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Correspondence

Combination of sildenafil and bosentan for nitric oxide withdrawal

Behrends, M.; Beiderlinden, M.; Peters, J.

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European Journal of Anaesthesiology: February 2005 - Volume 22 - Issue 2 - p 155-157
doi: 10.1017/S0265021505220288

EDITOR:

The acute respiratory distress syndrome (ARDS) is frequently associated with a profound increase in pulmonary vascular resistance resulting in pulmonary hypertension and, sometimes, right ventricular failure. Inhaled vasodilators, such as nitric oxide (NO) and prostacyclin (PGI2) have been shown to decrease pulmonary artery pressure (PAP) and to increase arterial oxygen tension without systemic side-effects. However, withdrawal from inhaled vasodilators can result in rebound pulmonary hypertension and subsequent right heart failure, most likely due to inhibition of endothelial NO synthase activity and increase of endothelin-1 levels by exogenous NO. Therefore, alternatives for inhaled vasodilators may be required to facilitate their discontinuation.

The phosphodiesterase V inhibitor sildenafil and the endothelin receptor antagonist bosentan are potent pulmonary vasodilators used increasingly in the treatment of primary pulmonary hypertension [1,2]. Furthermore, sildenafil has been used successfully in patients to ameliorate the rebound pulmonary hypertension due to inhaled NO withdrawal [3,4]. However, their effects on pulmonary hypertension in ARDS have not been investigated so far.

We report the case of a patient with severe ARDS who underwent extracorporeal membrane oxygenation (ECMO) therapy for 30 days. Successful weaning from ECMO required aggressive therapy to ameliorate pulmonary hypertension and right ventricular failure. The patient subsequently failed several NO withdrawal attempts due to severe pulmonary hypertension. Eventually, the patient was weaned successfully from inhaled NO using vasodilatatory treatment with sildenafil and bosentan.

A 37-yr-old female with ARDS due to community-acquired pneumonia was admitted from a peripheral hospital following 2 weeks of mechanical ventilation. Upon admission the patient was ventilated with biphasic positive airway pressure (BIPAP), a peak airway pressure of 40 mbar, and a positive end-expiratory pressure of 20 mbar. Breathing 100% oxygen, the arterial oxygen tension was 43 mmHg, arterial carbon dioxide tension (PaCO2) 96 mmHg, and pH 7.12. The chest computed tomography (CT) scan revealed bilateral interstitial and alveolar infiltration. The lung injury score was 4 and venous admixture 50%. Mean PAP was 31 mmHg and cardiac index 4.3 L min−1 m−2 while on high-dose norepinephrine (0.83 μg kg−1 min−1) and epinephrine (0.55 μg kg−1 min−1) to maintain a mean arterial pressure of 64 mmHg. Echocardiography excluded cardiac causes of hypoxaemia.

ECMO was immediately established. Frequent supine-prone postural changes were applied and antibiotic therapy was changed as indicated. Recurrent pneumothoraces required repeated insertions of chest drains.

With improved respiratory and cardiocirculatory function, weaning from ECMO was attempted after 5 days but failed with PaCO2 increasing from 45 to 77 mmHg, evoking pulmonary hypertension. Over the following weeks four more ECMO weaning trials were performed, each failing due to an increase in PaCO2 and PAP resulting in severe circulatory failure. To potentially minimize these changes, therapy using a combination of enalapril (0.083 μg kg−1 min−1) and enoximone (1.4 μg kg−1 min−1) was started and inhaled NO (25 ppm) was supplemented with inhaled PGI2 (50 μg six times per day). With this treatment, PAP decreased from 38 to 32 mmHg, pulmonary vascular resistance from 502 to 192 dyns cm−5, and cardiac index increased from 2.5 to 4.4L min−1 m−2. During the next ECMO weaning trial on day 30 of ECMO therapy, PAP and cardiac index remained unaltered and the patient was successfully weaned from ECMO, despite an increase of PaCO2 to 106 mmHg.

