Abstract
OBJECTIVES
Pulmonary hypertension in paediatric patients with ventricular septal defect remains one of the most important determinants of perioperative morbidity and mortality. Sildenafil is an oral, well-tolerated pulmonary vasodilator with few drug interactions. We studied the effect of oral sildenafil, when given before and after surgical closure compared with starting it postoperatively, on the pulmonary artery pressure and patients' outcome.
METHODS
We enrolled 101 infants with large ventricular septal defects who had moderate-to-severe pulmonary hypertension scheduled for surgical closure. They were randomly assigned to the sildenafil group (n = 51, mean age 10 months and mean weight 6.5 kg), in which oral sildenafil was started 2 weeks before surgery to be continued postoperatively, and to the control group (n = 50, mean age 11 months and mean weight 7.3 kg), in which sildenafil was started only postoperatively. It was started at 0.5 mg/kg and increased gradually to a maximum dose of 2 mg/kg in both groups.
RESULTS
Overall hospital mortality was 4.9%. Mean pulmonary artery pressure decreased significantly at all time points of recording in both groups (P < 0.0001). In the sildenafil group, it decreased preoperatively after sildenafil administration from 75.4 to 59.4 mmHg and postoperatively from 50.4 mmHg immediate post-cardiopulmonary bypass to reach 44.2 mmHg before discharge. In the control group, it decreased from 74.6 mmHg to 51 mmHg immediate post-cardiopulmonary bypass to reach 42.7 mmHg before discharge. No adverse effects have been recorded. Although there was no difference in the duration of mechanical ventilation and hospital stay between the two groups, intensive care unit stay was significantly shorter in the sildenafil group. Dobutamine doses were significantly higher in the sildenafil group; however, milrinone and epinephrine have been used more significantly in the control group.
CONCLUSIONS
The low cost, the oral availability and the good tolerability of sildenafil make it a suitable and simple alternative therapy for secondary pulmonary hypertension including persistent postoperative pulmonary hypertension associated with ventricular septal defect in resource limited places. However, starting sildenafil early before surgery does not add a great benefit in terms of improving postoperative pulmonary hypertension or patients' outcome.
Keywords: Congenital heart disease, Ventricular septal defect, Pulmonary hypertension, Sildenafil
INTRODUCTION
The most frequent congenital heart disease (CHD) is the ventricular septal defect (VSD) [1]. Many of VSDs are complicated by pulmonary hypertension (PH) of variable severity as a result of high pulmonary blood flow and this remains one of the most important determinants of perioperative morbidity and mortality, as well as long-term survival after cardiac operations [2].
By expert consensus, PH is regarded as a mean pulmonary artery pressure (of >25 mmHg in the setting of normal or reduced cardiac output and a normal pulmonary capillary wedge pressure. Transthoracic Doppler echocardiography is considered the screening tool for the presence of PH because of the high level of correlation of estimated right ventricular systolic pressure with invasively measured pulmonary artery pressure. However, confirmation by right heart catheterization is warranted before considerations of prognosis or treatment [3–5].
There are many treatment options which include prostacyclin infusion, oral calcium channel blockers, and anticoagulation. Newer therapies are emerging such as endothelin receptor blockers, continuous inhalation of nitric oxide (NO) and aerosolized prostacyclin and analogues [6].
There are serious disadvantages with some of these therapies, including cost, systemic side-effects, complications of prolonged intravenous (IV) access and rebound PH [6]. Moreover, the endothelial dysfunction during and following cardiopulmonary bypass (CPB) with its deleterious effects on the pulmonary circulation may explain the limited efficacy of endothelium-dependent vasodilator therapy as nitroglycerine or prostaglandins for the persistent postoperative type of PH [7].
Sildenafil is a phosphodiesterase inhibitor type 5 that has been shown to selectively reduce pulmonary vascular resistance (PVR) in both animal models and adult humans.
Sildenafil produces vasodilatation by increasing cyclic guanosine monophosphate (cGMP) through inhibition of the phosphodiesterase involved in the degradation of cGMP to guanosine monophosphate [8].
