- Email: [email protected]
Enhanced detection of patent foramen ovale by systematic transthoracic saline contrast echocardiography
International Journal of Cardiology 152 (2011) 24–27
Contents lists available at ScienceDirect
International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Enhanced detection of patent foramen ovale by systematic transthoracic saline contrast echocardiography Yat-Yin Lam, Cheuk-Man Yu ⁎, Qing Zhang, Bryan P. Yan, Gabriel Wai-Kwok Yip Division of Cardiology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Peoples’ Republic of China
a r t i c l e
i n f o
Article history: Received 2 November 2009 Received in revised form 8 June 2010 Accepted 11 June 2010 Available online 8 July 2010 Keywords: Agitated saline Valsalva maneuver patent foramen ovale
a b s t r a c t Objective: We aimed to evaluate the effectiveness of transthoracic saline contrast echocardiography (TSCE) in detecting patent foramen ovale (PFO). Background: Transesophageal echocardiography (TEE) is semi-invasive and not ideal for PFO screening. Methods: 112 patients (48 males, 46 ± 14 years) with suspected PFO received intravenous agitated-saline contrast at rest and stress (strain and release phases of Valsalva maneuver and coughing). The presence of interatrial shunting was defined as N 5 bubbles appearing in the left heart within 3 cardiac cycles. The stage of the maneuver at which interatrial shunting occurred was recorded. The TSCE findings were validated by TEE. Results: TEE identified PFO in 45% of patients. The sensitivities of TSCE in detecting PFO at rest, during strain and release of Valsalva maneuver, and coughing were 12.0%, 38.0%, 80.0% and 94.0% respectively (each p b 0.05 when compared to previous stage). Specificities were similar and N 95% for all stages. Moreover, the release phase of the maneuver improved the diagnostic accuracy [defined as (number of true positives+ true negatives) divided by total in sample] with incremental value over the preceding strain phase (89.2 vs. 70.5%, p b 0.001). Conclusions: Patent foramen ovale can be identified confidently with proper conduct of the Valsalva maneuver during the transthoracic saline contrast echocardiography. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Patent foramen ovale (PFO), which is present in 25% of the normal population, refers to the persistence of the flap-like opening at interatrial septum (IAS) after birth [1]. This lesion allows right-to-left shunting (RLS) during the crossover of pressure that occurs in the respiratory cycle, often at end-diastole or in situations when right atrial pressure increases (i.e. Valsalva maneuver, coughing). Presence of PFO is associated with cryptogenic stroke and transcatheter closure may be warranted in selected patients [2]. While transesophageal echocardiography (TEE) remains the reference standard [3,4] in diagnosing PFO, it is semi-invasive and not ideal for screening. TEE also fails to detect PFO in sedated subjects due to ineffective or inadequate Valsalva maneuver [5,6]. Use of second harmonic imaging [7–9], agitated saline or contrast medium injection [10,11] with or without repetitive Valsalva maneuver [3,4,12–14] can all improve the sensitivity of PFO detection by transthoracic echocardiography. However, there is a lack of studies to address the phase of the maneuver to be imaged and the value of additional cough test in demonstrating RLS that occurs in PFO patients. We, therefore, sought to evaluate the diagnostic utility of different
⁎ Corresponding author. Division of Cardiology, Department of Medicine and Therapeutics, SH Ho Cardiovascular and Stroke Centre, Institute of Vascular Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR, Peoples’ Republic of China. Tel.: + 86 852 2632 3594; fax: + 86 852 2637 5643. E-mail address: [email protected] (C.-M. Yu). 0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.06.018
phases of Valsalva maneuver and the cough test during transthoracic saline contrast echocardiography (TSCE). 2. Methods A consecutive of 112 patients suspected to have PFO prospectively received TSCE and TEE at the Prince of Wales Hospital between 2005 and 2009. They were suspected to have PFO because of: 1) presence of suspicious 2-dimensional color Doppler flow at interatrial septum (Fig. 1) or 2) previous history of cryptogenic stroke. Patients with suboptimal echocardiographic windows, contra-indications for TEE, secundum atrial septal defects, intrapulmonary shunting and significantly raised left atrial pressure (restrictive LV filling pattern or severe mitral regurgitation or stenosis) were excluded from the study. Informed consent was obtained from all participants and the study was approved by local ethical committee. 2.1. Contrast administration protocol Standard 2-dimensional and Doppler echocardiography was performed using a 3.5-MHz probe on Vivid 5 system (General Electric Medical Systems, Milwaukee, WI, USA) with second harmonic imaging, followed by multiplanar TEE on the same day using either Vivid 5 or iE33 system (Philips Medical System, Andovor, MA, USA). Patients were taught to perform standard Valsalva maneuver and a post-maneuver cough test before their echocardiographic examination: First, sustained straining against a closed epiglottis causing abdominal distension for 10 seconds before sudden release of the strain by deep inspiration, followed by forceful coughing for 5 seconds. Adequate performance of Valsalva maneuver was checked quantitatively by a ≥ 10% reduction of early Doppler mitral inflow velocity [15,16], and qualitatively by a decrease in the left atrial and ventricular sizes with IAS bulging to the left atrium. An 18 French angiocatheter was inserted at the right antecubital vein, which was connected by an extension tube to a 3-way stopcock with two 10 ml Luer Lock syringes. One ml of patient's blood was drawn from the angiocatheter into a syringe containing
Y.-Y. Lam et al. / International Journal of Cardiology 152 (2011) 24–27
25
Table 1 Baseline Patient Characteristics. Variables
Patients (n = 112)
Age (yrs) Men Co-morbidities Diabetes Mellitus Hypertension Coronary artery disease Clinical indications: 1. 2D Color Doppler flow detected at interatrial septum 2. Follow-up for suspected paradoxical embolism Cryptogenic stroke Transesophageal echocardiogram diagnoses Absence of interatrial shunt Patent foramen ovale
46 ± 14 48 (43%) 8 (7%) 11 (10%) 2 (2%) 66 (59%) 46 (41%)
62 (55%) 50 (45%)
2D = two-dimensional.
