|Year : 2013 | Volume
| Issue : 1 | Page : 36-40
The role of sildenafil in perioperative management of parturients with pulmonary hypertension undergoing cesarean section
Afaf Abdalla, Amina Omran, Nevan El-Mekawy, Tamer Safan, Reham Magdy
Department of Anaesthesiology and Intensive Care, Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||01-Oct-2012|
|Date of Acceptance||15-Nov-2012|
|Date of Web Publication||26-Jun-2014|
MD, Department of Anaesthesiology and Intensive Care, Faculty of Medicine, Cairo University, 11516 Cairo
Source of Support: None, Conflict of Interest: None
This study was carried out to evaluate the effects of sildenafil in perioperative management of parturients with pulmonary hypertension undergoing cesarean section in Kasr El Aini hospitals.
Patients and methods
Twenty-four parturients subjected to elective cesarean section were anesthetized with epidural anesthesia. Incremental doses (5 ml) of lidocaine (1%) and bupivacaine (0.25%) mixture (up to 20 ml) were administered to attain sensory block at the T4 level. Patients were randomized to receive either oral sildenafil 50 mg 1 h before anesthesia and then 25 mg three times daily postpartum for 1 month (sildenafil group) (n=12 patients) or placebo tablets (control group) (n=12 patients). An epicardial transthoracic echocardiography was performed postoperatively daily for 3 days and then after 1 month to obtain information on pulmonary blood pressure and ejection fraction (EF), hemodynamic parameters, and arterial blood gases analysis, and maternal and neonatal outcomes were compared between the groups.
There were no significant differences in mean arterial pressure and heart rate between the two groups or from the baseline. The sildenafil group showed a significant improvement in maternal oxygenation and the pulmonary artery pressure (PAP) decreased from 47.33±6.80 to 34.50±4.92 mmHg after 1 month of treatment. In the sildenafil group, EF increased from 56.00±1.95 to 62.83±3.80% after 1 month. However, in the control group, there were no statistically significant changes in maternal oxygenation, PAP, or EF. There were no significant differences between the two groups in neonatal outcomes using the APGAR score at 1 and 5 min.
The use of oral sildenafil has promising results in parturient with pulmonary hypertension as it is effective in improving maternal oxygenation, decreasing PAP, and increasing EF.
Keywords: epidural anesthesia, pregnancy, pulmonary hypertension, sildenafil
|How to cite this article:|
Abdalla A, Omran A, El-Mekawy N, Safan T, Magdy R. The role of sildenafil in perioperative management of parturients with pulmonary hypertension undergoing cesarean section. Egypt J Cardiothorac Anesth 2013;7:36-40
|How to cite this URL:|
Abdalla A, Omran A, El-Mekawy N, Safan T, Magdy R. The role of sildenafil in perioperative management of parturients with pulmonary hypertension undergoing cesarean section. Egypt J Cardiothorac Anesth [serial online] 2013 [cited 2020 Feb 26];7:36-40. Available from: http://www.ejca.eg.net/text.asp?2013/7/1/36/135461
| Introduction|| |
Pulmonary circulation is normally a low-pressure [mean pulmonary artery pressure (PAP) 15 mmHg] and low-resistance circulation. Pulmonary hypertension (PH) is defined as a mean PAP of at least 25 mmHg at rest or 30 mmHg during exercise 1. No underlying cause can be found for some PH, and secondary forms of PH are often related to collagen vascular disease, congenital systemic to pulmonary shunts, HIV infection, porto-PH, and drugs 2.
In patients with PH, altered vascular endothelial and smooth muscle function lead to vasoconstriction, localized thrombosis, and vascular growth and remodeling 3. These processes increase pulmonary vascular resistance and lead to right ventricular failure, inadequate oxygenation, and death 4. Hypoxemia can occur in conjunction with reduced cardiac output and pulmonary blood flow. It can also result from right-to-left intracardiac shunting. PH increases morbidity and mortality markedly among patients undergoing surgery 5.
During pregnancy, physiological cardiovascular and pulmonary changes worsen PH and right ventricular dysfunction. Additional hemodynamic changes occur with labor, especially during uterine contractions. After placental extraction, cardiac output and systemic vascular resistance increase markedly; return to the previous state can take up to 6 months 6. Therefore, physiological changes during pregnancy and also during delivery and the postpartum period are critical for patients with PH 7. It is important to provide a new series of consecutive parturients with severe PH. This should help in counseling patients with PH before they become pregnant and also provide new insights into cardiopulmonary, obstetric, and anesthetic management during pregnancy, delivery, and the postpartum period.
