1. Introduction

Patent foramen ovale (PFO) is a common congenital atrial septal defect with an incidence of 15 to 35% in the adult population.[1] In some patients, PFO may lead to cardiac right-to-left shunting (RLS), which has been associated with various diseases, such as migraine,[2] cryptogenic stroke,[3] and decompression illness.[4] RLS can be divided into cardiogenic RLS and pulmonary RLS. In cardiogenic RLS, blood flows from the right heart chambers to the left through abnormal channels (e.g., atrial septal defect or PFO) between the chambers. In pulmonary RLS, blood flows directly from pulmonary arteries into pulmonary veins through abnormal channels (e.g., pulmonary arteriovenous malformations) without undergoing gaseous exchange in pulmonary capillaries. Contrast transcranial Doppler (c-TCD), contrast transthoracic echocardiography (c-TTE), and contrast transesophageal echocardiography (c-TEE) can be used to detect PFO-related RLS.[5] However, it is still unclear which ultrasound modalities are the most practical and cost-effective. Therefore, reliable techniques for detecting RLS are essential for diagnosis.

c-TEE is the current gold standard in detecting PFO,[5] although it is semi-invasive and may cause some discomfort to patients. In addition, some patients, especially the elderly and those with neurological dysfunction, cannot perform a Valsalva maneuver (VM) during the test. As a result, c-TEE is unsuitable for use as a screening modality for PFO.

c-TCD is a noninvasive, inexpensive, easily repeatable, and highly reproducible screening tool for detecting RLS. c-TCD appears to be more sensitive than c-TEE at detecting RLS at rest,[6,7] but it is less specific when compared with c-TEE.[8] c-TTE is the most commonly used method for PFO imaging but has the lowest sensitivity amongst RLS detection methods and cannot differentiate between cardiac and pulmonary shunts.[9] Since both c-TTE and c-TCD have advantages and limitations in diagnosing a patient with RLS, combining these 2 ultrasound modalities can improve the specificity of PFO diagnosis.[5] Some clinicians[10] have used c-TCD and c-TEE asynchronously to screen for RLS. However, this requires patients to undergo 2 contrast echocardiography procedures, thereby increasing the risks and costs associated with the tests. In this study, we evaluated the effectiveness and feasibility of a synchronous test of c-TCD and c-TTE in detecting an RLS.

2. Materials and methods

The study was approved by the ethics review board of the First Affiliated Hospital of Shenzhen University (Approval No. 20220413006). It was performed per the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The risks and benefits of the study were fully discussed with eligible patients. All enrolled participants provided written informed consent.

2.1. Study population

We prospectively designed and continuously recruited 100 patients who were admitted with migraine, unexplained syncope, and dizziness for a right-to-left shunt in Shenzhen Second People’s Hospital between February 2020 and August 2020. The inclusion criteria were as follows: an age of 18 to 80 years, voluntary participation, and good image quality obtained during all examinations. Our exclusion criteria were as follows: congenital heart disease, such as atrial and ventricular septal defects, and inability to perform VM. Ninety-five patients met the inclusion criteria; their demographic characteristics are shown in Table 1. The diagnosis of cryptogenic stroke was made according to the Trial of Org 10172 in Acute Stroke Treatment classification standards.[11] The diagnoses of hypertension,[12] diabetes,[13] hyperlipidemia,[14] migraines,[15] and transient ischemic attack[16] were based on the corresponding guidelines.

Table 1 - Demographic characteristics of the population. Characteristics Result Patients 95 Age, yr; median (interquartile range) 45.6 (35–60) Males 43 (45.3%) Females 52 (54.7%) *Smoking 31 (32.6%) *Hypertension 21 (22.1%) *Diabetes mellitus 9 (9.5%) *Hyperlipidemia 25 (26.3%) *Cryptogenic stroke 41 (43.2%) *Migraines 29 (30.5%) *Transient ischemic attack 15 (15.8%) *Unexplained syncope 8 (8.4%) *Unexplained dizziness 7 (7.4%)

Data are expressed as n (%) or mean ± standard deviation (range).

*Conditions present in the patients’ medical history.

2.2. Production and use of a contrast-saline mixture

We used a contrast-saline mixture consisting of 8 mL saline solution, 1 mL air, and 1 mL participant’s blood. The resulting fluid was vigorously mixed, at least 20 times, within two 10-mL syringes using a sterile 3-way IV connector.[17] Next, we administered an intravenous bolus injection of the contrast-saline mixture into the left antecubital vein using an 18G needle to allow the bolus to reach the right atrium.[18]

2.3. Methods and requirements of VM

Patients were trained to perform the VM before the tests. The patients were instructed to blow into a small soft plastic tube connected to a manometer. Subsequently, they were required to maintain a pressure of 40 mm Hg for 5 seconds. We evaluated an effective VM using the Doppler peak systolic velocity, which decreased by at least 25%.[19] The contrast-saline mixture was injected 5 seconds before the start of the VM.

2.4. Synchronous testing

Two experienced ultrasound technicians performed mutually blinded synchronous c-TTE and c-TCD tests in 95 patients. The remaining 5 patients were excluded. The imaging of 5 patients was uncompleted due to poor TTE image quality or inability to complete the VM. Synchronous meant that both c-TCD and c-TTE were performed during the same session (i.e., during the same process of contrast-enhanced ultrasound). During the contrast-enhanced ultrasound session, we examined the intracranial vessels and heart for microbubble signals via TCD and TTE, respectively. Both tests were performed with the same contrast-saline mixture, posture, and VM. A trained examiner instructed the patients to perform the VM. The procedure with the appearance of microbubbles was used in the analysis. We used the maximal microemboli signal count to determine the RLS grade during synchronous testing of c-TTE or c-TCD.

2.5. c-TCD

The c-TCD test was performed with a TCD ultrasound machine (Delica EMS-9PB; Delica, Shenzhen, China) with a probe frequency of 2 MHz. For this test, the participants laid down in a comfortable left lateral position. We performed a single-channel TCD and double-depth monitoring. The middle cerebral artery was observed through the temporal window. If the temporal window sound transmission was poor, a suboccipital window was selected to monitor vertebral arteries. The contrast-saline mixture was first injected during rest and subsequently with the VM. The test was repeated after the first VM, and the Doppler spectrum was recorded for 25 seconds. We defined the c-TCD outcome as positive for RLS when the TCD detected >1 microbubble within 25 seconds after injection of the contrast-saline mixture.[5] The maximal microbubble signal count was used to determine the RLS grade. The shunt grades in the c-TCD were as follows[20]: Grade 0TCD (negative) = no microbubbles detected; Grade ITCD = small shunt (1–10 microbubbles); Grade IITCD = moderate shunt (10–30 microbubbles but no curtain); and Grade IIITCD = large shunt (>30 microbubbles, including a curtain pattern) (Fig. 1).

Figure 1.:

Grading classification of right-to-left shunts in contrast transcranial Doppler ultrasonography; (A) Grade 0TCD = no microbubbles; (B) Grade ITCD = 1 to 10 microbubbles (arrow); (C) Grade IITCD = 10 to 30 microbubbles but no curtain (arrow); and (D) Grade IIITCD = curtain-like microbubbles (arrow).

2.6. c-TTE

c-TTE was performed with EPIQ 7C Color Doppler Ultrasound (Philips Healthcare, Best, Netherlands), with an X5-1 probe and a 1.0 to 5.0 MHz frequency. We focused the ultrasound probe on the atrial septum. We observed whether there was an interruption of echo continuity in the atrial septum and whether there was color blood flow through the interrupted site of the atrial septum. This was combined with color Doppler flow imaging. Before the contrast study, a TTE test was conducted to exclude other causes of cardiac abnormalities. We continuously recorded the apical 4-chamber view during contrast injections, which can better display the atria and ventricles. When the TTE detected microbubbles in the left atrium within 3 to 5 cardiac cycles, the results of c-TTE were considered positive.[9] The operation in which the most microbubbles appeared in the left atrium was regarded as the final result.[19] The degree of shunt severity in c-TTE was quantified as follows, based on the detected microbubbles in the left atrium[19]: GradeTTE 0 (negative) = no occurrence of microbubbles; Grade ITTE = 1 to 10 microbubbles; Grade IITTE = 11 to 30 microbubbles; and Grade IIITTE = >30 microbubbles and the left atrium is nearly filled with microbubbles or the presence of left atrial opacity (Fig. 2).

Figure 2.:

Semiquantitative grading of right-to-left shunt in contrast transthoracic echocardiography; (A) Grade 0TTE = negative; (B) Grade ITTE = 1 to 10 microbubbles (arrow); (C) Grade IITTE = 11 to 30 microbubbles (arrow); and (D) Grade IIITTE = >30 microbubbles (arrow); or (E) the left atrium is almost filled with microbubbles (arrow).

2.7. Statistical analysis

All statistical analyses were performed using SPSS version 22.0 (IBM, Armonk, NY). Categorical variables were summarized as counts and proportions. The differences between these 2 groups were analyzed using a 2 × 4 chi-squared test (independent 4 grid table chi-square test). Statistical significance was established at P < .05.

3. Results

Table 2 presents the comparisons between the synchronous test and each test individually. Ninety-five patients successfully underwent synchronous c-TCD and c-TTE (during the same session), with the data analyzed for each individual. The positive detection rates (percentage of patients with RLS) of Grade I, II, and III shunts with synchronous c-TCD and c-TTE were higher than with c-TTE alone or c-TCD alone (P = .047, P = .002, and P = .024, respectively). Overall, the positive detection rates of synchronous tests, c-TCD alone, and c-TTE were 69.5%, 51.6%, and 31.6%, respectively (P = .000, and P = .012).

Table 2 - Comparison of synchronous c-TCD and c-TTE with c-TCD alone and c-TTE alone. N = 95 Number of positive cases (%) Grade III Grade II Grade I Positive cases (n, %) Negative cases (n, %) c-TCD + c-TTE 13 (13.6%)* 19 (20.0%)‡ 34 (35.8%)† 66 (69.5%)§ 29 (30.5%) c-TCD alone 5 (5.3%)* 5 (5.3%)‡ 20 (21.1%)† 30 (31.6%)¥ 65 (68.4%) c-TTE alone 10 (10.5%) 17 (17.8%) 22 (23.2%) 49 (51.6%) 46 (48.4%) Chi-squared value * and *: 3.928 ‡ and ‡: 9.347 † and †: 5.071 § and ¥: 27.287
§ and : 6.366 P value * and *: .047 ‡ and ‡: .002 † and †: .024 § and ¥: .000
§ and : .012

c-TCD = contrast transcranial Doppler, c-TTE = contrast transthoracic echocardiography.

* Number of positive cases in RLS Grade III.

¥ Number of positive cases in c-TCD alone.

† Number of positive cases in RLS Grade I.

‡ Number of positive cases in RLS Grade II.

§ Number of positive cases in c-TCD + c-TTE.

Number of positive cases in c-TTE alone.

Among the 66 patients who were double-RLS-positive (both c-TTE and c-TCD showed positive results), as detected by the simultaneous test, 26 (39.3%) patients who underwent c-TTE alone had higher shunt grades detected than those who underwent c-TCD alone. Conversely, 5 (7.6%) patients who underwent c-TCD alone had higher shunt grades detected than those who had c-TTE alone (P = .000).

4. Discussion

This study shows that synchronous c-TTE and c-TCD can significantly improve the detection rate of RLS, leading to a more accurate classification of RLS. The synchronous test can create a synergistic effect of detections, significantly improve the overall detection rate of RLS, particularly for medium or large RLS, and help determine whether the patient has cardiogenic RLS.

In this study, the detection rate of simultaneous c-TCD and c-TTE was 2-fold higher than that of c-TCD alone and 12.8% higher than that of c-TTE alone. Furthermore, at different RLS grades, the synchronous test detected more cases than c-TTE alone, which detected more cases than c-TCD alone. Our findings show that sole studies of c-TCD and c-TTE may not accurately assess the presence of an RLS. For all grades, synchronous testing had higher rates of RLS detection than individual testing.

The reasons for the results mentioned above are as follows. First, synchronous c-TCD and c-TTE can combine the advantages of the 2 individual tests and avoid or reduce their shortcomings. This synergy increases the detection rate in patients with PFO. Specifically, c-TTE is disturbed and affected by body positioning, subcutaneous fat in the thorax, and gas in the air-tissue interface of the lungs.[9] However, these specific interference limitations could be avoided by using c-TCD. Regarding the microbubble analysis of c-TTE, the manual microbubble counts may be inaccurate, as the ultrasound probe may not capture a single small microbubble.[21] Generally, patients are in nonstationary conditions when performing VM, which would affect the TTE image quality.

We can calculate microbubbles by counting or using software that automatically identifies and calculates microbubble signals and can detect them at multiple depths in cerebral arteries during c-TCD testing. This is a more sensitive method of monitoring microbubbles compared to c-TTE evaluation. However, c-TCD can neither display intracardiac structures nor identify the source (e.g., pulmonary or cardiac) of RLS.[10,22] Alternatively, we can observe atrial septum and intracardiac structures[9] and conveniently identify which cardiac cycle the microbubbles appear in using c-TTE, which helps determine whether there is a cardiogenic RLS. Most sonographers define a positive intracardiac RLS as comprising the passage of ≥1 microbubble into the left atrium within 3 cardiac cycles.[9]