Fig. 1. An example of a patient with 2-dimensional color Doppler flow (white arrow) at interatrial septum which is suspicious of patent foramen ovale.
of the TEE results. Disagreement results would be discussed among them to reach final conclusions. 2.2. Statistical analysis
8 ml of sterile normal saline solution and 1 ml of air [11]. The content was forcefully injected back and forth for few times between the two syringes to become a cloudy and foamy pink emulsion. It was then rapidly administered intravenously to the patient at baseline, before the Valsalva maneuver on transthoracic and subsequent TEE examinations (Fig. 2). Presence of RLS was defined as the appearance of N 5 bubbles in left heart within 3 cardiac cycles [8,17] when the contrast first appeared in the right atrium. Gain settings were individually adjusted to enhance the visualization of IAS and bubble contrast in apical 4-chamber view. The stage of the maneuver at which RLS occurred was recorded. For the TEE examination, subjects were only given topical pharyngeal anesthesia to allow adequate performance of Valsalva maneuver. The diagnosis of PFO was confirmed on TEE by both visualization of the defect and demonstration of interatrial shunting either by saline contrast or color Doppler imaging. Those patients with bubble contrast appeared in left heart after 3 cardiac cycles would receive additional contrast administration for further examination of all pulmonary veins. Any contrast emergence from pulmonary veins confirmed presence of intrapulmonary shunting. All images were digitally stored as cine-loops and recorded on videotapes for off-line analysis. The TSCE findings were later interpreted by 2 independent cardiologists who were unaware
Continuous and categorical variables were expressed as mean ± SD and percentage respectively. Sensitivity, specificity, and accuracy of various phases of the maneuver for detecting RLS on transthoracic echocardiography were calculated using TEE as the “reference standard”. Diagnostic accuracy was defined as: ðtrue positivesÞ + ðtrue negativesÞ total in sample Comparisons for dichotomous variables were performed using Chi-square or Fisher's Exact test as appropriate. A significant difference was defined as p b 0.05. Statistical analysis was performed by dedicated software (SPSS 13.0, Chicago, Illinois, USA).
3. Results One hundred and fourteen patients were recruited initially. Two patients were excluded from analysis because of evidence of
Fig. 2. Flow Chart of the Design of the Study.
26
Y.-Y. Lam et al. / International Journal of Cardiology 152 (2011) 24–27
Using TEE as the reference standard, the overall sensitivities of TSCE in detecting PFO at rest, during strain and release phases of Valsalva maneuver, and cough were 12.0%, 38.0%, 80.0% and 94.0% respectively (each p b 0.05 when compared to previous stage, Fig. 3A). Specificities were similar and N95% for all stages. In addition, the release phase of the Valsalva maneuver improved the diagnostic accuracy of PFO with incremental value over the preceding strain phase (89.2 vs. 70.5%, x [2] 12.3, p b 0.001) (Table 2, Fig. 3B). 4. Discussion To our knowledge, this is the largest study that examined in depth the contribution of different phases of Valsalva maneuver in detection of PFO-associated RLS during transthoracic contrast echocardiography, and addressed which phase should be imaged. Our study showed that imaging the IAS during the release phase of Valsalva maneuver was highly sensitive and specific in detecting PFO by transthoracic contrast echocardiography. Furthermore, it improved diagnostic accuracy with incremental value over the preceding strain phase. Additional postmaneuver cough test that transiently raises right atrial pressure could further improve the test sensitivity. 4.1. Different phases of Valsalva maneuver in the detection of PFO
Fig. 3. Performance of Transthoracic and Transesophageal Echocardiography. (A) Bar chart comparing the sensitivity of transthoracic echocardiography and transesophageal echocardiography for detecting patent foramen ovale. (B) Bar chart comparing the accuracy of transthoracic echocardiography and transesophageal echocardiography for detecting patent foramen ovale. N = number of patients. TTE = transthoracic echocardiogram. TEE = transesophageal echocardiogram.
