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Chooklin S, Chuklin S, Posivnych M, Krystopchuk S. Portopulmonary hypertension: peculiarities of diagnosis and treatment. EMERGENCY MEDICINE 2024; 20:146-158. [DOI: 10.22141/2224-0586.20.3.2024.1686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Portopulmonary hypertension is defined as the development of pulmonary hypertension secondary to portal one. Its exact prevalence is difficult to determine due to the lack of routine screening in patients with portal hypertension. Hemodynamic changes associated with portal hypertension, including the hyperdynamic state, portosystemic shunts, and splanchnic vasodilation, cause significant disturbances in the pulmonary vasculature and play a key role in the pathogenesis of the disease. Without treatment, portopulmonary hypertension leads to progressive right ventricular failure with a poor prognosis. Although Doppler echocardiography is the best initial screening tool for symptomatic patients and candidates for liver transplant, right heart catheterization remains the gold standard for disease diagnosis. Treatment of patients with portopulmonary hypertension is aimed at improving cardiac function, reducing pulmonary vascular resistance, and optimizing functional capacity. Pulmonary hypertension-specific therapy, which includes prostacyclin and its receptor agonists, endothelin receptor antagonists, phosphodiesterase inhibitors, and guanylate cyclase stimulators, plays a key role in the treatment of patients with portopulmonary hypertension. Small uncontrolled and recent single randomized controlled trials have reported promising results of vasodilator therapy in terms of clinical and hemodynamic improvement in patients, allowing certain patients to undergo liver transplantation. This review discusses the epidemiology, approach to diagnosis and treatment of patients with portopulmonary hypertension. We used MEDLINE database on the PubMed platform and the Cochrane library to search for literature sources using the keywords: portopulmonary hypertension, portal hypertension, pulmonary hypertension, liver cirrhosis, pulmonary complications.
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Izquierdo-Altarejos P, Cabrera-Pastor A, Martínez-García M, Sánchez-Huertas C, Hernández A, Moreno-Manzano V, Felipo V. Extracellular vesicles from mesenchymal stem cells reduce neuroinflammation in hippocampus and restore cognitive function in hyperammonemic rats. J Neuroinflammation 2023; 20:1. [PMID: 36593485 PMCID: PMC9806918 DOI: 10.1186/s12974-022-02688-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 12/25/2022] [Indexed: 01/03/2023] Open
Abstract
Chronic hyperammonemia, a main contributor to hepatic encephalopathy (HE), leads to neuroinflammation which alters neurotransmission leading to cognitive impairment. There are no specific treatments for the neurological alterations in HE. Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) reduce neuroinflammation in some pathological conditions. The aims were to assess if treatment of hyperammonemic rats with EVs from MSCs restores cognitive function and analyze the underlying mechanisms. EVs injected in vivo reach the hippocampus and restore performance of hyperammonemic rats in object location, object recognition, short-term memory in the Y-maze and reference memory in the radial maze. Hyperammonemic rats show reduced TGFβ levels and membrane expression of TGFβ receptors in hippocampus. This leads to microglia activation and reduced Smad7-IkB pathway, which induces NF-κB nuclear translocation in neurons, increasing IL-1β which alters AMPA and NMDA receptors membrane expression, leading to cognitive impairment. These effects are reversed by TGFβ in the EVs from MSCs, which activates TGFβ receptors, reducing microglia activation and NF-κB nuclear translocation in neurons by normalizing the Smad7-IkB pathway. This normalizes IL-1β, AMPA and NMDA receptors membrane expression and, therefore, cognitive function. EVs from MSCs may be useful to improve cognitive function in patients with hyperammonemia and minimal HE.
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Affiliation(s)
- Paula Izquierdo-Altarejos
- grid.418274.c0000 0004 0399 600XLaboratory of Neurobiology, Centro Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012 Valencia, Spain
| | - Andrea Cabrera-Pastor
- grid.418274.c0000 0004 0399 600XLaboratory of Neurobiology, Centro Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012 Valencia, Spain ,grid.476458.c0000 0004 0427 8560Fundación Investigación Hospital Clínico, Instituto de Investigación Sanitaria, INCLIVA, Valencia, Spain
| | - Mar Martínez-García
- grid.418274.c0000 0004 0399 600XLaboratory of Neurobiology, Centro Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012 Valencia, Spain
| | - Carlos Sánchez-Huertas
- grid.418274.c0000 0004 0399 600XNeuronal and Tissue Regeneration Laboratory, Centro Investigación Príncipe Felipe, Valencia, Spain ,grid.466805.90000 0004 1759 6875Laboratory of Bilateral Neural Circuits, Instituto de Neurociencias (CSIC-UMH), Alicante, Spain
| | - Alberto Hernández
- grid.418274.c0000 0004 0399 600XOptical and Confocal Microscopy Service, Centro Investigación Príncipe Felipe, Valencia, Spain
| | - Victoria Moreno-Manzano
- grid.418274.c0000 0004 0399 600XNeuronal and Tissue Regeneration Laboratory, Centro Investigación Príncipe Felipe, Valencia, Spain
| | - Vicente Felipo
- grid.418274.c0000 0004 0399 600XLaboratory of Neurobiology, Centro Investigación Príncipe Felipe, Eduardo Primo-Yufera 3, 46012 Valencia, Spain
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Tollefson CR, Seitz MA, Natalini CC, Lee AM. Sildenafil does not have a significant effect on the portal vein velocity, cross-sectional area, and congestion index in the dog. Front Vet Sci 2022; 9:920423. [PMID: 35928120 PMCID: PMC9343762 DOI: 10.3389/fvets.2022.920423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/28/2022] [Indexed: 11/19/2022] Open
Abstract
In veterinary medicine, sildenafil is most frequently used to treat pulmonary hypertension, but has also been investigated and used as a treatment for congenital megaesophagus and ischemic infarcts. With the increasing use, the effects of sildenafil on the portal vasculature in the dog have not been previously evaluated. The purpose of this study was to evaluate the effects sildenafil has on the portal vasculature, which anecdotally may have caused decreased portal vein pressure in an adult dog. The ultrasound cross-sectional area of the aorta, cross-sectional area of the portal vein, and portal vein blood flow velocity were acquired in dogs prior to administration, and 45, 90, and 120 min after oral administration of sildenafil for the treatment of pulmonary hypertension. Thirteen dogs were enrolled in the study. No statistically significant difference was detected between all measured values and the congestion index at all time points. A trend was identified that demonstrated progressively lower portal vein velocity with each evaluation, but this was not significant. Although this study had a small sample size, sildenafil was not shown to have a significant effect on the size or blood flow velocity of the portal vasculature. The hepatic buffer system, designed to maintain a constant blood flow to the liver, may be a contributing factor, but further studies with a larger sample size will be required for further evaluation.
