关于A Hole in the Argument的原因,关于A Hole in the Argument的相关知识。 An 80-year-old man presented to his physician's office for evaluation of shortness of breath and fatigue four weeks after repair of a hiatal hernia. He reported a mild, nonproductive cough and abdominal bloating. Prior to the surgery, he had been very active and had had no dyspnea.
Postoperative shortness of breath may be due to many conditions, including atelectasis, pulmonary embolism, pneumonia, pneumothorax, cardiac arrhythmia, myocardial ischemia, heart failure, or even anemia. The absence of preoperative symptoms suggests that surgery was the precipitating event. Given the type of surgery performed, one possible sequela is bronchospasm due to gastroesophageal reflux.
The patient had a history of hypertension, hypercholesterolemia, and osteoarthritis. Ten years earlier, he had undergone percutaneous coronary intervention for angina and single-vessel coronary artery disease. He had undergone laparoscopic fundoplication for gastroesophageal reflux and hiatal hernia seven years before the current problem, but required repeated fundoplication four weeks before he reported his current symptoms. Before his recent fundoplication, a stress test with myocardial perfusion imaging was performed. The patient exercised for 4 minutes 50 seconds and attained a maximum heart rate of 140 beats per minute without symptoms or electrocardiographic abnormalities. The perfusion images showed no evidence of ischemia. This patient's preoperative medications included aspirin, isosorbide mononitrate, atenolol, and simvastatin, which were unchanged after the surgery.
There was no history suggestive of pulmonary disease. Although the patient does have a history of coronary artery disease, his preoperative stress test demonstrated a good functional capacity, and there was no evidence of myocardial ischemia.
On physical examination, the patient appeared younger than his chronologic age and he was not in distress. His blood pressure was 103/61 mm Hg, heart rate 66 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 82 percent. His weight was 84 kg and height 173 cm (body-mass index , 28.1). His sclerae were anicteric. His lungs were clear on auscultation. The jugular venous pressure and heart sounds were normal, without murmur, gallop, or rub. There was no evidence of hepatosplenomegaly or ascites. There was mild (1+) bilateral edema below the knees and mild cyanosis of the lips and nail beds, but no clubbing was evident. The remainder of his physical examination was normal.
The patient was found to have a substantial reduction in arterial oxygen saturation, with unremarkable findings on physical examination. The normal cardiac examination and clear lung fields suggest that heart failure or significant pulmonary parenchymal disease is unlikely to explain his dyspnea. I am particularly worried about pulmonary embolism, especially given the onset of symptoms after surgery. Methemoglobinemia may occur in patients taking nitrates (particularly with very high doses or additional oxidant stresses) and may cause arterial oxygen desaturation. However, isosorbide mononitrate was not a newly prescribed medication, and the risk of clinically important methemoglobinemia with long-term nitrate use is low.
The white-cell count was 4700 per cubic millimeter, the hemoglobin level 13.7 g per deciliter, and the platelet count 199,000 per cubic millimeter. The levels of serum electrolytes were normal. Levels of hepatic transaminases, serum alkaline phosphatase, bilirubin, total protein, and albumin were normal. The level of B-type natriuretic peptide was 117 pg per milliliter (normal range, 0 to 100). Arterial blood gas values obtained while the patient was breathing room air revealed a pH of 7.49, a partial pressure of carbon dioxide of 35 mm Hg, a partial pressure of oxygen of 35 mm Hg, a bicarbonate level of 27 mmol per liter, and an oxygen saturation of 73 percent. While the patient was breathing pure oxygen by face mask, arterial blood gas values included a pH of 7.45, a partial pressure of carbon dioxide of 35 mm Hg, a partial pressure of oxygen of 44 mm Hg, a bicarbonate level of 25 mmol per liter, and an oxygen saturation of 82 percent. Measurement of blood gases with co-oximetry demonstrated a normal methemoglobin level of 0.6 percent. A chest radiograph (Figure 1) showed an enlarged cardiac silhouette and a tortuous descending aorta, but there was no evidence of pulmonary infiltrate or edema. An electrocardiogram showed sinus rhythm.
Figure 1. Chest Radiograph Showing Enlarged Cardiac Silhouette, Tortuous Aorta, and Intraabdominal Surgical Clips from Recent Fundoplication.
The absence of erythrocytosis is consistent with the subacute duration of the patient's hypoxemia. The fact that his severe hypoxemia did not improve with the administration of pure oxygen suggests the presence of right-to-left "shunt physiology." The refractoriness of shunt-related hypoxemia to treatment with inhaled oxygen is attributable to the transit of deoxygenated blood directly into normally oxygenated blood, without oxygen uptake in the pulmonary capillaries. In addition to pulmonary embolism, causes of right-to-left shunting of blood include other intrapulmonary shunts (for example, arteriovenous malformations) as well as intracardiac conditions (e.g., atrial or ventricular septal defects), or extracardiac conditions (patent ductus arteriosus with severe pulmonary hypertension).
