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- PATIENTS AND METHODS
Portopulmonary hypertension (POPH), a complication of chronic liver disease, may be a contraindication to liver transplantation (LT) because of the elevated risk of peritransplant and posttransplant morbidity and mortality. Because POPH is frequently asymptomatic, screening with echocardiography is recommended. The only reliable technique, however, for diagnosing POPH is right heart catheterization (RHC). The aims of this study were to evaluate the current estimated systolic pulmonary artery pressure (sPAP) cutoff value of 30 mm Hg and to determine a better cutoff value. One hundred fifty-two patients underwent pretransplant echocardiography between January 2005 and December 2010. These echocardiographic results were compared with pulmonary artery pressures measured during the pretransplant workup or at the beginning of the transplantation procedure (both by catheterization). With a cutoff value of 30 mm Hg, 74 of the 152 patients met the criteria for POPH on echocardiography, although the diagnosis was confirmed in only 7 patients during catheterization; this resulted in a specificity of 54%. It would have been more accurate to use a cutoff value of 38 mm Hg, which had a maximal specificity of 82% and, at the same time, guaranteed a sensitivity and negative predictive value of 100%. With the incorporation of the presence or absence of right ventricular dilatation, the specificity even increased to 93% for this new cutoff value. In conclusion, the prevalence of POPH was 4.6% among LT candidates in this study. We can recommend that LT candidates with an sPAP > 38 mm Hg should be referred for RHC. With the cutoff value increased from 30 to 38 mm Hg, the number of patients undergoing invasive RHC during their evaluation could be safely reduced. Liver Transpl 19:602–610, 2013. © 2013 AASLD.
Portopulmonary hypertension (POPH), the presence of pulmonary hypertension in association with portal hypertension, is a known complication of chronic liver disease.[1-9] Prospective studies and case-control studies have documented that POPH occurs in approximately 5% to 6% of patients with advanced liver disease. In patients with portal hypertension, the association with pulmonary hypertension is seen in 2% to 6%.[10, 11] The incidence of POPH in patients referred for liver transplantation (LT) is 4% to 6%. Although Doppler echocardiography has proven to be a useful noninvasive screening tool for the detection of POPH, right heart catheterization (RHC) remains the gold standard for diagnosis.[3, 13, 14] The criteria for POPH include a mean pulmonary artery pressure (mPAP) > 25 mm Hg, a pulmonary vascular resistance (PVR) > 240 dyne·second·cm−5, and a pulmonary capillary wedge pressure (PCWP) < 15 mm Hg (measured during RHC).[1-9] In the setting of LT, the presence of POPH is associated with poor outcomes.[1, 4, 15] An elevated risk of morbidity and mortality due to right heart failure has been reported in patients with moderate (mPAP ≥ 35 mm Hg and < 45 mm Hg) to severe POPH (mPAP ≥ 45 mm Hg).[16-19] Mortality rates of 50% and 100% have been reported for patients with moderate and severe POPH, respectively. Krowka et al. demonstrated that patients with POPH have significantly poorer outcomes (with respect to survival rates and freedom from all-cause hospitalizations) than patients with idiopathic pulmonary hypertension, although patients with POPH have better hemodynamics at the time of diagnosis. mPAP values > 35 mm Hg are considered a contraindication for LT. This is the reason that patients with moderate to severe POPH are treated with vasodilator therapy before LT (ie, to lower mPAP to a value < 35 mm Hg because this is not associated with an additional intraoperative risk). Without medical intervention, a mean survival of approximately 15 months can be expected for patients with POPH.[4-6, 11, 18, 21, 22] In order to improve survival, patients with POPH should be treated with medication or undergo LT. A noninvasive estimation of the systolic pulmonary artery pressure (sPAP), documented during echocardiography, allows us to screen LT candidates as part of their pretransplant evaluation.[7, 13, 14, 21] Although it is generally agreed that LT candidates should be screened with echocardiography, different sPAP cutoff values at which patients should be referred for RHC are used at different centers. At our institution, an sPAP cutoff value of 30 mm Hg is used to detect POPH at an early stage in accordance with the results of the prospective study by Colle et al in 2003. With a cutoff value of 30 mm Hg, positive and negative predictive values of 59% and 100%, respectively, were reported for 165 LT candidates undergoing successive echocardiography and RHC. In other words, repeated sPAP measurements ≤ 30 mm Hg rule out POPH. By using this low cutoff value, which detects all degrees of POPH, we aim to reduce to a minimum the risk of missing patients with POPH during the preoperative evaluation. However, a drawback of this low cutoff value is the high number of false positives. In this study, the accuracy of Doppler echocardiography was assessed with different cutoff values, which ranged from 30 to 50 mm Hg.
