key: cord-0006853-ysd1iykp authors: Coz Yataco, Angel; Aguinaga Meza, Melina; Buch, Ketan P.; Disselkamp, Margaret A. title: Hospital and intensive care unit management of decompensated pulmonary hypertension and right ventricular failure date: 2015-10-20 journal: Heart Fail Rev DOI: 10.1007/s10741-015-9514-7 sha: 8e48c3dfa8421df90112f15b841948809cfec5e1 doc_id: 6853 cord_uid: ysd1iykp Pulmonary hypertension and concomitant right ventricular failure present a diagnostic and therapeutic challenge in the intensive care unit and have been associated with a high mortality. Significant co-morbidities and hemodynamic instability are often present, and routine critical care unit resuscitation may worsen hemodynamics and limit the chances of survival in patients with an already underlying poor prognosis. Right ventricular failure results from structural or functional processes that limit the right ventricle’s ability to maintain adequate cardiac output. It is commonly seen as the result of left heart failure, acute pulmonary embolism, progression or decompensation of pulmonary hypertension, sepsis, acute lung injury, or in the perioperative setting. Prompt recognition of the underlying cause and institution of treatment with a thorough understanding of the elements necessary to optimize preload, cardiac contractility, enhance systemic arterial perfusion, and reduce right ventricular afterload are of paramount importance. Moreover, the emergence of previously uncommon entities in patients with pulmonary hypertension (pregnancy, sepsis, liver disease, etc.) and the availability of modern devices to provide support pose additional challenges that must be addressed with an in-depth knowledge of this disease. The understanding of the function of the right ventricle (RV) in health and disease is an understudied field that has evolved considerably over the last century. The RV, once considered a passive conduit of blood and a bystander in disease, is now recognized to play an important role in determining the outcome of many patients admitted to the intensive care unit (ICU) [1] [2] [3] . Acute dysfunction of the RV, irrespective of baseline pulmonary vascular resistance (PVR), has been a well-recognized entity in ICU patients with septic shock and acute respiratory distress syndrome (ARDS) [4, 5] . The decompensation of the RV function is detrimental to survival, especially in patients with pulmonary hypertension (PH) who often have compromised RV function at baseline [6] . Despite the better understanding and available therapies for PH, the mortality of patients admitted to the ICU with decompensated PH and right ventricular failure (RVF) remains unacceptably high [7] [8] [9] [10] . This review will describe the epidemiology, evaluation, and management of patients requiring hospitalization and ICU admission for decompensated PH and RVF. (PAH) which is around 15 per million people [12, 13] . Left heart disease is the most common cause of PH and comprises group 2 with an estimated 25-100 % of patients with left heart disease having PH [14] . Chronic obstructive pulmonary disease (COPD) is the most common cause of group 3 PH, with prevalence varying with disease severity. Over 90 % of patients with severe COPD have a mean pulmonary artery pressure (mPAP) [ 20 mmHg, and 3-5 % have mPAP [ 35-40 mmHg [15, 16] . Chronic thromboembolic pulmonary hypertension (CTEPH), group 4, occurs in up to 3.8 % of patients suffering from an acute pulmonary embolism (PE) with an estimated prevalence of 3.2 cases per million adults [15] [16] [17] . Group 5 includes patients with PH from multifactorial mechanisms with an unknown prevalence. As a whole, groups 2-5 are more common than group 1 and can progress to RVF conveying a higher mortality risk [18] [19] [20] [21] . RVF results from a structural or functional process that limits the right ventricle's ability to effectively pump blood through the pulmonary circulation to maintain adequate filling of the left ventricle (LV) and cardiac output (CO) [9, 22] . These processes cause derangements in RV preload, contractility, or afterload ( Table 2 ). The most frequent causes of decompensation are infection, anemia, trauma, surgery, unplanned modification or withdrawal of pulmonary vasodilator therapy, unplanned withdrawal of diuretics, cardiac arrhythmias, pregnancy, and PE. However, up to 48 % of cases have no apparent causative factor and mortality is very high, ranging from 32 to 61 % [10] . The RV is more effective at adapting to volume overload than it is to pressure overload, and the outcome of RVF depends on the underlying cause. A gradual increase in RV afterload leads to chronic adaptation of the RV enabling it to tolerate a significant elevation in pulmonary artery pressures (PAP), whereas the RV without pre-existing hypertrophy will be unable to generate a systolic PAP above 50-60 mmHg [7-10, 23]. RVF secondary to PE has a much better prognosis compared to decompensated PH in a patient with underlying connective tissue disease (CTD) [10] . The management of the patient with RVF is complex and should include