intrapulmonary shunt. Patients’ characteristics were shown in Table 1. All patients tolerated the TSCE and TEE well without adverse event. TEE identified PFO in 50 patients (45% of the studied cohort). Fourteen patients (13% of the cohort) performed Valsalva maneuver inadequately with reduction of early Doppler mitral inflow velocity ≦10%. Of the 3 PFOs missed by the transthoracic approach, 2 failed to perform adequate Valsalva measures. Of the 3 cases with falsepositive transthoracic findings, one was found to have “pseudocontrast” produced by Valsalva maneuver. The inter-observer variability for the occurrence of RLS with respect to different stages of maneuver was 1%. 3.1. Right-to-left interatrial shunting detection Forty-seven out of 50 (94%) patients with PFO were detected by TSCE during the Valsalva maneuver or the post-maneuver cough test.
Table 2 Performance of Transthoracic Contrast Echocardiography.
Rest Strain phase of Valsalva Release phase of Valsalva Additional cough test
Sensitivity (%)
Specificity (%)
Accuracy (%)
12.0 38.0 80.0 94.0
98.3 96.8 96.8 95.2
59.8 70.5 89.2 94.6
Our findings underscored the importance of imaging the IAS during the release phase of Valsalva maneuver. Although the performance of the maneuver is generally regarded as essential in most contrast echocardiographic studies [17], few actually specified as to which phase of the maneuver that imaging of the IAS should be performed. We proposed it was during the release phase that sudden influx of caval blood into the right atrium abruptly raises the right atrial pressure, allowing maximal degree of RLS to occur. Twodimensional examination of the IAS often showed a corresponding leftward bulging. Our results in fact corroborated and extended the finding of a case report of a patient suffering from PFO-associated paradoxical cerebral embolism in which maximal degree of RLS occurred only at the release phase of Valsalva maneuver as confirmed by indicator dilution method [12]. It was therefore, extremely important to continue the imaging not only during strain but also at the release phase of the maneuver in order to enhance the diagnostic accuracy of transthoracic contrast studies. Johansson et al. reported at least 5 contrast injections were needed to confidently exclude the presence of PFO [14]. Such protocol was difficult to apply clinically given its lengthy and complicated nature. On the other hand, a small study addressed the superiority of cough test to Valsalva maneuver in detecting PFO [18]. Our findings added to the previous study that the post-maneuver cough test could further enhance the sensitivity without compromising specificity of the test. The overall sensitivity of the Valsalva maneuver and cough test in detecting PFO compared favorably to that of TEE. Two out of 3 patients with false negative results failed to achieve optimal Valsalva measures, highlighting need of checking adequacy of the maneuver qualitatively before the contrast study. We also suggest screening for the presence of “pseudo-contrast” phenomenon [17,19] before contrast administration – this was thought to be related to transient stagnation of pulmonary venous blood with rouleaux formation and its subsequent release into left atrium upon left atrial relaxation. However, no obvious cause could be found in 2 out of 3 false positive cases. One potential explanation could be the presence of tiny PFO that is even missed by TEE although it is often practically regarded as the reference standard. Diagnostic cardiac catheterization perhaps needs to be considered in this rare clinical scenario. Patent foramen ovale was found in 45% of the studied population, which is substantially higher than previously reported. This is likely due to the better selection of patients by either suspicious transthoracic echocardiographic findings or history of probable paradoxical embolism.
Y.-Y. Lam et al. / International Journal of Cardiology 152 (2011) 24–27
4.2. Implications of the study Our study has important clinical implication. Patent foramen ovale could be identified confidently with proper conduct of the Valsalva maneuver during the transthoracic echocardiographic examination. It is the release phase of the Valsalva maneuver that imaging of the interatrial septum should be performed. Its high accuracy supports its role as a routine screening tool for patients with suspected PFO and TEE should be reserved as a confirmatory test. This is of particular importance to those who are intolerant to semi-invasive TEE procedure, in whom the application of deep sedation often prevents effective or adequate performance of Valsalva maneuver, which is considered the essential part of the examination. 4.3. Limitations Firstly, by excluding patients with "suboptimal windows" this study skews the results of the TSCE test to be more sensitive and specific. Moreover, other reported techniques such as the application of transcranial Doppler [20] or injection through femoral veins [12] for improving the performance of test were not included in our protocol. However, trans-cranial Doppler is operator-dependent and femoral vein injection is not without risk. Our comprehensive yet simple echocardiographic protocol, if conducted properly, already has high sensitivity and specificity to warrant its routine clinical application. 5. Conclusions Patent foramen ovale can be identified confidently with proper conduct of the Valsalva maneuver during the transthoracic saline contrast echocardiography. Acknowledgements This project was sponsored by the Direct Grant for Research of the Chinese University of Hong Kong. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [21]. References [1] Cruz-González I, Solis J, Kiernan TJ, et al. Clinical manifestation and current management of patent foramen ovale. Expert Rev Cardiovasc Ther 2009;7:1011–22. [2] Windecker S, Meier B. Is closure recommended for patent foramen ovale and cryptogenic stroke? Patent foramen ovale and cryptogenic stroke: to close or not to close? Closure: what else! Circulation 2008;118:1989–98.