Computed tomography (CT) of the chest with the administration of intravenous contrast material showed no evidence of pulmonary emboli or pulmonary arteriovenous malformations. The ascending aorta and proximal descending thoracic aorta were mildly dilated. The esophagus appeared mildly distended with fluid and gas. A high-resolution CT scan of the chest showed mild scarring in the right lung without infiltrate or pleural effusion. A transthoracic echocardiogram showed normal size and function of both the left and right ventricles. There was mild mitral-valve and tricuspid-valve regurgitation; estimated pulmonary-artery systolic pressure was 30 mm Hg, based on the velocity of the tricuspid regurgitation jet. No intracardiac shunt was evident with the use of two-dimensional or color Doppler flow imaging. Pulmonary-function tests demonstrated normal spirometry, lung volumes, and diffusion capacity of carbon monoxide.
A sleep study revealed a total of 80 obstructive apneic episodes, 13 central apneic episodes, 7 mixed apneic episodes, and 23 hypopneic episodes (apnea–hypopnea index of 21 events per hour). The baseline oxygen saturation was 91 percent, and the lowest recorded saturation value during sleep was 77 percent. Continuous positive airway pressure (CPAP) at 9 cm of water reduced the apnea–hypopnea index to 2.6 events per hour, and the minimal oxygen saturation increased to 89 percent. The patient was prescribed home oxygen therapy and CPAP by nasal mask when sleeping.
Although the findings meet the criteria for the diagnosis of moderate obstructive sleep apnea (15 to 30 apneic–hypopneic events per hour of sleep), this diagnosis does not adequately explain the patient's dyspnea and hypoxemia. Chronic hypoventilation syndromes, such as the obesity-hypoventilation syndrome, may be associated with hypoxemia, but the normal values for partial pressure of carbon dioxide measured in prior arterial blood gas tests do not support hypoventilation as the cause of his hypoxemia.
The patient underwent a cardiac catheterization for evaluation of persistent hypoxemia, which revealed a right atrial pressure of 3 mm Hg, a right ventricular pressure of 25/5 mm Hg, a pulmonary artery pressure of 25/10 mm Hg (mean pressure, 15 mm Hg), a pulmonary-capillary wedge pressure of 5 mm Hg, a left-ventricular systolic pressure and an end-diastolic pressure of 125 and 8 mm Hg, respectively, and an aortic pressure of 125/80 mm Hg. Left ventriculography revealed an ejection fraction of 60 percent, without mitral regurgitation or ventricular septal defect. The results of coronary angiography were normal. Oximetry data obtained with the patient breathing room air showed the following oxygen-saturation values: inferior vena cava, 70 percent (normal, 65 to 87 percent); superior vena cava, 68 percent (normal, 67 to 83 percent); right atrium, 69 percent (normal, 65 to 87 percent); right ventricle, 65 percent (normal, 67 to 84 percent); pulmonary artery, 65 percent (normal, 67 to 84 percent); pulmonary-capillary wedge, 88 percent (normal left atrial saturation, 92 to 98 percent); left ventricular, 93 percent (normal, 92 to 98 percent); and descending aortic, 89 percent (normal, 92 to 98 percent). The decrease in oxygen saturation between the left ventricle and the descending aorta prompted concern for a possible extracardiac right-to-left shunt. However, a magnetic resonance imaging (MRI) scan with angiography showed no evidence of an intrathoracic right-to-left shunt.
The oximetric measurements obtained during cardiac catheterization may suggest the presence and location of a shunt, apparent as a decrement in oxygen saturation at a site in the pulmonary venous or systemic arterial circulation. Measurement of the partial pressure of oxygen may be more sensitive than measurement of oxygen saturation, since hemoglobin saturation is preserved over a wide range of values for oxygen partial pressure.
The patient's oximetric results are difficult to interpret. The pulmonary-capillary wedge oxygen saturation was measured as a surrogate for the pulmonary venous saturation to differentiate between a pulmonary shunt (low pulmonary venous saturation) and a cardiac shunt (normal pulmonary venous saturation). However, if the catheter is not occlusive, this sample may be partially diluted by pulmonary arterial (mixed venous) blood, resulting in a falsely low estimate of the true pulmonary venous oxygen content. This contamination is suggested by the fact that the left ventricular oxygen saturation is higher than that of the pulmonary-capillary wedge saturation.
