Grading of PFO Shunt Severity on Bubble Study
The degree of right-to-left shunt on a positive bubble study is graded based on the number of microbubbles appearing in the left atrium, with the most widely used system classifying shunts as: Grade 0 (no bubbles), Grade 1 (small: <20 or <30 bubbles), Grade 2 (moderate: 20-30 to ~25 bubbles or moderate filling), and Grade 3 (large: >25-30 bubbles or complete opacification of the left atrium).
Grading Systems
The evidence reveals two main semi-quantitative grading approaches used in clinical practice and research:
Standard Classification System
The grading is performed during contrast echocardiography (bubble study) with agitated saline:
- Grade 0: No microbubbles in the left atrium (no shunt)
- Grade 1: Small shunt with <20-30 microbubbles in the left atrium
- Grade 2: Moderate shunt with 20-30 bubbles or moderate filling of the left atrium
- Grade 3: Large shunt with >25-30 microbubbles or complete opacification of the left atrium 1
Clinical Trial Definitions
The major stroke prevention trials used slightly different thresholds but similar concepts:
REDUCE trial: Classified shunts as moderate (6-25 microbubbles) or large (>25 microbubbles), with 81% of enrolled patients having moderate or large shunts 2
CLOSE trial: Defined a large interatrial shunt as >30 microbubbles in the left atrium within three cardiac cycles after right atrial opacification 2
RESPECT trial: Used "substantial" shunt size (grade 3) as a predictor of benefit from closure 2
Technical Considerations
Timing of Bubble Appearance
Critical distinction: Bubbles appearing in the left atrium within 3-4 cardiac cycles after right atrial opacification indicate an intracardiac shunt (PFO or atrial septal defect). Bubbles appearing after 3-8 cardiac cycles suggest an intrapulmonary shunt rather than a PFO 1, 3.
Enhancing Detection
- Valsalva maneuver transiently increases right atrial pressure and enhances sensitivity for detecting PFO, particularly smaller shunts 4, 5
- The grading should ideally be performed both at rest and with provocation
Measurement Correlation
When color Doppler is used in addition to contrast, the maximal color Doppler jet width within the atrial septum correlates well with actual PFO diameter (r=0.99) 5.
Clinical Significance of Grading
Higher grades correlate with increased clinical risk:
- Grades 2 and 3 have positive predictive values of 0.21 and 0.87 respectively for requiring treatment 1
- Larger shunts are associated with higher rates of cerebral complications 1
- Patients with large shunts (>25-30 microbubbles) combined with atrial septal aneurysm derive the greatest benefit from PFO closure for stroke prevention 2, 6
Diagnostic Modality Considerations
- Transthoracic echocardiography (TTE) with contrast: 98-99% sensitivity, 67-91% specificity for detecting PFO 1
- Transesophageal echocardiography (TEE) with contrast: Considered gold standard with 100% specificity and superior ability to detect mild/moderate shunts 5, 7
- Transcranial Doppler (TCD): 100% negative predictive value, 92% positive predictive value compared to TEE 8
Common Pitfall
Do not rely on transthoracic echo alone for small shunts: TTE has only 65% negative predictive value and inferior detection of mild/moderate shunts compared to TEE. If clinical suspicion remains high despite negative TTE, proceed to TEE 7.