Portopulmonary hypertension (PPH) is a severe complication of liver cirrhosis and until recently it was considered to be a contraindication for liver transplantation (LT) (1). However, this contraindication has been re-examined as a result of improved anesthetic and critical care management, advances in understanding of PPH physiology and improved pharmacologic treatment for primary pulmonary hypertension (2).
Many factors may contribute to the development of PPH in patients with an end-stage liver disease (ESLD) and portal hypertension: hyperdynamic circulation (3), pulmonary artery vasoconstriction and /or obliteration, caused by increased release of endothelin, leads to increased pulmonary vascular resistance (4). Reports on the incidence of PPH in patients with ESLD vary greatly. Autopsy studies have demonstrated pulmonary vascular changes consistent with PPH in 0.7% of patients with cirrhosis (5). Based on different diagnostic criteria in published studies, 2–10% of ESLD patients have been estimated to be at risk of developing PPH (4, 6). It has been estimated that up to 16% of patients assessed for liver transplantation may have PPH (7). As only 60% of patients with PPH are overtly symptomatic, the PPH diagnosis requires a high degree of medical alertness and skills. The clinical signs are often very similar or even indistinguishable from those of ESLD (8). The recommended preliver transplantation work-up includes echocardiography and electrocardiography (9), to assess noninvasively the heart function. Based on early reports of high perioperative mortality in LT recipients (mainly caused by a right heart failure), many clinicians have become very conservative with regards to inclusion of patients with PPH on liver transplantation candidates’ lists (10). Based on their retrospective analysis of seven patients with PPH that were transplanted at the Mayo Clinic and the thirty-six patients that they retrieved from the literature, Krowka and colleagues (11) concluded that patients with severe PPH (MPAP >50 mm Hg) should not undergo LT because they had a 100% mortality. Moreover, patients with MPAP between 35 and 50 mm Hg had a mortality rate of 50%. This absolute contraindication could not be confirmed in a prospective follow-up study of the Multicenter Liver Transplant Database that reported a 60% postLT-survival of patients with MPAP >50 mm Hg, and a 36% mortality (13/36) in the total group of patients with MPAP >35 mm Hg (12). All deaths occurred within 18 days of LT. Recently, an increasing number of patients with PPH successfully underwent liver transplantation (6, 7, 13, 14), and two reports (7, 15) showed that patients with mild or moderate PPH had similar long-term outcome after LT than patients without PPH.
Because PPH is not an absolute contraindication for LT in our center, we were able to study the incidence of PPH in LT recipients and it’s influence on the 30-day mortality rate following LT. Furthermore, we wanted to determine the sensitivity and specificity of transthoracic Doppler echocardiography and electrocardiography as noninvasive tools to determine PPH in patients undergoing LT.
PATIENTS AND METHODS
Seventy-four consecutive patients who underwent LT for ESLD at our department and were postoperatively monitored and treated at our Intensive Care Unit (ICU) were included in this prospective, observational study. All the transplanted patients agreed to the participation in the study. The transplantations were performed between February 2004 and November 2005. The study was undertaken with the approval of the local Research Ethics Committee and only after obtaining written informed consent from each patient or their next of kin. Majority of the recipients were classified as Eurotransplant T2, which is comparable to United Network for Organ Sharing status 2a. This includes also patients with acute decompensation of advanced liver cirrhoses requiring preoperative intensive care treatment.
All patients were operated using standardized surgical and anesthesiological techniques. The transplantations were performed with a classical cava replacement (n=41) and piggy-back technique (n=31) without venovenous bypass. The induction of anesthesia was performed with propofol, fentanyl, and rocuronium for facilitating tracheal intubation. The anesthesia was maintained by continuous infusion of propofol and fentanyl. Inhalational iloprost was used intraoperatively in two cases with severe PPH. On the ICU, we used routinely inhalational iloprost (6×20 μg per day), as long as MPAP exceeded 30 mm Hg.
Standard intra- and postoperative monitoring included pulmonary artery catheter, which was used for continuous measurement of systolic and diastolic pulmonary arterial pressure (SPAP, DPAP), MPAP, as well as regular periodic determination of pulmonary capillary wedge pressure (PCWP), pulmonary vascular resistance (PVR), and cardiac index (CI). PPH was defined as a MPAP higher than 25 mm Hg and a PVR of more than 120 dyn·sec·cm−5 (1, 16). The first measurements in all patients were performed after induction of anesthesia in a stable state before the surgical intervention. Hemodynamic evaluation was repeated during surgery and on admission to ICU.
Patients were divided into four groups according to the MPAP: normal PAP (nPAP) <25 mm Hg, mild PPH (25–34 mm Hg), moderate (35–44 mm Hg) and severe PPH (MPAP >45 mm Hg). Preoperative cardiac work-up consisted of transthoracic Doppler echocardiography in all patients, as well as standard 12-lead electrocardiogram (ECG). Complete two-dimensional and Doppler transthoracic echocardiography were performed by cardiologists who are board certified in echocardiography. Echocardiograms were analyzed to assess valvular anatomy, left- and right-sided chamber, septum, and cardiac function. Tricuspid regurgitant flow was identified by color flow Doppler techniques and the maximum jet velocity (v) was measured by continuous wave Doppler. Right ventricular systolic pressure (RVP) was estimated based on the modified Bernoulli equation and was considered to be equal to the SPAP in the absence of right ventricular outflow obstruction: SPAP (mm Hg) = RVP = 4v2 + right atrial pressure (RAP) (17, 18). RAP was estimated to be 5, 10, and 15 mm Hg based on the degree of vascular filling of the inferior vena cava (19). Sonographer’s reports were reviewed for following abnormalities: dilated or hypertrophic right ventricle, interventricular septum shift, estimated SPAP >40 mm Hg. Electrocardiograms were reviewed for right ventricle hypertrophy, right axis deviation, and right bundle-branch block (RBBB), as signs of possible PPH. The possibility of PPH was raised if any of the cited variables suggested pulmonary hypertension.
Patents’ clinical status was assessed by determining the SAPS II score (Simplified Acute Physiology II score) (20). Le Gall (20) developed the SAPS II score which includes only 17 variables: 12 physiological variables, age, type of admission (scheduled surgical, unscheduled surgical, or medical), and three underlying disease variables (acquired immunodeficiency syndrome, metastatic cancer, and hematologic malignancy). This score provides an estimate of the risk of death without having to specify a primary diagnosis. The risk for death increases with the score exponentially (e.g., a SAPS II score of 25 predicts a hospital mortality of 6.5%, whereas a SAPS II of 49 predicts a hospital mortality of 43.8%).
Data are expressed as mean and SD. Categorical variables were analyzed by Chi-squared test with Yates correction. Continuous variables were analyzed by one-way analysis of variance and t test when normal distribution was given. Nonnormally distributed continuous variables were analyzed by Kruskal-Wallis one-way analysis of variance on ranks. Mann-Whitney Rank Sum test was performed when equal variance test failed. P<0.05 was considered significant.
Of the 74 liver transplanted patients, 40 were men and 34 women. The main diagnoses leading to transplantation were alcoholic cirrhosis, hepatitis B and C virus, and primary scleroziting cholangitis (Table 1). Mean age of the patients was 49.6±11.6 years. Median SAPS II for all patients was 32 (range: 4–92). No statistically significant differences were found regarding the cause of liver disease in patients with normal PAP compared to the patients with PPH.
