| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 1997;63:814-821
© 1997 The Society of Thoracic Surgeons
Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina
Accepted for publication December 9, 1996.
 |
Abstract |
|---|
 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Methods. Eight mongrel dogs underwent pulmonary artery catheterization to measure right-sided hemodynamic indices before and 6 weeks after a right atrial injection of monocrotaline pyrrole. Six weeks after injection, all hearts were instrumented with a pulmonary artery flow probe, ultrasonic dimension transducers, and micromanometers. Data were collected at baseline and after milrinone infusion.
Results. Six weeks after monocrotaline pyrrole injection, significant increases in the pulmonary artery pressure and pulmonary vascular resistance were observed. Milrinone led to significant increases in right ventricular function as well as significant improvements in pulmonary vascular resistance, pulmonary blood flow, and left ventricular filling.
Conclusions. This investigation demonstrates the well-known hemodynamic and inotropic effects of milrinone which, in the setting of monocrotaline pyrrole–induced pulmonary hypertension, were also associated with significant increases in pulmonary blood flow and left ventricular filling.
|
Introduction |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Milrinone is a bipyridine phosphodiesterase III inhibitor possessing not only positive inotropic, but also vasodilatory effects [4]. These hemodynamic properties may offer potential benefits for improving pulmonary hemodynamic indices and right ventricular dysfunction after cardiac transplantation in the setting of recipient pulmonary hypertension. This study was therefore designed to examine the hemodynamic and inotropic effects of intravenous (IV) milrinone in the setting of chronically elevated pulmonary vascular pressures using a recently established adult canine model of monocrotaline pyrrole–induced chronic pulmonary hypertension [5], load-insensitive means for assessment of right ventricular mechanics, and Fourier analysis for characterization of pulmonary vascular impedance and right ventricular hydraulic power.
|
Material and Methods |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Anesthesia, Hemodynamic Monitoring, and Monocrotaline Pyrrole Injection
All animals were anesthetized with 5 mg/kg IV thiopental sodium (Gensia Laboratories, Irvine, CA) and 20 mg/kg intramuscular ketamine sodium (Fort Dodge Laboratories, Fort Dodge, IA) before all studies, including baseline and follow-up hemodynamic measurements, drug injection, and milrinone studies. Each animal also received 900,000 U of penicillin G benzathine and penicillin G procaine (Fort Dodge Laboratories). All animals were intubated with a 9F endotracheal tube and mechanically ventilated with a Bear 1 ventilator (Inter Med; Bear Medical Systems, Inc, Riverside, CA). The tidal volume was set at 15 mL/kg, fraction of inspired oxygen at 0.21, and the respiratory rate at 10 breaths/min. Arterial blood samples were drawn from the right femoral artery and processed using a Gem-Stat blood gas analyzer (Mallinckrodt Sensor Systems, Ann Arbor, MI).
All hemodynamic measurements and drug injections were done under sterile conditions. For each animal, an 8.5F introducer sheath (Baxter Healthcare, Irvine, CA) was placed percutaneously into the external jugular vein using the Seldinger technique. A 5F Swan-Ganz catheter (Baxter Healthcare) was then advanced through the introducer sheath into the right atrium, right ventricle, and pulmonary artery for measuring right atrial, right ventricular, and pulmonary artery pressures. All pressures were monitored by a Horizon 2000 hemodynamic monitor (Mennen Medical Inc, Clarence, NY). Hemodynamic measurements were done at baseline and 6 weeks after injection. Monocrotaline pyrrole was injected into the right atrium after measurement of baseline pulmonary hemodynamic indices.
