By Stanopoulos, I Manolakoglou, N; Pitsiou, G; Trigonis, I; Et al
SUMMARY We report three cases of mechanically ventilated chronic obstructive pulmonary disease patients who were intubated due to an exacerbation of their disease and who presented with repeated spontaneous breathing trial failures. Patients were given 50 mg of sildenafil through the nasogastric tube, under close monitoring of haemodynamic and ventilatory parameters. After sildenafil, pulmonary artery pressure, pulmonary artery occlusion pressure, the respiratory frequency to tidal volume ratio and the P^sub a^CO^sub 2^-P^sub Et^CO2 (arterial minus end-tidal carbon dioxide pressure) decreased. Cardiac output increased in two of the patients, while all of them were successfully extubated. This is the first report of successful extubation after sildenafil use.
Key Words: sildenafil, COPD, mechanical ventilation
Discontinuation of ventilatory support can be difficult in about one third of mechanically ventilated patients’. The highest rate of weaning failure has been reported in chronic obstructive pulmonary disease (COPD) patients’2 and may result in prolonged mechanical ventilation, reintubation, tracheostomy and the associated complications that increase morbidity and mortality. A treatment preventing the pathophysiological mechanisms which lead to weaning failure could prove of significant clinical benefit in this group of patients.
The pathophysiology of weaning failure in COPD patients has been associated with worsening of lung mechanics that lead to inefficient ventilation’. Increased ventilatory requirements during weaning in COPD patients may result in dynamic hyperinflation and mechanical disadvantage for the respiratory muscles. Hyperinflation increases pulmonary artery pressure, impeding right ventricular ejection and increasing deadspace4. Large swings in intrathoracic pressure during unassisted breathing increase venous return and both right and left ventricular afterload5″ and may lead to inadequate oxygen supply to the respiratory muscles7. Currently, there is limited data on pharmacotherapy which may facilitate weaning in mechanically ventilated COPD patients; the only available data is on diuretics, which have been shown to be beneficial in weaning COPD patients with left heart disease5.
The current report was based on the observation that pulmonary artery pressure (PAP) is elevated in most COPD patients, during spontaneous breathing trials. Sildenafil has been recently approved in patients with pulmonary hypertension, due to its selective vasodilatory effects on the pulmonary circulation. Our hypothesis was that sildenafil could reduce right ventricular afterload, preventing an interdependence effect on left ventricular performance; by increasing lung perfusion, sildenafil might also improve ventilatory efficiency and attenuate hyperinflation. The magnitude of negative inspiratory pressure swings might thus decrease, preventing an increase in left ventricular afterload. Based on this hypothesis, we evaluated the effects of sildenafil in three male COPD patients who repeatedly failed weaning trials.
CASE HISTORIES
Three male COPD patients were mechanically ventilated in the Respiratory Failure Unit of our hospital, after they presented with hypercapnic respiratory failure during an exacerbation of their disease. There was no indication of pneumonia or pulmonary oedema on their chest X-ray and none of them had a known history of coronary artery disease. The first patient was 45 years old and had a? – antitrypsin deficiency. The other two were 67 and 73 years old, correspondingly. All three patients, who have given their free consent for the preparation of this manuscript, were in an advanced stage of COPD, had emphysema, had been hospitalised at least once during last year and were on long-term home oxygen therapy.
While on mechanical ventilation, patients were treated with bronchodilators and antibiotics. In order to avoid fluid overload and oedema, they received intravenous frusemide. After a period of nine days for the first patient, five days for the second and three days for the third, sedation was stopped and ventilatory support gradually reduced, provided that the patients were haemodynamically stable without vasopressors, afebrile and without severe bronchospasm. When they were fully awake and cooperative, they underwent a spontaneous breathing trial through the endotracheal tube (T-piece) with oxygen supplementation, to ensure adequate oxygenation. All three patients had at least two failed T-piece trials in two consecutive days, characterised by dyspnoea, tachypnoea, accessory respiratory muscle recruitment, diaphoresis and worsening respiratory acidosis.
