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Heart, Lung and Circulation (2014) xx, 1–6 1443-9506/04/$36.00 http://dx.doi.org/10.1016/j.hlc.2013.12.014

ORIGINAL ARTICLE

Effects of Sildenafil on Prognosis in Patients with Pulmonary Hypertension After Left-sided Valvular Surgery Gengxi Jiang, MD, Bailing Li, MD, Guanxin Zhang, MD, Enhong Xu, MD, Yang Liu, MD, Zhiyun Xu, MD* Received 21 August 2013; received in revised form 18 November 2013; accepted 30 December 2013; online published-ahead-of-print xxx

Introduction

Sildenafil (Viagra, Pfizer) is being used to treat pulmonary hypertension (PH). However, there are limited data on the effects of sildenafil on patients with PH after left-sided valvular surgery. The purpose of this study was to determine the optimal dosage and the effects of sildenafil on prognosis of patients with PH after left-sided valvular surgery.

Methods

This randomised controlled trial, double-blind study enrolled patients with PH undergoing left-sided valvular surgery in our hospital from January to December, 2010. Ninety patients were enrolled. And 0.5 mg/kg sildenafil citrate or placebo was administered through nasogastric tubes, the haemodynamics changes in the 0.5/1/2/4 hours were assessed. The sildenafil citrate/placebo was continued to the discharges and the early prognoses of these patients were compared.

Results

Compared with placebo, a 0.5 mg/kg dose of sildenafil significantly reduced the time of mechanical ventilation, stay-in-ICU and hospitalisation duration.

Conclusions

Sildenafil might be beneficial to the early prognosis of patients with PH after left-sided valvular surgery.

Keywords

Valvular heart disease  Pulmonary artery hypertension  Postoperative period  Haemodynamic  Sildenafil citrate

Introduction Pulmonary hypertension (PH) is defined as mean pulmonary artery pressure (mPAP), exceeds 25 mmHg at rest and is a major complication of long-standing left-sided valvular diseases. In the perioperative period of left-sided valvular surgery, PH can be exacerbated by cardiopulmonary bypass or lung ischaemia-reperfusion injury. Thus complicates perioperative management of patients and has adverse effects on prognosis. Therefore, it is of vital importance to control the rising of mPAP. Management strategies for postoperative PH include sedation, moderate hyperventilation (maintaining PaCO2 between 30 and 35 mmHg), moderate alkalosis, increased inspired oxygen, positive end-expiratory pressure (to optimise functional residual capacity), pulmonary vasodilators

(e.g., inhaled nitric oxide [iNO] and inhaled intravenous prostacyclin), and creating or maintaining an intracardiac right-to-left shunt in an attempt to maintain cardiac output [1]. More recently, the selective phosphodiesterase-5 (PDE-5) inhibitor sildenafil has also been shown to decrease pulmonary vascular resistance (PVR) in patients when given as a single dose [2,3]. PDE-5 specifically hydrolyzes guanosine 3’,5’-cyclic monophosphate (cGMP), and increased intracellular cGMP in turn leads to the hyperpolarisation of smoothmuscle membranes and subsequent vascular relaxation [4]. Sildenafil produces acute and relatively selective pulmonary vasodilatation and acts synergistically with iNO [5–8]. Available evidence suggests that sildenafil may have significant effects in decreasing PH, particularly in the chronic therapy of PH and in attenuating rebound effects after discontinuing

*Corresponding author at: Department of Cardiothoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200433, China. Tel.: +86 15721571236, Email: [email protected] © 2014 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier Inc. All rights reserved.

Please cite this article in press as: Jiang G, et al. Effects of Sildenafil on Prognosis in Patients with Pulmonary Hypertension After Left-sided Valvular Surgery. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2013.12.014

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G. Jiang et al.

iNO [9]. Sildenafil is well tolerated and available as an oral preparation. However, there is limited data available to suggest dosage regimens of sildenafil, and to show the haemodynamic changes and influence on the prognostic markers in patients with PH after left-sided valvular surgery. The purpose of this study was to determine the optimal dosage and the effects of sildenafil on the prognosis of patients with PH after left-sided valvular surgery.

Methods Ethics approval was obtained from the Ethics Committee Board of The First Affiliated Hospital of Second Military Medical University for this study’s methods and conduct. All patients voluntarily joined this study with informed consent. We studied 90 adult patients in our hospital undergoing selective valvular surgery from January to December 2010. Inclusion criteria were mPAP>25 mmHg and PAPs  45 mmHg. Patients with baseline mPAP  25 mmHg or had the reoperation were excluded. We designed a randomised and doubled-blind study of sildenafil versus placebo. Randomisation was performed by using a simple random table and the study patients were randomly allocated to one of the two arms of the study: Study group (sildenafil, n=45) or control group (placebo, n=45). The placebo was formulated by a pharmacist to have similar base with the drug but not containing the active ingredient. Patient demographics are listed in Table 1 and there was no statistically significant difference between the two groups. In the sildenafil group, 22 patients underwent mitral valve replacement (MVR); 23 underwent double valve replacement (DVR). There was 30 MVR and 15 DVR in the placebo group. All patients were under moderate hypothermic cardiopulmonary bypass and had catheters (Swan Ganz, Arrow Inc.) inserted during surgery, and central venous pressure (CVP), PAP, pulmonary capillary wedge pressure (PCWP) and right ventricular pressure (RVP) were recorded. The ventilator

