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Ann Thorac Surg 2007;83:68-71
© 2007 The Society of Thoracic Surgeons

Original Articles: Cardiovascular

Effect of Sildenafil on Pulmonary Artery Pressure, Systemic Pressure, and Nitric Oxide Utilization in Patients With Left Ventricular Assist Devices

Charles T. Klodell, Jr, MDa,b,*, Timothy E. Morey, MDb, Emilio B. Lobato, MDb, Juan M. Aranda, Jr, MDc, Edward D. Staples, MDa, Richard S. Schofield, MDc, Philip J. Hess, MDa,b, Tomas D. Martin, MDa, Thomas M. Beaver, MDa,b

a Department of Surgery, University of Florida College of Medicine, Gainesville, Florida
b Department of Anesthesiology, University of Florida College of Medicine, Gainesville, Florida
c Department of Medicine, University of Florida College of Medicine, Gainesville, Florida

Accepted for publication August 22, 2006.

* Address correspondence to Dr Klodell, Thoracic and Cardiovascular Surgery, PO Box 100286, 1600 SW Archer Rd, Gainesville, FL 32610 (Email: klodell{at}surgery.ufl.edu).

Presented at the Forty-second Annual Meeting of The Society of Thoracic Surgeons, Chicago, IL, Jan 30–Feb 1, 2006.


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Discussion
 References
 
BACKGROUND: Pulmonary artery hypertension can complicate the early postoperative care of patients with left ventricular assist devices (LVADs). Inhaled nitric oxide (INO) is frequently used to manipulate pulmonary resistance after LVADs have been placed. We evaluated the effect of oral sildenafil therapy on pulmonary artery pressure, systemic pressure, and nitric oxide utilization.

METHODS: After Institutional Review Board approval, the records of 10 consecutive adult patients with LVADs and pulmonary hypertension who received sildenafil were reviewed. Demographics, surgical history, INO use, inotrope requirements, and hemodynamic response to oral sildenafil at multiple intervals were collected. Hemodynamic data were analyzed with a two-way analysis of variance of repeated measures with correction for multiple comparisons.

RESULTS: There were 8 men and 2 women with 6 Heartmate XVE LVADs and 4 Thoratec LVADs (both, Thoratec, Pleasanton, California). When weaning was attempted, 8 patients who received INO demonstrated rebound pulmonary hypertension or increased right heart dysfunction. All patients were on inotropic therapy with dobutamine and milrinone. Sildenafil produced a significant reduction in pulmonary artery systolic pressure within 90 minutes of oral administration (p = 0.042). Significant changes in systolic blood pressure, mean arterial pressure, systemic vascular resistance, and heart rate were not observed. All 8 patients receiving INO were weaned within 12 hours without recurrent pulmonary hypertension. All 10 patients were weaned from inotropic support within 72 hours. No patient suffered right-side heart failure requiring intervention.

CONCLUSIONS: Oral sildenafil represents a useful adjunctive therapy for patients with LVADs. In our series, it provided additional reduction of pulmonary artery pressure, and facilitated weaning from INO and inotropes without deleterious hemodynamic consequences.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Discussion
 References
 
Pulmonary hypertension and right-side heart failure are important considerations in the management of patients after implantation of a left ventricular assist device (LVAD). Pulmonary vascular resistance can be lowered by enhancing cyclic adenosine monophosphate (cAMP) using ß-agonists or with the phosphodiesterase type III inhibitor, milrinone [1, 2]. Vascular resistance can also be lowered with nitroso vasodilators (nitroglycerin, sodium nitroprusside, and inhaled nitric oxide [INO]), which increase cyclic guanine monophosphate (cGMP). Although INO is extremely efficacious, its use is complicated by the requirement for an inhaled delivery system and rebound pulmonary hypertension upon its withdrawal [3].

Oral sildenafil is a type V phosphodiesterase inhibitor that maintains cGMP levels and has been shown to be effective for primary pulmonary hypertension [4–7]. Significant advantages of sildenafil include the eliminated need for an inhaled delivery system and lack of rebound pulmonary hypertension owing to effects lasting for at least 3 hours [8–11]. Increasing experience has shown that sildenafil can be used to manage pulmonary hypertension in the perioperative care of cardiac surgery patients [12–14].