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Affiliation(s)
- Christopher R. Tollefson
- The Department of Clinical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, United States
| | - Marc A. Seitz
- The Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Oktibbeha, MS, United States
| | - Claudio C. Natalini
- The Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Oktibbeha, MS, United States
| | - Alison M. Lee
- The Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Oktibbeha, MS, United States
- *Correspondence: Alison M. Lee
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Mazzola M, Madonna R, Badagliacca R, Caterina RD. Porto-pulmonary arterial hypertension: Translation of pathophysiological concepts to the bedside. Vascul Pharmacol 2022; 145:107022. [PMID: 35738494 DOI: 10.1016/j.vph.2022.107022] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/02/2022] [Accepted: 06/10/2022] [Indexed: 11/30/2022]
Abstract
Porto-pulmonary arterial hypertension (PoPAH) is a form of pulmonary arterial hypertension (PAH) that affects patients with cirrhosis, and - to a lesser extent - patients with non-cirrhotic liver diseases. Compared with other forms of PAH, PoPAH is more prevalent in male, in older subjects, and is characterized by lower mean pulmonary arterial pressure (mPAP) and lower pulmonary vascular resistance (PVR) with higher cardiac output. Despite more favorable hemodynamics and functional class, patients with PoPAH have a significantly worse survival than patients with other forms of PAH, likely because of liver-related events and therapeutic barriers to PAH-specific therapy. Furthermore, here cardiopulmonary and hepatic complications may affect treatment efficacy. These patients have been excluded from most randomized clinical trials testing PAH-specific treatments. To date, there is only one study investigating efficacy, safety, tolerability and pharmacokinetics of PAH-specific therapy in patients with PoPAH in a randomized placebo-controlled setting. In this trial the use of the endothelin-1 receptor antagonist macitentan showed clear hemodynamic benefit without safety concerns. However, the drug effects on functional capacity and mortality remain unclear. Here we review the current knowledge on the pathophysiology and management of PoPAH and report a case vignette of a patient with PoPAH due to hepatorenal polycystic disease.
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Affiliation(s)
- Matteo Mazzola
- Cardiovascular Division, Pisa University Hospital and University of Pisa, Pisa, Italy
| | - Rosalinda Madonna
- Cardiovascular Division, Pisa University Hospital and University of Pisa, Pisa, Italy.
| | - Roberto Badagliacca
- Department of Clinical, Anesthesiological and Cardiovascular Sciences, University of Rome La Sapienza, Rome, Italy
| | - Raffaele De Caterina
- Cardiovascular Division, Pisa University Hospital and University of Pisa, Pisa, Italy
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Blanco-Rivero J, Xavier FE. Therapeutic Potential of Phosphodiesterase Inhibitors for Endothelial Dysfunction- Related Diseases. Curr Pharm Des 2021; 26:3633-3651. [PMID: 32242780 DOI: 10.2174/1381612826666200403172736] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Accepted: 02/08/2020] [Indexed: 02/08/2023]
Abstract
Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3', 5'-monophosphate (cGMP) and adenosine 3', 5'-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.
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Affiliation(s)
- Javier Blanco-Rivero
- Departamento de Fisiologia, Facultad de Medicina, Universidad Autonoma de Madrid, Madrid, Spain
| | - Fabiano E Xavier
- Departamento de Fisiologia e Farmacologia, Centro de Biociencias, Universidade Federal de Pernambuco, Recife, Brazil
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Portopulmonary hypertension in the current era of pulmonary hypertension management. J Hepatol 2020; 73:130-139. [PMID: 32145258 DOI: 10.1016/j.jhep.2020.02.021] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 02/17/2020] [Accepted: 02/19/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND & AIMS Long-term outcomes in portopulmonary hypertension (PoPH) are poorly studied in the current era of pulmonary hypertension management. We analysed the effect of pulmonary arterial hypertension (PAH)-targeted therapies, survival and predictors of death in a large contemporary cohort of patients with PoPH. METHODS Data from patients with PoPH consecutively enrolled in the French Pulmonary Hypertension Registry between 2007 and 2017 were collected. The effect of initial treatment strategies on functional class, exercise capacity and cardiopulmonary haemodynamics were analysed. Survival and its association with PAH- and hepatic-related characteristics were also examined. RESULTS Six hundred and thirty-seven patients (mean age 55 ± 10 years; 58% male) were included. Fifty-seven percent had mild cirrhosis, i.e. Child-Pugh stage A. The median model for end-stage liver disease (MELD) score was 11 (IQR 9-15). Most patients (n = 474; 74%) were initiated on monotherapy, either with a phosphodiesterase-5 inhibitor (n = 336) or with an endothelin-receptor antagonist (n = 128); 95 (15%) were initiated on double oral combination therapy and 5 (1%) on triple therapy. After a median treatment time of 4.5 months, there were significant improvements in functional class (p <0.001), 6-minute walk distance (6MWD) (p <0.0001) and pulmonary vascular resistance (p <0.0001). Overall survival rates were 84%, 69% and 51% at 1, 3 and 5 years, respectively. Baseline 6MWD, sex, age and MELD score or Child-Pugh stage were identified as independent prognostic factors. Survival from PoPH diagnosis was significantly better in the subgroup of patients who underwent liver transplantation (92%, 83% and 81% at 1, 3 and 5 years, respectively). CONCLUSION Survival of patients with PoPH is strongly associated with the severity of liver disease. Patients who underwent liver transplantation had the best long-term outcomes. LAY SUMMARY Portopulmonary hypertension is defined by the presence of pulmonary arterial hypertension in the context of chronic liver disease and is characterized by progressive shortness of breath and exercise limitation. The presence of severe pulmonary arterial hypertension in liver transplant candidates represents a contraindication for such a surgery; however, treatments targeting pulmonary arterial hypertension are efficacious, allowing for safe transplantation and conferring good survival outcomes in those who undergo liver transplantation.
