Oral Sildenafil Reduces Pulmonary Hypertension
`After Cardiac Surgery
`Aaron L. Trachte, MD, Emilio B. Lobato, MD, Felipe Urdaneta, MD, Phillip J. Hess, MD,
`Charles T. Klodell, MD, Tomas D. Martin, MD, Edward D. Staples, MD, and
`Thomas M. Beaver, MD
`Departments of Surgery, Division of Thoracic and Cardiovascular Surgery, and Anesthesiology, University of Florida College of
`Medicine, and Department of Anesthesiology, Malcolm B. Randall Veterans Affairs Medical Center, Gainesville, Florida
`
`Background. Treatment of postoperative pulmonary
`hypertension with intravenous (IV) pulmonary vasodila-
`tors is hampered by the lack of selectivity. Inhaled nitric
`oxide produces selective pulmonary vasodilation; how-
`ever, it requires a special device, and weaning can cause
`rebound. Oral sildenafil is a phosphodiesterase type V
`inhibitor. Sildenafil can produce sustained pulmonary
`vasodilatation in patients with hypoxic or primary pul-
`monary hypertension; however, experience with postop-
`erative pulmonary hypertension is limited. We report our
`initial experience with eight patients who received oral
`sildenafil as adjunctive therapy for postoperative pulmo-
`nary hypertension
`Methods. We reviewed the charts of eight adult pa-
`tients with postoperative pulmonary hypertension who
`received oral sildenafil (25 to 50 mg) to facilitate weaning
`of IV (milrinone, nitroglycerine, and sodium nitroprus-
`side) and inhaled (nitric oxide) pulmonary vasodilators.
`
`Hemodynamic data were recorded before and 30 and 60
`minutes after the initial dose of sildenafil.
`Results. After the initial dose of sildenafil, mean pul-
`monary artery pressure was reduced by 20% and 22% at
`30 and 60 minutes, respectively (p < 0.05). Pulmonary
`vascular resistance index decreased by 49% and 44% at 30
`and 60 minutes, respectively (p < 0.05). Sildenafil had no
`clinically significant effects on cardiac index, mean arte-
`rial pressure, or systemic vascular resistance. Subsequent
`doses of sildenafil were administered at regular intervals,
`allowing successful weaning of concomitant pulmonary
`vasodilators.
`Conclusions. Oral sildenafil is an effective agent for
`treatment of postoperative pulmonary hypertension and
`can be used to facilitate weaning of inhaled and IV
`pulmonary vasodilators.
`(Ann Thorac Surg 2005;79:194 –7)
`© 2005 by The Society of Thoracic Surgeons
`
`Pulmonary hypertension can present a formidable
`
`challenge in the management of patients undergo-
`ing cardiac surgery. Strategies to reduce pulmonary
`vascular tone aim to enrich vascular smooth muscle
`cyclic adenosine monophosphate levels through beta
`agonists (isoproterenol) or with phosphodiesterase type
`III inhibitors (milrinone). Alternatively, increasing cyclic
`guanine monophosphate (cGMP) with nitroso vasodila-
`tors (sodium nitroprusside, nitroglycerin, inhaled nitric
`oxide [NO]) also reduces pulmonary vascular tone. Even
`though inhaled NO is extremely efficacious in reducing
`mean pulmonary artery pressure (MPAP) in cardiac
`patients, its application has been limited because it must
`be administered through a closed inhalation circuit be-
`cause of toxic byproducts [1]. In addition, withdrawal of
`inhaled NO therapy can lead to dangerous rebound
`pulmonary hypertension.