Instrumentation and Operation
A standard median sternotomy and an anterior pericardiotomy were performed to expose the hearts of all animals 6 weeks after injection during the milrinone studies. An ultrasonic flow probe (T208X; Transonic Systems Inc, Ithaca, NY) was placed around the main pulmonary trunk to measure pulmonary blood flow. Hemispheric ultrasonic dimension transducers (1.5 mm outer diameter, no. 1-1015-5A; Vernitron, Bedford, OH) were positioned across the base-apex major axis and the anteroposterior minor axis diameters of the left ventricle as well as across the septal–free wall minor axis diameters of both the right and left ventricles to measure right and left ventricular cavitary volumes. Micromanometers (MPC-500; Millar Instruments Inc, Houston, TX) were placed in the right and left ventricles, right and left atria, and pulmonary artery for continuous pressure recordings of the right and left ventricular pressures, right and left atrial pressures, and pulmonary artery pressures.
Assessment of Biventricular Function
Right and left ventricular function was assessed with load-insensitive means. The relation between stroke work and end-diastolic chamber volume for both the right and left ventricles was fit to a highly linear relation during vena cava occlusion using least-squares linear regression. The slope of these linear regressions is known as the preload recruitable stroke work and represents a load-independent index of systolic function and myocardial contractility [7]. Dynamic right ventricular volume was measured according to the ellipsoidal shell subtraction method [8].
Milrinone Administration and Experimental Protocol
Six weeks after monocrotaline pyrrole injection, baseline postinjection functional and hemodynamic data were collected in every animal following the instrumentation procedure. Milrinone was given IV through the 8.5F introducer sheath previously placed in the external jugular vein. After a loading dose of 50 µg/kg given over 10 minutes, milrinone was administered in sequential fashion at infusion rates of 0.5 and 1.0 µg·kg-1·min-1, and data were again collected at each respective infusion rate. After each incremental increase in the milrinone infusion rate, the animal's condition and hemodynamic indices were allowed to equilibrate for 10 minutes before any further data collection.
Data Acquisition During Baseline and Milrinone Studies
All data were digitized on-line, collected, and stored on a microprocessor (PDP 11/23; Digital Equipment Corp, Maynard, MA). Hemodynamic and functional data were analyzed with software developed in our laboratory and described elsewhere [7]. Briefly, all data were digitized at 500 Hz and filtered by a 50-Hz low-pass filter, stored on magnetic media, and analyzed on a Dell Dimension XPS P90 personal computer (Dell Computer Corp, Austin, TX).
Fourier Analysis
Calculation of pulmonary vascular impedance from the collected raw data was done with Fourier analysis. Fourier analysis is based on the principle that all periodic waveforms may be broken down into a series of pure sine waves or harmonics [9]. Harmonics exist at frequencies that are multiples of the frequency of the original waveform (the "fundamental frequency") and are described in terms of an amplitude and phase. Each harmonic represents an oscillatory component of the original waveform at its respective frequency. The net effect of Fourier analysis is to transform a waveform from the time domain, ie, described as a function of time, to the frequency domain, in which the waveform is described as a function of frequency.
The pulsatile waveforms of the pulmonary artery pressure and flow can be treated as periodic waveforms possessing a fundamental frequency (ie, the heart rate). At each individual harmonic, division of the pressure amplitude by the flow amplitude allows one to obtain the oscillatory counterpart of resistance, impedance, at that respective harmonic. The array of individually calculated impedance values from every harmonic represents the impedance spectrum. Input resistance is the impedance calculated at the zeroth harmonic and is a measure of resistance to mean pulmonary blood flow. Characteristic impedance is estimated as the mean impedance between 2 and 12 Hz and is a measure of resistance to pulsatile blood flow. In theoretic terms, characteristic impedance is an index of the overall distensibility or stiffness of the pulmonary vascular bed.