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Yan G, Wang J, Yi T, Cheng J, Guo H, He Y, Shui X, Wu Z, Huang S, Lei W. Baicalin prevents pulmonary arterial remodeling in vivo via the AKT/ERK/NF-κB signaling pathways. Pulm Circ 2019; 9:2045894019878599. [PMID: 31723406 PMCID: PMC6831981 DOI: 10.1177/2045894019878599] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 09/05/2019] [Indexed: 02/06/2023] Open
Abstract
Pulmonary arterial hypertension is a rapidly progressive and often fatal disease. As the pathogenesis of pulmonary arterial hypertension remains unclear, there is currently no good drug for pulmonary arterial hypertension and new therapy is desperately needed. This study investigated the effects and mechanism of baicalin on vascular remodeling in rats with pulmonary arterial hypertension. A rat pulmonary arterial hypertension model was constructed using intraperitoneal injection of monocrotaline, and different doses of baicalin were used to treat these rats. The mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP) were measured with a right heart catheter. Moreover, the hearts were dissected to determine the right ventricular hypertrophy index (RVHI). The lung tissues were stained with H&E and Masson's staining to estimate the pulmonary vascular remodeling and collagen fibrosis, and the expression of proteins in the AKT, ERK, and NF-κB p65 phosphorylation (p-AKT, p-ERK, p-p65) was examined by Western blot analysis. We found that compared with untreated pulmonary arterial hypertension rats, baicalin ameliorated pulmonary vascular remodeling and cardiorespiratory injury, inhibited p-p65 and p-ERK expression, and promoted p-AKT and p-eNOS expression. In conclusion, baicalin interfered with pulmonary vascular remodeling and pulmonary arterial hypertension development in rats through the AKT/eNOS, ERK and NF-κB signaling pathways.
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Affiliation(s)
- Guosen Yan
- Laboratory of Cardiovascular Diseases, Guangdong Medical University, Zhanjiang, China.,Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Jinxia Wang
- Laboratory of Cardiovascular Diseases, Guangdong Medical University, Zhanjiang, China.,Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Tao Yi
- Laboratory of Cardiovascular Diseases, Guangdong Medical University, Zhanjiang, China.,Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Junfen Cheng
- Department of Respiration, the Second Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Haixu Guo
- Laboratory of Cardiovascular Diseases, Guangdong Medical University, Zhanjiang, China.,Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Yuan He
- Laboratory of Cardiovascular Diseases, Guangdong Medical University, Zhanjiang, China
| | - Xiaorong Shui
- Laboratory of Vascular Surgery, Guangdong Medical University, Zhanjiang, China
| | - Zeyong Wu
- Department of Plastic Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Shian Huang
- Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Wei Lei
- Laboratory of Cardiovascular Diseases, Guangdong Medical University, Zhanjiang, China.,Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
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Riou M, Jutant EM, Mignard X, Canuet M, Humbert M, Sitbon O, Savale L, Montani D. Hépatopathies et maladies vasculaires pulmonaires. Rev Med Interne 2018; 39:925-934. [DOI: 10.1016/j.revmed.2018.07.015] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 07/23/2018] [Indexed: 12/26/2022]
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9
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Koulava A, Sannani A, Levine A, Gupta CA, Khanal S, Frishman W, Bodin R, Wolf DC, Aronow WS, Lanier GM. Diagnosis, Treatment, and Management of Orthotopic Liver Transplant Candidates With Portopulmonary Hypertension. Cardiol Rev 2018; 26:169-176. [PMID: 29608499 DOI: 10.1097/crd.0000000000000195] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Portopulmonary hypertension (POPH) is seen in 5-8% of orthotopic liver transplantation (OLT) candidates and has significant implications for clinical outcomes. POPH is characterized by vasoconstriction and remodeling of the pulmonary vasculature. It is exacerbated by the hyperdynamic circulation that is common in advanced liver disease. Screening all OLT candidates with transthoracic echocardiography to assess pulmonary pressures and right ventricular function is crucial, as clinical symptoms alone are not reliable. Any significant right ventricular dysfunction or dilatation along with an elevation in estimated pulmonary pressures usually triggers further investigation with right heart catheterization. The mainstays of therapy of POPH are vasodilators that are used in pulmonary arterial hypertension. They include monotherapy or combination therapy with prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors/guanylate cyclase stimulator. Limited evidence from smaller studies and case series suggests that a timely diagnosis of POPH and the early initiation of treatment improve patient outcomes, whether or not OLT is ultimately undertaken. Given the historically high perioperative mortality rate of more than 35%, POPH remains a contraindication to OLT unless it is treated and responsive to vasodilator therapy. We review the current literature and International Liver Transplant Society practice guidelines (2016) for the latest in understanding POPH, its pathogenesis, diagnosis, modern pharmacological treatment, indications, and contraindications for OLT, as well as perioperative management.