the investigation of the underlying causes, appropriate routine ICU care, and hemodynamic optimization (Fig. 1 ). The initial evaluation of any patient in the ICU should focus on promptly establishing the cause of decompensation and identifying reversible conditions. Owing to the increasing awareness of PH, most patients suspected of having RVF from PH have a pre-existing diagnosis [23] . However, physical examination findings may be helpful in the unknown patient, and, although no specific biomarkers for RVF exist, several serum chemistries, cardiac enzymes, imaging, and diagnostic tests aid in the diagnosis and prognosis. Physical examination, especially in the early stages, is neither sensitive nor specific. Patients can present with tachycardia, tachypnea, hypotension, hypoxia, anxiety, cyanosis, and facial plethora. Cardiac examination is characterized by an elevated jugular venous pulse with a large ''v'' wave, a prominent pulmonary component of the second heart sound (P2), a palpable RV heave, and a holosystolic tricuspid regurgitant murmur along the left lower sternal border that increases during inspiration. The height of the jugular venous distention and the quality of the venous wave pattern should be assessed (elevated a vs. v wave). The distance from the sternal angle to the top of the waveform is measured in centimeters, and by convention, the distance between the right atrium (RA) and the sternal angle is added (approximately 5 cm) [24] . Auscultation of the lungs is usually unremarkable unless an underlying condition exists (COPD, pulmonary fibrosis, ARDS). Patients often have tender, palpable hepatomegaly, ascites, and peripheral edema. Cyanosis and digital clubbing may be seen, especially in patients with chronic hypoxemia. Findings of underlying conditions such as CTD (e.g., telangiectasia, sclerodactyly, and malar rash) may also be apparent [25, 26] . Although no specific test exists to diagnose RVF, several routine and disease-specific biochemical parameters aid in the [42] [43] [44] . However, ECG parameters reflective of physiologic and anatomic abnormalities in the RV are significant predictors of mortality in patients with PAH. These include p-wave amplitude [0.25 mV in lead II, presence of qR in V1, and the WHO RVH criteria (Fig. 2) [45]. In addition, the ECG may reveal signs of RV ischemia or infarct. Radiographic examinations of the chest including chest X-ray and CT scan lack sensitivity or specificity in the diagnosis of early RV decompensation or failure, and their use is limited. Nonetheless, they can play an important role in defining an underlying pulmonary disease (pneumonia, pulmonary fibrosis, PE, etc.) [46] . Cardiac magnetic resonance imaging is a very effective noninvasive method to assess RV function, but is rarely used in the management of critically ill patients due to logistical issues [47]. Since electrocardiography and different biomarkers are not sensitive for the diagnoses of RVF in the ICU, the most reliable methods of diagnosis and monitoring of treatment response in the ICU are echocardiography (transthoracic and/or transesophageal) and the pulmonary artery catheter (PAC). Bedside echocardiography has a pivotal role in the critically ill patient with decompensated PH and RVF, as it can provide information regarding the morphology and function of the RV, estimate RA and RV pressures, and identify cardiac causes of PH (Table 4 ) [48, 49] . Disease states that cause RV volume or pressure overload will lead to dilation and eventual hypertrophy of the RV. Findings of significant PH on echocardiography include: inferior vena cava dilatation, RA enlargement, RV enlargement and/or hypertrophy, decreased RV function, intraventricular septal flattening (D-shaped LV), and tricuspid regurgitation (TR) (Figs. 3, 4, 5) . The TR jet or the pulmonary regurgitation jet velocities, in conjunction with an estimated RA pressure, are used to calculate the right ventricular systolic pressure (RVSP). RVSP correlates well with systolic PAP in the absence of pulmonary stenosis and can diagnose PH with a sensitivity of 83 % and specificity of 72 % (Fig. 5) [50, 51]. However, about 10-25 % of patients will have an insufficient spectral Doppler profile of the TR jet to measure the RV to RA pressure gradient; in these instances, the presence of right heart chamber enlargement or septal flattening suggests elevated right heart pressures [52, 53] . The severity of symptoms in patients with PH is strongly associated with RV function. This can be evaluated by echocardiography using multiple parameters including the fractional area change (FAC), RV free-wall longitudinal systolic tissue velocity(s'), tricuspid annular plane systolic excursion (TAPSE) (Fig. 6 ), RV myocardial performance index (MPI or Tei index), isovolumic contraction velocity (IVCv), RV strain, and 3D RV ejection fraction [54] [55] [56] [57] . Echocardiography provides prognostic information in patient with PH and RVF (Table 5) . Several echocardiographic parameters of RV dysfunction predict worse outcomes including an increased RV diameter, a decreased showing ventricular interdependence. Normally, LV enddiastolic pressure is greater than RV end-diastolic pressure, and the septum bows toward the RV during diastole (a, b). In patients with pulmonary hypertension and RV failure, RV end-diastolic pressure exceeds that of the LV and the septum bows toward the LV during diastole forming a ''D''-shaped pattern and impaired LV filling. Also, notice red arrow pointing to pericardial effusion (c). The combination of high RV systolic pressure and decreased LV filling may lead to near obliteration of the LV at end-systole (d) TAPSE, an elevated Tei, an increased RA area, a decreased isovolumic contraction velocity (IVCv), and alterations in RV free-wall strain [58] [59] [60] [61] [62] [63] [64] [65] . In addition, the presence and severity of a pericardial effusion, theoretically caused by elevated RA pressures due to RV dysfunction leading to impaired lymphatic drainage through the thoracic duct, are a strong predictor of mortality ( Fig. 4) [63, 66, 67] . Accurate and complete invasive assessment of pulmonary hemodynamics is essential in the evaluation of patients with RVF, especially in those with RVF due to PH, as some hemodynamic values are predictors of survival [68] [69] [70] [71] . In patients with newly diagnosed primary PH, the NIH registry showed that mortality was closely associated with an increased mean RA pressure, an increased mPAP, and a decreased cardiac index. An increase in mPAP from \55 mmHg to C85 mmHg correlated with a decrease in median survival from 48 months to 12 months, an increase in RA pressure from \10 mm Hg to C20 mm Hg was associated with a decrease in median survival from 46 months to 1 month, and an increase in cardiac index from \2.0 L/min/m 2 to C4.0 L/min/m 2 correlated with an increase in survival time from 17 months to 43 months. Although these parameters have prognostic implications in chronic disease, their significance in acute decompensated PH or RVF has not been established [68]. In the critically ill patients, the hemodynamic values obtained when placing a PAC can help to assess the response to pharmacologic agents and aid in their titration to meet specific endpoints. When evaluating hemodynamic variables in a patient with RVF, the clinician must keep in mind that the mPAP may decrease as the RV function worsens. While patients who respond to the acute vasoreactivity test have excellent prognosis (95 % survival at The placement of a PAC, albeit invasive, is a relatively safe procedure, especially when performed by experienced operators. A large cohort study reviewed, retrospectively and prospectively, the placement of 7218 PACs at 20 major pulmonary vascular centers over a 5-year period [74] . The overall number of serious adverse events was 76 (1.1, 95 CI 0.8-1.3 %). The most frequent complications were related to venous access (e.g., hematoma, pneumothorax), arrhythmias, and hypotension related to vagal reactions or pulmonary vasoreactivity testing. Only four fatal events were recorded, resulting in an overall procedure-related mortality of 0.055 %. Similar results have been published in more recent but smaller cohorts [74, 75] . Although the evidence does not support the routine placement of PACs in the overall critical care population, this intervention has not been studied in patients with acute RVF and its use is advocated by most experts to monitor hemodynamic parameters and mixed venous oxygen saturation (SvO 2 ) [9, 23, 76, 77]. The hemodynamic optimization of patients with RVF is complex and encompasses the precise manipulation of different variables to improve systemic perfusion including optimization of preload, enhancement of cardiac contractility, RV afterload reduction, and maintenance of systemic perfusion pressure. The optimization of right-sided filling pressures is crucial in the management of RVF as both hypovolemic and hypervolemic states have deleterious effects leading to decreased CO. In hypovolemic patients, fluid loading produces a 30 % mean increase in right ventricular enddiastolic volume index (RVEDVI) and a 17 % increase in LV end-diastolic volume index (LVEDVI) resulting in an enhanced stroke volume index (SVI) [78] . Similar response to fluid loading has been described in patients with RVF caused by massive PE [79] . The clinician must exert caution because excessive fluid administration in patients with increased PVR can have adverse effects that are explained by the phenomenon of ventricular interdependence (displacement of the interventricular septum toward the LV leading to decreased LV preload as seen in Fig. 4 ) and increased RV free-wall tension that result in increased myocardial oxygen consumption and decreased perfusion [80-83]. Therefore, liberal volume administration should be discouraged. Most cases of RVF are associated with volume overload requiring the administration of diuretics or ultrafiltration to achieve a negative fluid balance. However, excessive volume removal can also be detrimental by reducing the already impaired CO. Although the optimal filling Simple to perform, highly reproducible, not limited by endocardial border recognition, correlates well with RVEF, right heart remodeling and RV-LV disproportion [59, 294] A TAPSE \ 18 mm correlates with worse survival [59] RV myocardial performance index (MPI or Tei index) Index of combined RV systolic and diastolic function assessed by PW Doppler of the RVOT, TV inflow or regurgitation, or using DTI of the tricuspid annulus [61] Less affected by load and heart rate; may be underestimated in high RA pressure (as IVRT decreases) A value C0.83 has shown to correlate with adverse outcomes [61, 62] Isovolumic contraction velocity (IVCv) Doppler tissue imaging, relatively preload and afterload independent and may reflect a more global ventricular contractility [295] A value B9 cm/s correlates with worse survival [65] RV strain By speckle-tracking strain, requires additional processing, vendor specific deformation Worsening of RV longitudinal strain has been associated with increased mortality [296, 297] RA indicates right ventricle, RV right ventricle, RVEF right ventricular ejection fraction, PAH pulmonary arterial hypertension, LV left ventricle, PW pulse wave, RVOT right ventricular outflow tract, TV tricuspid valve, DTI Doppler tissue imaging, IVRT isovolumic relaxation time pressures vary considerably between individual patients, preload should be kept at a goal between 8 and 12 mm Hg and subsequently adjusted to optimize cardiac output [22] . In summary, the clinician will need to closely monitor the effect of fluid administration or removal on filling pressures, CO, and perfusion parameters. The enhancement of RV contractility with the addition of inotropic agents (Table 6 ) is important in the management of RVF. Dobutamine, the most commonly used agent, has very dose-specific hemodynamic effects. At low doses (up to 5 lg/Kg/min), it produces increased cardiac contractility and decreased systemic vascular resistance (SVR) and PVR. At higher doses, it is associated with tachycardia and premature ventricular contractions without further reduction in the PVR [84] . In animal studies, doses [ 10 lg/Kg/ min were associated with increased PVR and hypotension [85] . The clinician must be aware of the latter complication that often necessitates vasopressors. Dobutamine is more effective than norepinephrine at improving CO, but it can increase the shunt fraction (venous admixture) affecting oxygenation (PaO2). Simultaneous administration of dobutamine and inhaled nitric oxide can improve cardiac output without impairing oxygenation [86-88]. Milrinone produces a significant improvement in RV contractility, decrease in PVR, and improvement in LV filling [89, 90] . However, because of its vasodilator properties, it can cause or worsen preexisting hypotension [91] . Several studies report that inhaled delivery is well tolerated and produces similar effects in PAP and PVR with a higher SVR and less hypotension than the intravenous form [92] [93] [94] . In addition, the combination of milrinone and iNO has been associated with a more pronounced decrease in PAP than either agent alone [95] . Levosimendan has inotropic and vasodilator properties without increasing oxygen demand [96] . It increases right ventricular contractility and produces pulmonary vasodilation in patients with ARDS and RVF caused by PE [97, 98] . In canine models, levosimendan had similar inotropic effects and stronger pulmonary vasodilatory effects than dobutamine [99] . In comparison with milrinone, levosimendan exerts a positive inotropic effect with a smaller increase in myocardial oxygen consumption [100] . In spite of these promising results, levosimendan has not been fully investigated in patients with RVF and its use can be complicated by arrhythmias and a low SVR leading to hypotension [98, [101] [102] [103] . Therefore, more evidence is needed before levosimendan can be widely used for this indication. Maintaining adequate systemic arterial pressure has a dual importance in patients with RVF as it allows the organs to maintain autoregulation of perfusion and preserves blood flow to the right coronary artery (RCA) territory which is perfused throughout the cardiac cycle. The reduced RCA driving pressure due to lower aortic root pressure and/or higher RV pressure is detrimental to RV coronary perfusion. Therefore, increasing the aortic root pressure and SVR by using vasopressors in the setting of increased RV afterload will improve perfusion to the RCA territory [81, 104] . The ideal vasopressor agent should increase systemic arterial pressure (SVR) with minimal effect on the PVR (reduce the PVR/SVR ratio) and improve contractility of the RV. The clinician must exert caution because these drugs (Table 7) can increase PVR and cause unwanted effects. Norepinephrine predominantly produces systemic vasopressor effects through the a1 receptors. Doses of 0.5 lg/Kg/min do not cause a significant increase in PAP, whereas doses of 10 lg/Kg/min are sufficient to produce a 50 % increase in PVR. However, such high doses are not typical in the management of ICU patients [86, 105] . Norepinephrine reduces the