The product of the impedance amplitude, the square of the flow amplitude, and the cosine of the impedance phase angle for each individual harmonic gives the individual power at that particular harmonic. These products across all harmonics constitute the power spectrum, which represents the amount of energy, or hydraulic power, produced by the right ventricle to maintain pulmonary blood flow, and are expressed as follows:
|
| (1) |
where Q = the flow amplitude; Z = the impedance amplitude; and 
= the impedance phase angle. Hydraulic power can be divided into two components: steady power and oscillatory power. Steady power is the power obtained at the zeroth harmonic and represents the energy required to move blood forward at a steady state. Oscillatory power is taken from the remainder of the power spectrum exclusive of the zeroth harmonic and reflects the energy that is wasted in oscillatory acceleration of the blood and that eventually disseminates into the vessel walls.
Transpulmonary efficiency was defined as the ratio of mean pulmonary blood flow divided by right ventricular hydraulic power. Pulmonary vascular resistance was calculated by the standard formula applying mean pulmonary artery pressure, left atrial pressure, and cardiac output.
Humane Animal Care
All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985). The experiments were approved by the Duke University Institutional Animal Care and Use Committee (DUIACUC Assigned Registry no. A621-95-9R1).
Statistical Analysis
Statistical analysis was performed on a Dell personal computer using commercially available software (SigmaStat; Jandel Corp, San Rafael, CA). Data taken before and after injection of monocrotaline pyrrole were analyzed with standard two-tailed paired Student's t tests. In addition, hemodynamic and functional data taken after the administration of milrinone were also compared with baseline postinjection data using paired Student's t tests. The results are expressed as mean ± standard error of the mean. A difference was considered statistically significant at p less than 0.05.
|
Results |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Hemodynamic Changes Before and After Monocrotaline Pyrrole Injection
Six weeks after monocrotaline pyrrole injection, the mean right ventricular pressure and mean pulmonary artery pressure were significantly increased (13.23 ± 0.61 and 20.57 ± 0.83 mm Hg, respectively; p < 0.0005) compared with preinjection levels (9.16 ± 0.33 and 9.71 ± 0.62 mm Hg, respectively). Significant increases were also observed in the pulmonary vascular resistance (980 ± 148 versus 460 ± 37 dyne·s·cm-5; p < 0.005) and pulmonary capillary wedge pressure (5.72 ± 0.59 versus 3.71 ± 0.27 mm Hg; p < 0.05) 6 weeks after injection compared with preinjection. No significant changes were observed in the heart rate (120 ± 15 versus 118 ± 9 beats/min) after monocrotaline pyrrole injection.
Effect of Intravenous Milrinone on Pulmonary Vascular Mechanics in the Setting of Monocrotaline Pyrrole–Induced Chronic Pulmonary Hypertension
No significant differences in the mean systemic arterial pressure were observed after milrinone infusion at both 0.5 µg·kg-1·min-1 (70.7 ± 3.4 mm Hg) and 1.0 µg·kg-1·min-1 (73.1 ± 4.6 mm Hg) when compared with 0 µg·kg-1·min-1 (76.7 ± 1.0 mm Hg). There were decreases in the mean pulmonary artery pressure after milrinone infusion at both 0.5 and 1.0 µg·kg-1·min-1 when compared with 0 µg·kg-1·min-1, which were not statistically significant (Fig 1
). On the other hand, the pulmonary vascular resistance was significantly decreased at infusion rates of 0.5 and 1.0 µg·kg-1·min-1 when compared with 0 µg·kg-1·min-1 (Fig 2). No further significant decrease in the pulmonary vascular resistance was observed at 1.0 µg·kg-1·min-1 as compared with 0.5 µg·kg-1·min-1. Levels of pulmonary vascular resistance after milrinone infusion were not significantly different from baseline levels in the animals before monocrotaline pyrrole injection. Input resistance was also significantly decreased after milrinone administration at both 0.5 and 1.0 µg·kg-1·min-1 compared with 0 µg·kg-1·min-1, and again, there was no further significant decrease at 1.0 µg·kg-1·min-1 as compared with 0.5 µg·kg-1·min-1 (Fig 3). Although decreases in the characteristic impedance were observed after milrinone infusion, these changes were not statistically significant (see Fig 3).