27
[3] Belkin RN, Pollack BD, Ruggiero ML, et al. Comparison of transoesophageal and transthoracic echocardiography with contrast and color flow Doppler in the detection of patent foramen ovale. Am Heart J 1994;128:520–5. [4] Soliman OI, Geleijnse ML, Meijboom FJ, et al. The use of contrast echocardiography for the detection of cardiac shunts. Eur J Echocardiogr 2007;8:S2–S12. [5] Pfleger S, Konstantin Haase K, Stark S, et al. Haemodynamic quantification of different provocation manoeuvres by simultaneous measurement of right and left atrial pressure: implications for the echocardiographic detection of persistent foramen ovale. Eur J Echocardiogr 2001;2:88–93. [6] Trevelyan J, Steeds RP. Comparison of transthoracic echocardiography with harmonic imaging with transoesophageal echocardiography for the diagnosis of patent foramen ovale. Postgrad Med J 2006;82:613–4. [7] Ha JW, Shin MS, Kang S, et al. Enhanced detection of right-to-left shunt through patent foramen ovale by transthoracic contrast echocardiography using harmonic imaging. Am J Cardiol 2001;87:669–71. [8] Van Camp G, Franken P, Melis P, et al. Comparison of transthoracic echocardiography with second harmonic imaging with transoesophageal echocardiography in the detection of right-to-left shunts. Am J Cardiol 2000;86:1284–7. [9] Kühl HP, Hoffmann R, Merx MW, et al. Transthoracic echocardiography using second harmonic imaging: diagnostic alternative to transoesophageal echocardiography for the detection of atrial right-to-left shunt in patients with cerebral embolic events. J Am Coll Cardiol 1999;34:1823–30. [10] Thanigaraj S, Valika A, Zajarias A, et al. Comparison of transthoracic versus transoesophageal echocardiography for detection of right-to-left atrial shunting using agitated saline contrast. Am J Cardiol 2005;96:1007–10. [11] Fan S, Nagai T, Luo H, et al. Superiority of the combination of blood and agitated saline for routine contrast enhancement. J Am Soc Echocardiogr 1999;12:94–8. [12] Cheng TO. The proper conduct of Valsalva manoeuvre in the detection of patent foramen ovale. J Am Coll Cardiol 2005;45:1145–6. [13] Lynch JJ, Schuchard GH, Gross CM, et al. Prevalence of right-to-left atrial shunting in a healthy population: detection by Valsalva manoeuvre contrast echocardiography. Am J Cardiol 1984;53:1478–80. [14] Johansson MC, Helgason H, Dellborg M, et al. Sensitivity for detection of patent foramen ovale increased with increasing number of contrast injections: a descriptive study with contrast transoesophageal echocardiography. J Am Soc Echocardiogr 2008;21:419–24. [15] Hurrell DG, Nishimura RA, Ilstrup DM, et al. Utility of preload alteration in assessment of left ventricular filling pressure by Doppler echocardiography: a simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol 1997;30:459–67. [16] Dumesnil JG, Gaudreault G, Honos GN, et al. Use of Valsalva manoeuvre to unmask left ventricular diastolic function abnormalities by Doppler echocardiography in patients with coronary artery disease or systemic hypertension. Am J Cardiol 1991;68:515–9. [17] Woods TD, Patel A. A critical review of patent foramen ovale detection using saline contrast echocardiography: when bubbles lie. J Am Soc Echocardiogr 2006;19:215–22. [18] Stoddard MF, Keedy DL, Dawkins PR. The cough test is superior to the Valsalva manoeuvre in the delineation of right-to-left shunting through a patent foramen ovale during contrast transesophageal echocardiography. Am Heart J 1993;125: 185–9. [19] Van Camp G, Cosyns B, Vandenbossche JL. Non-smoke spontaneous contrast in left atrium intensified by respiratory manoeuvres: a new transoesophageal echocardiographic observation. Br Heart J 1994;72:446–51. [20] Droste DW, Reisener M, Kemény V, et al. Contrast transcranial Doppler ultrasound in the detection of right-to-left shunts. Reproducibility, comparison of 2 agents, and distribution of microemboli. Stroke 1999;30:1014–8. [21] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.
Contents lists available at ScienceDirect
International Journal of Cardiology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / i j c a r d
Enhanced detection of patent foramen ovale by systematic transthoracic saline contrast echocardiography Yat-Yin Lam, Cheuk-Man Yu ⁎, Qing Zhang, Bryan P. Yan, Gabriel Wai-Kwok Yip Division of Cardiology, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, Peoples’ Republic of China
a r t i c l e
i n f o
Article history: Received 2 November 2009 Received in revised form 8 June 2010 Accepted 11 June 2010 Available online 8 July 2010 Keywords: Agitated saline Valsalva maneuver patent foramen ovale
a b s t r a c t Objective: We aimed to evaluate the effectiveness of transthoracic saline contrast echocardiography (TSCE) in detecting patent foramen ovale (PFO). Background: Transesophageal echocardiography (TEE) is semi-invasive and not ideal for PFO screening. Methods: 112 patients (48 males, 46 ± 14 years) with suspected PFO received intravenous agitated-saline contrast at rest and stress (strain and release phases of Valsalva maneuver and coughing). The presence of interatrial shunting was defined as N 5 bubbles appearing in the left heart within 3 cardiac cycles. The stage of the maneuver at which interatrial shunting occurred was recorded. The TSCE findings were validated by TEE. Results: TEE identified PFO in 45% of patients. The sensitivities of TSCE in detecting PFO at rest, during strain and release of Valsalva maneuver, and coughing were 12.0%, 38.0%, 80.0% and 94.0% respectively (each p b 0.05 when compared to previous stage). Specificities were similar and N 95% for all stages. Moreover, the release phase of the maneuver improved the diagnostic accuracy [defined as (number of true positives+ true negatives) divided by total in sample] with incremental value over the preceding strain phase (89.2 vs. 70.5%, p b 0.001). Conclusions: Patent foramen ovale can be identified confidently with proper conduct of the Valsalva maneuver during the transthoracic saline contrast echocardiography. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Patent foramen ovale (PFO), which is present in 25% of the normal population, refers to the persistence of the flap-like opening at interatrial septum (IAS) after birth [1]. This lesion allows right-to-left shunting (RLS) during the crossover of pressure that occurs in the respiratory cycle, often at end-diastole or in situations when right atrial pressure increases (i.e. Valsalva maneuver, coughing). Presence of PFO is associated with cryptogenic stroke and transcatheter closure may be warranted in selected patients [2]. While transesophageal echocardiography (TEE) remains the reference standard [3,4] in diagnosing PFO, it is semi-invasive and not ideal for screening. TEE also fails to detect PFO in sedated subjects due to ineffective or inadequate Valsalva maneuver [5,6]. Use of second harmonic imaging [7–9], agitated saline or contrast medium injection [10,11] with or without repetitive Valsalva maneuver [3,4,12–14] can all improve the sensitivity of PFO detection by transthoracic echocardiography. However, there is a lack of studies to address the phase of the maneuver to be imaged and the value of additional cough test in demonstrating RLS that occurs in PFO patients. We, therefore, sought to evaluate the diagnostic utility of different
⁎ Corresponding author. Division of Cardiology, Department of Medicine and Therapeutics, SH Ho Cardiovascular and Stroke Centre, Institute of Vascular Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong SAR, Peoples’ Republic of China. Tel.: + 86 852 2632 3594; fax: + 86 852 2637 5643. E-mail address: [email protected] (C.-M. Yu). 0167-5273/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2010.06.018
phases of Valsalva maneuver and the cough test during transthoracic saline contrast echocardiography (TSCE). 2. Methods A consecutive of 112 patients suspected to have PFO prospectively received TSCE and TEE at the Prince of Wales Hospital between 2005 and 2009. They were suspected to have PFO because of: 1) presence of suspicious 2-dimensional color Doppler flow at interatrial septum (Fig. 1) or 2) previous history of cryptogenic stroke. Patients with suboptimal echocardiographic windows, contra-indications for TEE, secundum atrial septal defects, intrapulmonary shunting and significantly raised left atrial pressure (restrictive LV filling pattern or severe mitral regurgitation or stenosis) were excluded from the study. Informed consent was obtained from all participants and the study was approved by local ethical committee. 2.1. Contrast administration protocol Standard 2-dimensional and Doppler echocardiography was performed using a 3.5-MHz probe on Vivid 5 system (General Electric Medical Systems, Milwaukee, WI, USA) with second harmonic imaging, followed by multiplanar TEE on the same day using either Vivid 5 or iE33 system (Philips Medical System, Andovor, MA, USA). Patients were taught to perform standard Valsalva maneuver and a post-maneuver cough test before their echocardiographic examination: First, sustained straining against a closed epiglottis causing abdominal distension for 10 seconds before sudden release of the strain by deep inspiration, followed by forceful coughing for 5 seconds. Adequate performance of Valsalva maneuver was checked quantitatively by a ≥ 10% reduction of early Doppler mitral inflow velocity [15,16], and qualitatively by a decrease in the left atrial and ventricular sizes with IAS bulging to the left atrium. An 18 French angiocatheter was inserted at the right antecubital vein, which was connected by an extension tube to a 3-way stopcock with two 10 ml Luer Lock syringes. One ml of patient's blood was drawn from the angiocatheter into a syringe containing
Y.-Y. Lam et al. / International Journal of Cardiology 152 (2011) 24–27
25
Table 1 Baseline Patient Characteristics. Variables
Patients (n = 112)
Age (yrs) Men Co-morbidities Diabetes Mellitus Hypertension Coronary artery disease Clinical indications: 1. 2D Color Doppler flow detected at interatrial septum 2. Follow-up for suspected paradoxical embolism Cryptogenic stroke Transesophageal echocardiogram diagnoses Absence of interatrial shunt Patent foramen ovale
46 ± 14 48 (43%) 8 (7%) 11 (10%) 2 (2%) 66 (59%) 46 (41%)
62 (55%) 50 (45%)
2D = two-dimensional.