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Affiliation(s)
| | | | | | | | | | | | - Roxana Bodin
- Division of Transplant Hepatology, New York Medical College/Westchester Medical Center, Valhalla, NY
| | - David C Wolf
- Division of Transplant Hepatology, New York Medical College/Westchester Medical Center, Valhalla, NY
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Numerical investigation of the haemodynamics in the human fetal umbilical vein/ductus venosus based on the experimental data. Biosci Rep 2016; 36:BSR20160099. [PMID: 27512094 PMCID: PMC5041159 DOI: 10.1042/bsr20160099] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 08/10/2016] [Indexed: 11/25/2022] Open
Abstract
Abortion of the fetus due to a disease, in an early stage of pregnancy, has been dramatically increased in the last decades. There is a still lack of knowledge on the various types of diseases which lead fetus to a vulnerable circumstance. The transport of oxygenated blood from the placenta to the human fetus has been an important clinical feature in Doppler velocimetry studies, especially the ductus venosus (DV). The DV connects intra-abdominal portion of the umbilical vein and the inferior vena cava (IVC) at the inlet of the right atrium and is, therefore, important when examining the fetus state of health. An abnormal flow in the DV can indicate a fetal disease such as, chromosomal abnormalities, cardiac defect, hypoxaemia and intrauterine growth restriction (IUGR). The blood flow in the fetal circulation has not been investigated much in detail. The blood flow in the fetal circulation provides necessary information for physician to make a suitable decision on abortion or alternative medical practice before or even after birth. The present study performed a comparative study to quantify the blood velocity in DV by a combination approach based on 3D computational simulation and Doppler measurement. The results showed that the velocity value in DV is significant and can be considered as an indicator of any kind of disease in fetal. The nodal displacement of the model was also analysed. It shows that DV tolerates a higher level of displacement compared with the other regions of the model, whereas the nodal pressure shows different results as the lowest values are located in DV.
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Surani SR, Mendez Y, Anjum H, Varon J. Pulmonary complications of hepatic diseases. World J Gastroenterol 2016; 22:6008-6015. [PMID: 27468192 PMCID: PMC4948262 DOI: 10.3748/wjg.v22.i26.6008] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Revised: 05/01/2016] [Accepted: 05/21/2016] [Indexed: 02/06/2023] Open
Abstract
Severe chronic liver disease (CLD) may result from portal hypertension, hepatocellular failure or the combination of both. Some of these patients may develop pulmonary complications independent from any pulmonary pathology that they may have. Among them the hepatopulmonary syndrome (HPS), portopulmonary hypertension (PPH) and hepatic hydrothorax (HH) are described in detail in this literature review. HPS is encountered in approximately 15% to 30% of the patients and its presence is associated with increase in mortality and also requires liver transplantation in many cases. PPH has been reported among 4%-8% of the patient with CLD who have undergone liver transplantation. The HH is another entity, which has the prevalence rate of 5% to 6% and is associated in the absence of cardiopulmonary disease. These clinical syndromes occur in similar pathophysiologic environments. Most treatment modalities work as temporizing measures. The ultimate treatment of choice is liver transplant. This clinical review provides basic concepts; pathophysiology and clinical presentation that will allow the clinician to better understand these potentially life-threatening complications. This article will review up-to-date information on the pathophysiology, clinical features and the treatment of the pulmonary complications among liver disease patients.
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Hernandez-Rabaza V, Agusti A, Cabrera-Pastor A, Fustero S, Delgado O, Taoro-Gonzalez L, Montoliu C, Llansola M, Felipo V. Sildenafil reduces neuroinflammation and restores spatial learning in rats with hepatic encephalopathy: underlying mechanisms. J Neuroinflammation 2015; 12:195. [PMID: 26511444 PMCID: PMC4625867 DOI: 10.1186/s12974-015-0420-7] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 10/21/2015] [Indexed: 02/07/2023] Open
Abstract
Background There are no specific treatments for the neurological alterations of cirrhotic patients with minimal hepatic encephalopathy (MHE). Rats with MHE due to portacaval shunt (PCS) show impaired spatial learning. The underlying mechanisms remain unknown. The aims of this work were to assess: (a) whether PCS rats show neuroinflammation in hippocampus, (b) whether treatment with sildenafil reduces neuroinflammation and restores spatial learning in PCS rats, and (c) analyze the underlying mechanisms. Methods Neuroinflammation was assessed by determining inflammatory markers by Western blot. Phosphorylation of MAP-kinase p38 was assessed by immunohistochemistry. Membrane expression of GABA and glutamate receptors was analyzed using BS3 cross-linker. Spatial learning was analyzed using the radial and Morris water mazes. To assess if sildenafil reverses the alterations, rats were treated with sildenafil in the drinking water. Results PCS rats show increased IL-1β and TNF-α levels and phosphorylation (activity) of p38 in hippocampus. Membrane expression of subunits α1 of GABAA receptor and GluR2 of AMPA receptor are increased in PCS rats, while subunits GluR1 of AMPA receptors and NR1 and NR2a of NMDA receptors are reduced. PCS rats show reduced spatial learning in the radial and Morris water mazes. Sildenafil treatment normalizes IL-1β and TNF-α levels, p38 phosphorylation, and membrane expression of GABAA, AMPA, and NMDA receptors and restores spatial learning. Conclusions Increased IL-1β alters GABAergic and glutamatergic neurotransmission in hippocampus and impairs spatial learning in rats with MHE. Sildenafil reduces neuroinflammation and restores learning. Phosphodiesterase-5 inhibitors may be useful to improve cognitive function in patients with MHE.
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Affiliation(s)
- Vicente Hernandez-Rabaza
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Calle Eduardo Primo Yufera, 3, 46012, Valencia, Spain
| | - Ana Agusti
- Fundación Investigación Hospital Clínico de Valencia. Instituto de Investigación Sanitaria-INCLIVA, Valencia, Spain
| | - Andrea Cabrera-Pastor
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Calle Eduardo Primo Yufera, 3, 46012, Valencia, Spain
| | - Santos Fustero
- Laboratorio de Moleculas Orgánicas, Centro de Investigación Príncipe Felipe, Valencia, Spain.,Departamento de Química Organica, Universidad de Valencia, Valencia, Spain
| | - Oscar Delgado
- Laboratorio de Moleculas Orgánicas, Centro de Investigación Príncipe Felipe, Valencia, Spain.,Departamento de Química Organica, Universidad de Valencia, Valencia, Spain
| | - Lucas Taoro-Gonzalez
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Calle Eduardo Primo Yufera, 3, 46012, Valencia, Spain
| | - Carmina Montoliu
- Fundación Investigación Hospital Clínico de Valencia. Instituto de Investigación Sanitaria-INCLIVA, Valencia, Spain
| | - Marta Llansola
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Calle Eduardo Primo Yufera, 3, 46012, Valencia, Spain
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Calle Eduardo Primo Yufera, 3, 46012, Valencia, Spain.