PVR/SVR ratio in patients with chronic PH and can improve myocardial oxygen delivery to the RV in septic patients with RVF [106, 107] . The stimulation of b1 receptors improves the CO and the RV/PA coupling which is a measure of the efficiency of transmission of energy from RV to PA [86, 107, 108] . Dopamine increases CO and SVR. It exerts a pulmonary vasoconstrictor effect that can increase the PVR/SVR ratio leading to a decrease in the left to right shunt seen in infants with patent ductus arteriosus [109, 110] . Animal studies show that doses B10 lg/Kg/min increase CO leading to an increase in PAP without increasing the PVR [111, 112] . Nonetheless, dopamine has been associated with tachycardia in patients with PH, increased risk of arrhythmias in patients with septic shock, and increased mortality in patients with cardiogenic shock [113, 114] . Epinephrine has a potent vasoconstrictor effect due to its a1 activity. In animal models, epinephrine at doses from 0.2 to 3.2 lg/Kg/min was superior to dopamine in decreasing the PVR/SVR ratio [115] . After epinephrine administration, patients with RVF caused by septic shock experienced improved RV contractility, CO and mPAP without significantly affecting the PVR [116] . Phenylephrine has vasopressor but no inotropic activity. It has the ability to improve perfusion to the RCA because of the elevation of SVR [81, 117] . However, due to its effect of increasing the PVR, it can significantly impair RV function and decrease CO [106, 108] . Vasopressin produces systemic vasoconstriction while relatively sparing the pulmonary circulation; such combined effects produce a desirable decrease in the PVR/SVR ratio [118] [119] [120] [121] [122] [123] . Vasopressin has been used in pediatric and adult settings as a rescue agent in the management of PH and RVF [120, [124] [125] [126] . However, at high doses ([0.4 U/min), vasopressin can cause bradycardia and decrease in RV contractility and CO likely related to a decrease in coronary blood flow [127] [128] [129] [130] . In summary, norepinephrine is the preferred agent given its effects on SVR, PVR, and improvement in RV/PA coupling. Vasopressin at low doses, dopamine, and norepinephrine are reasonable alternatives. Phenylephrine must be used with caution given the isolated a1 effect that will increase systemic perfusion but will also increase PVR, potentially worsening RV function. Reduction in PVR is one of the most important components in the management of RVF because of the particular sensitivity of the RV to afterload changes. The pharmacologic agents (Table 8) to reduce PVR must be used with caution as they have the potential to cause hypotension. Inhaled nitric oxide (iNO) is a very potent pulmonary vasodilator. Once inhaled, it diffuses across the alveolar capillary membrane into the smooth muscle of the pulmonary vessels and is rapidly inactivated by hemoglobin [131, 132] . iNO decreases PVR, has a neutral effect on SVR, and increases CO [133, 134] . In patients with RVF secondary to ARDS, iNO decreases PAP, increases PaO 2 by improving the ventilation perfusion relationship, and may decrease inflammatory cytokine production in the lungs [135] [136] [137] . iNO improves oxygenation with lower doses than those required to decrease mPAP, but it can have the opposite effect on oxygenation at higher doses [138] . Small studies have shown that iNO produces hemodynamic improvement in different settings of RVF including those caused by RV infarct, acute PE, post-surgical, post-left ventricular assist device (LVAD) implantation, and cardiac transplantation [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] [153] [154] [155] . Complications encountered with the use of iNO include: accumulation of potentially toxic reactive metabolites, rebound PH, and rarely methemoglobinemia [156] [157] [158] [159] [160] [161] . Despite reducing afterload and improving hypoxemia in RVF and ARDS, there is no demonstrated survival benefit [162] [163] [164] . Combination of iNO and prostacyclin derivatives has been reported with success in the perioperative management of portopulmonary hypertension (PoPH) and in RVF after high-risk cardiac surgery, LVAD insertion, and pulmonary endarterectomy [165-169]. The phosphodiesterase-5 (PDE5) inhibitors prevent the hydrolysis of cyclic guanosine monophosphate (cGMP), producing vasodilatory and antiproliferative effects in the pulmonary vasculature [170] . Sildenafil produces an acute decline in mPAP and PVR associated with an increase in CO. The vasodilatory effect of sildenafil is comparable to the effect of iNO with the added benefit of maintaining the pulmonary capillary wedge pressure (PCWP) and producing systemic vasodilatory effects [171-173]. Sildenafil has been used with success in patients with RVF at induction of Prostacyclin derivatives are potent systemic and pulmonary vasodilators. These drugs act on the prostacyclin receptor (present in platelets and endothelial cells) that produces an increase in cyclic adenosine monophosphate (cAMP), resulting in inhibition of platelet aggregation, relaxation of smooth