Portopulmonary Hypertension: An Updated Review.

Portal hypertension may have major consequences on the pulmonary vasculature due to the complex pathophysiological interactions between the liver and lungs. Portopulmonary hypertension (PoPH), a subset of group 1 pulmonary hypertension (PH), is a serious pulmonary vascular disease secondary to portal hypertension, and is the fourth most common subtype of pulmonary arterial hypertension. It is most commonly observed in cirrhotic patients; however, patients with noncirrhotic portal hypertension can also develop it. On suspicion of PoPH, the initial evaluation is by a transthoracic echocardiogram in which, if elevated pulmonary pressures are shown, patients should undergo right heart catheterization to confirm the diagnosis. The prognosis is extremely poor in untreated patients; therefore, management includes pulmonary arterial hypertension therapies with the aim of improving pulmonary hemodynamics and moving patients to orthotopic liver transplantation (OLT). In this article, we review in detail the epidemiology, pathophysiology, process for diagnosis, and most current treatments including OLT and prognosis in patients with PoPH. In addition, we present a diagnostic algorithm that includes the current criteria to properly select patients with PoPH who are candidates for OLT.

Arginine vasopressin receptor 2 activation promotes microvascular permeability in sepsis.

Methicillin-resistant Staphylococcus aureus (MRSA) sepsis is a severe condition associated with vascular leakage and poor prognosis. The hemodynamic management of sepsis targets hypotension, but there is no specific treatment available for vascular leakage. Arginine vasopressin (AVP) has been used in sepsis to promote vasoconstriction by activating AVP receptor 1 (V1R). However, recent evidence suggests that increased fluid retention may be associated with the AVP receptor 2 (V2R) activation worsening the outcome of sepsis. Hence, we hypothesized that the inhibition of V2R activation ameliorates the severity of microvascular hyperpermeability during sepsis. The hypothesis was tested using a well-characterized and clinically relevant ovine model of MRSA pneumonia/sepsis and in vitro assays of human lung microvascular endothelial cells (HMVECs). in vivo experiments demonstrated that the treatment of septic sheep with tolvaptan (TLVP), an FDA-approved V2R antagonist, significantly attenuated the sepsis-induced fluid retention and markedly reduced the lung water content. These pathological changes were not affected by the treatment with V2R agonist, desmopressin (DDAVP). Additionally, the incubation of cultured HMVECs with DDAVP, and DDAVP along with MRSA significantly increased the paracellular permeability. Finally, both the DDAVP and MRSA-induced hyperpermeability was significantly attenuated by TLVP. Subsequent protein and gene expression assays determined that the V2R-induced increase in permeability is mediated by phospholipase C beta (PLCß) and the potent permeability factor angiopoietin-2. In conclusion, our results indicate that the activation of the AVP-V2R axis is critical in the pathophysiology of severe microvascular hyperpermeability during Gram-positive sepsis. The use of the antagonist TLVP should be considered as adjuvant treatment for septic patients. The results from this clinically relevant animal study are highly translational to clinical practice.

Nebulized Epinephrine Limits Pulmonary Vascular Hyperpermeability to Water and Protein in Ovine With Burn and Smoke Inhalation Injury.

OBJECTIVES: To test the hypothesis that nebulized epinephrine ameliorates pulmonary dysfunction by dual action-bronchodilation (ß2-adrenergic receptor agonism) and attenuation of airway hyperemia (α1-adrenergic receptor agonism) with minimal systemic effects. DESIGN: Randomized, controlled, prospective, and large animal translational studies. SETTING: University large animal ICU. SUBJECTS: Twelve chronically instrumented sheep. INTERVENTIONS: The animals were exposed to 40% total body surface area third degree skin flame burn and 48 breaths of cooled cotton smoke inhalation under deep anesthesia and analgesia. The animals were then placed on a mechanical ventilator, fluid resuscitated, and monitored for 48 hours in a conscious state. After the injury, sheep were randomized into two groups: 1) epinephrine, nebulized with 4 mg of epinephrine every 4 hours starting 1 hour post injury, n = 6; or 2) saline, nebulized with saline in the same manner, n = 6. MEASUREMENTS AND MAIN RESULTS: Treatment with epinephrine had a significant reduction of the pulmonary transvascular fluid flux to water (p < 0.001) and protein (p < 0.05) when compared with saline treatment from 12 to 48 hours and 36 to 48 hours, respectively. Treatment with epinephrine also reduced the systemic accumulation of body fluids (p < 0.001) with a mean of 1,410 ± 560 mL at 48 hours compared with 3,284 ± 422 mL of the saline group. Hemoglobin levels were comparable between the groups. Changes in respiratory system dynamic compliance, mean airway pressure, PaO2/FiO2 ratio, and oxygenation index were also attenuated with epinephrine treatment. No considerable systemic effects were observed with epinephrine treatment. CONCLUSIONS: Nebulized epinephrine should be considered for use in future clinical studies of patients with burns and smoke inhalation injury.