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13
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Luks AM, Swenson ER. Evaluating the Risks of High Altitude Travel in Chronic Liver Disease Patients. High Alt Med Biol 2015; 16:80-8. [PMID: 25844541 DOI: 10.1089/ham.2014.1122] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Luks, Andrew M., and Erik R. Swenson. Clinician's Corner: Evaluating the risks of high altitude travel in chronic liver disease patients. High Alt Med Biol 16:80-88, 2015.--With improvements in the quality of health care, people with chronic medical conditions are experiencing better quality of life and increasingly participating in a wider array of activities, including travel to high altitude. Whenever people with chronic diseases travel to this environment, it is important to consider whether the physiologic responses to hypobaric hypoxia will interact with the underlying medical condition such that the risk of acute altitude illness is increased or the medical condition itself may worsen. This review considers these questions as they pertain to patients with chronic liver disease. While the limited available evidence suggests there is no evidence of liver injury or dysfunction in normal individuals traveling as high as 5000 m, there is reason to suspect that two groups of cirrhosis patients are at increased risk for problems, hepatopulmonary syndrome patients, who are at risk for severe hypoxemia following ascent, and portopulmonary hypertension patients who may be at risk for high altitude pulmonary edema and acute right ventricular dysfunction. While liver transplant patients may tolerate high altitude exposure without difficulty, no information is available regarding the risks of long-term residence at altitude with chronic liver disease. All travelers with cirrhosis require careful pre-travel evaluation to identify conditions that might predispose to problems at altitude and develop risk mitigation strategies for these issues. Patients also require detailed counseling about recognition, prevention, and treatment of acute altitude illness and may require different medication regimens to prevent or treat altitude illness than used in healthy individuals.
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Affiliation(s)
- Andrew M Luks
- 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington , Seattle, Washington
| | - Erik R Swenson
- 1 Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington , Seattle, Washington.,2 Division of Pulmonary and Critical Care Medicine. VA Puget Sound Health Care System , Seattle, Washington
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Abstract
Liver failure affects brain function, leading to neurological and psychiatric alterations; such alterations are referred to as hepatic encephalopathy (HE). Early diagnosis of minimal HE reveals an unexpectedly high incidence of mild cognitive impairment and psychomotor slowing in patients with liver cirrhosis - conditions that have serious health, social and economic consequences. The mechanisms responsible for the neurological alterations in HE are beginning to emerge. New therapeutic strategies acting on specific targets in the brain (phosphodiesterase 5, type A GABA receptors, cyclooxygenase and mitogen-activated protein kinase p38) have been shown to restore cognitive and motor function in animal models of chronic HE, and NMDA receptor antagonists have been shown to increase survival in acute liver failure. This article reviews the latest studies aimed at understanding how liver failure affects brain function and potential ways to ameliorate these effects.
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Kalambokis GN, Mouzaki A, Rodi M, Pappas K, Korantzopoulos P, Tsianos EV. Circulating endotoxin and interleukin-6 levels are associated with Doppler-evaluated pulmonary vascular resistance in cirrhotic patients. Hepatol Int 2012. [PMID: 26201526 DOI: 10.1007/s12072-011-9337-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
PURPOSE Endotoxin and interleukin-6 levels (IL-6) have been involved in the development of pulmonary hypertension (PH) in non-cirrhotic experimental models and subjects. High circulating levels of both substances have been detected in cirrhosis. The association between circulating endotoxin and IL-6 levels and echocardiographically evaluated pulmonary vascular resistance (PVR) in cirrhotic patients are investigated. METHODS Thirty-seven cirrhotic patients were studied: 25 with PVR <120 dynes s cm(-5) (group 1) and 12 with PVR >120 dynes s cm(-5) (group 2). Plasma endotoxin and serum IL-6 levels were measured. The PVR and cardiac output (CO) by Doppler ultrasound, mean arterial pressure (MAP), and systemic vascular resistance (SVR) as the ratio MAP/CO were evaluated. RESULTS Child-Pugh scores, MAP, CO, and SVR were similar in both groups. Endotoxin levels were correlated significantly with IL-6 levels (r = 0.342; P = 0.03). Endotoxin and IL-6 levels were significantly higher in group 2 compared to group 1 (2.26 [0.39-8.4] vs. 0.85 [0.37-7.6] EU/mL; P = 0.04 and 37.4 [7.85-106.5] vs. 8.36 [3.15-53.7] pg/mL; P < 0.001, respectively). The PVR was correlated significantly with endotoxin levels in group 2 (r = 0.587; P = 0.04) and with IL-6 levels in group 1 (r = 0.529; P = 0.01) and group 2 (r = 0.760; P = 0.004), respectively. CONCLUSIONS Our results suggest that endotoxin and IL-6 may contribute to cirrhosis-associated PH. In this regard, modulation of these substances could improve pulmonary pressures in cirrhotic patients.
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Affiliation(s)
- Georgios N Kalambokis
- First Division of Internal Medicine and Hepato-Gastroenterology Unit, Medical School of Ioannina, University Hospital, 45110, Ioannina, Greece.
| | - Athanasia Mouzaki
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | - Maria Rodi
- Division of Hematology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece
| | | | | | - Epameinondas V Tsianos
- First Division of Internal Medicine and Hepato-Gastroenterology Unit, Medical School of Ioannina, University Hospital, 45110, Ioannina, Greece.