- Top of page
- PATIENTS AND METHODS
POPH is known to be associated with an elevated risk of intraoperative and postoperative morbidity and mortality due to right heart failure. In this study, POPH was seen in 4.6% of the LT candidates. Because POPH is frequently asymptomatic, systematic screening is recommended.[4, 13, 14, 21] Previous studies have described the successful use of transthoracic Doppler echocardiography as a noninvasive technique for the detection of POPH as part of the pretransplant evaluation.[3, 7, 21, 25] However, there is considerable variation at different centers in the sPAP cutoff values at which patients should be referred for RHC. At our hospital, a cutoff value of 30 mm Hg for the estimated sPAP, which is measured during echocardiography, is used for referring patients for RHC to confirm or to rule out the diagnosis of POPH; this value was previously determined in a prospective study published in 2003 by Colle et al. They reported positive and negative predictive values of 59% and 100%, respectively, for 165 LT candidates undergoing successive echocardiography and RHC. Our institution chose to follow this approach in an attempt to reduce the risk of missing patients with POPH during the preoperative evaluation to a minimum. A drawback to date is the high number of false positives, which is represented by a low positive predictive value. Here, a positive predictive value of only 10% was calculated for the currently used cutoff value of 30 mm Hg. A false-positive test result can be interpreted as follows: a significant proportion of the false positives had an mPAP > 25 mm Hg measured during RHC, but in contrast to true POPH, this elevated value of mPAP was associated with a PCWP ≥ 15 mm Hg. In groups 2 and 3 (false POPH and no POPH, respectively), a highly significant correlation between mPAP and PCWP was documented. In group 1 (true POPH), there was no correlation. This difference in correlations between group 1 and groups 2 and 3 represents one of the main criteria for differentiating between true and false POPH (or no POPH). Showing the importance of RHC, Krowka et al. demonstrated that only 66% of patients with an sPAP > 50 mm Hg on echocardiography also have an elevated PVR. In our study, only 58% (7/12) of the patients with an sPAP > 50 mm Hg on echocardiography also had an elevated PVR. RHC is considered the only reliable tool for differentiating between patients with increased PVR (true POPH) and patients with normal PVR (false POPH), for whom an elevated mPAP is a result of hyperdynamic circulation, which is frequently seen in patients with cirrhosis. A mildly increased pulmonary pressure is found in 20% to 50% of patients with cirrhosis because of increased CO with normal PVR.[9, 27] This differentiation between true and false POPH is of great importance because there is no elevated risk of intraoperative and postoperative morbidity or mortality in patients with an increased mPAP due to a hyperdynamic circulation; this is in contrast to patients with true POPH. Krowka and Golbin and Krowka also proposed TPG as a hemodynamic parameter for diagnosing true POPH. An elevated TPG (>12 mm Hg) correlates with an elevated PVR and reflects the severity of the obstruction of pulmonary blood flow. Therefore, including TPG as one of the diagnostic criteria is another way of distinguishing an elevated mPAP in the setting of POPH from an elevated mPAP caused by hyperdynamic flow and volume overload. Consequently, we can argue that RHC is the only method for identifying true POPH. In contrast to its low specificity, the cutoff value of 30 mm Hg is also associated with maximal sensitivity and a negative predictive value of 100%. With this cutoff value, no patients with POPH would be missed during the preoperative workup. In summary, echocardiography with a cutoff value of 30 mm Hg can be considered a highly sensitive and safe screening method for the detection of POPH, although it has important limitations in terms of its specificity and positive predictive value. In this context, a new cutoff value, associated with a higher specificity yet guaranteeing a 100% negative predictive value, was determined.
With the aid of a receiver operating characteristic curve, a better cutoff value of 38 mm Hg was determined, and it was associated with a sensitivity and specificity of 100% and 82%, respectively. With the actual cutoff value increased from 30 to 38 mm Hg, the number of false positives could be safely reduced. With a cutoff value of 30 mm Hg, 74 patients underwent RHC, whereas if a cutoff value of 38 mm Hg had been used, only 32 patients would have been referred for RHC. In contrast to the use of 30 mm Hg, at which 44% (67/152) were wrongly referred, only 16% (25/152) would have been wrongly referred for RHC with a cutoff value of 38 mm Hg. Here we can conclude that with an increase in the cutoff value from 30 to 38 mm Hg, the number of patients referred for RHC could be safely reduced.