The decrement in oxygen saturation from the left ventricle to the femoral artery probably reflects variability in the measurement of oxygen saturation. A systemic venous-to-arterial shunt is not a likely finding because the normal right heart and pulmonary arterial pressures are much lower than systemic arterial pressure.
The patient was referred to our institution for evaluation of hypoxemia. On examination, his oxygen saturation was found to be 94 percent when he was in the supine position and 76 percent in the standing position.
This finding of orthodeoxia, a decrease in arterial oxygen saturation from the recumbent to the erect position, may occur with a number of conditions, including recurrent pulmonary emboli, chronic lung disease, liver disease (specifically, hepatopulmonary syndrome), previous pneumonectomy, pulmonary arteriovenous malformations, and patent foramen ovale. Most of the potential causes have been ruled out in this patient on the basis of previous testing, but the possible presence of a patent foramen ovale has not been adequately evaluated.
Transthoracic echocardiography was repeated with an intravenous injection of agitated saline in both the supine and standing positions. This demonstrated minimal shunting of microbubbles in the supine position, but significant opacification of the left atrium and ventricle by microbubbles when the patient was standing (Figure 2; and Video Clips 1 and 2 in the Supplementary Appendix, available with the full text of this article at www.nejm.org). A transesophageal echocardiogram confirmed the presence of a patent foramen ovale, with markedly increased right-to-left shunting across the foramen ovale when the patient was in the sitting position (Figure 3).
Figure 2. Transthoracic Echocardiogram with Injection of Agitated Saline.
The echocardiogram in Panel A was obtained while the patient was in the supine position and shows opacification of the right atrium and ventricle (thin arrow), with minimal microbubbles in the left ventricle (thick arrow). The echocardiogram in Panel B was obtained with the patient standing, and shows opacification of the right heart chambers (thin arrow) as well as the left ventricle (thick arrow). IVS denotes interventricular septum.
Figure 3. Transesophageal Echocardiogram Showing the Patent Foramen Ovale by Color Doppler.
The image in Panel A, with minimal right-to-left shunting through the patent foramen ovale (arrow), was obtained when the patient was in the supine position. In Panel B, increased right-to-left shunting (arrow) was evident when the patient was in the sitting position. LA denotes left atrium, RA right atrium, and Ao aorta.
Contrast injection during echocardiography may be used to evaluate the presence of a right-to-left shunt. Upon transit to the right heart of the agitated saline bolus, which has increased echogenicity because of the creation of microbubbles, the right atrium and right ventricle are filled with this contrast solution. In the absence of a shunt, these small bubbles are trapped in the pulmonary capillaries and gradually dissipate without being visualized in the left heart chambers. Visualization of microbubbles in the left heart within a few cardiac cycles of their opacification of the right heart chambers suggests the presence of an intracardiac shunt, whereas their delayed appearance in the left heart suggests an intrapulmonary shunt.
Review of the operative note from the recent fundoplication revealed that the hiatal hernia was densely adherent in the mediastinum and that the fundoplication was secured in the abdomen by sutures to the preaortic fascia.
Mobilization of the stomach out of the mediastinum and retraction of the fundoplication may have contributed to the dynamic alteration of atrial geometry and the patency of the foramen ovale in the upright position.
The patient underwent percutaneous closure of the patent foramen ovale in the cardiac catheterization laboratory with implantation of a septal defect occlusion device without complication. At a three-month follow-up, he no longer experienced shortness of breath. His oxygen saturation while breathing room air was 98 percent in the supine position and 97 percent when standing.
Commentary
An understanding of pathophysiology often guides the formulation of a differential diagnosis. Findings from the patient's evaluation may then be used to support or refute proposed diagnoses. In this case, the clinicians recognized correctly that the hypoxemia was due to a shunt, and an appropriate differential diagnosis was formulated. However, the intermittent, positional nature of shunting through the patent foramen ovale obscured its detection. Oxygen saturation measurements that were made intraoperatively and postoperatively were likely performed with the patient supine, as were subsequent measurements in the cardiac-catheterization laboratory. These measurements demonstrated no or mild hypoxemia, in contrast to the measurements that were obtained during other evaluations.
Orthodeoxia may be accompanied by the symptom of platypnea, the sensation of difficulty in breathing when erect that is relieved by recumbency (a condition termed the platypnea–orthodeoxia syndrome). When present, the platypnea–orthodeoxia syndrome is usually caused by a patent foramen ovale, intrapulmonary vascular shunt, or severe ventilation-perfusion mismatching and should be considered when hypoxemia is positional or more pronounced than expected on the basis of cardiac and pulmonary findings.