Sildenafil is an endothelium-independent pulmonary vasodilator, administered orally, is well tolerated with few drug interactions and does not require intensive monitoring, all these making it a suitable drug for treatment of PH secondary to congenital heart defects.
Those VSD patients with moderate-to-severe PH are considered a perioperative challenge especially in developing countries in which close medical service is lacking with subsequent delayed presentation of patients and, unfortunately, there is resource-limited setting for expensive management options. Therefore, we aimed in this study to investigate the effect of an inexpensive oral sildenafil when given early before surgery and continued postoperatively on controlling persistent postoperative PH following VSD closure and whether there is any superior advantage of starting it early before cardiac surgery instead of its use postoperatively only. Secondary endpoint is an evaluation of its effect on patients' outcome.
MATERIALS AND METHODS
From January 2009 to December 2012, 104 patients with large VSDs and moderate-to-severe preoperative PH referred to the paediatric cardiac surgery unit at Atfal Masr Insurance Hospital for corrective surgery were enrolled in this prospective, randomized, open-label study. The inclusion criteria were the presence of unrestrictive VSD complicated by moderate-to-severe PH [>40 mmHg and systolic PAP >50% of systemic pressure; and PVR >3 Wood units (WU)], associated atrial septal defect (ASD) or patent ductus arteriosus (PDA) and infants over 3 months of age. Patients with PVR >8 WU, complete atrioventricular septal defect, Down syndrome, multiple congenital anomalies, patients with hepatic or renal diseases and patients with postoperative residual intracardiac shunts were excluded from this study.
Informed consent from parents or guardians and approval of our local ethics committee were obtained.
Preoperative echocardiography was done for all patients to confirm the diagnosis and to measure calculated pulmonary artery (PA) pressures. Postoperatively, it was done to follow the PA pressures up and to diagnose any residual leaks.
All patients underwent preoperative cardiac catheterization for assessment of the PH severity and operability status and to exclude patients with pulmonary vascular disease with high PVR >8 WU. All catheterization data are summarized in Table 1.
Table 1:
Findings by preoperative catheterization
| Variable | Sildenafil group (n = 51) | Control group (n = 50) | P-value |
|---|---|---|---|
| Baseline mPAP (mmHg) | 75.4 (7.8) | 74.6 (8.2) | 0.616 |
| PVR (WU) | 4.7 (1.0) | 4.7 (1.0) | 0.766 |
| SVR (WU) | 11.7 (3.3) | 11.7 (3.2) | 0.929 |
| PVR/SVR ratio before O2 | 41.8 (8.8) | 41.5 (8.9) | 0.851 |
| PVR/SVR ratio after O2 | 27.8 (6.9) | 27.5 (7.0) | 0.833 |
| Qp (l/min) | 13.3 (2.2) | 13.4 (2.2) | 0.780 |
| Qs (l/min) | 8.1 (1.1) | 8.1 (1.1) | 0.889 |
| Qp/Qs before O2 | 1.7 (0.2) | 1.7 (0.2) | 0.643 |
| Qp/Qs after O2 | 2.1 (0.3) | 2.2 (0.3) | 0.756 |
Data are presented as mean (SD).
Patients were randomly allocated to two groups according to the admission numbers. The first group (sildenafil group) included 52 patients who were given sildenafil (Viagra, Pfizer Egypt, Cairo, A.R.E) for 2 weeks before surgery to be continued after surgery till patient discharge. Sildenafil was given to these patients via the oral route (0.5 mg/kg) 6 hourly with the final dose 6 h before induction of anaesthesia. Postoperatively, the dose was increased stepwise by 0.5 mg/kg every 24 h up to a maximum dose of 2 mg/kg. The control group included 52 patients who were given sildenafil with the same protocol only after surgery. Patients were monitored for compliance and adverse events including systemic hypotension, nasal congestion, epistaxis and gastrointestinal side-effects.
All patients received IV midazolam (0.05 mg/kg) as a preanaesthetic sedation. All operations were performed under general anaesthesia which was induced by IV doses of fentanyl (10 µg/kg), midazolam (0.05 mg/kg) and a small dose of propofol (0.5–1 mg/kg). Anaesthesia was maintained by further IV doses of fentanyl (5 µg/kg) in addition to isoflurane inhalation (0.5–2%). Pancuronium (0.1 mg/kg) was used for muscle relaxation as indicated.