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Kalambokis GN, Pappas K, Tsianos EV. Differential effects of terlipressin on pulmonary and systemic hemodynamics in patients with cirrhosis and pulmonary hypertension: an echo study. Angiology 2011; 63:199-205. [PMID: 21733953 DOI: 10.1177/0003319711411704] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Terlipressin has been associated with pulmonary arterial vasodilation in patients with pulmonary hypertension (PH). We investigated the effects of terlipressin on pulmonary vascular resistance (PVR) in patients with cirrhosis without and with PH. Pulmonary vascular resistance and cardiac output (CO) by Doppler ultrasound, mean arterial pressure (MAP), and systemic vascular resistance (SVR) were evaluated in patients with cirrhosis with PVR -120 dyne s cm⁻⁵ (group 1, n = 20) and PVR >120 dyne s cm⁻⁵ (group 2, n = 10) before and 30 minutes after terlipressin infusion (2 mg). After terlipressin, PVR increased significantly in group 1 (96.1 ± 20.2 vs 85.1 ± 18 dyne s cm⁻⁵; P = .004) but decreased significantly in group 2 (170.4 ± 37.8 vs 157.8 ± 28.1 dyne s cm⁻⁵; P= .04). Pulmonary vascular resistance changes in group 2 correlated significantly with baseline PVR (r = -0.632; P = .04). Terlipressin induced a significant increase in MAP and SVR and a significant decrease in CO in both groups. Terlipressin significantly reduces pulmonary pressures in patients with cirrhosis having PH together with systemic hemodynamic improvement.
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Affiliation(s)
- Georgios N Kalambokis
- 1st Division of Internal Medicine and Hepato-Gastroenterology Unit, University Hospital, Ioannina, Greece
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Kähler CM, Graziadei I, Vogelsinger H, Desole S, Cima K, Vogel W. Successful treatment of portopulmonary hypertension with the selective endothelin receptor antagonist Sitaxentan. Wien Klin Wochenschr 2011; 123:248-52. [DOI: 10.1007/s00508-011-1540-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2010] [Accepted: 11/24/2010] [Indexed: 01/09/2023]
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Son SB, Kim KA, Yun SY, Ko SY, Lee YK, Shin SM. Oral Sildenafil in Persistent Pulmonary Hypertension of the Newborn. ACTA ACUST UNITED AC 2011. [DOI: 10.5385/jksn.2011.18.1.124] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Affiliation(s)
- Su Bin Son
- Department of Pediatrics, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul, Korea
| | - Kyung Ah Kim
- Department of Pediatrics, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul, Korea
| | - So Young Yun
- Department of Pediatrics, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul, Korea
| | - Sun Young Ko
- Department of Pediatrics, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul, Korea
| | - Yeon Kyung Lee
- Department of Pediatrics, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul, Korea
| | - Son Moon Shin
- Department of Pediatrics, Cheil General Hospital and Women's Healthcare Center, Kwandong University College of Medicine, Seoul, Korea
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Halverscheid L, Deibert P, Schmidt R, Blum HE, Dunkern T, Pannen BHJ, Kreisel W. Phosphodiesterase-5 inhibitors have distinct effects on the hemodynamics of the liver. BMC Gastroenterol 2009; 9:69. [PMID: 19765284 PMCID: PMC2753560 DOI: 10.1186/1471-230x-9-69] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2009] [Accepted: 09/18/2009] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The NO--cGMP system plays a key role in the regulation of sinusoidal tonus and liver blood flow with phosphodiesterase-5 (PDE-5) terminating the dilatory action of cGMP. We, therefore, investigated the effects of PDE-5 inhibitors on hepatic and systemic hemodynamics in rats. METHODS Hemodynamic parameters were monitored for 60 min. after intravenous injection of sildenafil and vardenafil [1, 10 and 100 microg/kg (sil1, sil10, sil100, var1, var10, var100)] in anesthetized rats. RESULTS Cardiac output and heart rate remained constant. After a short dip, mean arterial blood pressure again increased. Systemic vascular resistance transiently decreased slightly. Changes in hepatic hemodynamic parameters started after few minutes and continued for at least 60 min. Portal (var10 -31%, sil10 -34%) and hepatic arterial resistance (var10 -30%, sil10 -32%) decreased significantly (p < 0.05). At the same time portal venous (var10 +29%, sil10 +24%), hepatic arterial (var10 +34%, sil10 +48%), and hepatic parenchymal blood flow (var10 +15%, sil10 +15%) increased significantly (p < 0.05). The fractional liver blood flow (total liver flow/cardiac output) increased significantly (var10 26%, sil10 23%). Portal pressure remained constant or tended to decrease. 10 microg/kg was the most effective dose for both PDE-5 inhibitors. CONCLUSION Low doses of phosphodiesterase-5 inhibitors have distinct effects on hepatic hemodynamic parameters. Their therapeutic use in portal hypertension should therefore be evaluated.
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Affiliation(s)
| | - Peter Deibert
- Department of Preventive and Rehabilitative Sport Medicine, University Hospital Freiburg, Germany
| | - René Schmidt
- Department of Anesthesiology and Critical Care Medicine, University Hospital Freiburg, Germany
| | - Hubert E Blum
- Department of Medicine II, University Hospital Freiburg, Germany
| | | | | | - Wolfgang Kreisel
- Department of Medicine II, University Hospital Freiburg, Germany
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Yeshua H, Blendis LM, Oren R. Pulmonary manifestations of liver diseases. Semin Cardiothorac Vasc Anesth 2009; 13:60-9. [PMID: 19336439 DOI: 10.1177/1089253209334615] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Respiratory problems are common in patients with chronic liver diseases. The most common causes are disorders that are not related to liver diseases such as asthma and COPD. In addition certain liver diseases that are associated with specific pulmonary abnormalities, and conditions associated with end stage liver disease like tense ascites and intercostal muscular wasting are considered. Finally two unique disorders characterizing by vascular abnormalities independent of cardiorespiratory disorder-the hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are observed. These disorders have different pathogenesis, different clinical pictures, treatment and prognosis. This article reviews the epidemiology, pathophysiology, clinical features, evaluation and current therapy of these two disorders.
