performance might be a potential explanation. The inhibition of AMP breakdown by GMP has already been
shown in a platelet cell model by Maurice and Haslam in 1990 (13). Increased myocardial AMP is consistent with the increases in CI and heart rate observed in our experiment. Although the pattern of ventilation was maintained, significant
depression of arterial PO2 was noted in the presence of increased cardiac output. A positive correlation between shunt
flow and cardiac output was first suggested by Kelman and coworkers (14). Rennotte and associates found that the inotropic effect of dopamine and dobutamine is linked to a redistribution of blood flow to lung units with a A/ ratio of zero
(intrapulmonary shunt flow) (15). In addition Prielipp and colleagues have shown that the inotropic amrinone (a PDE III
inhibitor) significantly increases pulmonary shunt flow in extubated patients 24 h after aortocoronary bypass graft (16). However, it cannot be stated to what extent the changes in gas exchange can be attributed to presumed vasodilatatory effects on the one hand, or to the substantial increase in CI on the
other hand. The falls in observed after low- and high-dose
sildenafil are consistent with the presence of PDE isozyme
types I, III, IV, and V in the human pulmonary artery (3). Calculation of RLva showed no significant differences in comparing treatment groups with control. The latter was presumably
due to the distension of the pulmonary blood vessels in the
presence of an elevated cardiac output (Table 1). Although no
significant difference between the treatment groups could be
detected, normal- and high-dose sildenafil caused the highest
response with respect to depression of PaO2 and increase in CI.
The dose applied did not have an effect on onset time or similar other response.
On the basis of the results of this study, sildenafil-associated modulation of hemodynamics and pulmonary gas exchange may be associated with specific risks. First, in patients
with chronic obstructive pulmonary disease there is already a
large amount of blood flow going to lung units with very low
A/ ratios. Further increase in A/ heterogeneity will
worsen hypoxemia. Second, the marked decrease in Pa O2 associated with an increase in cardiac output may be deleterious in
patients with coronary heart disease.
Some limitations of this study should be mentioned. In the present study, the drug was administered via gastric tube. Because the amount of enteral resorption is variable, the plasma concentrations of sildenafil remained uncertain even though all animals had been fasted overnight and all animals were of similar age and weight. However, sildenafil is available only as a tablet, so our experiment resembled oral administration in humans. Also, differences between anesthetized pigs and awake humans must be remembered, as pigs do not have a collateral ventilation but a very reactive pulmonary vascular system and therefore more easily develop intrapulmonary right-to-left shunt.
Sildenafil represents a novel orally effective substance with cardiotonic actions. Arterial PO2 decrease has been associated with significant rises in pulmonary shunt flow and CI.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Axel Kleinsasser, M.D., Department of Anesthesiology and Critical Care Medicine, Leopold-Franzens-University of Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. E-mail: axel.kleinsasser{at}uibk.ac.at
(Received in original form March 7, 2000 and in revised form July 14, 2000).
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References |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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1. U.S. Food and Drug Administration. Postmarketing safety of sildenafil citrate. Summary of reports of deaths in sildenafil citrate users from late March through mid-November 1998. Washington DC: U.S. Food and Drug Administration (Center for Drug Evaluation and Research); 1998.
2. Fischmeister R, Mery PF. Regulation of cardiac calcium current by cGMP/NO route. CR Seances Soc Biol Fil 1996; 190: 181-206 [Medline].
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Hanson KA,
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