Surgery was achieved through a midline sternotomy, on CPB, using mild-to-moderate hypothermia at 28–32°C, with alpha-stat cooling, non-pulsatile perfusion at a flow rate of (body surface area × 2.4 l min m2) and conventional ultrafiltration during rewarming was utilized in all patients. After aortic cross-clamping, the heart was arrested using intermittent cold-blood cardioplegia. All VSDs were closed through the right atrium with an autologous pericardial patch, pretreated with glutaraldehide 6% for 15 min, using a continuous suture technique. The weaning off bypass was helped by 5–10 μg/kg/min of dobutamine infusion as standard practice in all patients. Haemodynamic management was achieved by increasing dobutamine dose to 15 μg/kg/min, adding 0.05–0.2 μg/kg/min of epinephrine infusion and adding 0.3–0.7 μg/kg/min of milrinone infusion.
Postoperatively, patients were transferred to the intensive care unit (ICU). All patients were on controlled mechanical ventilation in order to attain blood pH values between 7.35 and 7.45, partial pressure of arterial oxygen (PaO2) above 100–120 mmHg and partial pressure of arterial carbon dioxide (PaCO2) at 35–45 mmHg. All patients received propofol infusion (1–1.5 mg/kg/h) with small increments of fentanyl, and they were protected from hypothermia. All patients started their postoperative sildenafil therapy from zero day in ICU via nasogastric tube till extubation and then via an oral route.
Hyperventilation with an excess high inspiratory concentration of oxygen was used as a line of treatment for postoperative PH crisis (acute elevation of PA pressure reflected by hypotension, tachycardia, hypoxaemia, elevated central venous pressure).
The recorded preoperative cardiac catheterization and echocardiographic data, preoperative and postoperative haemodynamic data, oxygen saturation levels, inotropic requirements, CPB and aortic cross-clamp times, post-CPB mPAP direct measurement, postoperative calculated PA pressures by echocardiography, occurrence of PH crisis, mechanical ventilation time and ICU and hospital stays were compared between the two groups.
STATISTICAL METHODS
The required sample size was calculated using the G*Power© software version 3.1.0 (Institut für Experimentelle Psychologie, Heinrich Heine Universität, Düsseldorf, Germany). The primary outcome measure was the difference between the two groups as regards mPAP after surgery. It was estimated that a sample of 45 patients in each study group would have a power of 80% to detect an effect size (d) of 0.6 between the two groups. The unpaired t-test was used for sample size calculation and significance was targeted at a two-sided type I error of 0.05.
Statistical analysis was done on a personal commuter using MedCalc© version 12.2.1.0 (MedCalc Software, Mariakerke, Belgium). The D'Agostino-Pearson test was used to test the normality of numerical data distribution. Normally distributed numerical data were presented as mean and standard deviation and differences between the two groups were compared using the unpaired Student t-test. Multiple within-group measures were compared using repeated-measures analysis of variance (ANOVA) with Bonferroni correction for pairwise comparisons. Non-normally distributed numerical data were presented as median and interquartile range and between-group differences were compared non-parametrically using the Mann–Whitney U-test. Categorical data were presented as number and percentage, and differences between the two groups were compared using the Pearson χ2 test with the application of Fisher's exact test, if appropriate.
All P-values are two-sided. P < 0.05 is considered statistically significant.
RESULTS
All patients underwent successful VSD closure; however, 3 patients (1 in the sildenafil group and 2 in the control group) were excluded from the study because of postoperative residual shunting. Additional surgical manoeuvres included PDA closure in 34 patients and ASD closure in 19 patients. Demographic data, VSD types and associated congenital heart lesions are presented in Table 2.
