iloprost and Hypertension--Portal

Epoprostenol and the structurally related compounds treprostinil, iloprost, and beraprost are collectively referred to as prostanoids. The discovery of epoprostenol in 1976 and unequivocal demonstration of its efficacy in 1996 dramatically altered the approach to therapy for pulmonary arterial hypertension (PAH). Development of prostanoids available through multiple routes of administration and the discovery and development of other agents acting through alternative pathways continue to expand the array of therapeutic options. The use of prostanoids in combination with other PAH drugs and for treating pulmonary hypertensive disorders outside of the PAH classification are areas of ongoing research.

Topics: Antihypertensive Agents; Chronic Disease; Epoprostenol; Heart Defects, Congenital; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Prostaglandins; Randomized Controlled Trials as Topic; Respiratory Distress Syndrome

Patients with portal hypertension may develop pulmonary complications such as hepatopulmonary syndrome (HPS) or portopulmonary hypertension (PPHT). PPHT is defined as elevated pulmonary pressure, elevated pulmonary vascular resistance, a normal pulmonary capillary wedge pressure, and portal hypertension in the absence of other known causes pulmonary hypertension. Various factors such as hyperdynamic circulation, volume overload, and circulating vasoactive mediators are suspected to be involved in the pathogenesis of PPHT. The prognosis of patients with severe PPHT is significantly reduced due to the risk of right heart failure. In patients with moderate to severe PPHT liver transplantation is associated with a significantly increased mortality. The chief symptom of PPHT may be dyspnoe in the presence of typical histomorphological alterations comparable with idiopathic pulmonary hypertension. Continuous intravenous application of prostacyclin is currently regarded as the treatment of choice for patients with severe PPHT. Inhaled prostacyclin or its analogue iloprost or oral treatment with the endothelin-receptor antagonist bosentan may be promising alternatives which should be further investigated in randomized controlled trials.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Bosentan; Epoprostenol; Hepatopulmonary Syndrome; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Lung; Pulmonary Wedge Pressure; Sulfonamides; Survival Rate; Treatment Outcome; Vascular Resistance; Vasodilator Agents

Portopulmonary hypertension (PPHTN) is associated with poor prognosis and high perioperative mortality after orthotopic liver transplantation. This study documents the first case of a patient with PPHTN who was successfully bridged to orthotopic liver transplantation with i.v. iloprost, a stable prostacyclin analogue. The PPHTN had resolved completely 4 months after successful transplantation. In conclusion, portopulmonary hypertension is a relative contraindication to orthotopic liver transplantation, which should be attempted only if pulmonary haemodynamics improve with prostanoids. In this context, iloprost may be a valuable alternative to epoprostenol.

Topics: Alcoholism; Carcinoma, Hepatocellular; Hepatitis C, Chronic; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Infusions, Intravenous; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Middle Aged; Preoperative Care; Vasodilator Agents

Portopulmonary hypertension (PoPH) is a serious condition without an established treatment. Drugs used to treat pulmonary hypertension may have detrimental effects on portal hypertension. This study was designed to assess in patients with PoPH the acute effects of inhaled iloprost (iILO) on pulmonary and hepatic hemodynamics and to evaluate the clinical outcome after 12 months of treatment. We conducted 2 separate studies. In the first one, 21 patients with PoPH were acutely tested with 2.8 microg of iILO. Pulmonary and hepatic hemodynamics were assessed at the baseline and through 60 minutes after iILO. In the second one, we retrospectively evaluated 12 patients treated with iILO (30 microg/day) for more than 1 year. The 6-minute walk distance (6MWD), functional class (FC), and echocardiogram were analyzed at the baseline and after 12 months of treatment. In the acute study, iILO rapidly reduced pulmonary artery pressure (PAP; -16% + or - 8%, P < 0.001) and pulmonary vascular resistance (-18% + or - 14%, P < 0.001). The cardiac output did not change initially but decreased after 30 minutes. The hepatic venous pressure gradient (HVPG) and hepatic blood flow did not vary through the study. Pulmonary vasodilation induced by iILO was inversely related to HVPG. In the long-term evaluation, iILO improved FC by 1 or more in 7 patients (P = 0.04) and increased 6MWD by 67 + or - 59 m at 12 months (P < 0.001). No change in systolic PAP was observed. Two patients died because of hepatic complications, and 4 additional patients presented clinically significant events that were related to hepatic disease in 2 and worsening of pulmonary hypertension in 2. We conclude that in patients with PoPH, iILO produces rapid and selective pulmonary vasodilation without altering the hepatic hemodynamics. Its long-term use may provide sustained improvements in symptoms and exercise tolerance in some patients with PoPH. A randomized, controlled trial is warranted to establish its clinical role in this serious condition.