The perioperative management of patients with LVADs depends upon preservation of right heart function. Frequently, that involves both inotropic support of the right side of the heart and the manipulation of pulmonary artery resistance and, consequently, pulmonary artery pressure [15]. Attempted weaning of INO and inotropic support often causes rebound pulmonary hypertension and decreased filling of the LVAD, necessitating ongoing inotropic support. The relatively long duration of action on pulmonary artery pressure makes sildenafil an attractive option to facilitate the weaning of INO and inotropic agents after LVAD implantation [14]. We sought to evaluate the effect of oral sildenafil on pulmonary artery pressure, systemic arterial pressure, and INO use in patients after LVAD implantation.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Discussion
 References
 
After Institutional Review Board approval for retrospective review with waiver of consent (received March 17, 2005), 10 adult patients with end-stage heart failure necessitating LVAD placement and subsequently receiving sildenafil were identified by cross-referencing the pharmacy database with the mechanical circulatory support database. The records of these 10 consecutive adult patients with persistent pulmonary hypertension after LVAD implantation were reviewed. Demographics, surgical history, INO use, inotrope requirements, and hemodynamics at several points before sildenafil administration, as well as 0, 30, 60, 90, 120, 180, 240, and 300 minutes after sildenafil were collected.

In all patients, the indication for LVAD implantation was persistent heart failure and low cardiac output despite optimal medical management and inotropic therapy. In all cases, the LVAD was implanted with left ventricular apical cannulation and ascending aortic outflow. Cardiopulmonary bypass was only used during apical cannulation and insertion of the device. All patients were separated from bypass with milrinone, dobutamine, and INO as per our usual routine. Vasopressin was used selectively in patients with significant refractory vasodilation. The usual postoperative weaning routine included slowly weaning of INO in stepwise fashion over the first 12 to 18 hours. Failure of the wean was determined at the care team discretion, and usually was secondary to increased central venous pressure, rebound pulmonary hypertension, or reduced LVAD flows secondary to decreased filling. For these patients, sildenafil was initiated in an effort to facilitate the weaning of INO and inotropic therapy, while preserving right heart function. The initial dose of sildenafil was 25 mg for patients with less than 2.0 body surface area, and 50 mg for larger patients, based on our previous experience [12, 16]. Sildenafil was administered either orally or by nasogastric tube initially, and continued orally every 8 hours after extubation.

Statistical Analysis
Descriptive and inferential statistical analysis was performed using SigmaStat 3.1 (Systat Software, Point Richmond, California). Measurements are reported as mean ± SEM. Before parametric testing, the assumption of normality was validated using the Kolmogorov-Smirnov test with Lilliefors’ correction. For normally distributed data, one-way (factor: time) repeated measures analysis of variance was used to test for overall statistical significance followed by Tukey post-hoc pairwise testing, when appropriate, to analyze multiple comparisons. For nonparametric data, Friedman repeated measures analysis of variance on ranks was used followed by Tukey testing when appropriate. A p value less than 0.05 was considered to be statistically significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Discussion
 References
 
Eight men and 2 women, with a mean age of 56 years (range, 43 to 62) were identified. Six patients received Heartmate XVE and 4 received Thoratec LVADs (both, Thoratec, Pleasanton, California; Table 1). Eight patients were receiving INO with weaning attempts associated with rebound pulmonary hypertension, and remained on ventilatory support at the initiation of sildenafil therapy. The INO dose ranged from 20 to 50 parts per million at the time of sildenafil administration. Two additional patients had been successfully weaned from INO and extubated, but several hours later suffered significant rebound pulmonary hypertension and decreased filling of the LVAD, which prompted the initiation of sildenafil.


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  		Table 1. Patient Characteristics
 
All patients were receiving inotropic therapy with dobutamine and milrinone. Sildenafil produced a significant reduction in pulmonary artery systolic pressure within 90 minutes of oral administration in these patients (Table 2). Seven of 10 patients experienced decrements in systolic pulmonary blood pressure, whereas 2 patients underwent an increase in systolic pulmonary blood pressure, and 1 patient had no change (Fig 1). In the 2 patients who had increased pulmonary artery pressure after sildenafil, we noted that both patients had received volume infusions concurrently for decreased LVAD output. Significant changes in systolic blood pressure, mean arterial pressure, systemic vascular resistance, or heart rate were not observed although several changes approached statistical difference (Fig 2, Table 2). All 8 patients receiving INO were weaned within 12 hours without recurrent pulmonary hypertension. All 10 patients were weaned from inotropic support within 72 hours. No patient suffered right heart failure requiring intervention.


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  		Table 2. Hemodynamic Response to Sildenafil
 

Figure 1
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  		Fig 1. Effect of sildenafil on systolic pulmonary artery pressure in patients with left ventricular assist devices. Shown is baseline, 30-, 60-, and 90-minute data as mean ± SEM for 10 patients after sildenafil (25 to 50 mg) ingestion. *p < 0.05 for summary data, p = 0.042 at 90-minute interval.