Phosphodiesterase inhibition has been shown to treat PH by reducing cyclic guanosine monophosphate breakdown, making pulmonary vascular smooth muscle more sensitive to endogenous and administrated nitric oxide; this reduces the ventilation perfusion mismatch and hypoxia. Sildenafil has the greatest selectivity for the pulmonary circulation and arterial oxygenation 8. Its proven effectiveness and safety in other forms of PH, coupled with ease of oral administration and its apparent lack of teratogenicity, mean that it is the highly promising therapy for PH in pregnant patients 9.
The aim of the study was to assess the effect of sildenafil in the perioperative management of PH parturient undergoing elective cesarean section on maternal hemodynamic, arterial oxygenation, PAP, ejection fraction (EF), and maternal and neonatal outcomes (APGAR score).
| Patients and methods|| |
This study was carried out prospectively in Kasr El Aini obstetric and gynecological hospital on 24 parturients with PH undergoing elective cesarean section after obtaining patients’ consent and approval from the local ethical and scientific committee.
The inclusion criteria were as follows: parturients pregnant with a single baby, gestational age more than 37 weeks, with systolic PH (>40 mmHg), and scheduled for elective cesarean section.
The exclusion criteria were as follows: patients with hepatic or renal impairment, systolic pulmonary blood pressure (BP) higher than 70 mmHg, right ventricular hypertrophy, dilatation or failure, Eisenmenger’s syndrome, cardiomyopathy, ischemic heart disease, cyanosis, left heart obstruction or poor function (EF<50%), severe valvular (native and prosthetic) heart disease, hypertension (BP>140/95 mmHg) or hypotension (<100/60 mmHg), endocrinal or metabolic disorders, and with the concomitant use of drugs that interact with sildenafil, that is nitrate or α-blockers were excluded.
Clinical assessment and laboratory assessments including complete blood picture, prothrombin time, prothrombin concenteration, international normalized ratio, blood sugar, liver, and kidney functions were performed for all patients. Also, ECG, echocardiogram, chest radiograph, and assessment of arterial blood gases (ABGs) were performed.
Patient receiving therapy for chronic PH were continued on this therapy.
Attempts to reduce PH before surgery were made for all patients, such as O2 administration, bronchodilators, and steroids.
Each patient (in both groups) was prepared by the insertion of an intravenous cannule, and received ranitidine 50 mg and metoclopramide 10 mg intramuscularly and 0.3 mol/l sodium citrate 30 ml orally 1 h before anesthesia.
Patients were allocated randomly to two equal groups (12 patients each) using the closed envelopes method.
Control group: This group received placebo sugary tablets.
Sildenafil group: This group received sildenafil 50 mg orally 1 h before anesthesia and then 25 mg three times daily postpartum for 1 month.
In the anesthesia room, O2 was supplied 4 l/min through a face mask and ECG, pulse oximetery was attached; then, under local anesthesia, the radial artery (in the nondominant hand after confirming the site of insertion by a negative Allen’s test) and the right internal jugular vein were cannulated. Measurements of baseline central venous pressure (CVP) and ABGs were performed. Prehydration was carried out by 500–1000 ml Ringer’s solution in 1 h guided by CVP (8 mmHg).
Epidural anesthesia was administered through the indwelling catheter inserted at L3–4 interspaces. Incremental doses (5 ml) of a lidocaine (1%) and bupivacaine (0.25%) mixture (up to 20 ml) after a negative test dose (3 ml lidocaine 2% containing 5 µg/ml epinephrine) were administered to achieve sensory block up to the T4 level. All patients were kept supine with left lateral tilt.
Ringer’s solution infusion was continued at 4 ml/kg/h. Blood loss was calculated and compensated by crystalloids, synthetic colloids (Haes-Steril 6%, Fresenius Kabi, Deutschland GmbH, Bad Homburg, v.d.H., Germany), or blood as needed to maintain the CVP at 5–8 mmHg. The patient was administered syntocinon (10 U) as an infusion over 20 min after the delivery of the baby.
All patients were monitored by ECG, pulse Oximetry, invasive BP, CVP, measurement of blood gases (every1 h), and urine output from the indwelling urinary catheter.
Mean arterial pressure (MAP) was maintained within 20% from the preanesthetic level. Hypotension was treated by increasing the rate of infusion plus 5 mg increments of ephedrine. Heart rate (HR) was maintained within 20% of the preanesthetic level or above 60 beats/min. Bradycardia was treated with atropine intravenously 0.5 mg increments. Low BP with elevated CVP was treated by an infusion of dobutamine (2–10 µg/kg/min).
Patients were transferred to the coronary care unit for 3 days and postoperative analgesia was provided by a continuous infusion of bupivacaine (0.06%) 8–12 ml (with fentanyl 2 ug/ml)/h for 24 h postoperatively. Group II was continued on sildenafil (25 mg three times daily) for 1 month.