All patients were catheterised with a pulmonary artery catheter (Swan-Ganz) during support ventilation and baseline haemodynamic parameters were measured during the first 15 minutes of a new T- piece trial. The respiratory frequency to tidal volume index (f/VT) was calculated during spontaneous ventilation using a Wright respirometer and end-tidal CO2 was measured with a capnometer (Capnocheck, BCI International). After measurements were completed, patients were reconnected to the ventilator in a comfortable pressure support mode and a tablet of 50 mg sildenafil citrate (Viagra, Pfizer CO) was given through the nasogastric tube. Ninety minutes after sildenafil administration, patients underwent a new T- piece trial and haemodynamic and ventilatory measurements were repeated during the first 15 minutes.
Values of basic haemodynamic and respiratory parameters during T- piece trials before and 90 minutes after sildenafil administration for each patient are shown in Table 1. After receiving sildenafil, they completed at least one hour of spontaneous breathing without clinical deterioration and were extubated; they continued treatment with sildenafil 50 mg t.d.s. and were eventually discharged from the hospital.
DISCUSSION
In this case report we present three COPD patients with repeated spontaneous breathing trial failures, who were successfully extubated after receiving sildenafil. The results demonstrated a beneficial effect of sildenafil on the pulmonary circulation, indicating a possible therapeutic role of the phosphodiesterase type 5 inhibitors in such cases.
The common mechanism underlying weaning failure is inequality between respiratory muscles’ energy demand and supply. The increased work of spontaneous breathing in COPD patients is associated with a high rate of weaning failure. In a group of COPD patients who failed a weaning trial, development of rapid shallow breathing with high dynamic lung elastance and intrinsic positive end-expiratory pressure (PEEPi) was observed, suggestive of dynamic hyperinflation as the dominant pathophysiological mechanism. Such an increase in lung elastance during weaning may also be due to microatelectasis from tidal volume decrease and pulmonary oedema from left ventricular (LV) dysfunction3.
Cardiopulmonary interactions may significantly influence weaning outcome. Large swings in intrathoracic and abdominal pressure during spontaneous breathing increase venous return and may contribute to weaning failure in COPD patients with left heart disease5. Negative inspiratory swings can also increase afterload, as was suggested by a decrease in LV ejection fraction during weaning in COPD patients in whom myocardial ischaemia was excluded”. Alternatively, myocardial ischaemia may complicate weaning in some patients with coronary artery disease”. In a study including COPD patients, elevated right and left ventricular afterload was associated with inability to increase O, transport during unsuccessful weaning and this was reflected in a progressive decrease in venous oxygen saturation SvO^sub 2^(7).
In our report, during the first T-piece trial in all three patients, PAP and pulmonary artery occlusion pressure (PAOP) were both elevated (Table 1). This increase in PAP was probably related to dynamic hyperinflation (alveolar vessel compression), although worsening hypoxaemia (microatelectasis) and increase in venous return may have also contributed. As transmural PAOP was not measured, the increase in PAOP could either indicate acute left ventricular dysfunction or represent an effect of hyperinflation and PEEPi. Myocardial ischaemia seems not to be the case, as all patients had a medical history free of coronary artery disease and there were no electrocardiographic changes during or after spontaneous breathing. In concert, systemic haemodynamics did not worsen during the observation period.
There is limited data in the literature on the medical management of weaning failure in COPD patients”. By decreasing preload, after 10 days of frusemide treatment, Lemairc5 successfully weaned nine of 15 failed COPD patients with left heart disease. The beneficial effect of diuretics on left ventricular function was documented by a significant reduction in transmural PAOP5. Although our patients were receiving frusemide continuously to prevent fluid overload, a temporary increase in venous return elevating PAP and PAOP cannot be excluded. However, acute diuretic administration in hyperinflated COPD patients with a negative fluid balance might have increased deadspace and P^sub a^CO^sub 2^.
Sildenafil is a potent phosphodiesterase type 5 inhibitor, with a proven vasodilatory effect on pulmonary circulation, improving exercise capacity and haemodynamics in patients with pulmonary arterial hypertension”. It has minimal effects on systemic circulation during exercise”1 and improves gas exchange in patients with lung fibrosis, acting selectively in well ventilated areas of the lung”. In the ICU setting phosphodiesterase type 5 inhibitors have proven to be effective; sildenafil was substituted for inhaled nitric oxide successfully in a mechanically ventilated patient with right ventricular dysfunction and pulmonary hypertension secondary to obesity, COPD and sleep-disordered breathing12, while vardenafil use allowed nitric oxide withdrawal in a mechanically ventilated patient with pulmonary hypertension secondary to ARDS”. In a recent study of six COPD patients with pulmonary hypertension, PAP and pulmonary vascular resistance were significantly reduced one hour after administration of 50 mg of intravenous sildenafil14. In this report, systemic arterial pressure changes were clinically insignificant in all patients, PAP and PAOP decreased, SvO, remained unchanged, while cardiac output increased in two patients; the cardiac output decrease observed in the other patient was possibly related to a decrease in catecholamine levels. Since transmural PAOP was not measured, the decrease in PAOP could be either the result of a lower PEEPi or an improvement in left ventricular function. The latter could be caused by preventing RV dilation and interventricular septal shift and/or by a modest systemic vasodilation caused by sildenafil.
The effect of sildenafil on ventilatory parameters was evaluated by simple bedside measurements and this is a limitation in our report. However, sildenafil decreased the f/VT ratio of spontaneous breathing, which is a reliable predictor of weaning outcome”, probably by improving lung mechanics. Sildenafil also decreased P^sub a^CO^sub 2^-P^sub ET^CO^sub 2^, indicating a reduction in VD/ VT16. Although a possible bronchodilatory action of sildenafil has been reported17, it should be clinically insignificant in patients already receiving high doses of bronchodilators. By increasing lung perfusion preferably to high V/Q areas11, sildenafil probably improved ventilatory efficiency and attenuated hyperinflation; sildenafil has been shown to improve ventilatory efficiency in chronic heart failure patients during exercise, as was suggested by a significant reduction of VE/VC02 slope18. However, the mechanism of improvement may differ in this group of patients.
In conclusion, this is the first case series to indicate that sildenafil may facilitate weaning of mechanically ventilated COPD patients, by reducing right ventricular afterload and improving ventilatory efficiency, while a reduction in left ventricular afterload may also contribute. A well designed study of the ventilatory and haemodynamic effects of sildenafil in COPD patients who fail weaning is justified, in order to provide further and solid evidence of the proposed mechanism of action.
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I. STANOPOULOS*, N. MANOLAKOGLOU[dagger], G. PITSIOU*, I. TRIGONIS[dagger], E. A. TSIATA[dagger], A. K. BOUTOU[double dagger], R K. KONTOU[dagger], R ARGYROPOULOU[section]
Respiratory Failure Unit, Aristotle University, G. Papanikolaou Hospital, Thessaloniki, Greece
* M.D., Ph.D., Pneumonologist and Critical Care Medicine Specialist.
[dagger] M.D., Pncumonology and Critical Care Medicine Trainee.
[double dagger] M.D., M.Sc. Pncumonology and Critical Care Medicine Trainee.
[section] M.D., Ph.D., Professor. Pneumonologist and Critical Care Medicine Specialist.
Address for reprints: Dr A. K. Boutou, 3ft. Ag Vasileiou str.. Kalamaria. 55133, Thessaloniki. Greece.
Accepted for publication on April 2ft. 2007.
Copyright Australian Society of Anaesthetists Aug 2007
(c) 2007 Anaesthesia and Intensive Care. Provided by ProQuest Information and Learning. All rights Reserved.
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