Table 2:
Demographic and preoperative data
| Variable | Sildenafil group (n = 51) | Control group (n = 50) | P-value |
|---|---|---|---|
| Male/female | 25/26 | 31/19 | 0.104 |
| Age (months) | 10 (7–12) | 11 (9–17) | 0.122 |
| Weight (kg) | 6.5 (1.4) | 7.3 (2) | 0.017 |
| VSD type | |||
| PM | 26 (51%) | 25 (50%) | 1.0 |
| SA | 12 (23.5%) | 12 (24%) | |
| DC | 2 (4%) | 1 (2%) | |
| M | 11 (21.5%) | 12 (24%) | |
| VSD size (mm) | 9 (7.5–10) | 8 (8–11) | 0.634 |
| Associated cardiac anomalies | |||
| PDA | 18 (36.7%) | 16 (32.7%) | 0.776 |
| ASD | 8 (16.3%) | 11 (32.7%) | |
| MPA aneurysm | 1 (2%) | 0 (0%) | |
Data are presented as a ratio, median (interquartile range), mean (SD) or number (%).
VSD: ventricular septal defect; PM: perimembranous; SA: subarterial; DC: double committed; M: muscular; PDA: patent ductus arteriosus; ASD: atrial septal defect; MPA: main pulmonary artery.
The hospital mortality rate in both groups was 4.9%, 2 patients in the sildenafil group and 3 patients in the control group. The main causes of death were low cardiac output and sepsis that proved unresponsive to aggressive medical management.
Postoperative complications encountered during the study were pneumonia in 2 patients, the need for reintubation for respiratory distress in 3 patients, pulmonary hypertensive crisis in 1 patient, haematemesis in 1 patient and renal shutdown that required peritoneal dialysis in 1 patient in the sildenafil group and pneumonia in 2 patients, the need for reintubation in 4 patients, pulmonary hypertensive crisis in 3 patients and renal shutdown that required peritoneal dialysis in 3 patients in the control group.
Mean preoperative blood pressure was 52.69 ± 7.54 mmHg in the sildenafil group and 58.82 ± 6.72 mmHg in the control group with no significant difference between the two groups and oxygenation saturation was ∼99% in all patients. There were no significant haemodynamic changes or other adverse effects during and after sildenafil treatment either preoperatively or postoperatively.
Preoperatively, mPAP decreased significantly after sildenafil administration in the sildenafil group. Postoperatively, mPAP was getting significantly lower in both groups till discharge of patients. However, there was no significant difference between the two groups in mPAP immediately after CPB or before discharge, as given in Table 3. Changes in the mPAP pressure, in the two groups, from baseline till reaching the maximum dose of sildenafil before discharge is shown in Fig. 1.
Table 3:
Changes in mean pulmonary artery pressure (mPAP) in both groups
| Variable | Sildenafil group (n = 49) | Control group (n = 49) | P-value |
|---|---|---|---|
| Baseline mPAP (mmHg) | 75.4 (7.8) | 74.6 (8.2) | 0.616 |
| mPAP after sildenafil (mmHg) | 59.4 (7.4)* | – | |
| mPAP after CPB (mmHg) | 50.4 (6.8)*† | 51 (7.6)* | 0.685 |
| mPAP before discharge (mmHg) | 44.2 (10.3)*,†,‡ | 42.7 (9.4)*,‡ | 0.449 |
| P-valuea | <0.001 | <0.001 |
aEstimated with repeated-measures ANOVA.
*P < 0.0001 vs baseline mPAP (estimated with the Bonferroni post hoc test).
†P < 0.0001 vs mPAP after sildenafil (estimated with the Bonferroni post hoc test).
‡P < 0.0001 vs mPAP after CPB (estimated with the Bonferroni post hoc test).
Figure 1:
Change in mean pulmonary artery pressure (mPAP) in both study groups. Error bars represent SD. T1: baseline; T2: after sildenafil; T3: after CPB; T4: before discharge.
There was no significant difference in operative data regarding aortic cross-clamping time and CPB time. Although IV dobutamine infusion (5–10 µg/kg/min) was added as standard practice in all patients, dobutamine doses were significantly higher in the sildenafil group. However, the use of milrinone and epinephrine was significantly higher in the control group, as given in Table 4.