Fig. 1. An example of a patient with 2-dimensional color Doppler flow (white arrow) at interatrial septum which is suspicious of patent foramen ovale.
of the TEE results. Disagreement results would be discussed among them to reach final conclusions. 2.2. Statistical analysis
8 ml of sterile normal saline solution and 1 ml of air [11]. The content was forcefully injected back and forth for few times between the two syringes to become a cloudy and foamy pink emulsion. It was then rapidly administered intravenously to the patient at baseline, before the Valsalva maneuver on transthoracic and subsequent TEE examinations (Fig. 2). Presence of RLS was defined as the appearance of N 5 bubbles in left heart within 3 cardiac cycles [8,17] when the contrast first appeared in the right atrium. Gain settings were individually adjusted to enhance the visualization of IAS and bubble contrast in apical 4-chamber view. The stage of the maneuver at which RLS occurred was recorded. For the TEE examination, subjects were only given topical pharyngeal anesthesia to allow adequate performance of Valsalva maneuver. The diagnosis of PFO was confirmed on TEE by both visualization of the defect and demonstration of interatrial shunting either by saline contrast or color Doppler imaging. Those patients with bubble contrast appeared in left heart after 3 cardiac cycles would receive additional contrast administration for further examination of all pulmonary veins. Any contrast emergence from pulmonary veins confirmed presence of intrapulmonary shunting. All images were digitally stored as cine-loops and recorded on videotapes for off-line analysis. The TSCE findings were later interpreted by 2 independent cardiologists who were unaware
Continuous and categorical variables were expressed as mean ± SD and percentage respectively. Sensitivity, specificity, and accuracy of various phases of the maneuver for detecting RLS on transthoracic echocardiography were calculated using TEE as the “reference standard”. Diagnostic accuracy was defined as: ðtrue positivesÞ + ðtrue negativesÞ total in sample Comparisons for dichotomous variables were performed using Chi-square or Fisher's Exact test as appropriate. A significant difference was defined as p b 0.05. Statistical analysis was performed by dedicated software (SPSS 13.0, Chicago, Illinois, USA).
3. Results One hundred and fourteen patients were recruited initially. Two patients were excluded from analysis because of evidence of
Fig. 2. Flow Chart of the Design of the Study.
26
Y.-Y. Lam et al. / International Journal of Cardiology 152 (2011) 24–27
Using TEE as the reference standard, the overall sensitivities of TSCE in detecting PFO at rest, during strain and release phases of Valsalva maneuver, and cough were 12.0%, 38.0%, 80.0% and 94.0% respectively (each p b 0.05 when compared to previous stage, Fig. 3A). Specificities were similar and N95% for all stages. In addition, the release phase of the Valsalva maneuver improved the diagnostic accuracy of PFO with incremental value over the preceding strain phase (89.2 vs. 70.5%, x [2] 12.3, p b 0.001) (Table 2, Fig. 3B). 4. Discussion To our knowledge, this is the largest study that examined in depth the contribution of different phases of Valsalva maneuver in detection of PFO-associated RLS during transthoracic contrast echocardiography, and addressed which phase should be imaged. Our study showed that imaging the IAS during the release phase of Valsalva maneuver was highly sensitive and specific in detecting PFO by transthoracic contrast echocardiography. Furthermore, it improved diagnostic accuracy with incremental value over the preceding strain phase. Additional postmaneuver cough test that transiently raises right atrial pressure could further improve the test sensitivity. 4.1. Different phases of Valsalva maneuver in the detection of PFO
Fig. 3. Performance of Transthoracic and Transesophageal Echocardiography. (A) Bar chart comparing the sensitivity of transthoracic echocardiography and transesophageal echocardiography for detecting patent foramen ovale. (B) Bar chart comparing the accuracy of transthoracic echocardiography and transesophageal echocardiography for detecting patent foramen ovale. N = number of patients. TTE = transthoracic echocardiogram. TEE = transesophageal echocardiogram.
