Ann Thorac Surg 2004;78:1635-1642
© 2004 The Society of Thoracic Surgeons
Original article: cardiovascular
Severity of Intraoperative Tricuspid Regurgitation Predicts Poor Late Survival Following Cardiac Transplantation
Curtis A. Anderson, MDa,
Stanton K Shernan, MDc,
Marzia Leacche, MDa,
James D. Rawn, MDa,
Subroto Paul, MDa,
Tomislav Mihaljevic, MDa,
John A. Jarcho, MDb,
Lynne W. Stevenson, MDb,
James Chen-Tson Fang, MDb,
Eldrin F. Lewisb,
Gregory S. Couper, MDa,
Gilbert H. Mudge, MDb,
John G. Byrne, MDa,*
a Division of Cardiac Surgery, Boston, MA, USA
b Cardiovascular Division, Boston, MA, USA
c Division of Cardiac Anesthesia, Brigham and Women's Hospital, Boston, Massachusetts, USA
Accepted for publication May 4, 2004.
* Address reprint requests to Dr Byrne, Division of Cardiac Surgery, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA
jbyrne{at}partners.org
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Abstract
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BACKGROUND: This study evaluates the significance of tricuspid regurgitation (TR) on long-term survival as detected by intraoperative transesophageal echocardiography at the time of orthotopic heart transplantation. Although significant (2+ to 4+) TR after orthotopic heart transplantation is rare, its influence on long-term survival is unknown, warranting further investigation.
METHODS: Between January 1992 and July 2001, 181 consecutive patients underwent orthotopic heart transplantation. Tricuspid regurgitation was graded by intraoperative transesophageal echocardiography after final separation from cardiopulmonary bypass in 130 of 181 patients (72%).
RESULTS: Although 80% (104/130) of patients had either no (0, n = 77) or trace (1+, n = 27) TR, 9% (12/130 patients) had mild (2+), 10% (13/130 patients) had moderate (3+), and 0.8% (1/130 patients) had severe (4+) TR. The severity correlated strongly with the presence of right ventricular dysfunction (p < 0.001). In a multivariate regression model, gender mismatch (p = 0.002) and right ventricular dysfunction (p < 0.001) were independent predictors for equal to or greater than mild (2+ to 4+) TR (p = 0.015). Although the degree of recipient pulmonary vascular resistance did not influence the grade (p = 0.600), higher pulmonary vascular resistance tended to increase the severity of TR in the setting of prolonged donor ischemic times (p = 0.054). Proportional hazards regression analysis demonstrated significantly decreased survival for patients with mild or greater (2+ to 4+) TR detected by transesophageal echocardiography at the time of transplantation (p < 0.001) and RV dysfunction (p = 0.023).
CONCLUSIONS: Even mild (
2+) TR identified by transesophageal echocardiography at the time of orthotopic heart transplant predicts poor late survival, suggesting a possible role for concomitant tricuspid valve repair at the time of transplant. Whether or not tricuspid valve repair will improve long-term survival is unknown.
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Introduction
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Despite the general success of orthotopic heart transplantation (OHT), a subset of patients still experiences early allograft dysfunction [1]. Right ventricular (RV) dysfunction is particularly common [2, 3], ranging in severity from clinically insignificant to fulminant right heart failure and death. Determining the cause of RV dysfunction is difficult, as it is often a multifactorial issue of donor-recipient compatibility. Although elevated recipient pulmonary vascular resistance (PVR) is considered a major risk factor [4], analysis of PVR has yielded inconsistent results [3, 5–8]. Additionally, RV failure remains a clinical problem despite screening for severe pulmonary hypertension [3, 7].
