Hypoxia in sickle cell disease due to right to left shunting
Authors: Payal C. Desai, Nicole Kendel, Ying Huang, Melanie Heinlein, Eric Kraut, Subha Raman
Journal: American Journal of Hematology (2018)

Sickle cell disease (SCD) is an inherited anemia that affects 1 in 500 African-American at birth, and it is estimated that 90 000-100 000 Americans have this disease. Clinical syndromes, including vaso-occlusive pain crisis, stroke, acute chest syndrome, and other chronic organ damage due to vascular complications, lead to cumulative morbidity and early mortality in many subjects with SCD. SCD is associated with significant and pleiotropic cardiovascular sequelae, including diastolic dysfunction, left atrial dilation, hyperdynamic cardiac output, pulmonary hypertension, tricuspid and mitral regurgitation, atrial arrhythmias, left ventricular dilation and hypertrophy, myocardial perfusion abnormalities and ischemia.1-4 A retrospective study of mortality in adult patients with SCD demonstrated that cardiac complications were commonly implicated in cause of death.5 During a review of cardiovascular complications seen in our clinic, we identified patients with SCD who had right-to-left shunting (RLS, venous to arterial) on saline-contrasted (“bubble”) echocardiography, both at steady state and crisis. These RLS were intracardiac (often a Patent Foramen Ovale [PFO]) or intrapulmonary. Anecdotally, many of these patients developed episodic hypoxemia, especially during hospitalizations. While sometimes attributable to acute chest syndrome or pulmonary embolism, clinically some of these patients developed hypoxemia without a clear etiology. We sought RLS in sickle cell patients and its relationship to unexplained hypoxemia. An IRB approved retrospective chart review was conducted to identify subjects with SCD who were seen at Ohio State University between July 1, 2005 and July 1, 2015. Subjects included in this study had echocardiograms that demonstrated any degree of RLS. Wherever possible, simultaneous clinical and laboratory features were recorded at the time that shunting was diagnosed. The presence or absence of shunting and type of shunting, approximated by “early” or “late” appearance of agitated saline in the left ventricle, was verified by review from a single cardiologist. Patient characteristics were summarized using descriptive statistics. The Kruskal-Wallis test or Fisher's exact test was used to compare characteristics between patients with intracardiac or intrapulmonary shunting for continuous and categorical variables, respectively. A total of 36 (18 female [F], 18 male [M]) of a total adult population of 352 (10%) patients seen at the Ohio State Comprehensive Sickle Cell Center were noted to have shunting on echocardiogram reported during the interval reviewed. Independent review by a single cardiologist confirmed the presence of a shunt in 32 patients (9%, 95% CI: 6%-13%) (15F,17M). Since not all patients underwent bubble echocardiography, this is an estimate of lowest possible prevalence. The median age at the time of reporting was 29 (range: 18-51 years). Shunting was observed in patients of all genotypes, but primarily in subjects with HbSS (94% SS/SB0; 6% SC/SBeta+). Fourteen subjects (6F, 8M, 44% of all shunts, 95% CI: 26-62) had intra-cardiac RLS and 18 subjects (9F, 9M, 56% of all shunts, 95% CI: 38%-74%) had intra-pulmonary RLS. 14/14 intra-cardiac shunts were via PFO. At the time of the index echo, 27/32 subjects (87%) were hospitalized and 19/32 (59%) had clinical hypoxia, defined as an spO2 < 92%. More patients with cardiac shunting had transient hypoxemia during crisis compared with patients with pulmonary shunting (n = 10/14, 71% vs. n = 9/18, 50%, respectively, P = 0.29). 19/32 subjects (59%) had concurrent CT angiography, one of whom (with a PFO) had a pulmonary embolism. Nine subjects (28%) had a concurrent diagnosis of acute chest syndrome (4 with cardiac shunting and 5 with pulmonary shunting). The median value of tricuspid regurgitant jet velocity (TRV) was 2.67 m/s (range: 2.0-3.8 m/s, n = 27) during crisis. The median TRV was 2.85 m/s (range: 2.0-3.27 m/s) during crisis in subjects with intra-cardiac shunting, but lower,2.6 m/s (range: 2.2-3.8 m/s), in subjects with intra-pulmonary shunting. We identified RLS, half intra-cardiac and half intra-pulmonary in 32 people with SCD, most of whom were examined during crisis. Patients with SCD may have either intra-cardiac or intra-pulmonary shunting, the degree of which may exacerbate during vaso-occlusive crises, as has been reported for elevated TRV.6 The exacerbation of RLS during acute crises and increased TRV may indeed be related. There may be a possible increase in right atrial pressure resulting in worsening of the intra-pulmonary shunt or transient opening of the intra-cardiac shunt (PFO) due to increased pressure. The late appearance of bubbles may represent a true intrapulmonary shunt via acquired (most likely) or congenital malformation. Intrapulmonary shunting has not previously been described specifically during acute chest syndrome, but has been described in people with SCD, primarily those with HbSS.7, 8 In patients without SCD, but with pneumonia, intrapulmonary shunting has also been described. The exacerbation of these shunts during crises could have significant implications for progressive hypoxia during crises and more dire complications, such as multi-organ failure. While the long-term implications of these findings are being studied, intra-cardiac or intra-pulmonary shunting should be considered in the differential of patients with SCD presenting with increasing hypoxemia of unclear etiology. We would like to acknowledge Dr Jane Little for her insight and editing of the article. P.D. designed the study, helped to conduct the study, and wrote the article, N.K. helped to conduct the study and write and edit the article, M.H helped to conduct the study and edit the article, Y.Y. helped with the statistical support and edit the article, E.K. helped design the study and wrote the article, S.R. helped to design the study, conduct the study, and edited the article. The authors have no conflicts of interest to declare pertinent to this article.