In case of poor temporal bone windows or suspicious microbubble signals[8] during c-TCD, c-TTE may be used. In addition, operators can mutually verify the examination results after synchronous c-TCD and c-TTE, which helps gain additional experience. A previous study showed that the specificity (100%) and misdiagnosis rate (0%) were significantly improved when c-TTE was simultaneously combined with c-TCD to diagnose PFO.[5] Previous studies have shown that the positive rate of c-TCD alone is approximately 30 to 40%,[19,23] which is consistent with our findings. In this study, the positive rate (51.6%) of c-TTE alone was slightly higher than in previously reported studies.[19] This may be related to the extensive experience of TTE operators in our study. This study showed that the positive rate of c-TTE was higher than that of c-TCD. We believe this may be because c-TTE detects RLS in the heart, which is the origin of cardiac RLS, while c-TCD detects only the intracranial part/branch of cardiogenic RLS.[24] The disagreement between the positive rates of RLS between c-TCD and c-TTE is likely because of the difference in research subjects, the quality of the VM, and the type of contrast agents used.[12,25] No convincing conclusion has been drawn so far; this scenario is not helpful for the clinical screening of RLS. The synchronous test effectively avoids the interference of the abovementioned factors in the examination results. Therefore, comparing the positive rate of c-TCD alone and c-TTE alone in the synchronous test was more convincing.

At different RLS grades, positive cases were more often detected by c-TTE than by c-TCD in this study. In a previous study, the detection rates of Grade 2 cases for c-TTE and c-TCD were 9.2% and 8.9%, respectively, while those of Grade 3 cases were 15.0% and 12.1%, respectively.[21] The number of positive cases detected by c-TCD was slightly higher than that by c-TTE, the results of the latter being similar to the synchronous test. Our experience suggests that different TTE examiners’ varying skills may impact the positive detection rate.

In our experience, synchronous c-TCD and c-TTE may save time, increase efficiency and patient compliance, and reduce the risk of the test, workload, and medical cost. Most hospitals use asynchronous testing,[10] which consists of c-TCD first, then c-TTE, or vice versa. To complete these tests sequentially rather than simultaneously, patients must undergo 2 contrast echocardiography procedures, reducing test efficiency and increasing the cost. Moreover, c-TCD and c-TTE are performed by different operators in separate places, which may impede the joint discussion and inspection of the test results. Synchronous c-TCD and c-TTE can address these shortcomings. This approach is noninvasive and can be simultaneously completed with only 1 intravenous contrast-enhanced ultrasound, which is associated with high patient compliance. However, this method can increase the testing costs for patients with negative results. Sonographers and neurologists should coordinate the test time and place to collaborate on the outcomes, increasing multidisciplinary cooperation.

The shortcoming of this study was that it was performed in a single center with a small sample size. Therefore, large, multicenter studies evaluating more patients are needed to confirm our findings.

5. Conclusion

In conclusion, performing synchronous c-TCD and c-TTE may significantly improve the detection rate and quantification of RLS. The synchronous test can save time, simplify the test process, and reduce the facilities’ risk, workload, and medical costs. This form of testing requires multidisciplinary cooperation. The synchronous test has great potential for clinical application, which deserves further study.

Author contributions

Conceptualization: Rong-bin Li, Liming Cao, Xu-dong Cai.

Data curation: Rong-bin Li, Liming Cao.

Formal analysis: Rong-bin Li, Liming Cao, Maolin Fu, Xu-dong Cai.

Methodology: Maolin Fu, Xu-dong Cai.

Writing – review & editing: Xu-dong Cai. RL and LC contributed equally to this work.

