Dyspnea and orthopnea are ubiquitous presenting findings but it is the presence of often refractory hypoxia that instigates further investigation. The incidence of PFO is reported as high as 27 % in the general population (6 % of them large). Orthodeoxia platypnea is a rare syndrome with less than 200 worldwide documented cases, so the diagnosis of this syndrome requires a high clinical suspicion. Review of the documented literature is replete with the diagnosis made either retrospectively at autopsy, incidentally by imaging or finally by a dedicated exclusion of a number of other diagnostic probabilities. The matter is made murky by the largest series being no more than a handful of cases in any single report or by any one investigator.

The diagnostic quandary of the syndrome stems from it’s being a rare symptom complex associated with a myriad of disparate medical or surgical entities interacting to different degrees with varying anatomical subsets, and thus with protean clinical presentations [33, 34].

It should be suspected in a setting of dyspnea and refractory systemic desaturation in spite of 100 % oxygen therapy. Cyanosis without pulmonary hypertension in the adult should also alert the clinician to the possibility of an unrecognized right-to-left shunt.

The initial assessment and screening should consist of demonstration of platypnea followed by measurements of O₂ saturation and arterial blood gas analysis in the supine and upright positions. Orthostatic desaturation should prompt further investigations. In the past, detection of a right-to-left shunt was performed by a 100 % oxygen inhalation test, and right heart catheterization [35] which can be used for diagnosis and quantification of the shunt.

In current practice, a definitive diagnosis may readily be established by echocardiography in conjunction with the use of contrast-enhanced echocardiography and postural maneuvers. Transcranial Doppler can also be used to establish the presence of an intracardiac shunt. The shunt can be localized, often directly visualized, and even semi-quantitated. Echocardiographic study also allows visualization of other cardiac abnormalities that could be present in conjunction with the atrial defect [36, 37].

The most sensitive test for the noninvasive diagnosis of a right-to-left shunt is peripheral contrast tilt-table transesophageal echocardiography, which should be performed with the patient both supine and as erect as possible [38, 39]. Rarely, an elusive shunt based on clinical suspicion may be seen only on Valsalva maneuvers or require a pure short alpha agonist agent such as IV metaraminol (to augment systemic vascular resistance and increase left atrial pressure) to delineate an interatrial shunt not first demonstrated by repeated transthoracic echocardiography [40]. If an intracardiac shunt cannot be detected, or there is a delayed appearance of echo-contrast appearance in the right atrium the possibility of intrapulmonary shunts within the lung should be considered.

The presence of intrapulmonary vascular dilatations (e.g., in Hepatopulmonary syndrome, pulmonary arteriovenoous malformations (AVMs) can be confirmed using one of several imaging modalities: contrast-enhanced echocardiography, 99mTc-labeled macroaggregated albumin scanning, pulmonary arteriography, and intra-cardiac bubble contrast injections with concomitant intracardiac echo or trans-esophageal echo [41]. Contrast-enhanced echocardiography is the method of choice for demonstrating pulmonary vascular abnormalities. Perfusion scan with macroaggregated albumin labeled with 99mTc shows uptake over thyroid, kidneys, liver, and spleen, suggesting an abnormal passage through the pulmonary vascular bed. Angiography is best reserved for patients with poor response to therapy and defines whether vascular abnormalities are of the diffuse “spongy” type or, less commonly, discrete arteriovenous communications amenable to embolization.

The diagnosis can also be made during cardiac catheterization showing the atrial right-to-left shunt and by monitoring blood oxygen saturations which are normal in the pulmonary veins but show desaturation at the level of arterial blood samples or in the left ventricle. The diagnosis is irrefutably confirmed when blood oxygen saturations on the left side and aorta return to normal values after an occlusion test of the atrial defect with a balloon catheter.

Chen et al. and others have postulated that there are often multiple mechanistic causes that operate in a synergistic mechanism to cause right-to-left atrial shunting despite normal intracardiac pressures and normal or near-normal pulmonary function through a patent foramen ovale (PFO) [42]. In 1987, this puzzle was described as “water flowing up a hill,” and several hypotheses were postulated to explain the mechanism [43–45].