The following days the patient demonstrated dependence on inhaled NO to control PAP. Attempts to decrease NO concentrations below 20 ppm always resulted in a severe increase in pulmonary vascular resistance and a critical decrease in cardiac index.

Sildenafil (25 mg orally four times per day) was started to facilitate weaning from NO and this allowed us to decrease the NO concentration to 10 ppm. When two additional NO weaning trials failed due to right heart failure, bosentan (62.5 mg orally twice a day) was also given. The patient was then weaned successfully from inhaled NO, 13 days after weaning from ECMO. The subsequent course was uneventful, with good recovery of respiratory function. Fifty days following admission she was transferred to a peripheral hospital, still on oral sildenafil. Four months later the patient was alive and well.

Pulmonary arterial hypertension is a characteristic feature of severe ARDS and correlates with the severity of lung injury. Furthermore, persisting pulmonary hypertension following correction of severe hypoxaemia and progressive pulmonary hypertension are associated with increased mortality.

In our patient pulmonary hypertension was complicated by severely impaired right ventricular performance. In ARDS, acute cor pulmonale is associated with the degree of hypercapnia [5]. In conscious dogs with increased right ventricular afterload, hypercapnic acidosis has been shown to impair right ventricular performance, whereas such an effect is not seen with normal loading conditions [6]. Therefore, ‘permissive’ hypercapnia is not well tolerated by all ARDS patients. Accordingly, in addition to NO and PGI2 inhalation, aggressive vasodilator and positive inotropic therapy was necessary to allow weaning from ECMO with associated CO2 retention. Hypercapnia of up to 106 mmHg was not associated with increased PAP and decreased cardiac index when quadruple therapy with NO, PGI2, enalapril and enoximone was applied.

However, further weaning was complicated by persistent NO dependency. Withdrawal of inhaled NO can result in rebound effects, characterized by a marked increase in right ventricular afterload and possible cardiopulmonary deterioration. The underlying increase in pulmonary vascular resistance is attributable to upregulation of endothelin-1 production and downregulation of endothelial NO synthase by inhaled NO.

The phosphodiesterase V inhibitor sildenafil is known to be a preferential pulmonary vasodilator in secondary pulmonary hypertension due to lung fibrosis, and has vasodilatatory potency similar to that of NO [1]. Furthermore, sildenafil has been shown to ameliorate the effects of inhaled NO withdrawal in small infants following correction of congenital heart disease [3] and in a patient following placement of a biventricular-assist device [4]. So far, however, the effects of sildenafil in ARDS have not been investigated. When sildenafil was started in our patient to facilitate withdrawal of inhaled vasodilators the effect was a decrease of NO requirements.

Complete NO withdrawal was possible only by addition of the endothelin receptor antagonist bosentan. Bosentan improves exercise capacity of patients with primary pulmonary hypertension. While bosentan apparently has not been evaluated in patients with secondary pulmonary hypertension, it completely abolished pulmonary hypertension during toxic shock in pigs [7].

Due to their pulmonary vasodilatatory properties sildenafil and bosentan may not only facilitate NO withdrawal, but may also serve as an alternative in patients who do not respond to inhaled NO and PGI2. However, a potential limitation in ARDS patients is the inhibition of hypoxic pulmonary vasoconstriction.

In conclusion, a combination of inhaled and systemic vasodilators may be required to treat pulmonary hypertension and right heart failure associated with withdrawal from ECMO. Furthermore, combined sildenafil and bosentan may ease withdrawal of inhaled vasodilators in ARDS. Further work is required to assess whether preferential pulmonary vasodilators such as sildenafil and bosentan are a feasible and cost effective alternative to inhaled vasodilators.

M. Behrends

M. Beiderlinden

J. Peters

Klinik für Anästhesiologie und Intensivmedizin, Universitätsklinikum Essen, Essen, Germany

References

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© 2005 European Society of Anaesthesiology