References [1]. Romano V, Gallinoro CM, Mottola R, et al. Patent foramen ovale – a not so innocuous septal atrial defect in adults. J Cardiovasc Dev Dis. 2021;8:60. [2]. Kumar P, Kijima Y, West BH, et al. The connection between patent foramen ovale and migraine. Neuroimaging Clin N Am. 2019;29:261–70. [3]. Giblett JP, Abdul-Samad O, Shapiro LM, et al. Patent foramen ovale closure in 2019. Interv Cardiol. 2019;14:34–41. [4]. Cantais E, Louge P, Suppini A, et al. Right-to-left shunt and risk of decompression illness with cochleovestibular and cerebral symptoms in divers: case control study in 101 consecutive dive accidents. Crit Care Med. 2003;31:84–8. [5]. Caputi L, Carriero MR, Falcone C, et al. Transcranial Doppler and transesophageal echocardiography: comparison of both techniques and prospective clinical relevance of transcranial Doppler in patent foramen ovale detection. J Stroke Cerebrovasc Dis. 2009;18:343–8. [6]. Wessler BS, Kent DM, Thaler DE, et al. The RoPE score and right-to-left shunt severity by transcranial doppler in the CODICIA study. Cerebrovasc Dis. 2015;40:52–8. [7]. Maillet A, Pavero A, Salaun P, et al. Transcranial doppler to detect right to left communication: evaluation versus transesophageal echocardiography in real life. Angiology. 2018;69:79–82. [8]. Katsanos AH, Psaltopoulou T, Sergentanis TN, et al. Transcranial Doppler versus transthoracic echocardiography for the detection of patent foramen ovale in patients with cryptogenic cerebral ischemia: a systematic review and diagnostic test accuracy meta-analysis. Ann Neurol. 2016;79:625–35. [9]. Mahmoud AN, Elgendy IY, Agarwal N, et al. Identification and quantification of patent foramen ovale-mediated shunts: echocardiography and transcranial doppler. Interv Cardiol Clin. 2017;6:495–504. [10]. Yang X, Wang H, Wei Y, et al. Diagnosis of patent foramen ovale: the combination of contrast transcranial Doppler, contrast transthoracic echocardiography, and contrast transesophageal echocardiography. Biomed Res Int. 2020;2020:8701759. [11]. Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in acute stroke treatment. Stroke. 1993;24:35–41. [12]. Wang W. New aspect of the 2010 china hypertension guideline [in Chinese]. Chin Commun Physici-Ans. 2011;24:21. [13]. Chinese medical association. China prevention and cure guidelines (2017) of type 2 diabetes [in Chinese]. Chin J Diabetes. 2018;10:4–67. [14]. Xu HY, Wu ZM, Lu ZL. Profile and interpretation of prevention and cure guidelines (2007) for chinese adult dyslipidemia [in Chinese]. Chin J Geriatr Cardiovasc Cerebrovasc Dis. 2008;10:238–240. [15]. Yu S. New classification and diagnosis of cephalagra [in Chinese]. Chin J Postgraduates Med. 2005;7:3–5. [16]. Department of Disease Prevention and Control, Ministry of Health, Society of Neurology, Chinese Medical Association. China prevention and cure guideline to cerebral vascular disease. Beijing: People’s Medical Publishing House. 2007:47–8. [17]. Cui F, Xu J, Cui W, et al. Special three-way pipe and matching syringe in contrast echocardiography of right heart and c-TCD: China. Patent ZL 201920722167.7 [P] [in Chinese]. 2020-02-18. [18]. González-Alujas T, Evangelista A, Santamarina E, et al. Diagnosis and quantification of patent foramen ovale. Which is the reference technique? Simultaneous study with transcranial Doppler, transthoracic and transesophageal echocardiography. Rev Esp Cardiol. 2011;64:133–9. [19]. Zhao E, Wei Y, Zhang Y, et al. A comparison of transthroracic echocardiograpy and transcranial doppler with contrast agent for detection of patent foramen ovale with or without the valsalva maneuver. Medicine (Baltim). 2015;94:e1937. [20]. Zhang Y, Jiang S, Zhu X. Chinese expert guidelines for the prevention of patent foramen ovaleassociated stroke [in Chinese]. Chin Heart J. 2021;1:1–10. [21]. Duan Z, Yang Z, Song B, et al. Combined application of c-TTE and c-TCD in detecting PFO-RLS [in Chinese]. Chin J Pract Nerv Dis. 2019;22:183–186. [22]. Droste DW, Schmidt-Rimpler C, Wichter T, et al. Right-to-left-shunts detected by transesophageal echocardiography and transcranial Doppler sonography. Cerebrovasc Dis. 2004;17:191–6. [23]. Tan Y, Zhang X, fan X, et al. Clinical analysis of c-TCD and c-TTE test in diagnosis and curative effect evaluation of migraine patients with patent foramen ovale and transcatheter closure treatment [in Chinese]. Jiangxi Med J. 2019:541309–1311,1340. [24]. Cao L, Huang X, Wang H. Relevance of small right-to-left shunt in contrast-enhanced transcranial Doppler in young and middle-aged patients with cryptogenic stroke: a report of two cases and literature review. Int J Neurosci. 2021;5:1–7. [25]. Chen W, Huang M, Chen H, et al. Comparison of transcranial Doppler (TCD) foam test and transthoracic echocardiography in diagnosis of cryptogenic ischemic stroke in middle-aged and young patients [in Chinese]. Chin J New Clinical Med. 2018;11:234–237.