Transesophageal echocardiography (TEE) is utilized at the time of OHT to aid in de-airing and to assess allograft function after separating from cardiopulmonary bypass. An uncommon but important finding on intraoperative TEE is functional tricuspid regurgitation (TR), typically resulting from RV strain or dysfunction [9]. Although it is well known that mortality caused by fulminant RV failure after OHT can exceed 50% [10], the impact of subtler degrees of dysfunction is not known. Establishing a relationship between TR at the time of OHT and long-term patient outcome may help to identify a high-risk subset of patients, provide insight into donor-recipient compatibility issues, and guide therapy. Defining this relationship may also help identify a cohort of patients in whom tricuspid valve repair may be appropriate before final separation from cardiopulmonary bypass at the time of OHT. In this study, we sought to determine the incidence, significance, and predictors of TR at the time of OHT as demonstrated by intraoperative TEE.
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Material and Methods
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Patient Population
Between January 1992 and July 2001, 181 consecutive patients underwent OHT at the Brigham and Women's Hospital. Patients with a similar clinical history but for whom intraoperative TEE data were unavailable or incomplete were excluded from analysis (n = 51). Exclusion occurred if TEE was not performed or if the degree of TR could not be determined after reviewing the videotaped TEE examination. On this basis, 130 patients (72%) were deemed eligible for analysis and represent the study cohort for this report. Tables 1 and 2 summarize the recipient and donor demographics, respectively. Sixty-two percent of OHTs were performed with bicaval technique and the remainder with biatrial technique, the latter occurring primarily in the earlier periods of the study.
Study Design and Data Collection
Intraoperative TEE examinations were performed, videotaped, and interpreted by experienced staff cardiac anesthesiologists at the time of OHT. After approval was obtained from the Brigham and Women's Hospital Institutional Review Board, data pertaining to the postcardiopulmonary bypass TEE evaluation of TR and RV function were obtained from a computerized database devoted entirely to intraoperative TEE examinations.
Degree of TR
The degree of TR was determined by the greatest percentage of right atrial area occupied by the color flow Doppler TR jet visualized in the mid-esophageal four-chamber or right ventricular inflow-outflow tract views. The degree of TR was defined as follows: none (0); trace (1+), if < 10% of the right atrial area was occupied by the color flow Doppler jet; mild (2+), if 10% to 25% of the right atrial area was occupied by the color-flow Doppler jet; moderate (3+), if 25% to 50% of the right atrial area was occupied by the color-flow Doppler jet; and severe (4+), if > 50% of the right atrial area was occupied by the color-flow Doppler jet [11, 12].
Right Ventricular Dysfunction
The patient was determined to have RV dysfunction if there was documented evidence in the computerized TEE database of right ventricular free wall hypokinesis and dilatation (ie, right ventricular area larger than left ventricular area on the transgastric, short-axis mid-papillary, and mid-esophageal four-chamber views) [13, 14]. We recognize that this quantitative two-dimensional echocardiographic evaluation of RV systolic function may be suboptimal. Standard geometric formulas for volume calculations have only limited applicability given the nonuniform shape of the RV. Additional echocardiographic features, including RV free wall hypokinesis, systolic and diastolic septal flattening, and dilation of the right atrium, inferior vena cava, and pulmonary artery may support a diagnosis of RV failure. However, in the intraoperative clinical setting, semiquantification of RV area compared to left ventricular area determined by documented evidence of ventricular free wall hypokinesis, or dilatation, or both on TEE is usually sufficient. Right ventricular dysfunction was graded as 1 (mild-moderate) or 2 (severe). For the purposes of this study, however, both grade 1 and 2 were considered to indicate RV dysfunction.
Patient medical records were reviewed to determine whether or not intraoperative TEE findings correlated with late patient outcomes. We also sought to identify any donor or recipient characteristics that may predict late outcomes.
Statistical Analysis
Cox proportional hazards regression analysis was used to model the association between the time to death after transplantation and preoperative and postoperative covariates. Logistic regression analysis was used to model the association between TR and specific preoperative donor and recipient factors. For both types of analyses, forward stepwise regression models were fit to assess the relative importance of covariates in multivariate models. Variables with a p value < 0.1 were entered in the multivariate logistic model. The specific interactions between certain preoperative factors of interest were included in various models in an attempt to clarify issues of donor-recipient compatibility. Many different variables were analyzed and no adjustment was made for multiple comparisons.