was in IPPV setting, with tidal volume of 10 ml/kg, 10-12/min, oxygen concentration at 100%. Cardiopulmonary bypass (CPB) was the same model, supplying blood with pump tube intubated into the aorta and draining with intubation in the inferior vena cava. Cold blood cardioplegia, 4 8C, was perfused every 25-30 min with initial dose at 10-20 ml/kg and the following at half of it. During the operation, the central body temperature was maintained at about 30-328C, CPB flow at 2.0-2.4 L/min/m2, MBP at 50-70 mmHg, Hct > 25%. Cardiac output was recorded by the multifunction patient monitor (Philips Inc.) When they first arrived at the ICU, the patients’ condition changed greatly, and they were given expansion, blood transfusion, rewarming, adjusting pH balance and other measures to maintain an appropriate volume load. Hct was raised to 28%, and central blood temperature to 36 8C. Dra¨gerEvita 2 Dura ventilator was connected, with tidal volume at 10 ml/kg, 10-12/min, PEEP at 5cmH2O, to maintain the PaCO2 at about 30-36 mmHg, and PaO2 at 100 mmHg. Epinephrine, dopamine and other vasoactive drugs had greater impact on haemodynamics, so after the design baseline measurement, the two drugs fixed at the same dose lasted for four hours or more. If, after surgery, the patient’s vital signs were unstable, the first haemodynamic measurement (baseline) was recorded when vital signs became relatively stable in the ICU. In Raja SG’s study, doses of 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, and 2.0 mg/kg caused significant reduction in pulmonary artery pressure with no significant effect on systemic arterial and central venous pressures [10]. In a double blind form, after the baseline was recorded, patients separately received 0.5 mg/kg sildenafil in 30 ml normal saline solution or 30 ml pure normal saline solution. Haemodynamic measurement and arterial blood gas test were processed 0.5, one, two and four hours after the initial dosage, and the administration of sildenafil and placebo continued every eight hours until the patients were discharged from ICU. The time of mechanical apparatus, stayin-ICU and the hospitalisation was also recorded. The criteria for extubation were: cardiovascular function is stable; cardiac

Table 1 Characteristics of patients in placebo and sildenafil (0.5 mg/kg) groups. Patient Characteristics

Placebo

Sildenafil (0.5 mg/kg)

(n = 45)

(n = 45)

p value

Age (y)

5214

5011

0.482

Sex (F/M)

21/24

16/29

0.284

BSA (m2)

1.620.16

1.570.18

0.313

AF (Y/N)

20/25

24/21

0.399

MVR/DVR

30/15

22/23

0.088

Operation Time (min) CPB Time (min)

203.946.1 106.431.9

191.740.1 96.824.5

0.320 0.216

BMT* (min)

244.994.3

239.6102.4

0.857

Vasoactive medication

Epinephrine, Dopamine

Epinephrine, Dopamine



Please cite this article in press as: Jiang G, et al. Effects of Sildenafil on Prognosis in Patients with Pulmonary Hypertension After Left-sided Valvular Surgery. Heart, Lung and Circulation (2014), http://dx.doi.org/10.1016/j.hlc.2013.12.014

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Effects of Sildenafil on Prognosis in Patients

Table 2 Comparisons of baselines of haemodynamics indexes between placebo group and sildenafil (0.5 mg/kg) group. Haemodynamics Index

Placebo

Sildenafil (0.5 mg/kg)

(n = 45)

(n = 45)

p value

CO (L/min)

5.171.43

5.561.53

0.297

CI (L/minm2)

3.230.71

3.570.77

0.079

HR (bpm)

10114

10411

0.214

14.423.98

13.243.62

0.101 0.972

PVWP (mmHg) CVP (mmHg)

8.272.97

8.242.65

mPAP (mmHg)

33.678.57

33.048.75

0.707

sPAP (mmHg)

49.4711.22

48.9611.28

0.804

PVR PVRI

319.60151.07 491.87192.55

307.36150.31 462.20192.94

0.715 0.490

ABPs (mmHg)

122.7116.11

123.5815.69

0.784

ABPm (mmHg)

85.4010.54

86.2011.05

0.701

0.410.11

0.400.11

0.763

PAPs/ABPs

index is greater than 2L / (minm2); ventilation should be less than 180 ml / (kgmin); oxygen concentration is less than 40%, PaO2 greater than 8.0 kPa (60 mmHg); PEEP  1.96 kPa (10cmH2O). The criteria for leaving ICU were: that patients have sinus or atrial rhythm; have no occasional premature ventricular contractions; heart rate

Effects of sildenafil on prognosis in patients with pulmonary hypertension after left-sided valvular surgery.

Sildenafil (Viagra, Pfizer) is being used to treat pulmonary hypertension (PH). However, there are limited data on the effects of sildenafil on patien...
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