Topics: Administration, Inhalation; Adult; Blood Pressure; Cohort Studies; Dose-Response Relationship, Drug; Female; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Circulation; Male; Middle Aged; Retrospective Studies; Treatment Outcome; Vascular Resistance; Vasodilator Agents

It has been widely accepted that development of porto-pulmonary hypertension (POPH) is independent of the cause of portal hypertension. The degree of hepatic damage and liver function do not correlate with predisposition to POPH or its severity. However, portal hypertension has been confirmed as a prerequisite for developing pulmonary hypertension. Transthoracic echocardiography is the best screening test for the presence of POPH, but a diagnosis of POPH can be established only by right heart catheterization. Randomized controlled trials comparing the efficacy and safety of different pharmacologic strategies are lacking in patients with POPH. The general management includes diuretics and oxygen supplementation. Notably, moderate to severe POPH predisposes candidates for orthotopic liver transplantation to a higher risk of perioperative mortality. Vasomodulating pharmacologic agents are used in patients with moderate to severe POPH to decrease pulmonary arterial hypertension, thereby permitting liver transplantation to be performed safely. Epo-prostenol is the best-studied medication, and bosentan appears promising.

Topics: Antihypertensive Agents; Bosentan; Cardiac Catheterization; Echocardiography; Epoprostenol; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Transplantation; Piperazines; Prognosis; Purines; Sildenafil Citrate; Sulfonamides; Sulfones; Vasodilator Agents

Portopulmonary hypertension (PPHTN) represents a constrictive pulmonary vasculopathy in patients with portal hypertension. Liver transplantation (LT) may be curative and is usually restricted to patients with mild-to-moderate disease severity characterized by a mean pulmonary artery pressure (mPAP < 35 mm Hg). Patients with severe disease (mPAP > 50 mm Hg) are usually excluded from transplantation. We describe a patient with severe PPHTN, initiated on sequential and ultimately combination therapy of prostacyclin, sildenafil, and bosentan (PSB) pretransplantation and continued for 2 years posttransplantation. Peak mPAP on PSB therapy was dramatically reduced from 70 mm Hg to 32 mm Hg pretransplantation, and continued therapy facilitated a further fall in mPAP to 28 mm Hg posttransplantation. The pulmonary vascular resistance index fell from 604 to 291 dyne second(-1) cm(-5). The perioperative mPAP rose to 100 mm Hg following an episode of sepsis and fell with optimization of PSB therapy. In conclusion, this is the first reported patient with severe PPHTN using this combination of vasodilator therapy as a bridge to LT and then as maintenance in the posttransplantation phase. This regimen may enable LT in similar patients in the future, without long-term consequences.

Topics: Adult; Blood Pressure; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Diseases; Liver Transplantation; Male; Piperazines; Pulmonary Artery; Purines; Severity of Illness Index; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome; Vasodilator Agents

Novel treatments, such as prostanoids or endothelin receptor antagonists, have been introduced for various forms of pulmonary arterial hypertension, but the long-term effects of these treatments on portopulmonary hypertension (PPHT) are unknown. In a retrospective analysis, the present authors assessed the safety and efficacy of inhaled iloprost, a prostacyclin analogue, and bosentan, an endothelin receptor antagonist, in patients with PPHT. In total, 31 consecutive patients with Child class A or B cirrhosis and severe PPHT were treated for up to 3 yrs with either inhaled iloprost (n = 13) or bosentan (n = 18), and the effects on exercise capacity, haemodynamics and survival were evaluated. In the iloprost group, the survival rates at 1, 2 and 3 yrs were 77, 62 and 46%, respectively. In the bosentan group, the respective survival rates were 94, 89 and 89%. Event-free survival rates, i.e. survival without transplantation, right heart failure or clinical worsening requiring the introduction of a new treatment for pulmonary hypertension, was also significantly better in the bosentan group. Bosentan had significantly better effects than inhaled iloprost on exercise capacity, as determined by the 6-min walk test, as well as on haemodynamics. Both treatments proved to be safe, especially in regards of liver function. In the present series of patients with well-preserved liver function and severe portopulmonary hypertension, treatment with both inhaled iloprost and bosentan appeared to be safe. Patients treated with bosentan had higher survival rates, but prospective controlled studies are required to confirm these findings.