|
|
|
.
|
). Right ventricular preload recruitable stroke work was also increased at 0.5 µg·kg-1·min-1 as compared with 0 µg·kg-1·min-1; however, this increase was not statistically significant. Significant increases in the left ventricular preload recruitable stroke work were also observed after milrinone administration at both 0.5 µg·kg-1·min-1 (114.5 ± 5.6 erg·103/mL, p < 0.005) and 1.0 µg·kg-1·min-1 (134.3 ± 9.5 erg·103/mL, p < 0.01) when compared with 0 µg·kg-1·min-1 (95.4 ± 5.6 erg·103/mL).
|
|
Comment |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Although vasorelaxation has been the primary strategy for effectively reducing pulmonary hypertension in this setting, other factors are also clearly important. After cardiac transplantation, right ventricular function can have a critical impact on left ventricular function, and thus the treatment approach toward this patient population should involve more than simply improving pulmonary hemodynamic indices. A positive inotropic agent would also be highly advantageous for improving overall right ventricular performance, and this effect, in combination with direct pulmonary vasorelaxation, is most likely to yield the greatest improvement in right ventricular dysfunction. An ideal medication suited for this clinical scenario should therefore possess both pulmonary vasodilatory and positive inotropic effects.
Pharmacologic strategies used previously for improving recipient pulmonary hypertension, and thus right ventricular dysfunction, have included vasodilators such as prostaglandin E1, prostacyclin, and sodium nitroprusside [10]. The effectiveness of these agents, however, is limited by lack of any substantial positive inotropic effects as well as by substantial reductions in systemic arterial pressure resulting from their use, which may worsen a preexisting state of systemic hypotension, decreased coronary artery perfusion, and right ventricular dysfunction. Nitric oxide is an endothelium-derived relaxing factor that can selectively vasodilate the pulmonary circulation without causing any pronounced effects on the systemic circulation; however, nitric oxide also does not possess any inherent positive inotropic properties [11].
Inotropic support for myocardial insufficiency traditionally has been achieved using sympathomimetic agents such as norepinephrine, epinephrine, dopamine, and dobutamine. Their mechanism of action involves the stimulation of ß-adrenergic receptors through a cyclic adenosine monophosphate–mediated pathway. Although sympathomimetic agents are potent cardiac stimulants, their use can also result in tachyarrhythmias, leading to increased myocardial oxygen demand, stimulation of peripheral sympathetic receptors causing peripheral shunting of blood, and increased pulmonary vascular resistance and right ventricular afterload [4, 12]. In addition, prolonged use of sympathomimetic drugs is further limited by desensitization associated with downregulation of ß-adrenergic receptors [4, 12], which can curtail the efficacy of these drugs.
Phosphodiesterase III inhibitors, on the other hand, enhance myocardial performance independent of adrenoreceptor activity and plasma catecholamine levels, and produce few undesirable side effects. Thus, milrinone may be a more appropriate agent in the treatment of right ventricular dysfunction after cardiac transplantation. Evidence for a favorable effect of milrinone on right ventricular function stems from its use both clinically and in experimental investigations. In the clinical setting, this agent has been used effectively to treat patients with pulmonary hypertension and right ventricular impairment in chronic congestive heart failure [13] and after cardiac operations [14], as well as being a pharmacologic bridge to heart transplantation [15]. Experimentally, milrinone reduced mean pulmonary artery pressure and pulmonary vascular resistance while increasing cardiac index in a canine model of embolism-induced pulmonary hypertension [16]. There are few reports, however, describing the hemodynamic and inotropic effects of milrinone on postoperative donor right ventricular dysfunction and recipient chronic pulmonary hypertension after cardiac transplantation. Furthermore, basic experimental investigation of this clinical problem has certainly been limited by lack of an appropriate large-animal model of stable chronic pulmonary hypertension.