`
`Oral sildenafil, a phosphodiesterase type V (PDE-V)
`inhibitor, prevents the degradation of cGMP and has
`been shown to be as effective as inhaled NO in the setting
`of primary pulmonary hypertension and pulmonary fi-
`brosis. However, sildenafil does not require an inhaled
`delivery system and does not cause rebound pulmonary
`hypertension [2– 4]. Furthermore, its effects have been
`noted to last for at least three hours without affecting
`systemic arterial pressure [5]. In the laboratory we have
`demonstrated an intravenous formulation of a sildenafil
`analogue, UK 343 to 664, shows sustained reduction of
`pulmonary hypertension in a porcine model of pulmo-
`nary hypertension [6]. Increasing evidence has shown
`that sildenafil is an effective pulmonary vasodilator for
`both children and adults with primary pulmonary hyper-
`tension [7–10]. We report our initial experience with the
`use of sildenafil as adjunctive therapy for the postoper-
`ative pulmonary hypertension following cardiac surgery.
`
`Accepted for publication June 25, 2004.
`Presented at the Fiftieth Annual Meeting of the Southern Thoracic
`Surgical Association, Bonita Springs, FL, Nov 13–15, 2003.
`
`Address reprint requests to Dr Beaver, Division of Thoracic and Cardio-
`vascular Surgery, University of Florida College of Medicine, Box 100286,
`Gainesville, FL 32611; e-mail: beavetm@surgery.ufl.edu.
`
`Material and Methods
`After Institutional Review Board approval, we conducted
`a retrospective review of the initial eight consecutive
`patients that received sildenafil to treat persistent pul-
`monary hypertension after mitral valve surgery (n ⫽ 6) or
`
`© 2005 by The Society of Thoracic Surgeons
`Published by Elsevier Inc
`
`0003-4975/05/$30.00
`doi:10.1016/j.athoracsur.2004.06.086
`
`CARDIOVASCULAR
`
`UNITED THERAPEUTICS CORP., EX1018, page 1
`UNITED THERAPEUTICS CORP. v. ACTELION PHARMACEUTICALS
`U.S. PATENT 8,268,847
`
`

`

`CARDIOVASCULAR
`
`Ann Thorac Surg
`2005;79:194 –7
`
`TRACHTE ET AL
`ORAL SILDENAFIL REDUCES PULMONARY HYPERTENSION
`
`195
`
`Table 1. Patient Demographics
`
`Patient #
`
`Age/Sex
`
`1
`2
`3
`4
`5
`
`6
`7
`8
`
`71/M
`50/M
`47/F
`64/M
`46/F
`
`49/F
`58/M
`40/M
`
`Primary
`Procedure
`
`MVR
`MVR
`MVR
`MVR
`MV Repair
`
`MVR
`LVAD Thoratec
`LVAD Heartmate
`
`Sildenafil (mg)
`
`Concomitant Therapy
`
`25 BID
`25 BID
`50 TID
`50 QD
`50 TID
`
`50 BID
`50 BID
`50 QID
`
`NTG, Milrinone
`NTG, nesiritide epinephrine, dopamine
`NO, milrinone, NTG
`NO, milrinone, nesiritide
`milrinone, epinephrine, NTG,
`isoproterenol
`NTG, milrinone, SNP, nesiritide
`NTG, milrinone, nesiritide
`Nesiritide, dopamine
`
`Disposition
`
`D/C Home 18 d
`D/C Home 21 d
`D/C Home 10 d
`D/C Rehab 90 d
`D/C Home 28 d
`
`D/C Home 28 d
`Heart tx 14 d
`Heart tx@8 mo
`
`LVAD ⫽ left ventricular assist device;
`d ⫽ day;
`D/C ⫽ discharge;
`BID ⫽ twice daily;
`NO ⫽ nitric oxide;
`NTG ⫽ nitroglycerine;
`MVR ⫽ mitral valve replacement;
`repair;
`Rehab ⫽ rehabilitation center;
`SNP ⫽ sodium nitroprusside;
`TID ⫽ three times daily.