From a physiological perspective, the confirmation, localization, and quantification of a shunt is most accurately performed by direct measurement of oxygen content at distinct sites throughout the cardiopulmonary system. However, such an oximetry series, often termed a shunt run, involves an invasive procedure. Furthermore, differentiating between a pulmonary cause and a cardiac cause of hypoxemia requires measurement of the oxygen content at the site where it is expected to be highest (in the pulmonary veins); this site may not be readily accessible in the absence of an atrial septal defect or without performing a transseptal catheterization.
Alternatively, a shunt may be diagnosed by imaging methods. Abnormalities of the pulmonary vasculature, such as pulmonary embolism or arteriovenous malformations, may be visualized by angiography during CT or MRI. Transthoracic echocardiography is highly sensitive for the presence of a ventricular septal defect, but may not clearly visualize the atrial septum because of its posterior location in the thorax. If an atrial septal defect or a patent foramen ovale is strongly suspected, a transesophageal echocardiogram is more sensitive and more likely to detect it. As described above, intravenous injection of contrast media during echocardiography may disclose the presence of a shunt1 and demonstrate whether a shunt is dynamic or positional in nature. The sensitivity of this technique may be augmented by having the patient cough or perform a Valsalva maneuver, thereby increasing intrathoracic pressure and right-to-left shunting.2 Right-to-left shunting may thus be detected through small defects, such as a patent foramen ovale, even in the setting of normal right heart pressures.3
Although it was a congenital heart defect, the patient's patent foramen ovale was not clinically apparent for 80 years. Furthermore, a patent foramen ovale is typically associated with no or minimal left-to-right shunting, and the development of right-to-left shunting was an acquired element of this anomaly. The platypnea–orthodeoxia syndrome due to a patent foramen ovale is often triggered by an intercurrent event or condition, such as aortic dilation,4,5 pulmonary embolus,6 pneumonectomy,7 or diaphragmatic paralysis.6,8 The acute onset of orthodeoxia in this patient cannot be attributed to a change in aortic dimensions in the absence of a dissection. Right-to-left shunting may result from elevated right heart pressures, such as might occur in the setting of a pulmonary embolus, but his right heart pressures were normal. A perioperative myocardial infarction involving the right ventricle may also lead to an acute elevation of right atrial pressure,9 but the right ventricle would have appeared dilated and hypocontractile on echocardiography. As theorized above, alteration of atrial geometry by the fundoplication may have resulted in a positional increase in the patency of and shunting through the patent foramen ovale.
This case also highlights the challenge of determining the clinical significance of a common anomaly. A patent foramen ovale is reported to be present in at least 10 percent of the general population.10 Although the majority of these findings are not clinically significant, a patent foramen ovale may be associated with important sequelae, including paradoxical embolism (with subsequent cerebrovascular accident)11,12 and hypoxemia, as illustrated in this case. Because of the high prevalence of the condition, an increased rate of detection by echocardiography, and the potential for percutaneous closure,13,14,15 careful consideration of the significance of a patent foramen ovale is important in clinical decision making, as described by Kizer and Devereux in this issue of the Journal.16 When confronted with such a puzzle, searching for holes in the data may allow the clinician to refine the diagnostic possibilities and ultimately to identify the underlying problem.
Source Information
From the Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, N.C.
Address reprint requests to Dr. Wang at Duke University Medical Center, DUMC Box 3428, Durham, NC 27710, or at a.wang@duke.edu.
References
Valdes-Cruz LM, Pieroni DR, Roland JM, Varghese PJ. Echocardiographic detection of intracardiac right-to-left shunts following peripheral vein injections. Circulation 1976;54:558-562.
Dubourg O, Bourdarias JP, Farcot JC, et al. Contrast echocardiographic visualization of cough-induced right to left shunt through a patent foramen ovale. J Am Coll Cardiol 1984;4:587-594.
Kronik G, Mosslacher H. Positive contrast echocardiography in patients with patent foramen ovale and normal right heart hemodynamics. Am J Cardiol 1982;49:1806-1809.
Popp G, Melek H, Garnett AR Jr. Platypnea-orthodeoxia related to aortic elongation. Chest 1997;112:1682-1684.
Savage EB, Benckart DH, Donahue BC, Casaday FM, Cho YD. Intermittent hypoxia due to right atrial compression by an ascending aortic aneurysm. Ann Thorac Surg 1996;62:582-583.
Rao PS, Palacios IF, Bach RG, Bitar SR, Sideris EB. Platypnea-orthodeoxia: management by transcatheter buttoned device implantation. Catheter Cardiovasc Interv 2001;54:77-82.
Vacek JL, Foster J, Quinton RR, Savage PJ. Right-to-left shunting after lobectomy through a patent foramen ovale. Ann Thorac Surg 1985;39:576-578.
