Oral sildenafil has been shown to be a potent pulmonary vasodilator in patients with pulmonary hypertension.1–3 Beneficial haemodynamic effects were reported in patients with primary pulmonary hypertension, using the drug alone or in combination with other agents.4, 5 Little is known about the efficacy or kinetics of sildenafil used intravenously.
Case report
We report a 7-month-old boy with known gastro-oesophageal reflux, who presented in acute respiratory failure after an episode of aspiration. The child was born prematurely at 27 weeks gestation, with a birth weight of 920 grams, this being below the 25th centile. He received surfactant, and required mechanical ventilation for the first 48 hours of life. He was extubated to continuous positive airway pressure ventilation at 2 days of age, but remained dependent on oxygen. The chest radiograph showed evidence of severe chronic lung disease. These abnormal findings persisted. Echo-cardiography at 6.5 months of age revealed pulmonary hypertension, with a right suprasystemic ventricular pressure. The heart was morphologically normal, with dilation of the right ventricle and moderately impaired right ventricular function. We commenced treatment with oral sildenafil. The requirement for oxygen decreased, and the child could subsequently be weaned from continuous positive airway pressure ventilation with saturations of oxygen above 90%.
At 7 months of age, he suddenly deteriorated, and was admitted to our intensive care unit. We commenced treatment with maximal respiratory support using high frequency oscillation, an inspired oxygen fraction of 100%, and inhaled nitric oxide at 20 parts per million. The course was aggravated by recurrent pulmonary hypertensive crises. Because the child had large gastric aspirates, we thought that the oral sildenafil was not being absorbed effectively, contributing to the poor clinical condition. Hence, sildenafil was administered intravenously as a continuous infusion at 0.3 milligrams per kilogram per minute (Fig. 1). Informed consent was obtained from the parents, and the administration of intravenous sildenafil was approved by the local ethics committee.
Figure 1. Haemodynamic and respiratory parameters, inotropic support, and use of nitric oxide related to the initiation of intravenous sildenafil. CPAP: continuous positive pressure ventilation; FiO2: fraction of inspired oxygen; HFO: high frequency ventilation; NO: nitric oxide; SIMV: spontaneous intermittent mandatory ventilation; SIPPV: spontaneous intermittent positive pressure ventilation; SO2: oxygen saturation; SV: spontaneous ventilation.
After commencing the intravenous treatment, the clinical condition stabilized, and the condition of the patient improved. Nitric oxide and inotropic support were withdrawn gradually, and after 5 days, the child was back on low-pressure conventional ventilation with an inspired oxygen fraction of 50%. No further pulmonary hypertensive crisis occurred. We did not see any adverse effect on systemic arterial pressure or increased need for inotropic support during the infusion of sildenafil. After stabilization, the child underwent a Nissen's fundoplication. Five days after the operation, he was successfully extubated and oral treatment with sildenafil was re-established.
On follow-up 4 months after acute presentation the patient was clinically well, continuing with oral Sildenafil and home oxygen. The echocardiogram at this time showed good biventricular function, mild right ventricular hypertrophy, and trivial tricuspid regurgitation.
Discussion
We report the successful use of intravenous sildenafil during a period of gastrointestinal malabsorption in a patient with pulmonary hypertension who had previously been receiving regular treatment with oral sildenafil. Presumably malabsorption of the drug when administered orally contributed to the severity of the presentation.
Sildenafil is an inhibitor of phosphodiesterase-5, which inhibits the deactivation of cyclic Guanosine 5′-Monophosphate and cyclic Adenosine 5′-Monophosphate. These second messengers lead to pulmonary vasodilation via activation of potassium channels and inhibition of calcium channels, thus causing smooth muscular relaxation.6
Several small observational studies have shown that sildenafil is a potent vasodilator in patients with primary pulmonary hypertension.4, 5, 7 The drug is not licensed for treatment of pulmonary hypertension, although preliminary data suggest that it is effective when given orally, and is a feasible agent for the long-term treatment of patients with pulmonary hypertension.4, 5
Experimental studies have revealed that sildenafil given intravenously is at least as effective as inhaled nitric oxide in reducing pulmonary vascular resistance, and is associated with an increase in cardiac output.8 In humans, intravenous sildenafil has been reported to be more effective in reducing elevated pulmonary vascular resistance than inhaled nitric oxide.9 In addition, intravenous sildenafil has been shown further to augment the pulmonary vasodilatory effect of inhaled nitric oxide early after cardiac surgery.10 While systemic hypotension may be of concern, it has been shown that the decrease in systemic blood pressure seen when the drug is given intravenously is clinically insignificant.9 Occasional side effects, such as gastrointestinal symptoms, hypersensitivity reactions, and visual disturbances, have been reported.
Over the last few years, there have been significant improvements in the treatment of infants with pulmonary hypertension, including the use of inhaled and intravenous vasodilators like nitric oxide, prostanoids, and calcium antagonists. As our patient had previously responded to sildenafil given orally, the introduction of another vasodilator was not considered.
Malabsorption is common in sick children requiring intensive care. Also, temporary omission of enteral feeding is often necessary. Intravenous sildenafil may represent an option when it is not feasible to give the drug orally. It is, of course, not possible to determine the extent to which inhaled nitric oxide, oxygen therapy, and high frequency oscillatory ventilation contributed to the recovery, but the institution of intravenous sildenafil produced an immediate improvement.
We conclude, therefore, that sildenafil, when given intravenously, might be an effective alternative therapy in infants with pulmonary hypertension during episodes of malabsorption, and can prevent life-threatening pulmonary hypertensive crises. The pharmacokinetics, efficacy, and safety of the agent given intravenously, nonetheless, need to be clarified in randomized trials.
Disclosures
Christine Pierce is in receipt of a research grant from Pfizer Limited, Sandwich, Kent, United Kingdom.