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Results
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Intraoperative Transesophageal Echocardiography
Competency of the tricuspid valve was assessed in 130 of 181 patients (72%) after final separation from cardiopulmonary bypass. Eighty percent (n = 103) had no or trace (0 to 1+) TR, whereas 20% (n = 27) had mild or greater (2+ to 4+) TR. Table 3 indicates the breakdown of the degrees of TR at the conclusion of cardiopulmonary bypass immediately after OHT. There were no morphologic abnormalities of the tricuspid valve. To determine the significance of TR observed on intraoperative TEE, we performed proportional hazards regression analysis on the variable, time to death. Time to death for individual degrees of TR is illustrated in Figure 1. There was an incremental decline in survival for those patients with equal to or greater than 2+ TR. Separating patients into groups with no or trace TR (0 to 1+) versus those with mild or greater TR (2+ to 4+) generated survival curves, which demonstrate significantly worse survival in patients with mild or greater grades of TR (2+ to 4+; Fig 2). The time to death in the four groups of RV and TR are illustrated in Figure 3. Patients with mild or greater grades of TR (2+ to 4+) demonstrated the poorest survival, with or without RV dysfunction.
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Fig 3. Time to death by degree of TR and presence or absence of RV dysfunction. (RV = right ventricle; TR = tricuspid regurgitation.)
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Overall Mortality
The 30-day, 1-year, 3-year, and 5-year estimated survival rates during this period were 93%, 83%, 79%, and 75%, respectively. The breakdown by degree of TR and presence of RV dysfunction is presented in Table 4. The most common causes of death in the study cohort were cardiac failure (14/130; 11%), stroke (1/130; 0.8%) sepsis (5/130; 4%), and multi-organ system failure (MOSF) (4/130; 3%). The causes of death in the group with mild or greater severity TR (2+ to 4+ group), which totaled 10, were cardiac failure (n = 5), stroke (n = 1), sepsis (n = 2), and MOSF (n = 2). In patients with trace TR (0–1), causes of death, which totaled 6, were cardiac failure (n = 3), sepsis (n = 1), and MOSF (n = 2).
Morbidity
Major postoperative complications for the entire cohort included a 3% rate of stroke (4/130 patients); 4% deep sternal wound infection (5/130 patients); 8% pneumonia (10/130 patients); and 5.4% renal failure (7/130 patients). Reoperation for bleeding occurred in 9% (12/130) of patients who received a nonventricular assist device. Eleven percent (14/130 patients) required intraaortic balloon counter-pulsation (IABP) either to separate from cardiopulmonary bypass (n = 9) or for hemodynamic support later in the postoperative period (n = 5). Five patients required post-transplant insertion of a ventricular assist device because of allograft dysfunction. Biventricular assistance was required in 3 patients, isolated right ventricular assistance in 1 patient for severe RV failure and mild or greater severity TR (2+ to 4+), and isolated left ventricular assistance in 1 patient.
Early Course of Patients According to Severity of TR
In patients with mild or greater severity TR (2+ to 4+), the operative mortality was 38% (10/26 patients). One-year survival with RV dysfunction was 63% versus 57% without RV dysfunction (Table 4).) Five of 26 patients (19%) required IABP plus right ventricular assist device (RVAD), and 2 of 26 (8%) required a left ventricular assist device (LVAD). Thirty-four percent (9/26 patients) required open chest procedures. One patient required tricuspid valvuloplasty for severe TR and congestive heart failure within 2 months of OHT. In patients with no or trace TR (0 to 1+), the operative mortality was 7% (7/104). One-year survival was 92% with normal RV function and 83% with RV dysfunction. Two of 104 patients (2%) required an IABP, 1 of 104 (1%) required RVAD; 1 of 104 (9%) required LVAD; and 7% (8/104) required an open chest procedure for hemodynamic instability in the operating room.