Wang A, Bashore TM, Kisslo KB, Das GS, O'Laughlin MP, Harrison JK. Hypoxemia after prior cardiac surgery due to interatrial shunting and its treatment with a novel transcatheter occlusion device. Catheter Cardiovasc Interv 1999;46:452-456.
Laham RJ, Ho KK, Douglas PS, et al. Right ventricular infarction complicated by acute right-to-left shunting. Am J Cardiol 1994;74:824-826.
Fisher DC, Fisher EA, Budd JH, Rosen SE, Goldman ME. The incidence of patent foramen ovale in 1,000 consecutive patients: a contrast transesophageal echocardiography study. Chest 1995;107:1504-1509.
Lechat P, Mas JL, Lascault G, et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988;318:1148-1152.
Di Tullio M, Sacco RL, Gopal A, Mohr JP, Homma S. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 1992;117:461-465.
Godart F, Rey C, Prat A, et al. Atrial right-to-left shunting causing severe hypoxaemia despite normal right-sided pressures: report of 11 consecutive cases corrected by percutaneous closure. Eur Heart J 2000;21:483-489.
Windecker S, Wahl A, Chatterjee T, et al. Percutaneous closure of paten
t foramen ovale in patients with paradoxical embolism: long-term risk of recurrent thromboembolic events. Circulation 2000;101:893-898.
Windecker S, Wahl A, Nedeltchev K, et al. Comparison of medical treatment with percutaneous closure of patent foramen ovale in patients with cryptogenic stroke. J Am Coll Cardiol 2004;44:750-758.
Kizer JR, Devereux RB. Patent foramen ovale in young adults with unexplained stroke. N Engl J Med 2005;353:2361-2372. (文章出处：《新英格兰医药杂志》)
Postoperative shortness of breath may be due to many conditions, including atelectasis, pulmonary embolism, pneumonia, pneumothorax, cardiac arrhythmia, myocardial ischemia, heart failure, or even anemia. The absence of preoperative symptoms suggests that surgery was the precipitating event. Given the type of surgery performed, one possible sequela is bronchospasm due to gastroesophageal reflux.
The patient had a history of hypertension, hypercholesterolemia, and osteoarthritis. Ten years earlier, he had undergone percutaneous coronary intervention for angina and single-vessel coronary artery disease. He had undergone laparoscopic fundoplication for gastroesophageal reflux and hiatal hernia seven years before the current problem, but required repeated fundoplication four weeks before he reported his current symptoms. Before his recent fundoplication, a stress test with myocardial perfusion imaging was performed. The patient exercised for 4 minutes 50 seconds and attained a maximum heart rate of 140 beats per minute without symptoms or electrocardiographic abnormalities. The perfusion images showed no evidence of ischemia. This patient's preoperative medications included aspirin, isosorbide mononitrate, atenolol, and simvastatin, which were unchanged after the surgery.
There was no history suggestive of pulmonary disease. Although the patient does have a history of coronary artery disease, his preoperative stress test demonstrated a good functional capacity, and there was no evidence of myocardial ischemia.
On physical examination, the patient appeared younger than his chronologic age and he was not in distress. His blood pressure was 103/61 mm Hg, heart rate 66 beats per minute, respiratory rate 18 breaths per minute, and oxygen saturation 82 percent. His weight was 84 kg and height 173 cm (body-mass index , 28.1). His sclerae were anicteric. His lungs were clear on auscultation. The jugular venous pressure and heart sounds were normal, without murmur, gallop, or rub. There was no evidence of hepatosplenomegaly or ascites. There was mild (1+) bilateral edema below the knees and mild cyanosis of the lips and nail beds, but no clubbing was evident. The remainder of his physical examination was normal.
The patient was found to have a substantial reduction in arterial oxygen saturation, with unremarkable findings on physical examination. The normal cardiac examination and clear lung fields suggest that heart failure or significant pulmonary parenchymal disease is unlikely to explain his dyspnea. I am particularly worried about pulmonary embolism, especially given the onset of symptoms after surgery. Methemoglobinemia may occur in patients taking nitrates (particularly with very high doses or additional oxidant stresses) and may cause arterial oxygen desaturation. However, isosorbide mononitrate was not a newly prescribed medication, and the risk of clinically important methemoglobinemia with long-term nitrate use is low.