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Affiliation(s)
- Hanny Yeshua
- Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Clalit Health Services, and the Sackler Faculty of Medicine Tel Aviv University, Tel Aviv, Israel
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Lee KC, Yang YY, Wang YW, Hou MC, Lee FY, Lin HC, Lee SD. Acute administration of sildenafil enhances hepatic cyclic guanosine monophosphate production and reduces hepatic sinusoid resistance in cirrhotic patients. Hepatol Res 2008; 38:1186-93. [PMID: 18631254 DOI: 10.1111/j.1872-034x.2008.00388.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
AIM In liver cirrhosis, the increased production of nitric oxide (NO) contributes to increased systemic and splanchnic vasodilatation. The inhibition of phosphodiesterase-5 (PDE-5), an enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP), is widely used in the treatment of erectile dysfunction. The aim of our study is to evaluate the overall effects of PDE-5 inhibitor administration on splanchnic, pulmonary and systemic hemodynamics in cirrhotic patients. METHODS Sildenafil, a specific PDE-5 inhibitor, was administrated orally to cirrhotic patients (n = 7) to see the hemodynamic changes. A control group receiving a placebo was used as a point of comparison (n = 6). RESULTS Compared to the control group, the hepatic vein NO and cGMP levels were significantly increased after sildenafil administration in the sildenafil group (NO from 112.3 +/- 43.5 to 325.3 +/- 117.5 nM, P = 0.018; cGMP from 7.3 +/- 0.4 to 19.2 +/- 4.2 pmol, P = 0.018). The hepatic venous pressure gradient in the sildenafil group did not differ from that of the control group. However, a significantly decreased hepatic sinusoidal resistance in the sildenafil group (1999 +/- 1243 vs. 1563 +/- 1014 dyne/s/cm(-5), P < 0.05) was noted. The study also found that the right arterial pressure, mean pulmonary arterial pressure and pulmonary capillary wedge pressure were reduced at 60 min after administration, compared with the basal parameters in cirrhotic patients receiving sildenafil (RAP1.3 +/- 2.0 vs -0.6 +/- 1.3 mmHg, MPAP 14.1 +/- 11.3 vs 11.7 +/- 9.5 mmHg, PCWP 4.6 +/- 1.7 vs 2.9 +/- 1.6 mmHg, P < 0.05 respectively). CONCLUSIONS An oral administration of 50 mg of sildenafil significantly decreased the mean pulmonary arterial pressure and hepatic sinusoid resistance with a significant increase in hepatic NO and cGMP production, and did not worsen portal hypertension in cirrhotic patients.
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Affiliation(s)
- Kuei-Chuan Lee
- Division of Gastroenterology, Department of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
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Luks AM, Swenson ER. Medication and dosage considerations in the prophylaxis and treatment of high-altitude illness. Chest 2008; 133:744-55. [PMID: 18321903 DOI: 10.1378/chest.07-1417] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
With increasing numbers of people traveling to high altitude for work or pleasure, there is a reasonable chance that many of these travelers have preexisting medical conditions or are receiving various medications at the time of their sojourn. As with all travelers to high altitude, they are at risk for altitude illnesses such as acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema. While there are clear recommendations for pharmacologic measures to prevent or treat these illnesses, these recommendations are oriented toward healthy individuals and do not take into account the presence of preexisting medical conditions. In this review, we consider how the choice and dose of the medications used in the management of altitude illness-acetazolamide, dexamethasone, nifedipine, tadalafil, sildenafil, and salmeterol-are affected by a patient's underlying medical conditions. We discuss the indications and current dosing recommendations for individuals without underlying disease, and then consider how drug selection or dosing regimens will be affected by the presence of renal insufficiency, hepatic insufficiency, other important medical conditions, and the potential for serious drug interactions. We include comments about interactions with antimalarial medications and antibiotics used in the treatment of traveler's diarrhea, as well as the safety of use during pregnancy. By giving these issues adequate consideration, clinicians can increase the chances that properly evaluated patients with underlying medical conditions will enjoy a safe trip to high altitude.
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Affiliation(s)
- Andrew M Luks
- Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, WA 98195-6522, USA.
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Kalambokis G, Korantzopoulos P, Nikas SA, Theodorou A, Tsianos EV. Significant improvement of portopulmonary hypertension after 1-week terlipressin treatment. J Hepatol 2008; 48:678-80. [PMID: 18280605 DOI: 10.1016/j.jhep.2007.12.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2007] [Revised: 11/25/2007] [Accepted: 12/06/2007] [Indexed: 12/04/2022]
Abstract
Cirrhosis associated with moderate and severe portopulmonary hypertension carries a poor prognosis. Optimal management has not yet been defined. Current treatment options, such as prostacyclin analogues, endothelin antagonists, and phosphodiesterase-5 inhibitors, are characterized by slow onset of action and various adverse effects, particularly in patients with advanced cirrhosis. Here, we report the significant reduction of pulmonary arterial pressure after 1-week terlipressin treatment in a patient with concomitant hepato-renal syndrome. Terlipressin could be a novel and safe treatment for portopulmonary hypertension.
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Affiliation(s)
- Georgios Kalambokis
- 1st Division of Internal Medicine, University of Ioannina, Medical School, 45110 Ioannina, Greece
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Sakai T, Planinsic RM, Mathier MA, de Vera ME, Venkataramanan R. Initial experience using continuous intravenous treprostinil to manage pulmonary arterial hypertension in patients with end-stage liver disease. Transpl Int 2008; 22:554-61. [PMID: 19175541 DOI: 10.1111/j.1432-2277.2008.00830.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Treprostinil is a prostacyclin analog and has been used on idiopathic pulmonary arterial hypertension (PAH). There is only limited clinical experience using treprostinil to manage PAH in patients with end-stage liver disease (ESLD). We report three ESLD patients with PAH, who were treated with continuous intravenous treprostinil. A 59-year-old woman with ESLD secondary to alcoholic hepatitis had portopulmonary hypertension with mean pulmonary arterial pressure (mPAP) of 44 mmHg and transpulmonary gradient (TPG) of 23 mmHg. Treprostinil at 45 ng/kg/min for 6 months decreased mPAP to 23 (TPG to 8). A 53-year-old man had ESLD secondary to alcoholic hepatitis with PAH caused by multiple pulmonary embolisms (mPAP of 32 and TPG of 23). Treprostinil at 36 ng/kg/min for 3 months decreased mPAP to 23 and TPG to 14. Both patients underwent uneventful liver transplantation. A 48-year-old man had ESLD secondary to hepatitis C and portopulmonary hypertension with mPAP of 60 and TPG of 44. Two years after intravenous treprostinil at 106 ng/kg/min, his mPAP decreased to 44 and TPG to 30. These results demonstrate that for a selected group of ESLD patients with PAH, a continuous intravenous infusion of treprostinil appears to be safe and effective.