This investigation used several approaches leading toward efforts to assess experimentally the vasodilatory and inotropic properties of IV milrinone after cardiac transplantation in the setting of recipient chronic pulmonary hypertension. First, the hemodynamic and inotropic effects of this agent were characterized in a suitable model of recipient pulmonary hypertension using a recently established adult canine model of monocrotaline pyrrole–induced chronic pulmonary hypertension. Admittedly, several large-animal models of pulmonary hypertension have been created and applied in numerous scientific investigations. Monocrotaline pyrrole–induced chronic pulmonary hypertension, however, more accurately reflects the clinical picture of chronic pulmonary hypertension that occurs as a result of end-stage left ventricular dysfunction, as seen in the population of potential cardiac transplant patients, and was previously well described [5].
Second, Fourier analysis was used to calculate pulmonary vascular impedance and right ventricular hydraulic power by separating pulmonary artery pressure and pulmonary blood flow into their respective steady-state and pulsatile components. Unfortunately, conventional steady-state hemodynamic measurements, including mean pulmonary artery pressure, mean pulmonary artery blood flow, pulmonary vascular resistance, and pulmonary artery capillary wedge pressure, do not fully characterize the nature of the pulmonary vasculature in terms of its physical state. Fourier analysis allows a complete and quantitative description of the pulmonary vascular bed in the form of vascular impedance and gives information regarding the physical state of the pulmonary vasculature. This analytic technique has been validated and applied in several experimental investigations [17–19].
Milrinone resulted in significant increases in right ventricular hydraulic power. However, a significantly higher percentage of this energy was not converted to forward blood flow, as reflected by the significant increase in the ratio of oscillatory power to steady power. Monocrotaline pyrrole–induced injury in the pulmonary vascular bed leads to a situation in which a larger proportion of the increased energy production by the right ventricle, after milrinone infusion, is wasted in the oscillatory movements of the blood. The mechanism for this observation remains unclear and will require further investigation.
In addition to the significant improvements in steady-state flow hemodynamic indices, milrinone led to significant decreases in the input resistance and insignificant changes in the characteristic impedance. Characteristic impedance represents an index of the overall distensibility or stiffness of the pulmonary vascular bed and was apparently not affected by milrinone infusion. The significant decrease in pulmonary vascular resistance can be explained if one examines the standard formula used for calculating this index. Pulmonary vascular resistance is inversely proportional to pulmonary blood flow and directly proportional to the transpulmonary gradient. There was a significant increase in pulmonary blood flow after milrinone administration, and therefore, one would expect a significant decrease in pulmonary vascular resistance given that insignificant changes were occurring in the transpulmonary gradient.
One interesting finding in this study is that although significant decreases in pulmonary vascular resistance were observed after milrinone infusion, no significant changes were seen in the mean pulmonary artery pressure. This observation cannot be fully explained by the data presented; however, a potential explanation may lie in the biochemical pathway by which milrinone causes vasodilatation in the pulmonary circulation. Vascular smooth muscle contains a phosphodiesterase III enzyme, which is inhibited by milrinone [4]. Administration of phosphodiesterase III inhibitors results in accumulation of cyclic adenosine monophosphate, which subsequently promotes calcium efflux across the sarcolemma, leading to relaxation of vascular smooth muscle [4]. Although a significant decrease in the mean pulmonary artery pressure after treatment with milrinone would have been desirable, it must be pointed out that this insignificant change in mean pulmonary artery pressure occurred in association with significant increases in the pulmonary blood flow. One would expect significant increases in pulmonary blood flow to lead to significant increases in mean pulmonary artery pressure under normal conditions in the absence of vasodilators. It appears that monocrotaline pyrrole injection may have partially impaired the phosphodiesterase III/cyclic adenosine monophosphate pathway in the vascular smooth muscle cells, such that milrinone was unable to effect enough vascular relaxation through this pathway, in the setting of significantly increased pulmonary blood flow, to result in the desired hemodynamic effect.