The white-cell count was 4700 per cubic millimeter, the hemoglobin level 13.7 g per deciliter, and the platelet count 199,000 per cubic millimeter. The levels of serum electrolytes were normal. Levels of hepatic transaminases, serum alkaline phosphatase, bilirubin, total protein, and albumin were normal. The level of B-type natriuretic peptide was 117 pg per milliliter (normal range, 0 to 100). Arterial blood gas values obtained while the patient was breathing room air revealed a pH of 7.49, a partial pressure of carbon dioxide of 35 mm Hg, a partial pressure of oxygen of 35 mm Hg, a bicarbonate level of 27 mmol per liter, and an oxygen saturation of 73 percent. While the patient was breathing pure oxygen by face mask, arterial blood gas values included a pH of 7.45, a partial pressure of carbon dioxide of 35 mm Hg, a partial pressure of oxygen of 44 mm Hg, a bicarbonate level of 25 mmol per liter, and an oxygen saturation of 82 percent. Measurement of blood gases with co-oximetry demonstrated a normal methemoglobin level of 0.6 percent. A chest radiograph (Figure 1) showed an enlarged cardiac silhouette and a tortuous descending aorta, but there was no evidence of pulmonary infiltrate or edema. An electrocardiogram showed sinus rhythm.
Figure 1. Chest Radiograph Showing Enlarged Cardiac Silhouette, Tortuous Aorta, and Intraabdominal Surgical Clips from Recent Fundoplication.
The absence of erythrocytosis is consistent with the subacute duration of the patient's hypoxemia. The fact that his severe hypoxemia did not improve with the administration of pure oxygen suggests the presence of right-to-left "shunt physiology." The refractoriness of shunt-related hypoxemia to treatment with inhaled oxygen is attributable to the transit of deoxygenated blood directly into normally oxygenated blood, without oxygen uptake in the pulmonary capillaries. In addition to pulmonary embolism, causes of right-to-left shunting of blood include other intrapulmonary shunts (for example, arteriovenous malformations) as well as intracardiac conditions (e.g., atrial or ventricular septal defects), or extracardiac conditions (patent ductus arteriosus with severe pulmonary hypertension).
Computed tomography (CT) of the chest with the administration of intravenous contrast material showed no evidence of pulmonary emboli or pulmonary arteriovenous malformations. The ascending aorta and proximal descending thoracic aorta were mildly dilated. The esophagus appeared mildly distended with fluid and gas. A high-resolution CT scan of the chest showed mild scarring in the right lung without infiltrate or pleural effusion. A transthoracic echocardiogram showed normal size and function of both the left and right ventricles. There was mild mitral-valve and tricuspid-valve regurgitation; estimated pulmonary-artery systolic pressure was 30 mm Hg, based on the velocity of the tricuspid regurgitation jet. No intracardiac shunt was evident with the use of two-dimensional or color Doppler flow imaging. Pulmonary-function tests demonstrated normal spirometry, lung volumes, and diffusion capacity of carbon monoxide.
A sleep study revealed a total of 80 obstructive apneic episodes, 13 central apneic episodes, 7 mixed apneic episodes, and 23 hypopneic episodes (apnea–hypopnea index of 21 events per hour). The baseline oxygen saturation was 91 percent, and the lowest recorded saturation value during sleep was 77 percent. Continuous positive airway pressure (CPAP) at 9 cm of water reduced the apnea–hypopnea index to 2.6 events per hour, and the minimal oxygen saturation increased to 89 percent. The patient was prescribed home oxygen therapy and CPAP by nasal mask when sleeping.
Although the findings meet the criteria for the diagnosis of moderate obstructive sleep apnea (15 to 30 apneic–hypopneic events per hour of sleep), this diagnosis does not adequately explain the patient's dyspnea and hypoxemia. Chronic hypoventilation syndromes, such as the obesity-hypoventilation syndrome, may be associated with hypoxemia, but the normal values for partial pressure of carbon dioxide measured in prior arterial blood gas tests do not support hypoventilation as the cause of his hypoxemia.
The patient underwent a cardiac catheterization for evaluation of persistent hypoxemia, which revealed a right atrial pressure of 3 mm Hg, a right ventricular pressure of 25/5 mm Hg, a pulmonary artery pressure of 25/10 mm Hg (mean pressure, 15 mm Hg), a pulmonary-capillary wedge pressure of 5 mm Hg, a left-ventricular systolic pressure and an end-diastolic pressure of 125 and 8 mm Hg, respectively, and an aortic pressure of 125/80 mm Hg. Left ventriculography revealed an ejection fraction of 60 percent, without mitral regurgitation or ventricular septal defect. The results of coronary angiography were normal. Oximetry data obtained with the patient breathing room air showed the following oxygen-saturation values: inferior vena cava, 70 percent (normal, 65 to 87 percent); superior vena cava, 68 percent (normal, 67 to 83 percent); right atrium, 69 percent (normal, 65 to 87 percent); right ventricle, 65 percent (normal, 67 to 84 percent); pulmonary artery, 65 percent (normal, 67 to 84 percent); pulmonary-capillary wedge, 88 percent (normal left atrial saturation, 92 to 98 percent); left ventricular, 93 percent (normal, 92 to 98 percent); and descending aortic, 89 percent (normal, 92 to 98 percent). The decrease in oxygen saturation between the left ventricle and the descending aorta prompted concern for a possible extracardiac right-to-left shunt. However, a magnetic resonance imaging (MRI) scan with angiography showed no evidence of an intrathoracic right-to-left shunt.