An epicardial transthoracic echocardiography was performed postoperatively daily for 3 days and then after 1 month to obtain information on pulmonary BP and EF%.
Hemodynamic parameters (including the mean ABP and HR) were monitored.
ABGs analysis was carried out preoperatively, intraoperatively, at the end of the surgery, and daily postoperatively for 3 days
Pulmonary BP and EF were monitored by echocardiography.
Neonatal outcomes including APGAR scores (at l and 5 min), birth weight, and neonatal mortality rate were also determined and compared between the two groups.
All results were expressed as means (±SD), median (range), or number (%) of patients as appropriate. Student’s t-test was used to compare between the two groups. Repeated-measures analysis of variance was used with post-hoc Dunnett’s test for multiple comparisons against the baseline value to further determine any statistically significant findings. Indices were analyzed using Fisher’s exact test as appropriate. Statistical analysis was carried out using the computer program SPSS 16.0 for Microsoft Windows (SPSS Inc., Chicago Illinois, USA). P value less than 0.05 was considered statistically significant.
| Results|| |
There were no significant differences between the two groups in demographic data such as age, weight, and height [Table 1].
There were no statistically significant differences in MAP and HR between the two groups before the administration of sildenafil and after the administration of sildenafil. [Table 2] and [Table 3].
For PaO2 measured in ABGs, the sildenafil group showed a significant improvement in maternal oxygenation in comparison with the control group [Table 4].
|Table 4: PaO2 in arterial blood gas measures recorded throughout the observation period (mean±SD)|
Click here to view
After the administration of sildenafil, PAP decreased from 47.33±6.80 to 34.50 ±4.92 mmHg after 1 month. In the control group, no significant changes in PAP were observed [Table 5].
|Table 5: Pulmonary artery pressure measures recorded throughout the observation period (mean±SD)|
Click here to view
There were significant differences in EF between the two groups. After the administration of sildenafil, EF increased from 56.00±1.95 to 62.83±3.80% after 1 month. In the control group, no statistically significant changes in EF were observed [Table 6].
|Table 6: Ejection fraction measures recorded throughout the observation period (mean±SD)|
Click here to view
No significant differences were found between the two study groups in the neonatal outcomes using APGAR score at 1 min (survival rate) and 5 min [Table 7].
All procedures were performed without intraoperative and postoperative complications in the two groups.
| Discussion|| |
PH is an increase in the mean pulmonary arterial pressure more than 25 mmHg at rest. During pregnancy, physiologic cardiovascular and pulmonary changes worsen PH and right ventricular dysfunction. Additional hemodynamic changes occur with labor, especially during uterine contractions. Marked increases in cardiac output and systemic vascular resistances occur after placental separation; then, return to the previous state can take up to 6 months. Currently, the improved medical care of patients with PH has increased their life expectancy and has resulted in more women of childbearing age considering pregnancy 10.
This study was carried out to determine the effect of a perioperative oral dose of 50 mg of sildenafil 1 h before anesthesia and then 25 mg three times daily postpartum for 1 month. In 12 parturients with PH undergoing cesarean section, PAP, hemodynamic effect, maternal oxygenation, and maternal and neonatal outcomes were assessed and compared with a control group of 12 parturients who did not receive sildenafil.
The sildenafil group showed a modest but statistically significant improvement in maternal oxygenation and maternal outcome and a decrease in PAP compared with the control group, in which there was no statistical difference in the hemodynamic effect and neonatal outcome.
In this study, there was no statistically significant difference between the two groups in the MAP and HR. There was an improvement in maternal arterial oxygen tension (PaO2 in ABG) in the sildenafil group; it increased from 68.66±4.29 mmHg (baseline) to 88.33±3.49 mmHg (30 min postoperatively). There was a statistically significant reduction in pulmonary arterial pressures from 47.33±6.80 mmHg (baseline) to34.50±4.92 mmHg (1 month postoperative) in the sildenafil group. The ejection friction increased from 56.00±1.95% (baseline) to 62.83±3.80% (1 month postoperative) in the sildenafil group. The neonatal outcome showed no statistically significant difference between the two groups.
Similar to this study, Michelakis et al. 11 evaluated the effects of oral sildenafil on PH in 13 patients. Their findings suggested that a single oral dose of sildenafil is as effective and selective on pulmonary vasodilatation as nitric oxide. Sildenafil may be superior to nitric oxide, where sildenafil tended to decrease pulmonary capillary wedge pressure. Systemic arterial pressure and the HR were not affected by treatment. The arterial oxygen saturation was improved by sildenafil; the preferential effect of sildenafil on the pulmonary circulation probably reflects the high expression of this isoform in the lung. However, phosphodiesterase-5 is also found in the myocardium, where it may be downregulated in heart failure. The finding that sildenafil decreases the wedge pressure and increases the cardiac index suggests that it does not exert negative inotropic effects, at least in this study. However, the fact that the HR did not change after sildenafil in our study suggests that sympathetic activation is not the basis for the observed increase in the cardiac index. Zhao et al. 12 suggested that sildenafil increases the cardiac index because of its selective pulmonary vasodilator effects and the resulting reduction in right ventricular afterload 12.