In a previous investigation examining the effects of milrinone on the pulmonary circulation, vascular relaxation was observed in vitro using isolated pulmonary artery rings [20]. A potential way to ascertain whether the phosphodiesterase III/cyclic adenosine monophosphate pathway is impaired in the setting of monocrotaline pyrrole–induced chronic pulmonary hypertension would be to use a similar experimental protocol to assess and compare the degree of vasodilatation in isolated pulmonary artery rings from monocrotaline pyrrole–treated animals versus untreated animals.
This report is also important in that a highly sensitive and previously validated model of assessing global ventricular function was applied to assess the effects of milrinone on both right and left ventricular function. This method of assessment allows estimation of intrinsic myocardial mechanics and function independent of any changes in ventricular loading conditions that may occur in the setting of pulmonary hypertension. The experiments outlined in this report demonstrate that milrinone has a significant impact on right as well as left ventricular function. In the setting of monocrotaline pyrrole–induced chronic pulmonary hypertension, right and left ventricular function was significantly enhanced by milrinone infusion. The significant increase in right ventricular myocardial performance was presumably somewhat responsible for the significant increases observed in the pulmonary blood flow as well as left ventricular filling.
Although positive inotropic effects of milrinone on right ventricular function are clearly demonstrated in this study in association with significant improvements in pulmonary blood flow and left ventricular filling, the vasodilatory properties of this agent can also play a key role in its overall effects and may partially account for the observed improvements in hemodynamic status. In an earlier investigation examining the inotropic and vasodilator actions of milrinone in patients with severe congestive heart failure, a positive inotropic action was found to have a significantly greater contribution to overall hemodynamic improvement than vasodilatation, and even occurred at drug levels at which marked vasodilatation was not observed [21]. In this study, the significant increase in right ventricular preload recruitable stroke work occurring in association with the slight decrease in mean pulmonary artery pressure after milrinone infusion appears to be consistent with those previous results. Any further quantification of the relative contributions of the inotropic and vasodilatory effects of milrinone in the setting of monocrotaline pyrrole–induced chronic pulmonary hypertension will require additional examination.
The significant increases in left atrial pressure and left ventricular volume after milrinone infusion are consistent with a previous investigation in which a significantly increased pulmonary capillary wedge pressure was associated with a decrease in pulmonary vascular resistance during adenosine infusion [22]. The increased left ventricular filling after milrinone administration observed in this report was presumably a result of improved right ventricular function and pulmonary blood flow, leading to significantly larger amounts of blood being transported to the left ventricle. Left ventricular performance, already improved as a result of milrinone infusion, was able to adapt to the significantly increased loading conditions without any apparent evidence of myocardial insufficiency.
Alterations in left ventricular function in the setting of right ventricular pressure overload secondary to pulmonary hypertension have been the subject of both clinical [23] and experimental [24] investigations. Left ventricular filling and systolic performance are secondarily influenced by an interdependence between the ventricles due to direct mechanical interactions with the right side of the heart through the shared interventricular septum [25]. Right ventricular pressure overload secondary to pulmonary hypertension can displace the ventricular septum toward the left ventricular cavity, resulting in altered function [23, 24]. In a previous report, left ventricular function, as measured by the preload recruitable stroke work relation, was not significantly worsened in this experimental model [26]. Furthermore, in the present study, milrinone infusion led to significant improvements in left ventricular contractility. These findings suggest that septal motion was not detrimental to left ventricular performance in the setting of monocrotaline pyrrole–induced chronic pulmonary hypertension. Full characterization of interventricular septal motion in this model, however, will require further studies.