The oximetric measurements obtained during cardiac catheterization may suggest the presence and location of a shunt, apparent as a decrement in oxygen saturation at a site in the pulmonary venous or systemic arterial circulation. Measurement of the partial pressure of oxygen may be more sensitive than measurement of oxygen saturation, since hemoglobin saturation is preserved over a wide range of values for oxygen partial pressure.
The patient's oximetric results are difficult to interpret. The pulmonary-capillary wedge oxygen saturation was measured as a surrogate for the pulmonary venous saturation to differentiate between a pulmonary shunt (low pulmonary venous saturation) and a cardiac shunt (normal pulmonary venous saturation). However, if the catheter is not occlusive, this sample may be partially diluted by pulmonary arterial (mixed venous) blood, resulting in a falsely low estimate of the true pulmonary venous oxygen content. This contamination is suggested by the fact that the left ventricular oxygen saturation is higher than that of the pulmonary-capillary wedge saturation.
The decrement in oxygen saturation from the left ventricle to the femoral artery probably reflects variability in the measurement of oxygen saturation. A systemic venous-to-arterial shunt is not a likely finding because the normal right heart and pulmonary arterial pressures are much lower than systemic arterial pressure.
The patient was referred to our institution for evaluation of hypoxemia. On examination, his oxygen saturation was found to be 94 percent when he was in the supine position and 76 percent in the standing position.
This finding of orthodeoxia, a decrease in arterial oxygen saturation from the recumbent to the erect position, may occur with a number of conditions, including recurrent pulmonary emboli, chronic lung disease, liver disease (specifically, hepatopulmonary syndrome), previous pneumonectomy, pulmonary arteriovenous malformations, and patent foramen ovale. Most of the potential causes have been ruled out in this patient on the basis of previous testing, but the possible presence of a patent foramen ovale has not been adequately evaluated.
Transthoracic echocardiography was repeated with an intravenous injection of agitated saline in both the supine and standing positions. This demonstrated minimal shunting of microbubbles in the supine position, but significant opacification of the left atrium and ventricle by microbubbles when the patient was standing (Figure 2; and Video Clips 1 and 2 in the Supplementary Appendix, available with the full text of this article at www.nejm.org). A transesophageal echocardiogram confirmed the presence of a patent foramen ovale, with markedly increased right-to-left shunting across the foramen ovale when the patient was in the sitting position (Figure 3).
Figure 2. Transthoracic Echocardiogram with Injection of Agitated Saline.
The echocardiogram in Panel A was obtained while the patient was in the supine position and shows opacification of the right atrium and ventricle (thin arrow), with minimal microbubbles in the left ventricle (thick arrow). The echocardiogram in Panel B was obtained with the patient standing, and shows opacification of the right heart chambers (thin arrow) as well as the left ventricle (thick arrow). IVS denotes interventricular septum.
Figure 3. Transesophageal Echocardiogram Showing the Patent Foramen Ovale by Color Doppler.
The image in Panel A, with minimal right-to-left shunting through the patent foramen ovale (arrow), was obtained when the patient was in the supine position. In Panel B, increased right-to-left shunting (arrow) was evident when the patient was in the sitting position. LA denotes left atrium, RA right atrium, and Ao aorta.
Contrast injection during echocardiography may be used to evaluate the presence of a right-to-left shunt. Upon transit to the right heart of the agitated saline bolus, which has increased echogenicity because of the creation of microbubbles, the right atrium and right ventricle are filled with this contrast solution. In the absence of a shunt, these small bubbles are trapped in the pulmonary capillaries and gradually dissipate without being visualized in the left heart chambers. Visualization of microbubbles in the left heart within a few cardiac cycles of their opacification of the right heart chambers suggests the presence of an intracardiac shunt, whereas their delayed appearance in the left heart suggests an intrapulmonary shunt.
Review of the operative note from the recent fundoplication revealed that the hiatal hernia was densely adherent in the mediastinum and that the fundoplication was secured in the abdomen by sutures to the preaortic fascia.
Mobilization of the stomach out of the mediastinum and retraction of the fundoplication may have contributed to the dynamic alteration of atrial geometry and the patency of the foramen ovale in the upright position.