Table 4:
Operative data
| Variable | Sildenafil group (n = 51) | Control group (n = 50) | P-value |
|---|---|---|---|
| CPB time (min) | 50 (44.5–60) | 55 (48.5–65) | 0.082 |
| Aortic cross-clamping time (min) | 35 (30–36) | 35 (32–40) | 0.225 |
| Dobutamine dose (μg/kg/min) | 10 (10–10) | 10 (5–10) | 0.002 |
| Use of milrinone, n (%) | 9 (17.6%) | 24 (48%) | 0.001 |
| Dose of milrinone (μg/kg/min) | 0.6 (0.1) | 0.6 (0.1) | 1.0 |
| Use of epinephrine, n (%) | 17 (33.3%) | 32 (64%) | 0.002 |
| Dose of epinephrine (ng/kg/min) | 101.8 (38.6) | 104.4 (31.2) | 0.799 |
Data are presented as median (interquartile range), mean (SD) or number (%).
Although there was no difference in duration of mechanical ventilation and hospital stay between the two groups, ICU stay was significantly shorter in the sildenafil group, as given in Table 5.
Table 5:
Postoperative data
| Variable | Sildenafil group (n = 51) | Control group (n = 50) | P-value |
|---|---|---|---|
| Duration of postoperative ventilation (h) | 12 (8–24) | 12 (8–24) | 0.813 |
| Mortality, n (%) | 2 (4%) | 3 (6%) | 0.161 |
| ICU length of stay (days) | 3 (2–4) | 4 (2–6) | 0.027 |
| Hospital length of stay (days) | 10 (3.7) | 11.2 (4.1) | 0.134 |
Data are presented as median (interquartile range), number (%) or mean (SD).
At the time of discharge, all 96 surviving patients were in stable condition and echocardiographic results before patients' discharge showed good biventricular contractility, no residual shunts and low values of PH, as given in Table 3, and patients continued on diuretics and ACE inhibitor drugs with no need to continue sildenafil therapy.
DISCUSSION
Pulmonary arterial hypertension secondary to CHDs is one of the main challenges in paediatric cardiac surgery. Over the past decade, there has been a significant advance in the treatment of PH to ameliorate its severity and to eliminate the effect of persistent postoperative PH to improve patients' outcome.
Inadequate response to conventional therapy and the need for special delivery systems for the administration of inhaled NO or the need to maintain continuous IV drug infusions, which are costly and not free from side-effects, encouraged us to conduct this study of sildenafil drug being available in oral forms, well tolerated with no patient withdrawal [6].
Many studies have proved the effectiveness of sildenafil in the treatment of PH of different aetiologies in adults. It lowers PAP and PVR, and it improves cardiac output, exercise tolerance and functional capacity [9–11]. The experience in children was also encouraging and there are available data on its efficacy in PH whether primary or secondary to CHD including postoperative PH. A 12-month, open-label study of 514 children with PH, of whom 10 exhibited PH secondary to CHD, reported improvements in exercise capacity and haemodynamics with sildenafil [6]. Similar results were reported on paediatric primary and secondary PH [9, 12, 13].
Effectiveness of sildenafil in controlling PH in children with CHDs was reported by many authors. Zeng et al. [14] studied the effect of sildenafil on pulmonary arterial hypertension in the different types of CHD and demonstrated significant improvement in exercise capacity and pulmonary haemodynamics in terms of PVR and pulmonary blood flow without deterioration in systemic haemodynamics and systemic arterial oxygen saturation in patients with PH secondary to ASD, VSD or PDA.
Similar results were reported by Molaei et al. [15], who demonstrated a good response to sildenafil in decreasing the pulmonary arterial blood pressure and they reported its usefulness in determining the pulmonary vascular bed reactivity via echocardiographic parameters which facilitate the decision-making for surgery in patients with CHDs and PH. These findings were compatible with many other studies [16, 17].
Based on these encouraging reports, we thought of the advantage of starting sildenafil preoperatively for better pulmonary vascular bed reactivity with subsequent better postoperative outcome. Our patients received a preoperative 0.5 mg/kg 6 hourly oral dose for 2 weeks and postoperatively the dose was increased stepwise by 0.5 mg/kg every 24 h up to a maximum dose of 2 mg/kg. Because there is no established dose regimen in children, we have based our doses on the current available literature, which recommends a dose for children ranging from 1 to 2 mg/kg/day [6, 9, 18, 19].