muscle, and vasodilation of the pulmonary arteries [182] . Prostacyclin derivatives decrease PVR and increase CO and exercise capacity in patients with PAH and have been used successfully in the perioperative setting in cardiac surgery and thoracic transplant [183] [184] [185] [186] [187] [188] [189] [190] [191] [192] [193] [194] . In the setting of life-threatening PE, inhaled aerosolized prostacyclin was associated with a transient improvement in pulmonary hemodynamics and gas exchange [195] . In ARDS, inhaled prostacyclins have been associated with important physiologic benefits (improved hypoxemia, lower PAP, and improved RV function and CO) with no systemic hemodynamic effects given the aerosolized alveolar delivery. Unfortunately, there is no evidence supporting outcome benefits and, although controversial, its use should be reserved as a rescue therapy in refractory hypoxemia associated with ARDS [196] [197] [198] . Although the other available vasodilator agents including endothelin receptor antagonists (ERAs) and soluble guanylate cyclase stimulator (riociguat) are effective in PH, their use is not recommended in the setting of RVF. The ERAs have long half-lives and are associated with liver toxicity [199, 200] . Riociguat is a potent pulmonary vasodilator that produces significant systemic vasodilation and hypotension [201] . In addition to routine ICU care (nutrition, prophylaxis, etc.), the specific goals for care provided in the ICU are aimed at managing the factors that would further impair the function of the failing RV. The management of hypoxemia, acidemia, increased intrathoracic pressures caused by mechanical ventilation, and the treatment of cardiac arrhythmias are extremely important. The management of the patient with RVF must address low oxygen saturation and acidemia as both increase mPAP and PVR with synergistic effects [202] [203] [204] [205] . An oxygen saturation level C92 % has been proposed as an ideal target by experts [9, 22] . While acidemia increases the sensitivity of the pulmonary vasculature to hypoxemia, alkalemia decreases such sensitivity and produces pulmonary vasodilation [202] . Therefore, the clinician must strive for a PCO 2 and pH as close to normal as possible. Mechanical ventilation, while often necessary in the management of patient with RVF, has the potential to produce unfavorable hemodynamic effects. The skillful adjustment of the ventilator to improve oxygenation and acidemia while minimizing the effects of increased intrathoracic pressures on the cardiovascular system becomes a priority. Positive pressure ventilation causes decreased venous return, decreased RV stroke volume, distention of alveoli and compression of alveolar blood vessels, and increased PVR. Lung volumes near the functional residual capacity (FRC) minimally affect the PVR, whereas atelectasis and overdistention increase it (Fig. 7) [206] [207] [208] . While the patient with normal RV function may tolerate these changes relatively well, the consequences can be severe in patients with impending RVF. Therefore, the ventilatory strategy in the patient with RVF must strive to achieve normoxia using conservative tidal volumes and PEEP to avoid atelectasis, overdistention, increased PVR, and elevated intrathoracic pressures. Although protective lung strategies are typically associated with respiratory acidosis, they confer a mortality benefit in ARDS that may be partially related to the lower incidence of RVF seen with lower tidal volumes and plateau pressures [209, 210] . Unfortunately, acute cor pulmonale is present in 20-25 % of patients with ARDS ventilated with protective lung strategies. Although this represents a decrease in the incidence of RVF from the preprotective lung strategies era, it is still associated with poor clinical outcomes [210] [211] [212] [213] [214] [215] . Prone positioning is associated with a significant decrease in airway pressures, PaCO 2 , and improvement in echocardiographic parameters of RV pressure overload [216] . Moreover, it provides a mortality benefit in patients with severe ARDS [217] . High-frequency oscillatory ventilation (HFOV) is associated with unfavorable hemodynamic effects including an increase in central venous pressure, PCWP, and decrease in CO [218] . In patients with ARDS, HFOV can worsen RV function and does not provide a mortality benefit when compared with conventional protective lung strategies [219] [220] [221] . Cardiac arrhythmias can be a cause or a complication of RVF in patients admitted to the ICU. Atrial flutter and fibrillation are the most common arrhythmias in this population, whereas bradyarrhythmias and ventricular arrhythmias are rare except in the setting of cardiac arrest [222] . The RV is very sensitive to abnormalities in cardiac rhythm and synchrony. In RVF, augmented RA contraction and intact atrioventricular (AV) synchrony are important determinants of CO. The augmented RA contractility constitutes a compensatory response to RV dysfunction [223] . Restoration of AV synchrony produced positive hemodynamic results in patients with RV infarct and