`
`mo ⫽ month;
`QD ⫽ once daily;
`
`MV repair ⫽ mitral valve
`QID ⫽ four times daily;
`
`left ventricular assist device (LVAD) placement (n ⫽ 2) at
`our institution. In each case, sildenafil was administered
`only if the patient had persistently elevated pulmonary
`artery pressures despite multiple, conventional pulmo-
`nary vasodilators (Table 1). Oral sildenafil was initiated
`in an intensive care setting, hemodynamics were closely
`monitored, and the dose was readministered based on
`pulmonary hemodynamics. Once initiated, sildenafil
`continued through discharge. Conventional agents were
`typically weaned 24 hours after administration of the first
`dose of sildenafil. The dose of sildenafil was recorded
`along with the hemodynamic factors. Pulmonary artery
`and systemic arterial vascular resistance indices were
`calculated according to standard formulas: PVRI ⫽
`MPAP ⫺ LAP/CI and SVRI ⫽ MAP ⫺ CVP/CI, where
`PVRI ⫽ Pulmonary vascular resistance index MAP ⫽
`mean arterial pressure, CVP ⫽ central venous pressure,
`MPAP ⫽ mean PAP, LAP ⫽ left atrial pressure, CI ⫽
`cardiac index, and SVRI ⫽ systemic vascular resistance
`index. Hemodynamic measurements were recorded be-
`fore the administration of the initial dose of sildenafil and
`30 and 60 minutes later. Statistical analysis was per-
`formed with SAS software (Cary, NC) using analysis of
`
`variance with repeated measures. A p value less than 0.05
`was considered significant.
`
`Results
`This review includes five males and three females. The
`mean age was 52 ⫾ 10 years. The initial dose of sildenafil
`was based on surgeon preference and ranged between 25
`and 50 mg. The same individual dose was repeated at
`regular intervals based on the tendency of pulmonary
`hemodynamics to return to baseline. Table 1 shows the
`patients’ demographics and the dose regimen for
`sildenafil.
`Following the administration of sildenafil, MPAP de-
`creased by 9 mm Hg at 30 and 60 minutes (p ⬍ 0.05)
`(Table 2). A relative high degree of pulmonary selectivity
`was observed. Although a statistically significant differ-
`ence in MAP was identified; it was not clinically signifi-
`cant (Fig 1). While systemic vascular index was not
`significantly different after sildenafil at 60 minutes, a
`marked decrease in PVRI was observed at both 30 and 60
`minutes (Fig 2). Other concomitant pulmonary vasodila-
`tors were weaned while sildenafil administration contin-
`
`Table 2. Hemodynamic Measurements
`
`Parameter
`
`Heart rate (bpm)
`MAP
`MPAP
`CVP
`LAP
`CI
`SVRI
`PVRI
`
`Baseline
`
`100.8 ⫾ 9.6
`68.7 ⫾ 8.6
`41.2 ⫾ 13.2
`9.1 ⫾ 2.5
`12.4 ⫾ 2.9
`3.8 ⫾ 0.7
`1249 ⫾ 295.7
`556.4 ⫾ 504.1
`
`30 Minutes
`Post Sildenafil
`
`100 ⫾ 7.9
`61.25 ⫾ 9.6
`32.87 ⫾ 9.1
`8.8 ⫾ 3.3
`13 ⫾ 5.2
`4.65 ⫾ 1.4
`928.9 ⫾ 334.5
`281.9 ⫾ 233.5
`
`60 Minutes
`Post Sildenafil
`
`99.6 ⫾ 7.9
`62.3 ⫾ 8.4
`32.3 ⫾ 7.1
`9.4 ⫾ 5.7
`15 ⫾ 5.7
`3.9 ⫾ 0.7
`1096.5 ⫾ 326.4
`313.6 ⫾ 246.1
`
`p value
`30 vs Baseline
`
`p value
`60 vs Baseline
`
`NS
`0.006
`0.01
`NS
`NS
`NS
`0.002
`0.026
`
`NS
`0.016
`0.007
`NS
`NS
`NS
`NS
`0.042
`
`LAP ⫽ left atrial
`CVP ⫽ central venous pressure (mm Hg);
`CI ⫽ cardiac index (liters/minute/body surface area);
`bpm ⫽ beats per minute;
`MAP ⫽ mean arterial pressure (mm Hg);
`MPAP ⫽ mean pulmonary arterial pressure (mm Hg);
`SVRI ⫽ (MAP ⫺ CVP)/CI
`pressure (mm Hg);
`⫻ 80;
`PVRI ⫽ (MPAP ⫺ LAP)/CI ⫻ 80.