intrapulmonary shunt. Patients’ characteristics were shown in Table 1. All patients tolerated the TSCE and TEE well without adverse event. TEE identified PFO in 50 patients (45% of the studied cohort). Fourteen patients (13% of the cohort) performed Valsalva maneuver inadequately with reduction of early Doppler mitral inflow velocity ≦10%. Of the 3 PFOs missed by the transthoracic approach, 2 failed to perform adequate Valsalva measures. Of the 3 cases with falsepositive transthoracic findings, one was found to have “pseudocontrast” produced by Valsalva maneuver. The inter-observer variability for the occurrence of RLS with respect to different stages of maneuver was 1%. 3.1. Right-to-left interatrial shunting detection Forty-seven out of 50 (94%) patients with PFO were detected by TSCE during the Valsalva maneuver or the post-maneuver cough test.
Table 2 Performance of Transthoracic Contrast Echocardiography.
Rest Strain phase of Valsalva Release phase of Valsalva Additional cough test
Sensitivity (%)
Specificity (%)
Accuracy (%)
12.0 38.0 80.0 94.0
98.3 96.8 96.8 95.2
59.8 70.5 89.2 94.6
Our findings underscored the importance of imaging the IAS during the release phase of Valsalva maneuver. Although the performance of the maneuver is generally regarded as essential in most contrast echocardiographic studies [17], few actually specified as to which phase of the maneuver that imaging of the IAS should be performed. We proposed it was during the release phase that sudden influx of caval blood into the right atrium abruptly raises the right atrial pressure, allowing maximal degree of RLS to occur. Twodimensional examination of the IAS often showed a corresponding leftward bulging. Our results in fact corroborated and extended the finding of a case report of a patient suffering from PFO-associated paradoxical cerebral embolism in which maximal degree of RLS occurred only at the release phase of Valsalva maneuver as confirmed by indicator dilution method [12]. It was therefore, extremely important to continue the imaging not only during strain but also at the release phase of the maneuver in order to enhance the diagnostic accuracy of transthoracic contrast studies. Johansson et al. reported at least 5 contrast injections were needed to confidently exclude the presence of PFO [14]. Such protocol was difficult to apply clinically given its lengthy and complicated nature. On the other hand, a small study addressed the superiority of cough test to Valsalva maneuver in detecting PFO [18]. Our findings added to the previous study that the post-maneuver cough test could further enhance the sensitivity without compromising specificity of the test. The overall sensitivity of the Valsalva maneuver and cough test in detecting PFO compared favorably to that of TEE. Two out of 3 patients with false negative results failed to achieve optimal Valsalva measures, highlighting need of checking adequacy of the maneuver qualitatively before the contrast study. We also suggest screening for the presence of “pseudo-contrast” phenomenon [17,19] before contrast administration – this was thought to be related to transient stagnation of pulmonary venous blood with rouleaux formation and its subsequent release into left atrium upon left atrial relaxation. However, no obvious cause could be found in 2 out of 3 false positive cases. One potential explanation could be the presence of tiny PFO that is even missed by TEE although it is often practically regarded as the reference standard. Diagnostic cardiac catheterization perhaps needs to be considered in this rare clinical scenario. Patent foramen ovale was found in 45% of the studied population, which is substantially higher than previously reported. This is likely due to the better selection of patients by either suspicious transthoracic echocardiographic findings or history of probable paradoxical embolism.
Y.-Y. Lam et al. / International Journal of Cardiology 152 (2011) 24–27
4.2. Implications of the study Our study has important clinical implication. Patent foramen ovale could be identified confidently with proper conduct of the Valsalva maneuver during the transthoracic echocardiographic examination. It is the release phase of the Valsalva maneuver that imaging of the interatrial septum should be performed. Its high accuracy supports its role as a routine screening tool for patients with suspected PFO and TEE should be reserved as a confirmatory test. This is of particular importance to those who are intolerant to semi-invasive TEE procedure, in whom the application of deep sedation often prevents effective or adequate performance of Valsalva maneuver, which is considered the essential part of the examination. 4.3. Limitations Firstly, by excluding patients with "suboptimal windows" this study skews the results of the TSCE test to be more sensitive and specific. Moreover, other reported techniques such as the application of transcranial Doppler [20] or injection through femoral veins [12] for improving the performance of test were not included in our protocol. However, trans-cranial Doppler is operator-dependent and femoral vein injection is not without risk. Our comprehensive yet simple echocardiographic protocol, if conducted properly, already has high sensitivity and specificity to warrant its routine clinical application. 5. Conclusions Patent foramen ovale can be identified confidently with proper conduct of the Valsalva maneuver during the transthoracic saline contrast echocardiography. Acknowledgements This project was sponsored by the Direct Grant for Research of the Chinese University of Hong Kong. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [21]. References [1] Cruz-González I, Solis J, Kiernan TJ, et al. Clinical manifestation and current management of patent foramen ovale. Expert Rev Cardiovasc Ther 2009;7:1011–22. [2] Windecker S, Meier B. Is closure recommended for patent foramen ovale and cryptogenic stroke? Patent foramen ovale and cryptogenic stroke: to close or not to close? Closure: what else! Circulation 2008;118:1989–98.