 

Figure 2
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  		Fig 2. Effect of sildenafil on systolic blood pressure in patients with left ventricular assist devices. Shown is baseline, 30-, 60-, and 90-minute data points expressed as mean ± SEM for 10 patients after sildenafil (25 to 50 mg) ingestion.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Discussion
 References
 
Inotropic support and use of INO are ubiquitous in the care of patients after LVAD implantation. The manipulation of pulmonary artery pressure remains an important adjunct for optimization of right ventricular function and LVAD filling. Early attempts at weaning INO and inotropic support may result in decreased LVAD filling and output, leading to poor perfusion and acidosis. This vicious cycle might be interrupted with preemptive use of sildenafil. Others have documented single case reports of sildenafil used to facilitate INO weaning in patients with LVADs [13]. Additionally, in patients without LVADs, it is known that sildenafil improves the 6-minute walking distance by approximately 15% and leads to an improvement in functional status for patients with pulmonary arterial hypertension [17].

In our series, sildenafil administered either orally or through nasogastric tube reached significant efficacy within 90 minutes. It provided additional reduction of pulmonary artery pressure, but perhaps more importantly, averted the predictable rebound pulmonary hypertension that often accompanies weaning of INO. Inhaled nitric oxide exerts its effect by increasing cGMP, which then causes smooth muscle relaxation and vasodilatation [18]. The cGMP is degraded by the phosphodiesterases, which accounts for INO termination of action. It is likely that the short half-life accounts for the rebound phenomenon associated with weaning.

Sildenafil is a longer acting oral phosphodiesterase V inhibitor that has also been shown to blunt the rebound pulmonary hypertension seen with weaning of INO [8, 14]. Additionally, the action of sildenafil augments and prolongs the hemodynamic effects of INO in patients with congestive heart failure and pulmonary hypertension [19]. The combination of longer duration of action and efficacy regarding the pulmonary arteries gives sildenafil additive benefits in weaning from INO and milrinone after LVAD implantation. In our series, these benefits augmented the reduction in pulmonary artery pressure achieved by INO without deleterious effect on systemic pressure. Sildenafil also facilitated the subsequent weaning of INO and inotropic support without adverse consequences.


   Discussion
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
References
 
DR JOHN V. CONTE, JR (Baltimore, MD): Were you unable to wean the patients off nitric oxide and that is why you tried the sildenafil? And if that is the case, what were your criteria for weaning nitric oxide? Because in any patient who is on nitric oxide, you are going to have a rebound increase in the pulmonary pressures because the drug will lower pulmonary pressures in any patient. So what were your criteria if that was the case?

DR KLODELL: Doctor Conte, thank you for your question. That is a very good question. My general practice is based on the idea that right heart failure is much easier to prevent than treat. Our standard protocol is that all patients come out of the operating room after an LVAD on inhaled nitric oxide, milrinone, and dobutamine. Subsequently, over the next 12 to 18 hours, we attempt to wean the nitric oxide, usually with specific parameters selected for each patient such as central venous pressure, pulmonary artery parameters, but more importantly, what we see as a change in the thermodilution cardiac output and what happens to the LVAD function. If we start to see any signs of either less LVAD filling or dropping thermodilution cardiac output as a result, then we tend to stop weaning the nitric oxide and initiate sildenafil.

DR CONTE: To follow up that answer, have you thought of using sildenafil preoperatively? We have done that in several different types of heart failure patients and found that our inotropic requirements and the need for nitric oxide is reduced by preoperatively giving these patients sildenafil, even a medium size dose of about 50 mg twice a day.

DR KLODELL: In answer to your second question, yes, we have considered it. I am very interested in studying that in a prospective fashion. And as many of the people who implant VADs in the audience know, we are all so enthusiastic about the new technology, and there is such a push to enroll the patients in the axial flow trials right now, it has been very hard to prospectively do very much with the VAD patients. Hopefully, with the impending approval of the HeartMate II device maybe in the first or second quarter of 2006 then, when that is FDA approved, we will be able to prospectively answer some of these questions.

DR ROBERT F. KORMOS (Pittsburgh, PA): Just a quick question. I may have missed it and I apologize if you mentioned it, but what dose did you use?

DR KLODELL: It was completely arbitrary, and I assigned it. If the patient was less than 2.0 body surface area, 25 mg three times daily; greater than 2.0, 50 mg three times daily, and that seemed to be a relatively effective dose.

DR SOON J. PARK (San Francisco, CA): Great paper! Could you share with us some of your hemodynamic data? Was there any change in the central venous pressure or ventricular assist device flow with your medical treatment?