`
`UNITED THERAPEUTICS CORP., EX1018, page 2
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`196
`
`TRACHTE ET AL
`ORAL SILDENAFIL REDUCES PULMONARY HYPERTENSION
`
`Ann Thorac Surg
`2005;79:194 –7
`
`tive acute pulmonary hypertension complicate the man-
`agement of patients with mitral valve disease. Our expe-
`rience showed that in six different patients undergoing
`mitral valve surgery, PAP and PVR decreased following
`sildenafil administration. Furthermore, conventional
`therapies for pulmonary hypertension were successfully
`weaned with no rebound pulmonary hypertension.
`Severe pulmonary hypertension can also lead to right
`ventricular failure in patients with LVADs. In order to
`assure delivery of preload to the LVAD, right ventricular
`function must be preserved. Sildenafil reduced pulmo-
`nary hypertension in both our patients with LVADs,
`improving LVAD filling and obviating the need for
`RVAD placement. Consequently both LVAD patients
`progressed to heart transplantation without difficulty.
`The ability of PDE-V inhibitors, including sildenafil,
`zaprinast, and dipyridamole to decrease MPAP and PVR
`has been previously demonstrated in experimental mod-
`els of pulmonary hypertension [11–14]. Their effective-
`ness correlates with the level of PDE-V inhibition and the
`increase in pulmonary vascular smooth muscle cGMP
`[15].
`This report has significant limitations, as it is a retro-
`spective review of a small number of patients with no
`controls. However, the findings are consistent with the
`few isolated case reports describing the use of PDE-V
`inhibitors as pulmonary vasodilators in patients under-
`going cardiac surgery. Intravenous dipyridamole was
`used successfully in a small series of pediatric heart
`surgery patients [16]. However, dipyridamole has anti-
`platelet effects that are undesirable in the perioperative
`period. Anecdotal reports of oral sildenafil in cardiac
`surgery patients include both the successful pulmonary
`vasodilation in a child with mitral stenosis and in an
`adult patient who underwent placement of a biventricu-
`lar assist device [17, 18]. While lack of an intravenous
`formulation for sildenafil may limit its use in the early
`postoperative period; the availability of an effective, oral
`selective pulmonary vasodilator facilitates later postop-
`erative management.
`In summary, this initial experience suggests that oral
`sildenafil can be an effective agent as part of a multimo-
`dal approach to postoperative pulmonary hypertension.
`Further studies are necessary to more clearly define the
`optimal dosing and role of sildenafil in patients following
`cardiac surgery.
`
`Special thanks to Esperanzo Olivo for her expert editorial and
`formatting assistance and to Diane Strong for coordinating the
`manuscript submission.
`
`References
`1. Fullerton DA, McIntyre RC. Inhaled nitric oxide: therapeutic
`application in cardiothoracic surgery. Ann Thorac Surg
`1996;61:1856 – 64.
`2. Weimann J, Ullrich R, Hromi J, et al. Sildenafil is a pulmo-
`nary vasodilator in awake lambs with acute pulmonary
`hypertension. Anesthesiology 2000;92:1702–12.
`3. Lepore JJ, Maroo A, Pereira NL, et al. Effect of sildenafil on
`the acute pulmonary vasodilator response to inhaled nitric
`
`Fig 1. Values of mean arterial pressure (MAP; ⽧) and mean pulmo-
`nary arterial pressure (MPAP; ) before and after the administra-
`tion of a single dose of oral sildenafil. There was a reduction in
`MPAP without a clinically significant change in MAP.
`
`ued. There were no in-hospital mortalities among the
`eight patients.
`
`Comment
`This retrospective review suggests that sildenafil pro-
`duces marked pulmonary vasodilation when added to a
`preexisting regimen of nitrosovasodilators in patients
`with pulmonary hypertension following cardiac surgery.