Admittedly, this model is somewhat different than the clinical situation in that the right ventricle was trained for several weeks after monocrotaline pyrrole injection. In the initial creation of this model, the dry weights of the right ventricular free wall were compared with the dry weights of the left ventricle and septum. In the setting of monocrotaline pyrrole–induced pulmonary hypertension, there was a significant increase in the dry weight ratio of the right ventricle to the left ventricle and septum of approximately 17%, which suggests that a degree of right ventricular hypertrophy had occurred. Although similar tissue analysis was not performed in the present investigation, it would be reasonable to assume that a comparable amount of right ventricular hypertrophy had developed in the animals in the current study.
It is important to keep in mind that in the clinical setting, recipient chronic pulmonary hypertension secondary to longstanding congestive heart failure possesses a reactive component that is not only responsive to pharmacologic therapy, but also gradually resolves after cardiac transplantation. Thus, before proceeding with any transplantation experiments in the setting of monocrotaline pyrrole–induced chronic pulmonary hypertension, it was important to characterize this model to determine how well it would mimic the reversible component of pulmonary hypertension observed in the transplant population. A reactive component of injury would allow more thorough evaluation of posttransplantation right ventricular dysfunction, as well as development of strategies to improve this dysfunction.
The results of this investigation demonstrate that the pulmonary vasculature in monocrotaline pyrrole–induced pulmonary hypertension is responsive to milrinone, suggesting that a component of reversible injury exists in this setting. These data provide further evidence that this model effectively replicates the type of pulmonary hypertension found in the cardiac transplant recipient population. Future investigations should proceed to experimental evaluation of the hemodynamic and inotropic effects of milrinone in a cardiac transplantation model in which hearts from canine donors with normal pulmonary hemodynamic indices are transplanted into recipients with monocrotaline pyrrole–induced chronic pulmonary hypertension.
It would have been interesting to compare the results obtained in this report with any hemodynamic effects that milrinone might have had in a group of canines with normal hemodynamic indices, as well as to use this model to assess directly the effects of other well-established pharmacologic agents, such as prostaglandin E1, sodium nitroprusside, and prostacyclin, which are often used to improve pulmonary hemodynamic indices and right ventricular function after cardiac transplantation. An earlier study, however, has already demonstrated that milrinone has no significant effect on pulmonary hemodynamic indices in normal canines [16]. In addition, the hemodynamic properties of many of the previously mentioned vasodilators have already been examined clinically after cardiac transplantation in the setting of recipient pulmonary hypertension [10]. Thus, experimentally reassessing the effects of milrinone in normal canines as well as the hemodynamic properties of these other vasodilators in the setting of monocrotaline pyrrole–induced chronic pulmonary hypertension would appear to be redundant and unnecessary.
In summary, a canine model of stable chronic pulmonary hypertension provides a potentially useful method for basic investigation and evaluation of one therapeutic option for improving pulmonary hemodynamic indices and right ventricular dysfunction after cardiac transplantation in the setting of chronically elevated pulmonary vascular pressures. Significant increases in the mean pulmonary artery pressure and pulmonary vascular resistance were observed 6 weeks after injection of 3 mg/kg monocrotaline pyrrole. This investigation demonstrates the well-known hemodynamic and inotropic effects of milrinone which, in the setting of monocrotaline pyrrole–induced pulmonary hypertension, were also associated with significant increases in pulmonary blood flow and left ventricular filling. Milrinone infusion led to significant improvements in right ventricular function and pulmonary hemodynamic indices and may offer a potential advantage over sympathomimetic agents in the treatment of right ventricular dysfunction after cardiac transplantation in the setting of recipient pulmonary hypertension.
|
Acknowledgments |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
We thank Robert A. Roth, PhD, and Kerry Ross for their invaluable assistance in the synthesis of monocrotaline pyrrole.
|
Footnotes |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
|
References |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  R. A. Cesnjevar, R. Feyrer, F. Walther, F. O. Mahmoud, Y. Lindemann, and J. von der Emde High-risk mitral valve replacement in severe pulmonary hypertension--30 years experience Eur. J. Cardiothorac. Surg., April 1, 1999; 13(4): 344 - 352. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
