Author + information
- Ankur Kalra, MD,
- Gautam R. Shroff, MD,
- Darryl Erlien, MS,
- David T. Gilbertson, PhD and
- Charles A. Herzog, MD∗ ()
- ↵∗Chronic Disease Research Group, Minneapolis Medical Research Foundation, 914 South 8th Street, Suite S4.100, Minneapolis, Minnesota 55404.
Use of second-generation perflutren-based echocardiographic contrast agents (perflutren) is currently contraindicated in patients with known right-to-left, bidirectional, or transient right-to-left intracardiac shunts (intracardiac shunts) according to the U.S. Food and Drug Administration. This contraindication is primarily a result of concerns related to neurological complications and/or systemic embolism from animal data describing entrapment of perflutren lipid microspheres (>5 μm in diameter) within small arterioles and capillaries in skeletal muscles after intra-arterial injection. To date, no definitive evidence demonstrates patient safety concerns from perflutren use in humans with intracardiac shunts. We sought to evaluate the association between perflutren use and adverse events in these patients.
A retrospective cohort study was performed to evaluate the association of perflutren use (Definity, Lantheus Medical Imaging, North Billerica, Massachusetts; Optison, GE Healthcare, Milwaukee, Wisconsin) and adverse events in patients with and without known intracardiac shunts using the echocardiography database at Hennepin County Medical Center (Minneapolis, Minnesota). The study was approved by the institutional review board. Patients with known intracardiac shunts (diagnosed using right heart contrast [agitated saline/50% dextrose] or color flow Doppler) were identified from the database. Per laboratory protocol, perflutren was not used in patients with cyanotic congenital heart disease. Documentation of all adverse events reported by laboratory personnel within a 30-min interval after perflutren administration was identified. Individual patient charts were reviewed to confirm clinical events in all patients who experienced adverse events. All adverse events were further categorized as primary or secondary. Primary events were defined as neurological (stroke/transient ischemic attack) and/or systemic embolism. Secondary events, collectively referred to as complement activation-related pseudoallergy (CARPA), included angioedema, bronchospasm, hypotension, hypoxemia, low back pain, and urticaria. Fisher exact test was used to evaluate statistical significance.
From February 1, 1998, through November 30, 2012, 39,020 echocardiograms were performed using perflutren (Definity: 34,598; Optison: 4,422). An intracardiac shunt was not identified in 38,602 patients (nonshunt group). An intracardiac shunt was identified in 418 patients in the perflutren group (40 detected at rest only, 128 detected following Valsalva maneuver only, 84 detected with both; 166 unknown). Patients with left-to-right shunts only (n = 63; detected by color Doppler) were excluded from analysis. No primary adverse events occurred in the shunt group; 1 occurred in the nonshunt group (p = 0.99) (Table 1). One secondary adverse event occurred in the shunt group, and 34 in the nonshunt group (p = 0.31). All events occurred in studies using Definity (vs. Optison; p = 0.03). Right heart contrast studies were performed in 3,661 patients (1,432 with perflutren, 2,229 without perflutren); intracardiac shunts were diagnosed in 839 patients (23%).
The International Contrast Ultrasound Society recently raised concerns about the current contraindication of perflutren use in patients with known/suspected intracardiac shunts, recommending that this contraindication be removed to improve patient care and reduce unnecessary downstream testing (1). Agitated saline, a first-generation echocardiographic contrast agent (hand-agitated, with tremendous heterogeneity in bubble size) has been widely used during transthoracic and transesophageal echocardiograms to detect intracardiac shunts, without regulatory oversight (1). However, the greater diffusibility of air in the circulation, and lack of CARPA reactions to agitated saline, probably do not allow for a direct comparison with perflutren. The current observational study is the first to assess the use of perflutren in patients with intracardiac shunts, and it demonstrates that the overall incidence of adverse events was low in patients receiving perflutren. Importantly, perflutren use in patients with these shunts (without cyanotic congenital heart disease) was not associated with significant adverse neurological and/or systemic embolic events compared with use in patients without diagnosed intracardiac shunts. Similarly, perflutren use was not associated with any significant difference in secondary adverse events (CARPA reaction) in patients with intracardiac shunts. Of note, all CARPA reactions in our cohort occurred with use of Definity and were consistent with previously published data from our laboratory (2).
Study limitations include potential underestimation of adverse event incidence due to incomplete registry ascertainment, occurrence more than 30 min after perflutren administration, or occurrence in sedated or unconscious patients. Also, relatively modest numbers of intracardiac shunts were noted in the perflutren group, which was attributable to potential selection bias and possibly the impact of the Food and Drug Administration’s 2001 contraindication of perflutren use in patients with intracardiac shunts.
The current proscription of perflutren is logically untenable in clinical practice, as it is based on a “don’t ask, don’t tell” paradigm for shunt detection in patients who are potential candidates for receiving perflutren. Our data indicate that the current proscription of perflutren use in patients with intracardiac shunts should be rescinded.
Please note: Dr. Herzog owns equity interest in General Electric. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation