Terlipressin improves pulmonary pressures in cirrhotic patients with pulmonary hypertension and variceal bleeding or hepatorenal syndrome

George N Kalambokis, Konstantinos Pappas and Epameinondas V Tsianos

Ioannina, Greece

Terlipressin improves pulmonary pressures in cirrhotic patients with pulmonary hypertension and variceal bleeding or hepatorenal syndrome

George N Kalambokis, Konstantinos Pappas and Epameinondas V Tsianos

Ioannina, Greece

Terlipressin has been shown to improve both pulmonary and systemic hemodynamics in stable cirrhotic patients with pulmonary hypertension, whereas other vasoconstrictors may cause pulmonary pressures to deteriorate.We investigated the pulmonary and systemic hemodynamic effects of the fi rst terlipressin dose (2 mg) in 7 cirrhotic patients with PH presenting with variceal bleeding (n=4) or hepatorenal syndrome (n=3). Terlipressin decreased pulmonary vascular resistance (158.8±8.9 vs 186.5±13.9 dynes • sec • cm-5; P=0.003)together with an increase in systemic vascular resistance (2143±126 vs 1643±126 dynes • sec • cm-5; P＜0.001). Terlipressin should be the vasoconstrictor treatment of choice when patients present with variceal bleeding or HRS.

(Hepatobiliary Pancreat Dis Int 2012;11:434-437)

terlipressin;pulmonary hypertension;cirrhosis;variceal bleeding;hepatorenal syndrome

Introduction

Pulmonary hypertension (PH) associated with cirrhosis, termed portopulmonary hypertension(POPH), is an uncommon but signi fi cant complication of cirrhosis, as it portends a poor outcome.A pulmonary vascular resistance (PVR) value ＞240 dynes • sec • cm-5is required for the diagnosis of PH of any etiology, although a value of 120 dynes • sec • cm-5continues to be considered the upper limit of normality in the setting of cirrhosis by several workers.[1]Diagnostic measurements of PVR are obtained by right heart catheterization (RHC).[1]Doppler evaluation of PVR has been found to be comparable to RHC in cirrhotic patients undergoing liver transplantation[2]and decreases the need for repeated invasive measurements.

Patients with variceal bleeding or hepatorenal syndrome (HRS) often receive large amounts of fl uid and vasoconstrictor agents, such as somatostatin and its analogues, and α-agonists, which may worsen the coexisting PH.[3-5]We recently have reported that terlipressin has differential effects on the pulmonary and systemic circulation in stable cirrhotic patients with PH,causing a signi fi cant reduction in pulmonary pressures together with systemic hemodynamic improvement.[6]Herein, we report the pulmonary hemodynamic effects of terlipressin in cirrhotic patients with PH presenting with variceal bleeding or HRS.

Methods

Seven cirrhotic patients (6 males; alcoholic/viral etiology, 5/2; all 7 Child-Pugh class C) with variceal bleeding (4) or HRS (3) were evaluated. POPH was suspected in 5 patients but they declined invasive diagnostic measurements prior to admission. In the remaining 2 patients, POPH was documented by RHC;one patient was treated with the phosphodiesterase-5 inhibitor sildena fi l (presented with variceal bleeding after 45 days of treatment) and the other with the combination of sildena fi l and the endothelin antagonist bosentan (presented with HRS after 2 months). PH due to other causes was excluded by chest radiography,high-resolution computed tomography of the lungs and immunology.[7]Pulmonary and systemic hemodynamic parameters were evaluated before and 1 hour after the fi rst dose of terlipressin (2 mg).

Pulmonary hemodynamic evaluation

Pulmonary hemodynamic evaluation was performed by a duplex-Doppler apparatus (Toshiba Sonolayer SSA 270, Tokyo, Japan). The right ventricular out fl ow tract velocity time integral (VTIRVOT) was obtained by placing a pulse-wave Doppler sample volume in the proximal RVOT at the level of the pulmonary valve, in the parasternal short-axis view, and tracing the outer boundaries of the spectral Doppler signal to obtain the VTIRVOT. This measurement was repeated up to 3 times if possible and the average value was recorded.Continuous-wave Doppler was used to determine peak tricuspid regurgitant velocity (TRV). The highest velocity from multiple views was used. PVR was calculated as the ratio of peak TRV × 10 to VTIRVOT as proposed by Abbas et al[8](Wood units; 1 Wood unit=80 dynes • sec • cm-5). Systolic pulmonary arterial pressure (SPAP) was estimated from the tricuspid regurgitant fl ow velocity tracing as the systolic pressure gradient between the right ventricle and right atrium plus 10 mmHg. Adequate tricuspid regurgitation signals were obtained in all 7 patients.

Systemic hemodynamic evaluation

Arterial blood pressure (BP) was assessed with a manual sphygmomanometer. Mean arterial pressure(MAP) was evaluated as diastolic BP+[(systolic BP-diastolic BP)/3]. Cardiac output (CO) was evaluated by recording the diastolic mitral fl ow with the duplex-Doppler apparatus as previously reported,[9]and measurements derived from at least 3 cardiac cycles were averaged. The ratio of MAP to CO was used as an index of systemic vascular resistance (SVR).