DR KLODELL: Neither the reduction of central venous pressure nor the increase in LVAD flow reached statistical significance, although there was a trend toward increase in the thermodilution cardiac output after the sildenafil.

DR PARK: So do you think this is a necessary treatment for everybody? I am trying to understand the clinical relevance and implication.

DR KLODELL: I think it probably warrants a prospective study as to whether this is a mechanism to reduce right heart dysfunction and need for RVADs after LVAD implantation. As Dr Conte pointed out in the previous paper, with the axial flow pumps and allowing the ventricle to remain at a little higher volume, we have not experienced any incidence of right heart failure with the HeartMate II device. This may be something we could look at in combination, to try and reduce RVAD implantation rates.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Discussion
 References
 

  1. Khazin V, Kaufman Y, Zabeeda D, et al. Milrinone and nitric oxide: combined effect on pulmonary artery pressures after cardiopulmonary bypass in children J Cardiothorac Vasc Anesth 2004;18:156-159.[Medline]
  2. Thelitz S, Oishi P, Sanchez LS, et al. Phosphodiesterase-3 inhibition prevents the increase in pulmonary vascular resistance following inhaled nitric oxide withdrawal in lambs Pediatr Crit Care Med 2004;5:234-239.[Medline]
  3. Oishi P, Grobe A, Benavidez E, et al. Inhaled nitric oxide induced NOS inhibition and rebound pulmonary hypertension: a role for superoxide and peroxynitrite in the intact lamb Am J Physiol Lung Cell Mol Physiol 2006;290:L359-L366.[Abstract/Free Full Text]
  4. Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective pulmonary vasodilator in childhood primary pulmonary hypertension Heart 2000;84:E4.[Medline]
  5. Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary hypertension N Engl J Med 2000;343:1342.[Medline]
  6. Schumacher YO, Zdebik A, Huonker M, Kreisel W. Sildenafil in HIV-related pulmonary hypertension AIDS 2001;15:1747-1748.[Medline]
  7. Stiebellehner L, Petkov V, Vonbank K, et al. Long-term treatment with oral sildenafil in addition to continuous IV epoprostenol in patients with pulmonary arterial hypertension Chest 2003;123:1293-1295.[Medline]
  8. Weimann J, Ullrich R, Hromi J, et al. Sildenafil is a pulmonary vasodilator in awake lambs with acute pulmonary hypertension Anesthesiology 2000;92:1702-1712.[Medline]
  9. Lepore JJ, Maroo A, Pereira NL, et al. Effect of sildenafil on the acute pulmonary vasodilator response to inhaled nitric oxide in adults with primary pulmonary hypertension Am J Cardiol 2002;90:677-680.[Medline]
  10. Ghofrani HA, Olschewski H, Seeger W, Grimminger F. [Sildenafil for treatment of severe pulmonary hypertension and commencing right-heart failure] Pneumologie 2002;56:665-672.[Medline]
  11. Ghofrani HA, Wiedemann R, Rose F, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension Ann Intern Med 2002;136:515-522.[Abstract/Free Full Text]
  12. Trachte AL, Lobato EB, Urdaneta F, et al. Oral sildenafil reduces pulmonary hypertension after cardiac surgery Ann Thorac Surg 2005;79:194-197.[Abstract/Free Full Text]
  13. Mychaskiw G, Sachdev V, Heath BJ. Sildenafil (Viagra) facilitates weaning of inhaled nitric oxide following placement of a biventricular-assist device J Clin Anesth 2001;13:218-220.[Medline]
  14. Atz AM, Wessel DL. Sildenafil ameliorates effects of inhaled nitric oxide withdrawal Anesthesiology 1999;91:307-310.[Medline]
  15. Klodell CT, Staples ED, Aranda Jr JM, et al. Managing the post-left ventricular assist device patient Congest Heart Fail 2006;12:41-45.[Medline]
  16. Lobato EB, Beaver T, Muehlschlegel J, et al. Treatment with phosphodiesterase inhibitors type III and V: milrinone and sildenafil is an effective combination during thromboxane-induced acute pulmonary hypertension Br J Anaesth 2006;96:317-322.[Abstract/Free Full Text]
  17. Galie N, Ghofrani HA, Torbicki A, et al. Sildenafil citrate therapy for pulmonary arterial hypertension N Engl J Med 2005;353:2148-2157.[Medline]
  18. Haddad E, Lowson SM, Johns RA, Rich GF. Use of inhaled nitric oxide perioperatively and in intensive care patients Anesthesiology 2000;92:1821-1825.[Medline]
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This Article
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Edward D. Staples
Philip J. Hess
Tomas D. Martin
Thomas M. Beaver
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