Predictors of TR and Mortality
Preoperative donor-recipient characteristics were investigated using a logistic regression model to determine what factors were predictive of outcome in the group with mild or greater TR (grades 2+ to 4+) immediately after transplantation (Table 5). The strongest predictor of TR greater than or equal to 2+ to 4+ was the presence of intraoperative RV dysfunction assessed by TEE, followed by gender mismatch with a female donor, and increasing donor age. Although higher elevations of PVR did not predict TR, when the interaction of numerous variables was investigated, both increasing donor age and gender mismatch with a female donor had a synergistic effect together with increasing PVR in producing TR at the time of transplantation.
Predictors of RV Dysfunction
Preoperative donor-recipient characteristics were investigated using a logistic regression model to determine factors predictive of RV dysfunction immediately after transplantation. No variables were significantly associated with RV dysfunction in the univariate logistic model. However, when the interactions between numerous variables were investigated, we found two different models to predict RV dysfunction (Table 6).
Predictors of Mortality
Numerous donor and recipient preoperative characteristics were analyzed in a proportional hazards model (Table 7). Degree of TR, presence of RV dysfunction, increasing donor age, and gender mismatch with a female donor were statistically significant predictors of shortened survival. When placed into a multivariate model, all of these factors except donor age were independently associated with time to death (Table 8). No apparent survival advantage was detected for patients who underwent bicaval versus biatrial transplantation technique. Analysis of postoperative complications revealed that stroke (risk ratio 8.271, p < 0.001), reoperation for bleeding (risk ratio 2.283, p = 0.014), renal failure (risk ratio 13.671, p = 0.055), and requirement for ventricular assist device or IABP (risk ratio 4.010, p < 0.001) were predictors of an earlier death.
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Comment
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The principal finding of this study is that even mild TR (2+) detected by intraoperative TEE immediately after OHT predicts poor late survival. Whether concomitant tricuspid valve repair before final separation from cardiopulmonary bypass after OHT would affect the natural history of associated right ventricular dysfunction and survival is unknown.
Significant TR (2+ to 4+) is not commonly detected by intraoperative TEE immediately after OHT. In this study, 80% of patients had either no or trace TR (0 to 1+), whereas 20% of had mild or greater TR (2+ to 4+). However, the relevance of mild or greater TR (2+ to 4+) to outcome has not been evaluated in previous studies. Because the tricuspid valve was morphologically normal in all donor hearts, the etiology of TR in this cohort is presumably related to the presence of right ventricular dysfunction. Tricuspid regurgitation has been shown to be a reliable marker of right ventricular dysfunction in previous studies [9]. We have documented a greatly reduced late survival in those patients who have even mild TR (2+) after final separation from cardiopulmonary bypass independent of the presence of RV dysfunction. Patients with mild or greater TR (2+ to 4+) alone died as early as those with TR (2+ to 4+) and RV dysfunction; however, the curves tend to coincide after the first twenty months (Fig 3). We recognize that the limited number of patients with isolated TR (2+ to 4+) makes it difficult to extrapolate our results. Both gender mismatch with a female donor and increasing donor age independently contributed to the occurrence of TR and shorter survival post-transplant. Although PVR did not affect survival of the overall group, it did influence the development of TR and length of survival in patients with female-donor gender mismatch and those with older donor hearts. This finding indicates that these subgroups are less able to tolerate even modestly elevated PVR.
More than one third of transplants performed during this study period involved gender mismatch. In nearly 80% of these cases, a female heart was transplanted into a male recipient. These patients had a higher frequency of significant TR and a shorter survival. As expected, in this subgroup of patients, recipient weight exceeded donor weight (mean = 2.2 kg). Although the weight differences are not dramatic, one could consider this as a potential predictor of poor outcome. However, a comparison of the size and contractile function of the man heart across gender lines based purely on weight may not be valid because of significant differences in lean body mass. Further investigation is required to fully understand these findings.