Forty-eight patients (69%) had normal MPAP (<25 mm Hg) at the time of transplantation. In 26 patients a MPAP >25 mm Hg was found, but only 23 patients (31% of the total number of the transplanted patients) fulfilled the additional criterion for PPH (PVR >120 dyn·sec·cm−5). The majority of the PPH patients (16 of 23 patients; 70%) had mild PPH, five patients (22%) suffered from moderate PPH and two patients (9%) had severe PPH. Mean PCWP was significantly lower in patients with normal PAP as compared to patients with PPH (8±3 mm Hg vs. 12±4 mm Hg, P<0.01). Increase in PCWP was more pronounced in the moderate (14.2±5.2 mm Hg) and in the severe group (15.5±0.7 mm Hg) then in the mild PPH group. Mean central venous pressure (CVP) of the patients with nPAP was significantly lower than in patients with PPH (6.2±4 mm Hg vs. 7.9±3.2 mm Hg, P<0.05). The increase in CVP in PPH was more prominent in patients with moderate and severe PPH (8.1±4.3 mm Hg and 12.1±2.8 mm Hg, respectively). However, although CVP and pulmonary arterial pressure were increased, cardiac index (CI) was not negatively affected. In patients with normal PAP, CI was 4.8±1.7 l/min/m2, as compared with 5.4±1.7 l/min/m2 in PPH patients.
Thirty-day Mortality Rate and Causes of Death
Thirty-day mortality rate (MR) for the group with normal PAP was somewhat lower as compared to the PPH group (12% vs. 22%), but this difference did not reach statistical significance (P=0.1). Mortality rate did not differ significantly between patients with mild PPH (4 of 16, 25%) and moderate PPH (1 of 5; 20%). Both of the patients with severe PPH survived. In the patients with normal PAP, a nonfunctional graft was the most common cause of death and sepsis was the most common cause of death in the PPH group (Table 2). Surprisingly, no death was related to cardiopulmonary dysfunction.
ICU Stay and Requirement for Ventilation
The duration of mechanical ventilation and ICU stay were not significantly different between the two groups (nPAP vs. PPH). There was only a slight trend for shorter ventilation time and length of stay in the ICU in patients with nPAP compared with patients with PPH (Figs. 1 and 2).
Predictive Value of Pretransplantation Echocardiogram and Electrocardiography
Preoperative Doppler echocardiography and ECG were obtained in all patients (Tables 3 and 4). Eighty-eight percent (48 of 51) of the patients with nPAP had normal ECG. Six percent of the patients with normal PAP had signs of right ventricular hypertrophy (right axis deviation and/or RBBB), suggesting pulmonary hypertension. Fifteen of the 23 patients in the PPH group had a normal ECG. Only in 8 of 23 patients the ECG revealed pathological changes suggestive of a right ventricular dysfunction. Recorded echocardiograms showed no indications for the affection of pulmonary circulation in 90% (46 of 51) of the patients in the nPAP group. Ten percent of the patients with nPAP had echocardiography results consistent with PPH.
The sensitivity of Doppler echocardiography in the diagnosis of PPH was 64%, whereas the specifity was 77%. The positive predictive value (PPV) of Doppler echocardiography for PPH was 39% and the negative predictive value (NPV) 90%. Echocardiograms of nine patients indicated possible PPH, but none of these patients was removed from the transplantation list.
The results of the ECG in the PPH were comparable with the data obtained from the echocardiography (see Tables 3 and 4).
The presented study showed that the incidence of PPH in our liver transplantation patients was high (31%), but this did not influence the 30-day mortality rate following LT. Importantly, the two patients with severe PPH survived and are currently (1 and 2 years after the transplantation) doing well.
In the present study, we also showed that the CVP and PCWP were significantly higher in the PPH group without any impact on the hemodynamics. Hemodynamic definition of PPH includes increased MPAP (MPAP >25 mm Hg) and elevated PVR (PVR >120 dyn·sec/cm−5) (1, 16). Thus, not all patients with ESLD and MPAP >25 mm Hg have PPH. In our study, 26 patients had a MPAP >25 mm Hg, but only 23 fulfilled the additionally criteria of increased PVR. Nevertheless, elevated MPAP in ESLD patients is the cardinal feature of this syndrome. Data on the incidence of PPH in patients with liver failure are conflicting. The reported incidence in patients with cirrhosis is between 0.6% and 4% (5, 13). However, the prevalence of PPH in patients referred for LT was reported to be between 8.5–26% (15, 21). The higher incidence of patients with PPH in our transplantation unit may be contributed to the difference in acceptable transplant criteria for liver transplantation between institutes and countries (22).