First, despite the fact that the mean right atrial pressure is normally lower than the mean left atrial pressure, a physiologically transient spontaneous reversal of the left-to-right atrial pressure differential is present during early diastole and during isovolumetric contraction of the right ventricle of each cardiac cycle. This reversal of gradient may drastically increase under the substantial hemodynamic changes caused by physiologic maneuvers that increase the right atrial pressure, such as posture, inspiration, cough, or Valsalva maneuver, or under some pathologic conditions resulting in high pulmonary vascular resistances, such as acute pulmonary embolism, hypoxemia due to obstructive sleep apnea, severe COPD, right ventricular infarction, and positive end-expiratory pressure during neurosurgical procedures performed in the sitting position, causing right-to-left shunting when coupled with a PFO.

Second, another theory to explain the right-to-left shunting with both normal atrial and pulmonary vascular pressures involves the preferential flow phenomenon, from the inferior vena cava (or less commonly from the superior vena cava) toward the atrial septum as a part of prominent remnants of the Eustachian valve and or a Chiari malformation. These are best detected by transesophageal echo bubble-contrast injected from the femoral veins.

Third, in the same way, a physiologic change in the relationship of the compliance of right-sided and left-sided chambers, probably exacerbated with age, with the right-sided chambers becoming stiffer than the left-sided chambers, has been advocated.

Finally, an anatomic distortion of the inferior or superior vena cava relative to the atrial septum due to mediastinal shift or counterclockwise heart rotation and/or distortion following ascending aorta enlargement, right pneumonectomy, or pericardial effusion may result in an atypically horizontal reorientation of the plane of the atrial septum, causing it to overly the inlet of the vena cava into the right atrium, facilitating part of the flow to stream directly into the left atrium via a PFO.

Modern diagnostic methods have helped to elucidate the underlying anatomy, physiology, and pathogenic interactions in the milieu of a wide variety of peculiar clinical conditions that lead to right-to-left atrial shunting with or without abnormal intracardiac pressures.

Treatment of the condition depends upon the underlying etiology. When the etiology is an intracardiac shunt alone then surgical [46] or percutaneous closure of the shunt has been documented to resolve the shunting and relieve symptoms [47–52].

The problem lies when, in a single case, there are multiple anatomical and physiologic causes that interact in a unique way [53]. For example, there are cases of orthodeoxia post pneumonectomy that may present months after the surgery. The interaction of the underlying problems may make it unclear whether, as an example, a patient with hepatopulmonary syndrome [29] with a co-existing PFO/ASD is likely to derive any long lasting benefit from closing the shunt alone [54].

There have been case reports of autonomic neuropathy, Parkinson disease and post-pneumonectomy [55] where medical therapy alone with hydration and fludrocortisone was successful. Treatment with almitrine bismesylate, a pharmacologically unique respiratory agonist of carotid body peripheral chemoreceptors, has been shown to potentiate normal pulmonary hypoxic vasoconstriction, thereby reducing the development of respiratory dead spaces in COPD [56]. At the same time it has also been documented that therapy with antibiotics [57], diuretics, propanolol [58], and indomethacin on occasion have been successful. In cases where the orthodeoxia is secondary to pulmonary causes, the treatment of the underlying etiology is usually required to resolve the issue. For example, coil embolization has resolved platypnea-orthodeoxia when associated with pulmonary AVMs. Discontinuation of amiodarone [59] has led to the resolution of orthodeoxia-platypnea when that was determined to be the cause of hypoxia. Liver transplantation [60] has also successfully resolved hypoxia when associated with end stage liver disease.

In conclusion, platypnea-orthodexia is a rare clinical syndrome which can arise in protean clinical settings. Diagnosis requires a heightened sense of clinical suspicion with a careful assessment of the underlying cause (Table 13.1). Correction of the underlying problem with device closure, medical therapy, or rarely with surgery often leads to a successful resolution of symptoms.