Other studies also used different ways to assess the effect of sildenafil on PAP and hemodynamics. A study by Wilkens et al. 13 showed that the maximal hemodynamic effects of sildenafil on the human pulmonary circulation were achieved with a 25 mg dose. They also showed that the maximal hemodynamic effects were achieved within 30 min after intake. These findings were in agreement with those of our study in that sildenafil might be a good candidate for long-term treatment of PH.
Lynch and Laffey 14 suggested sildenafil in the treatment of PH during pregnancy; its proven effectiveness and safety in other forms of PH, coupled with ease of oral administration and its apparent lack of teratogenicity, mean that it is a highly promising therapy for severe PH in pregnant patients. Sildenafil has other potentially beneficial effects in this context. It causes uterine artery vasodilatation and has been shown to improve uterine muscle wall thickness in-vitro fertilization patients with previous poor endometrial response 14. In addition, Sher and Fisch 15 used sildenafil and nitric oxide successfully to treat preterm and term neonatal and childhood PH. In this study, there was no significant change in neonatal outcome, whereas Weiss and Hess 16 showed that infant survival depended more strongly on maternal tolerance toward late pregnancy not on the technique of anesthetics used or administration of sildenafil.
In conclusion, we found in our study that sildenafil has a unique effect in reducing PAP, improving maternal oxygenation and maternal outcome without clinically significant hemodynamic changes on neonatal outcome.
| References|| |
|1.||Safdar Z.Pulmonary arterial hypertension in pregnant women.Ther Adv Respir Dis2013;7:51–63. |
|2.||Tygart SG, McRoyan DK, Spinnato JA, McRoyan CJ, Kitay DZ.Longitudinal study of platelet indices during normal pregnancy.Am J Obstet Gynecol1986;154:883–887. |
|3.||Chan SY, Loscalzo J.Pathogenic mechanisms of pulmonary arterial hypertension.J Mol Cell Cardiol2008;44:14–30. |
|4.||Carmosino MJ, Friesen RH, Doran A, Ivy DD.Perioperative complications in children with pulmonary hypertension undergoing noncardiac surgery or cardiac catheterization.Anesth Analg2007;104:521–527. |
|5.||Voelkel NF, Cool C, Lee SD, Wright L, Geraci MW, Tuder RM.Primary pulmonary hypertension between inflammation and cancer.Chest1998;114Suppl225S–230SS. |
|6.||Ramakrishna G, Sprung J, Ravi BS, Chandrasekaran K, McGoon MD.Impact of pulmonary hypertension on the outcomes of noncardiac surgery: predictors of perioperative morbidity and mortality.J Am Coll Cardiol2005;45:1691–1699. |
|7.||Duarte AG, Thomas S, Safdar Z, Torres F, Pacheco LD, Feldman J, et al..Management of pulmonary arterial hypertension during pregnancy: a retrospective, multicenter experience.Chest2013;143:1330–1336. |
|8.||Haj RM, Cinco JE, Mazer CD.Treatment of pulmonary hypertension with selective pulmonary vasodilators.Curr Opin Anaesthesiol2006;19:88–95. |
|9.||Benza RL, Park MH, Keogh A, Girgis RE.Management of pulmonary arterial hypertension with a focus on combination therapies.J Heart Lung Transplant2007;26:437–446. |
|10.||Hsu CH, Gomberg Maitland M, Glassner C, Chen JH.The management of pregnancy and pregnancy-related medical conditions in pulmonary arterial hypertension patients.Int J Clin Pract2011;65Suppl 1726–14. |
|11.||Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, Archer S.Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide.Circulation2002;105:2398–2403. |
|12.||Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov A, et al..Sildenafil inhibits hypoxia-induced pulmonary hypertension.Circulation2001;104:424–428. |
|13.||Wilkens H, Guth A, König J, Forestier N, Cremers B, Hennen B, et al..Effect of inhaled iloprost plus oral sildenafil in patients with primary pulmonary hypertension.Circulation2001;104:1218–1222. |
|14.||Lynch TD, Laffey JG.Sildenafil for pulmonary hypertension in pregnancy?Anesthesiology2006;104:382. |
|15.||Sher G, Fisch JD.Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development.Fertil Steril2002;78:1073–1076. |
|16.||Weiss BM, Hess OM.Pulmonary vascular disease and pregnancy: current controversies, management strategies and perspectives.Eur Heart J2000;21:104–115. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]