congenital heart disease [224] [225] [226] [227] [228] [229] . AV pacing in patients with right bundle-branch block and RV dysfunction augments RV and systemic performance [230] . Although there are no large-scale studies to support resynchronization therapy in RVF, this intervention could be considered as part of the management. Mechanical circulatory support is typically reserved for patients with persistent RVF in spite of medical interventions and used as a bridge to heart, lung, or dual heart-lung transplantation. The currently available mechanical circulatory support modalities include the different ventricular assist devices and extracorporeal membrane oxygenation (ECMO). The mechanical assist devices are available as left, right, or biventricular (LVAD, RVAD, or BiVAD, respectively). LVADs have been used with success in patients with PH and RVF caused by left heart dysfunction with the goal to reduce the mPAP and PVR, effects that are typically achieved in 3-6 months. A higher number of patients can be considered for heart transplantation after LVAD therapy with a possible benefit in post-transplant survival [231] [232] [233] [234] [235] [236] . Although beneficial for the RV in the long term, LVADs can exacerbate or cause new-onset RVF because the decrease in LV end-diastolic volume will shift the interventricular septum to the left, increasing the RV enddiastolic volume, compromising its contractility [237] . Approximately 6-10 % of patients with a LVAD will require the implantation of a RVAD [238] . RVADs have been successfully used for the management of RVF in patients with RV infarct, after cardiac surgery, after LVAD implantation, and following heart transplantation [239] [240] [241] [242] [243] [244] . RVADs will increase pressure but not sufficiently to overcome the increased RV afterload potentially injuring the lung [245] . BiVADs may be used in cases of bilateral ventricular failure as a bridge to transplantation [246] . Veno-arterial (V-A) ECMO has the ability to provide both cardiovascular and respiratory support as it drains deoxygenated blood from the venous circulation and returns oxygenated blood to the arterial circulation. V-A ECMO can be considered in patients with RVF secondary to increased afterload as a bridge to transplantation when medical interventions do not suffice. Although small studies suggest Fig. 7 Relationship of lung volumes and PVR. At volumes near FRC, the PVR is minimally affected. Atelectasis compresses extraalveolar blood vessels leading to increased PVR. At high lung volumes, alveolar overdistension compresses intra-alveolar blood vessels resulting in increased PVR. RV residual volume, FRC functional residual capacity, TLC total lung capacity favorable outcomes with the use of ECMO, further research is needed before general recommendations can be made and its use should be reserved for centers with expertise [247] . Given the improvement in survival in patients with PH produced by modern available therapies, an increase in other conditions that were not as common in this group of patients has occurred. The clinician must be familiar with the pathophysiologic differences of the PH patient to provide the best possible care. During pregnancy, significant physiologic changes occur including increased blood volume, increased CO, decreased SVR, and increased pulmonary blood flow [248] . During delivery, pain, anxiety, raised levels of catecholamine and uterine contractions produce an increase in CO. After delivery, the venous return increases significantly as a result of the involution of the uterus producing a sizeable increase in CO. Patients with normal PVR can readily tolerate these changes through vasodilation and recruitment of pulmonary vessels, whereas patients with PH cannot adapt making them prone to develop acute RVF [249] . Consequently, the mortality rate, albeit lower than in previous times, remains very high ranging from 17 to 28 %, with most complications occurring in the peripartum period [250, 251] . Vaginal delivery may be better tolerated by PH patients given the smaller shifts in blood volume and greater stability in hemodynamics, but cesarean section (CS) may become urgently necessary in cases of fetal distress or maternal deterioration. Recent literature reports a more frequent use of CS and a higher proportion of premature deliveries; this change in practice may be explained by closer surveillance and a lower threshold for intervention in cases of maternal deterioration or fetal distress [251] . A multidisciplinary team including the cardiac anesthesiologist, obstetrician, and neonatologist should be involved if a CS is the chosen route of delivery. The PH patient should undergo close monitoring during the peripartum period with particular attention to arterial oxygenation, cardiac rhythm, and hemodynamics. The use of invasive monitoring devices seems reasonable and should be considered on a case-by-case basis [252, 253] . Successful outcomes have been reported with the use of various pulmonary vasodilators during the peripartum period including epoprostenol, iNO, and