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Affiliation(s)
- Tetsuro Sakai
- Department of Anesthesiology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
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Ricci GL, Melgosa MT, Burgos F, Valera JL, Pizarro S, Roca J, Rodriguez-Roisin R, Barberà JA. Assessment of acute pulmonary vascular reactivity in portopulmonary hypertension. Liver Transpl 2007; 13:1506-14. [PMID: 17969197 DOI: 10.1002/lt.21173] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The role of acute pulmonary vasodilator testing in portopulmonary hypertension (PoPH), a current contraindication for orthotopic liver transplantation (OLT), has not been thoroughly elucidated. The purpose of this work was to analyze the results of acute vasodilator testing with inhaled nitric oxide (NO), to compare them with intravenous epoprostenol (PGI(2)), and to investigate the acute effects of the oral vasodilator isosorbide-5-mononitrate (Is-5-MN), in patients with PoPH. A total of 19 patients with PoPH (male/female = 9/10) were studied. Pulmonary hemodynamic measurements were performed at baseline and during NO inhalation (40 ppm); additionally, 15 patients were tested with PGI(2) (2-12 mug/kg/minute) and 8 were tested with Is-5-MN (20-40 mg). Inhaled NO reduced pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) by 5.7% and 11.0%, respectively. PGI(2) elicited greater reductions in PAP (11.8%) and PVR (-24.0%), and produced a 28% drop in systemic vascular resistance (SVR) and a 17% increase in the cardiac index (CI). Is-5-MN reduced PAP by 25.6% and PVR by 21.5%, without systemic changes. There was good agreement between the response to PGI(2) and Is-5-MN: 6 patients of the whole series (32%) decreased PAP >20% from baseline, reaching a final value < or = 35 mmHg, the current limit for OLT. In conclusion, acute vasodilator testing has a relevant role in PoPH, as it identifies one-third of patients able to reach a more favorable hemodynamic situation, which can be determinant for their management. For vasodilator testing, PGI(2) is more suitable than NO in PoPH. Is-5-MN exerts a selective effect on pulmonary circulation in patients who had already responded to PGI(2).
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Affiliation(s)
- Giovanni L Ricci
- Department of Clinical Sciences, Università; La Sapienza, Roma, Italy
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Bremer HC, Kreisel W, Roecker K, Dreher M, Koenig D, Kurz-Schmieg AK, Blum HE, Roessle M, Deibert P. Phosphodiesterase 5 inhibitors lower both portal and pulmonary pressure in portopulmonary hypertension: a case report. J Med Case Rep 2007; 1:46. [PMID: 17623085 PMCID: PMC1971060 DOI: 10.1186/1752-1947-1-46] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2007] [Accepted: 07/10/2007] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Portopulmonary hypertension (PPHTN) is a severe complication in liver cirrhosis. PDE5 inhibitors lower pulmonary arterial pressure (PAP) in PPHTN. However, their effect on portal hypertension has not yet been investigated. CASE PRESENTATION A 55 year old male patient presented with PPHTN and alcoholic liver cirrhosis. 10 mg of Tadalafil, a PDE5 inhibitor with a long half-life, was administered orally under continuous monitoring of pulmonary and portal hemodynamics. For maintenance therapy the patient received Sildenafil 20 mg bid.Tadalafil lowered mean PAP from 45 to 39 mmHg within 60 minutes. Cardiac output (CO) increased from 6.8 to 7.9 l/min. Central venous pressure (CVP) remained stable at 3 mmHg. Systolic and diastolic blood pressure was lowered from 167/89 to 159/86 mmHg. Pulse rate increased from 75 to 87 per min. Wedged hepatic vein pressure (WHVP) decreased from 21 to 18 mm Hg, hepatovenous pressure gradient (HVPG) decreased from 10 to 7 mmHg. Hemodynamic monitoring after 6 months of Sildenafil therapy revealed a sustained lowering of mean PAP. HVPG remained constant at 10 mmHg. Cardiac and pulmonary performance had further improved. CONCLUSION This case report shows for the first time, that phosphodiesterase 5 inhibitors lower both portal and pulmonary pressure in portopulmonary hypertension.
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Affiliation(s)
- Hinrich C Bremer
- Department of Pneumology, University Hospital, Freiburg, Germany
| | - Wolfgang Kreisel
- Department of Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, University Hospital, Freiburg, Germany
| | - Kai Roecker
- Department of Rehabilitative and Preventive Sports Medicine, University Hospital, Freiburg, Germany
| | - Michael Dreher
- Department of Pneumology, University Hospital, Freiburg, Germany
| | - Daniel Koenig
- Department of Rehabilitative and Preventive Sports Medicine, University Hospital, Freiburg, Germany
| | - Anna Katharina Kurz-Schmieg
- Department of Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, University Hospital, Freiburg, Germany
| | - Hubert E Blum
- Department of Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, University Hospital, Freiburg, Germany
| | - Martin Roessle
- Gastrointestinal and Endocrinological Center, Freiburg, Germany
| | - Peter Deibert
- Department of Rehabilitative and Preventive Sports Medicine, University Hospital, Freiburg, Germany
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Sola A, Baquero H. [Oral sildenafil in neonatal medicine: ''tested in adults also used in neonates'']. An Pediatr (Barc) 2007; 66:167-76. [PMID: 17306104 DOI: 10.1157/13098935] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- A Sola
- Mid Atlantic Neonatology Associates, Morristown Memorial Hospital, Morristown, NJ, USA.
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Liver transplantation and pulmonary hypertension: pathophysiology and management strategies. Curr Opin Organ Transplant 2007; 12:274-280. [DOI: 10.1097/mot.0b013e32814a599c] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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