`The pulmonary hypertension in this series of patients
`was refractory to conventional pharmacologic agents and
`was reduced on average by 20% with sildenafil. Sildenafil
`not only provided an additive pulmonary vasodilatory
`effect, but also allowed the successful weaning of inhaled
`and intravenous pulmonary vasodilators.
`Because experience with sildenafil and postoperative
`pulmonary hypertension is limited, the optimal dose has
`not been established. Initial doses were similar to that
`described in previous case reports, with intervals deter-
`mined by observation of pulmonary hemodynamics.
`Preexisting pulmonary hypertension and postopera-
`
`Fig 2. Changes in systemic vascular resistance index (⽧) and pul-
`monary vascular resistance index (PVRI; ) following the adminis-
`tration of sildenafil. The effect on PVRI is more pronounced, denot-
`ing relative pulmonary selectivity.
`
`CARDIOVASCULAR
`
`UNITED THERAPEUTICS CORP., EX1018, page 3
`UNITED THERAPEUTICS CORP. v. ACTELION PHARMACEUTICALS
`U.S. PATENT 8,268,847
`
`

`

`CARDIOVASCULAR
`
`Ann Thorac Surg
`2005;79:194 –7
`
`TRACHTE ET AL
`ORAL SILDENAFIL REDUCES PULMONARY HYPERTENSION
`
`197
`
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`nafil in HIV-related pulmonary hypertension. AIDS 2001;14:
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`nafil is a selective pulmonary vasodilator in lambs with acute
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`12. Kieler-Jensen N, Lundin S, Ricksten SE. Vasodilator therapy
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`14. Weimann J, Ullrich R, Hromi J, et al. Sildenafil is a pulmo-
`nary vasodilator in awake lambs with acute pulmonary
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`
`DISCUSSION
`
`DR JACOB DELAROSA (Atlanta, GA): Thank you for the paper.
`Great presentation. My question is quick. How did you deal with
`the tumescence using Viagra on these patients? Was it a blessing
`or was it a problem?
`
`the eight patients mentioned was on intravenous milrinone
`prior to reoperation. We have not used it preoperatively, but
`they have talked of trying to use that and are attempting to study
`that, and that is a very good question.
`
`DR TRACHTE: We did not note tumescence, nor did our nurses
`examine for that, but we did notice some increased sexual drive
`in some of our patients as anecdotal reports.
`
`DR ROBERT B. LEE (Jackson, MI): I appreciate your presenta-
`tion. It was well done. I would assume that at least some of these
`patients were known to have pulmonary hypertension prior to
`operation. Have you looked at using it prophylactically to
`decrease their pulmonary hypertension 24 to 48 hours preoper-
`atively and what would be your recommendation in that regard?
`
`DR TRACHTE: That is an excellent question. Thank you, Dr.
`Lee. Our anesthesia attendings that are interested in Viagra are
`especially interested in this concept. We did have patients who
`did have preoperative pulmonary hypertension. In fact, one of
`
`DR JOHN H. CALHOON (San Antonio, TX): This is a very nice
`paper. My question would be what benefit do you think there is
`in simply affecting the pulmonary artery pressure and the
`pulmonary vascular resistance when you didn’t make any
`change in the cardiac output?
`
`DR TRACHTE: Thank you, Dr Calhoon. That is a good point.
`When you look at our patients, we looked at the hemodynamic
`data and found that there were no changes. Particularly for the
`left ventricular assist device patients, though it should be noted
`that these patients did not require return trips to the operating
`room for right ventricular assist devices, and that is a significant
`outcome, but we don’t have enough numbers or data to make a
`firm projection on whether or not this really affects the clinical
`outcomes of the patients.
`
`UNITED THERAPEUTICS CORP., EX1018, page 4
`UNITED THERAPEUTICS CORP. v. ACTELION PHARMACEUTICALS
`U.S. PATENT 8,268,847
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