The rationale for screening for pulmonary hypertension in liver transplant candidates has been that the outcome of LT with PPH may be compromised. As the majority of deaths in LT patients occur in the first month following transplantation (23), we analyzed the 30-day mortality of our patients. Our data show only a small, statistically insignificant increase in 30-days mortality rate of patients with PPH compared with patients with normal PAP. The mortality rate in the nPAP group of our patients is comparable with the results of Sadler et al. (23), who published a 30 day survival rate of 92% in LT recipients without PPH. Among our patients with PPH who died, almost all had mild PPH. Interestingly, both our patients with severe PPH survived. The median SAPS II score (20) of the patients who died in the mild PPH group was 47, as compared to SAPS II scores of 34 and 29 for the two patients with severe PPH group (MPAP=61 mm Hg and 53 mm Hg). SAPS II Score of 47 is associated with a predictive mortality of 39.2% as compared with SAPS II of 34, which reveals a predictive mortality of 15.3% and SAPS II Score of 29 with only 9.8% (20). From this point of view, we are not surprised that the two patients with severe PPH had a better outcome as compared with patients with mild or moderate PPH. These two patients responded postoperatively very well to the treatment with inhalational iloprost, which lowered their MPAP for more than 10 mm Hg.
These results support earlier findings that the severity of ESLD does not correlate with the degree of MPAP (24) and that not every patient with PPH should be denied LT. If the patient is in a good general clinical condition, one should consider transplantation as soon as possible, as it is the only causative treatment for ESLD and an early LT increases the chances for a long term survival (3).
Some researchers have reported high mortality rates in patients with PPH undergoing liver transplantation (as high as 80 −100% in patients with severe PPH) (10, 11, 14) and this has significantly restricted the indication for liver transplantation in patients with PPH. However, Taura et al. (6) revealed that moderate PPH without a fixed level of pulmonary hypertension in patients undergoing liver transplantation was not related to a poor outcome. Furthermore, Starkel et al. (21) reported a good prognosis following liver transplantation even in patients with moderate to severe PPH when their cardiac index was preserved. In this context, our data strengthen their conclusion that patients with PPH should not be denied liver transplantation.
The length of stay in the ICU and the length of necessary mechanical ventilation did not differ significantly between the patients with and without PPH. The study by Starkel et al. (21) revealed similar results. Their data showed only a minor, statistically insignificant trend towards a longer stay in the ICU for the PPH patients.
Several studies have previously shown that echocardiography and electrocardiography are poor predictors of pulmonary hypertension in ESLD (25). This is supported by the finding that echocardiography overestimates SPAP in patients with cirrhosis (26). In contrast, the data of Kim et al. (27) revealed a strong correlation between SPAP obtained from echocardiography and pulmonary artery catheter. In our study, echocardiography provided a PPV of 39% and a NPV of 90% for the diagnosis of PPH. Our data are in accordance with the studies of Cotton et al. (26) and Torregrosa et al. (28), who reported similar results about the predictive value of Doppler echocardiography in the assessment of PPH in liver transplant candidates. Both groups concluded that Doppler echocardiography is a very useful tool to screen for PPH in LT candidates. In more than 60% of our patients with PPH, we were not able to predict the existence of PPH preoperatively based solely on echocardiography findings. Our data imply that if we need to diagnose PPH preoperatively, invasive right heart catheterization should be performed.
Several recent studies of continuous long-term therapy for pulmonary hypertension (intravenous prostacyclin or aerosolized, inhalational Iloprost) showed promising outcomes, even in patients with liver disease (2, 9, 14). Based on the aforementioned data from our and other studies, we would like to suggest that in case of echocardiographic findings suggestive of PPH, a preoperative hemodynamic assessment using a pulmonary artery catheter may be indicated. This assessment should include not only MPAP, PCWP, CI, but also a test of PPH response to inhalational (iloprost or NO) or intravenous (prostacyclin) therapy.
In conclusion, we believe that our data point out that PPH should not be considered an absolute contraindication for liver transplantation. Even patients with severe PPH, but normal right ventricular function and cardiac index, might benefit from liver transplantation.
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