However, our results revealed no significant difference between the two groups in patient's outcome in terms of mortality, PH crisis, mechanical ventilation duration or hospital stay and postoperative persistent PH either immediate post-CPB or before discharge despite the significant decrease of the preoperative mPAP in the sildenafil group after sildenafil administration. On the other hand, there was a statistically significant less ICU stay in the sildenafil group, which still reflects an advantage of adding preoperative sildenafil, and this can be explained by easier weaning of postoperative inotropic support with no need to maintain the patient on inotropic support for long time.
Moreover, our results revealed a statistically significant higher dobutamine doses used in the sildenafil group in contrast to statistically significant higher use of epinephrine and milrinone in the control group and this can be explained by the need to combine milrinone with epinephrine to counteract the effect of each other on systemic vascular bed reactivity and despite this result, it is considered, in our results, a positive response in the sildenafil arm of study because of the higher costs of milrinone and its more likely effect on systemic vascular resistance.
A similar study was performed by Palma et al. [20] on 38 children with moderate-to-severe PH who underwent cardiac surgery and they reported shortened CPB time, mechanical ventilation time and lengths of ICU and hospital stays in the 15 patients group who were given preoperative sildenafil for 1 week before surgery as well as 1 week postoperatively compared with the other 23 patients who comprised the control group and given postoperative sildenafil only, and they concluded that sildenafil therapy, as monotherapy, in low doses appears to control PH safely and effectively in children undergoing operations to correct congenital heart defects, with no sildenafil-related hypertensive crises or sequelae, and they suggested that giving sildenafil before cardiac surgery appears to have a positive effect on postoperative management.
Another randomized control trial on preoperative sildenafil administration was conducted by Vassalos et al. [21] on 12 patients who were given sildenafil the day before surgery vs placebo. This study had shown that preoperative sildenafil administration did not improve postoperative PVR as indicated by the insignificant increase in measured cGMP, NO breakdown products between both groups and they have demonstrated no difference in clinical outcomes between the two groups in addition to a significant reduction in biventricular contractility and in postoperative oxygen delivery in the sildenafil group. They highlighted the importance of selecting patients at high risk of postoperative PH and cautioned against routine of sildenafil in patients with pre-existing hypoxia or myocardial dysfunction.
Our study has demonstrated a marked effect of postoperative sildenafil administration on mPAP as reflected by the progressive significant decrease of the mPAP from immediate post-CPB till discharge of patients in both groups. These results are similar to the study conducted by Nemoto et al. [7], which provided evidence of the efficacy of sildenafil for lowering elevated PA pressure and preventing crisis over a range of ages (neonate to school age) in the postoperative course after various types of congenital cardiac surgery. This also adds to the findings reported by many other trials [19, 20, 22].
An evidence exists for the association between sildenafil and various systemic adverse effects, which have included the gastrointestinal, cardiovascular, visual and central nervous systems [23]. However, in our study, we did not encounter side-effects of sildenafil therapy. Similar results were reported by many studies [7, 20,21]. In contrast, sildenafil caused a significant decrease in the systolic blood pressure in the study done by Molaei et al. [15].
In conclusion, sildenafil is a safe, available, simple alternativ therapy for secondary PH associated with VSD including persistent postoperative PH and suitable for resource-limited places. However, despite starting preoperative sildenafil resulted in less ICU stay, it does not add a great benefit in terms of improving postoperative PH or other patients' outcome parameters. On the other hand, we may suggest its use in what is called the treat and repair’ approach for selected patients with severe PH in which treatment with sildenafil for relatively long time may result in significant improvement in PH and allow corrective repair of the cardiac defects; however, further studies are warranted to evaluate its role in this approach. Also, further studies for optimal dosing in children and the safest route of administration in newborns and children are required.
Funding
This study was self-funded.
Conflict of interest: non declared.
Acknowledgements
The authors thank Alaa Roshdy and Waleed Imam, pediatric cardiologists at Atfal Masr insurance Hospital for their assistance in studying the patients preoperatively as well as postoperatively.
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