Topics: Administration, Inhalation; Adult; Antihypertensive Agents; Bosentan; Catheterization; Disease-Free Survival; Female; Hemodynamics; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Male; Platelet Aggregation Inhibitors; Proportional Hazards Models; Sulfonamides; Treatment Outcome

Topics: Bosentan; Hemodynamics; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Patient Care; Sulfonamides; Survival Analysis

Severe portopulmonary hypertension (PPHTN) is a rare complication of liver cirrhosis and carries a poor prognosis. In the last years, intravenous (IV) epoprostenol has been suggested to be the optimal medical treatment for PPHTN, and recently oral bosentan has been shown to be efficacious and safe in selected patients with PPHTN. We report a case of PPHTN suffering from recurrent right heart failure while on treatment with IV iloprost, which was successfully managed by combination therapy with IV iloprost plus oral bosentan, providing sustained cardiopulmonary stabilization for at least two years. This report documents the first case of a patient with PPHTN successfully treated with the combination of IV iloprost and oral bosentan over an extended period. Thus, combination therapy with IV iloprost and oral bosentan might be a promising new option for selected patients suffering from PPHTN and recurrent right heart failure.

Topics: Administration, Oral; Adult; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Follow-Up Studies; Heart Failure; Hemodynamics; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Injections, Intravenous; Liver Cirrhosis, Alcoholic; Male; Recurrence; Sulfonamides; Time Factors

Portopulmonary hypertension (PPHTN) is a rare complication of liver cirrhosis. Prostanoids have been shown to be effective in the treatment of PPHTN and have been used as a bridge to orthotopic liver transplantation. However, inhibition of platelet aggregation might be a limitation of prostacyclin therapy in patients with end-stage liver disease having an increased risk of bleeding from esophageal varices. The effect of oral bosentan, a dual endothelin-receptor antagonist in the reversal of PPHTN, is still unclear. We report a case of PPHTN (mean pulmonary artery pressure [mPAP] of 51 mmHg) that was successfully switched from inhalative iloprost to oral bosentan therapy. Hemodynamic and symptomatic improvements were maintained after a 12-month long-term treatment with inhalative iloprost as well as after single oral bosentan therapy. This is the first reported case of a successful switch from therapy with an inhalative prostacyclin analogue to oral bosentan in a patient suffering from PPHTN. Thus, oral bosentan therapy might be a promising new option for patients suffering from PPHTN.

Topics: Administration, Inhalation; Administration, Oral; Antihypertensive Agents; Bosentan; Drug Therapy, Combination; Female; Follow-Up Studies; Hemodynamics; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Liver Cirrhosis; Liver Transplantation; Middle Aged; Platelet Aggregation Inhibitors; Sulfonamides; Time Factors

Topics: Administration, Inhalation; Adult; Aerosols; Humans; Hypertension, Portal; Hypertension, Pulmonary; Iloprost; Male; Vasodilator Agents

The aim of this study was to investigate the cytoprotective effect of Iloprost on the liver against carbon tetrachloride induced necrosis. The serum histamine-like activity was found to be increased when compared with that of controls after treatment with carbon tetrachloride for 18 weeks while prostaglandin E2- and leukotriene C4-like activities were unchanged. After pretreatment with Iloprost for 18 weeks the increased activity of histamine was found to be unchanged while prostaglandin E2-like activity was increased. It is concluded that Iloprost protects the liver against carbon tetrachloride-induced damage and reduces the level of histamine that has a role in the pathogenesis of portal hypertension.

Topics: Animals; Carbon Tetrachloride; Dinoprostone; Disease Models, Animal; Female; Histamine; Hypertension, Portal; Iloprost; Injections, Subcutaneous; Leukotriene C4; Liver; Liver Cirrhosis, Experimental; Male; Platelet Aggregation Inhibitors; Rats; Vasodilator Agents