Statistical analysis

The results are expressed as mean±standard error of the mean (SEM). Differences between the groups were evaluated using Student's t test. A P value of ＜0.05 was considered statistically signi fi cant.

Results

The range of PVR values prior to terlipressin treatment in the present series was 150-250 dynes • sec • cm-5. One patient had a PVR value ＞240 dynes • sec • cm-5. A decrease in PVR (158.8±8.9 vs 186.5±13.9 dynes • sec • cm-5;P=0.003) was noted after terlipressin infusion; terlipressin caused a reduction in PVR in all patients, ranging from 5.7% to 29.6% (Fig. A). Terlipressin also induced a signi fi cant reduction in SPAP (78.8±4.8 vs 85.2±5.5 mmHg) (Fig. B). Signi fi cant increases in MAP (100.3±2.6 vs 93.1±1.5 mmHg) and SVR (2143±126 vs 1643±126 dynes • sec • cm-5) together with a signi fi cant decrease in CO (4.79±0.27 vs 5.83±0.37 L/min) were demonstrated after terlipressin administration (Fig. C-E). No patient had evidence of volume overload that could affect pulmonary pressures before or during terlipressin treatment. Variceal bleeding and HRS were successfully managed with continuation of terlipressin treatment in all patients.

Fig. Individual changes in pulmonary vascular resistance (A),systolic pulmonary arterial pressure (B), mean arterial pressure(C), cardiac output (D), and systemic vascular resistance (E)after terlipressin treatment in cirrhotic patients with variceal bleeding or hepatorenal syndrome.

In conclusion, despite the small sample size and the non-invasive measurements of pulmonary pressures, our fi ndings suggest that terlipressin should be considered the vasoconstrictor treatment of choice when cirrhotic patients with PH present with variceal bleeding or HRS.

Discussion

Terlipressin (triglycyl lysine vasopressin) is a synthetic vasopressin analogue, which is slowly cleaved to vasopressin. It can be given by intermittent intravenous injections rather than by continuous intravenous infusion,as it is necessary for vasopressin. Terlipressin induces V1 receptor-mediated systemic arterial vasoconstriction,particularly in the splanchnic area, which reduces portal pressure and activation of renal vasoconstricting neurohumoral systems.[10]An intrinsic vasoconstrictor effect of terlipressin has also been suggested.[11]Due to its pharmacological effects, terlipressin is considered the most ef fi cient therapy for variceal bleeding and HRS.[10,11]

Our observations showed that the administration of terlipressin in cirrhotic patients with PH and variceal bleeding or HRS allows systemic hemodynamics and renal function to be supported with concomitant bene fi cial effects on pulmonary pressures. Consistent with the present results, we recently reported the case of a cirrhotic patient with HRS and POPH who showed a prompt marked reduction in pulmonary pressures and recovery of renal function after terlipressin treatment.[12]In another report, vasopressin improved the pulmonary hemodynamics in two patients with advanced idiopathic PH who developed severe right heart failure and systemic hypotension after delivery by Caesarean section.[13]Terlipressin possibly mediates a decrease in pulmonary arterial pressure in preconstricted pulmonary arteries,as previously shown in experimental vasopressin studies.[14,15]Vasopressin-induced pulmonary arterial vasodilation is most likely to result from V1 receptormediated endothelial nitric oxide release[14,15]and the production of endothelium-derived relaxing factor[16]and atrial natriuretic peptide.[17]

Adverse events of terlipressin are mostly cardiovascular and related to vasoconstriction. However, its safety pro fi le is favorable when considering the clinical ef fi cacy and the high mortality of variceal bleeding and HRS. Cardiac side-effects of terlipressin are signi fi cantly fewer and less severe than for vasopressin in studies that include cirrhotic patients with these clinical entities.Mortality and withdrawal of terlipressin due to adverse events are reported in ＜1% of patients.[10,11]However,its ef fi cacy to reduce pulmonary pressures and safety remains to be con fi rmed by large studies of patients with cirrhosis and pulmonary vascular dysfunction.

Contributors: KGN proposed the study. KGN and PK wrote the fi rst draft. KGN analyzed the data. All authors contributed to the design and interpretation of the study and to further drafts. TEV is the guarantor.

Funding: None.

Ethical approval: This study was approved by the Hospital Ethics Committee.

Competing interest: No bene fi ts in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Author Af fi liations: 1st Division of Internal Medicine and Hepato-Gastroenterology Unit (Kalambokis GN and Tsianos EV) and Department of Cardiology (Pappas K), University Hospital of Ioannina, Ioannina 45500, Greece

Epameinondas V Tsianos, MD, PhD, AGAF, Professor of Internal Medicine, 1st Division of Internal Medicine and Hepato-Gastroenterology Unit, Medical School of Ioannina, Ioannina 45110, Greece(Tel: 30-26510-97501; Fax: 30-26510-97016; Email: etsianos@uoi.gr)

© 2012, Hepatobiliary Pancreat Dis Int. All rights reserved.

10.1016/S1499-3872(12)60204-5

September 10, 2011

Accepted after revision January 3, 2012