27
[3] Belkin RN, Pollack BD, Ruggiero ML, et al. Comparison of transoesophageal and transthoracic echocardiography with contrast and color flow Doppler in the detection of patent foramen ovale. Am Heart J 1994;128:520–5. [4] Soliman OI, Geleijnse ML, Meijboom FJ, et al. The use of contrast echocardiography for the detection of cardiac shunts. Eur J Echocardiogr 2007;8:S2–S12. [5] Pfleger S, Konstantin Haase K, Stark S, et al. Haemodynamic quantification of different provocation manoeuvres by simultaneous measurement of right and left atrial pressure: implications for the echocardiographic detection of persistent foramen ovale. Eur J Echocardiogr 2001;2:88–93. [6] Trevelyan J, Steeds RP. Comparison of transthoracic echocardiography with harmonic imaging with transoesophageal echocardiography for the diagnosis of patent foramen ovale. Postgrad Med J 2006;82:613–4. [7] Ha JW, Shin MS, Kang S, et al. Enhanced detection of right-to-left shunt through patent foramen ovale by transthoracic contrast echocardiography using harmonic imaging. Am J Cardiol 2001;87:669–71. [8] Van Camp G, Franken P, Melis P, et al. Comparison of transthoracic echocardiography with second harmonic imaging with transoesophageal echocardiography in the detection of right-to-left shunts. Am J Cardiol 2000;86:1284–7. [9] Kühl HP, Hoffmann R, Merx MW, et al. Transthoracic echocardiography using second harmonic imaging: diagnostic alternative to transoesophageal echocardiography for the detection of atrial right-to-left shunt in patients with cerebral embolic events. J Am Coll Cardiol 1999;34:1823–30. [10] Thanigaraj S, Valika A, Zajarias A, et al. Comparison of transthoracic versus transoesophageal echocardiography for detection of right-to-left atrial shunting using agitated saline contrast. Am J Cardiol 2005;96:1007–10. [11] Fan S, Nagai T, Luo H, et al. Superiority of the combination of blood and agitated saline for routine contrast enhancement. J Am Soc Echocardiogr 1999;12:94–8. [12] Cheng TO. The proper conduct of Valsalva manoeuvre in the detection of patent foramen ovale. J Am Coll Cardiol 2005;45:1145–6. [13] Lynch JJ, Schuchard GH, Gross CM, et al. Prevalence of right-to-left atrial shunting in a healthy population: detection by Valsalva manoeuvre contrast echocardiography. Am J Cardiol 1984;53:1478–80. [14] Johansson MC, Helgason H, Dellborg M, et al. Sensitivity for detection of patent foramen ovale increased with increasing number of contrast injections: a descriptive study with contrast transoesophageal echocardiography. J Am Soc Echocardiogr 2008;21:419–24. [15] Hurrell DG, Nishimura RA, Ilstrup DM, et al. Utility of preload alteration in assessment of left ventricular filling pressure by Doppler echocardiography: a simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol 1997;30:459–67. [16] Dumesnil JG, Gaudreault G, Honos GN, et al. Use of Valsalva manoeuvre to unmask left ventricular diastolic function abnormalities by Doppler echocardiography in patients with coronary artery disease or systemic hypertension. Am J Cardiol 1991;68:515–9. [17] Woods TD, Patel A. A critical review of patent foramen ovale detection using saline contrast echocardiography: when bubbles lie. J Am Soc Echocardiogr 2006;19:215–22. [18] Stoddard MF, Keedy DL, Dawkins PR. The cough test is superior to the Valsalva manoeuvre in the delineation of right-to-left shunting through a patent foramen ovale during contrast transesophageal echocardiography. Am Heart J 1993;125: 185–9. [19] Van Camp G, Cosyns B, Vandenbossche JL. Non-smoke spontaneous contrast in left atrium intensified by respiratory manoeuvres: a new transoesophageal echocardiographic observation. Br Heart J 1994;72:446–51. [20] Droste DW, Reisener M, Kemény V, et al. Contrast transcranial Doppler ultrasound in the detection of right-to-left shunts. Reproducibility, comparison of 2 agents, and distribution of microemboli. Stroke 1999;30:1014–8. [21] Coats AJ. Ethical authorship and publishing. Int J Cardiol 2009;131:149–50.