Some hospitals use higher cutoff values up to 50 mm Hg, which were also previously studied.[31, 32] According to the statistical results of this study, cutoff values > 38 mm Hg may be associated with a higher risk of missing patients with POPH during the preoperative phase (no 100% negative predictive values). Using a cutoff value of 50 mm Hg, Cotton et al. determined positive and negative predictive values of 37.5% and 91.9%, respectively. Kim et al. reported positive and negative predictive values of 74% and 97%, respectively, with a cutoff value of 50 mm Hg. In other words, an sPAP > 50 mm Hg predicts moderate to severe POPH in 3 of 4 LT candidates. In our opinion, the use of cutoff values > 38 mm Hg should not be recommended because of the elevated risk of morbidity and mortality due to right heart failure. On the other hand, the specificity, positive predictive value, and accuracy improve as the cutoff value increases. This advantage, however, does not offset the increased risk of missing patients with POPH. If patients with POPH were missed during the pretransplant evaluation, elevated pulmonary pressures would, however, be detected at the time of LT. This situation should be avoided anyway because the intraoperative detection of POPH implies the discontinuation of surgery and the loss of the donor liver.
We can conclude that a cutoff value of 30 mm Hg means too many false positives. A safe alternative is to increase the cutoff value to 38 mm Hg, which guarantees a 100% negative predictive value. Using higher cutoff values (eg, 50 mm Hg) means the loss of the 100% negative predictive value, although the specificity would be higher (95%). Therefore, an sPAP < 38 mm Hg can be used to rule out POPH, whereas higher cutoff values are more specific for the diagnosis of POPH. Whether patients with an sPAP between 38 and 50 mm Hg need to be referred for RHC varies from institution to institution. We advocate a safe approach with a minimal risk of missing patients with POPH during the preoperative evaluation.
Of course, additional echocardiographic findings and morphological and functional right ventricle parameters (a dilated right ventricle, evidence of right ventricle dysfunction, or septal flattening) that can be seen as indirect signs of significant pulmonary hypertension need to be incorporated into the pretransplant assessment. In order to further reduce the number of false positives, we also tested the impact of adding the presence or absence of right ventricular dilatation on the accuracy of Doppler echocardiography for detecting POPH. Right ventricular dilatation was defined as an RVEDD > 3.3 cm. With the incorporation of this extra variable into the screening test, the number of false positives dramatically dropped, and this resulted in increased specificity. For example, the specificity increased from 82% to 93% with the new cutoff value of 38 mm Hg.
Another serious problem is the de novo development of POPH: patients who do not have POPH at the time of their evaluation but are found to have acquired elevated pulmonary pressures at the time of transplantation. Previous studies have shown that POPH is progressive and can develop within time periods as short as 2 to 3 months. Normal findings during echocardiography do not exclude the possibility of POPH developing in the future. This is the reason that the onset of new symptoms (eg, dyspnea) while being on the waiting list for LT requires control echocardiography. In this study, no patients (0%) with de novo POPH were identified by the 3-month anticipatory screening.
A limitation of this study may be the fact that measurements of the right heart pressure were undertaken in dissimilar settings: as part of the preoperative evaluation by elective catheterization, at the beginning of transplantation (after general anesthesia but before abdominal incision), or both. Here we compensated by screening patients with echocardiography every 3 months and by ensuring that the time interval between the last moment of screening and the moment of LT was at most 3 months.
In summary, POPH occurs in approximately 4.6% of LT candidates. Transthoracic Doppler echocardiography is considered a highly sensitive screening test for the detection of POPH during the preoperative evaluation. The current sPAP cutoff value of 30 mm Hg, at which patients are referred for RHC to confirm or rule out the diagnosis of POPH, leads to a high number of false positives, and this results in a low specificity and a low positive predictive value. In this context, we investigated opportunities to increase the actual cutoff to a value associated with a lower number of false positives and a higher specificity yet guaranteeing a 100% negative predictive value. With an increase in the current cutoff value of 30 mm Hg, the number of patients referred for RHC could be safely reduced. On the basis of the results of this study, we recommend that patients with an sPAP > 38 mm Hg (as measured during echocardiographic screening) be referred for RHC. The incorporation of right ventricular morphology variables (eg, the presence of right ventricular dilatation) is another way of further increasing the specificity of Doppler echocardiography screening for POPH.