Another potential prognostic factor, worsening survival with increasing age of the donor heart, has been previously reported [15]. In our analysis, donor age more than 45 years old correlated with poorer outcome. This negative impact was demonstrated independent of other risk factors, but within the subgroup of patients with donor hearts exceeding 45 years of age, increased PVR was less well tolerated. This threshold for donor age has been reported previously [15, 16].
Study Limitations
In this study, intraoperative TEE data were obtained retrospectively from a computerized database. Doppler techniques have been reported to have a sensitivity between 74% and 100% and a specificity of 85% to 100% for the diagnosis of TR [17]. A prospective, echocardiographic analysis including pulsed wave Doppler evidence of systolic hepatic vein or caval flow reversal, tricuspid valve annular width, and quantitative measures of regurgitant volumes, may provide a more thorough technique for evaluating TR. However, color flow Doppler is practical in the clinical setting and a relatively sensitive and specific technique for grading TR severity. For example, absolute jet length and area obtained with color flow Doppler have been shown to correlate reasonably well with angiographic grade [18]. On the other hand, jet area and length are related not only to regurgitant volume, but also to momentum, which is the product of flow and velocity [17]. A TR jet having the same absolute area as a mitral regurgitant jet may actually represent a greater volume because right ventricular pressure is typically less than left ventricular pressure. Consequently, one cannot simply extrapolate from criteria used to quantify mitral regurgitant jets to the tricuspid valve [17]. Thus, in the intraoperative clinical setting, color-flow Doppler is a practical, relatively sensitive and specific technique for grading TR severity.
Standard geometric formulas for volume calculations have only limited applicability given the shape of the right ventricle, which is another limiting feature of this retrospective analysis [13]. Additional echocardiographic features, including RV free wall hypokinesis, systolic and diastolic septal flattening [19], as well as dilation of the right atrium, inferior vena cava, and pulmonary artery may support a diagnosis of right ventricular failure [20–2223].
Other limitations related to the study's retrospective design include lack of ability to standardize the hemodynamic profiles of patients during TEE examination. In addition, intraoperative TEE data were not available for 51 patients undergoing OHT. Whether exclusion of these patients represents an unknown bias that would affect the results is unknown. These issues can probably only be addressed in a prospective trial.
We also acknowledge that many different variables were analyzed in a multivariate model with a limited data set and that no adjustment has been made for multiple comparisons. However, the mathematical tendency of stepwise regression is to adjust for each comparison while assessing the relative contribution of each variable. Moreover, the results of our analysis are concordant with the existing medical literature. Additionally, we recognize that other interpretations could be derived from this analysis.
Implications
The discrepancy between available donor hearts and the large number of patients with end-stage cardiac disease for whom OHT is the only definitive therapy has created an environment accepting of less than optimal donors. Deepening our understanding of the interactions between donor and recipient factors will enhance the appropriate distribution of organs, minimize early allograft dysfunction, and prolong the lives of OHT patients.
The role of elevated PVR in right ventricular dysfunction is variable, and an effort should be made to avoid matching less robust donor hearts with recipients who have significant but not prohibitory elevations in PVR. By our analysis, female donors transplanted into male recipients and donor hearts beyond the age of 45 fit this criterion.
Patients who demonstrate mild or greater TR (2+ to 4+) on intraoperative TEE after separation from cardiopulmonary bypass have a shortened long-term survival. This subset of patients merits particular attention with regard to vigilant postoperative management and close follow-up upon discharge. Tricuspid valve repair is a simple surgical procedure, which reliably corrects TR. Complications are rare, and the addition of this procedure after OHT in patients with mild or greater TR (2+ to 4+) should not affect the ability to perform right ventricular biopsy during the postoperative period. Whether or not repair of the tricuspid valve before final separation from cardiopulmonary bypass can change the natural history of TR in association with right ventricular dysfunction and late survival is unknown. This possible association warrants further retrospective study, and if confirmed, a randomized trial comparing OHT alone versus OHT plus tricuspid valve repair in patients who demonstrate mild or greater TR (2+ to 4+) on TEE after cessation of cardiopulmonary bypass.
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Abstract
Introduction
