Use of Inhaled Nitric Oxide To Reverse Flow through a Patent Foramen Ovale during Pulmonary Embolism

Case Report

A 74-year-old woman was admitted to our intensive care unit with deep coma and acute respiratory failure requiring mechanical ventilation. A complete right bundle-branch block was seen on the electrocardiogram. Despite clear lung fields on the chest radiograph, the pulmonary angiographic results showed a massive embolism (the Miller index [8], 23/34). A continuous intravenous infusion of heparin was immediately started. A cerebral computed tomographic scan showed several cerebral infarctions in the vertebrobasilar system. A patent foramen ovale was suspected, and transesophageal echocardiography using an Aloka SSD-870 device Aloka, Tokyo, Japan with a 5-MHz monoplane probe showed an atrial septal aneurysm (Figure 1, top left). A right-to-left shunt through a patent foramen ovale was observed using contrast by injecting gelatin into the right atrium; this shunt appeared as echoes massively moving from the right atrium to the left atrium (Figure 1, top right). Simultaneous hemodynamic measurements obtained with a fast-response thermistor Swan-Ganz catheter (Baxter, Irvine, California) and with transesophageal echocardiography were done while the patient was mechanically ventilated with a fraction of inspired oxygen (FIO₂) of 0.6.

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Figure 1. Atrial septal aneurysm ( ) bulging into the left atrium ( ). . Contrast echoes (microbubbles) massively moving from the right atrium ( ) to the left atrium and then to the left ventricle ( ). . Inhaled nitric oxide completely abolished the passage of microbubbles from right to left. Transesophageal echocardiography in the four-chamber plane. Top left.arrowsLATop rightRALVBottom left

The presence of a patent foramen ovale was considered life-threatening in this patient. We therefore decided to administer inhaled nitric oxide in the hope of promoting closure of the patent foramen ovale, following advice from two outside consultants (senior cardiologist and pulmonologist) not involved in the treatment of the patient. This treatment was explained to her family and they agreed that we could try the procedure.

Inhalation of 25 parts per million of nitric oxide (Compagnie Francaise de Produits Oxygenes, Paris, France) completely abolished the passage of microbubbles from the right to the left atrium (Figure 1, bottom left) and dramatically improved hemodynamic values and gas exchange. Although the mean systemic arterial pressure remained unchanged (115 mm Hg with vasopressor agents), the mean pulmonary arterial pressure decreased markedly (41 to 36 mm Hg). The right atrial pressure (12 to 13 mm Hg) increased less than the left atrial pressure (which was inferred from the pulmonary artery occlusive pressure [11 to 14 mm Hg]); the net effect was a reversal of the right-to-left atrial pressure gradient. The mixed venous partial pressure of oxygen increased from 34 to 41 mm Hg, whereas the venous admixture decreased from 31% to 14%. The PaO₂ increased from 61 to 133 mm Hg.

Surgical or transcatheter closure of this patent foramen ovale was not considered feasible because of the patient's poor neurologic status. The patient was therefore maintained on prolonged nitric oxide administration. Serial echographic examinations showed persistent closure of the patent foramen ovale; the patient's condition deteriorated, and brain death occurred on day four. Permission for autopsy was denied.

Discussion

To our knowledge, this is the first case of functional closure of a patent foramen ovale using inhaled nitric oxide or using nitric oxide during pulmonary embolism. The prevalence of a patent foramen ovale, as shown by contrast transesophageal echocardiography, is 20% to 30% in unselected patients [9]. Coexistence of an atrial septal aneurysm, as in our patient, seems to occur more frequently in patients with stroke [9]. A foramen ovale may open during massive pulmonary embolism when the right atrial pressure increases above the left atrial pressure. This creates a right-to-left shunt that worsens hypoxemia and favors paradoxical embolism. Early recognition and treatment of this complication may be life-saving.

However, the diagnosis of pulmonary embolism is difficult. In our patient, for example, the chest radiograph was normal despite the presence of massive pulmonary embolism. Diagnosis of the patent foramen ovale was facilitated by the availability of contrast echocardiography, which can be done accurately at the bedside [10]. Surgical or transcatheter closure has been advocated [3] but may not be easily done in unstable patients.

In pulmonary embolism, an increase of pulmonary vascular resistance is the consequence of anatomic obstruction and pulmonary arterial constriction [11]; therefore, we reasoned that a decrease of the latter factor using inhaled nitric oxide might abolish the right-to-left shunting. Indeed, nitric oxide is an endothelium-derived relaxing factor with important modulating effects on vascular smooth-muscle tone; nitric oxide can also decrease pulmonary vascular resistance in various forms of pulmonary hypertension [4-7]. Nitric oxide may also increase arterial oxygenation by improving ventilation-perfusion matching without producing systemic vasodilatation [7]; thus, we also administered nitric oxide to our patient in the hope of improving the ventilation-to-perfusion mismatch, which can contribute to altered gas exchange during pulmonary embolism [11].

In our patient, inhalation of nitric oxide markedly decreased the pulmonary artery pressure. This decrease occurred despite a probable increase in cardiac output as shown by a substantial increase in the mixed venous partial pressure of oxygen; this suggested that pulmonary vascular resistance had decreased. The loss of an indicator across the shunt prevented accurate computation of the cardiac output and derived variables. As a probable consequence of improved pulmonary hemodynamic values, we observed a reversal of the pressure gradient between the right and left atria. This was associated with a disappearance of right-to-left shunting on contrast studies. The marked increase in PaO₂ after nitric oxide inhalation was because of an increase in the mixed venous partial pressure of oxygen and a decrease of the venous admixture. The latter may be ascribed to suppression of intracardiac shunting and possibly improvement in the ventilation-perfusion distribution [7, 11].

This report suggests that using nitric oxide may be beneficial pending the decision to do surgical or transcatheter closure of the patent foramen ovale in patients with massive pulmonary embolism. However, additional studies are necessary to determine its utility during severe pulmonary embolism with or without patent foramen ovale.