The patient underwent percutaneous closure of the patent foramen ovale in the cardiac catheterization laboratory with implantation of a septal defect occlusion device without complication. At a three-month follow-up, he no longer experienced shortness of breath. His oxygen saturation while breathing room air was 98 percent in the supine position and 97 percent when standing.
Commentary
An understanding of pathophysiology often guides the formulation of a differential diagnosis. Findings from the patient's evaluation may then be used to support or refute proposed diagnoses. In this case, the clinicians recognized correctly that the hypoxemia was due to a shunt, and an appropriate differential diagnosis was formulated. However, the intermittent, positional nature of shunting through the patent foramen ovale obscured its detection. Oxygen saturation measurements that were made intraoperatively and postoperatively were likely performed with the patient supine, as were subsequent measurements in the cardiac-catheterization laboratory. These measurements demonstrated no or mild hypoxemia, in contrast to the measurements that were obtained during other evaluations.
Orthodeoxia may be accompanied by the symptom of platypnea, the sensation of difficulty in breathing when erect that is relieved by recumbency (a condition termed the platypnea–orthodeoxia syndrome). When present, the platypnea–orthodeoxia syndrome is usually caused by a patent foramen ovale, intrapulmonary vascular shunt, or severe ventilation-perfusion mismatching and should be considered when hypoxemia is positional or more pronounced than expected on the basis of cardiac and pulmonary findings.
From a physiological perspective, the confirmation, localization, and quantification of a shunt is most accurately performed by direct measurement of oxygen content at distinct sites throughout the cardiopulmonary system. However, such an oximetry series, often termed a shunt run, involves an invasive procedure. Furthermore, differentiating between a pulmonary cause and a cardiac cause of hypoxemia requires measurement of the oxygen content at the site where it is expected to be highest (in the pulmonary veins); this site may not be readily accessible in the absence of an atrial septal defect or without performing a transseptal catheterization.
Alternatively, a shunt may be diagnosed by imaging methods. Abnormalities of the pulmonary vasculature, such as pulmonary embolism or arteriovenous malformations, may be visualized by angiography during CT or MRI. Transthoracic echocardiography is highly sensitive for the presence of a ventricular septal defect, but may not clearly visualize the atrial septum because of its posterior location in the thorax. If an atrial septal defect or a patent foramen ovale is strongly suspected, a transesophageal echocardiogram is more sensitive and more likely to detect it. As described above, intravenous injection of contrast media during echocardiography may disclose the presence of a shunt1 and demonstrate whether a shunt is dynamic or positional in nature. The sensitivity of this technique may be augmented by having the patient cough or perform a Valsalva maneuver, thereby increasing intrathoracic pressure and right-to-left shunting.2 Right-to-left shunting may thus be detected through small defects, such as a patent foramen ovale, even in the setting of normal right heart pressures.3
Although it was a congenital heart defect, the patient's patent foramen ovale was not clinically apparent for 80 years. Furthermore, a patent foramen ovale is typically associated with no or minimal left-to-right shunting, and the development of right-to-left shunting was an acquired element of this anomaly. The platypnea–orthodeoxia syndrome due to a patent foramen ovale is often triggered by an intercurrent event or condition, such as aortic dilation,4,5 pulmonary embolus,6 pneumonectomy,7 or diaphragmatic paralysis.6,8 The acute onset of orthodeoxia in this patient cannot be attributed to a change in aortic dimensions in the absence of a dissection. Right-to-left shunting may result from elevated right heart pressures, such as might occur in the setting of a pulmonary embolus, but his right heart pressures were normal. A perioperative myocardial infarction involving the right ventricle may also lead to an acute elevation of right atrial pressure,9 but the right ventricle would have appeared dilated and hypocontractile on echocardiography. As theorized above, alteration of atrial geometry by the fundoplication may have resulted in a positional increase in the patency of and shunting through the patent foramen ovale.
This case also highlights the challenge of determining the clinical significance of a common anomaly. A patent foramen ovale is reported to be present in at least 10 percent of the general population.10 Although the majority of these findings are not clinically significant, a patent foramen ovale may be associated with important sequelae, including paradoxical embolism (with subsequent cerebrovascular accident)11,12 and hypoxemia, as illustrated in this case. Because of the high prevalence of the condition, an increased rate of detection by echocardiography, and the potential for percutaneous closure,13,14,15 careful consideration of the significance of a patent foramen ovale is important in clinical decision making, as described by Kizer and Devereux in this issue of the Journal.16 When confronted with such a puzzle, searching for holes in the data may allow the clinician to refine the diagnostic possibilities and ultimately to identify the underlying problem.
Source Information
From the Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, N.C.
Address reprint requests to Dr. Wang at Duke University Medical Center, DUMC Box 3428, Durham, NC 27710, or at a.wang@duke.edu.
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