combination of sildenafil and epoprostenol [254] [255] [256] [257] [258] [259] . PoPH is a complication of portal hypertension that occurs more commonly in patients with chronic liver disease. It is often asymptomatic and discovered during the perioperative period for liver transplantation when it poses the highest risk [260, 261] . The acute increase in CO at the time of reperfusion cannot be handled by the RV of the patient with PoPH leading to acute RVF [262] . The evaluation of risk, indications for advanced therapy, and contraindications to liver transplant are based on hemodynamic variables including mPAP and PVR. A mPAP [ 50 is considered a contraindication for liver transplant, whereas a mPAP \35 is considered safe [263, 264] . Pulmonary vasodilators are used in the management of PoPH to improve hemodynamics. Several small studies report the use of prostacyclin analogs [265] [266] [267] , ERAs [266, [268] [269] [270] , and PDE5 inhibitors [268, 271, 272] in the management of patients with PoPH. In the perioperative period, combined use of iNO and epoprostenol has been reported with good outcomes [165, 166] . Left ventricular failure is among the most common causes of RVF [9]. The backflow caused by left heart disease increases LV end-diastolic pressure and RV afterload. Therefore, the treatment of patients with biventricular failure should focus on optimizing LV function through improvement in preload, contractility, and afterload. However, even after optimization of the left heart function, the transpulmonary gradient (mPAP-PCWP) may remain elevated, a phenomena known as ''out of proportion'' PH that is thought to be caused by an intrinsic abnormality in the pulmonary vasculature [273, 274] . The persistent elevation in PVR is especially important in patients being considered for cardiac transplant or LVAD placement because of an increased perioperative risk and decreased long-term survival after transplantation and the potential need for additional mechanical RV support [238, 275] . Sildenafil has been linked to improved exercise capacity and pulmonary hemodynamics in secondary PH patients with systolic heart failure, but not in patients with diastolic heart failure [276] [277] [278] . Prostacyclin analogs have also been used with positive hemodynamic changes [279, 280] . ERAs have not been associated with improved clinical outcomes and may increase the risk of decompensation [281] [282] [283] [284] . Nevertheless, more evidence is needed before general recommendations can be made regarding the use of pulmonary vasodilators in this setting. Sepsis poses a myriad of physiologic derangements including increased vascular permeability, vasodilation, hypovolemia, and decreased SVR that must be overcome by an increment in CO [4] [5] [6] 10] . Low SVR leads to decreased RV coronary perfusion, myocardial ischemia, and failure. In addition, there is often an increase in PVR causing decreased RV output. An increase in RV afterload or intrinsic myocardial depression may be the dominant cause of RV dysfunction in sepsis [4] [5] [6] 10] . Given the increased PVR, increasing cardiac output may prove very difficult in patients with PH and sepsis can trigger acute RVF. The management of the septic patient with PH must include early administration of antibiotics and hemodynamic optimization that should encompass the optimization of preload, enhancement of SVR, improvement of CO, and prevention of increase in PVR (as discussed above) [285] . Fluid resuscitation should not be liberal in this population and ideally must be guided by invasive hemodynamic monitoring devices. The use of pulmonary vasodilators in sepsis should be reserved to cases where further decrease in PVR is needed to improve cardiac output and systemic perfusion, keeping in mind that these agents produce systemic effects that could worsen the hemodynamic status. The etiology of acute RVF largely influences the prognosis; patients with severe left heart disease or progressive PH in the setting of CTD have a worse prognosis compared to patients with acute PE [10, 286] . Despite the recent advancements in therapy that have improved the quality of life and survival in PH, it still remains a progressive disease that will ultimately have fatal outcomes. Therefore, it is important that the patient's wishes pertaining to end-oflife care be discussed in a serene environment during the course of the disease. Grinnan et al. reported that the majority of patients with PAH died in the hospital and most of those deaths happened in the ICU [287] . Unfortunately, the ICU may not be the best setting to have this conversation for the first time when decompensation typically occurs rapidly and decisions may need to be made very quickly. Cardiopulmonary resuscitation (CPR) is attempted in 25 % of patients that ultimately die of progression of the disease. The survival of PH patients who arrested and had CPR is quite low (0-6 %) compared to the survival from other causes of cardiac arrest, a fact that is not surprising given that chronic disease is associated with poor outcomes after CPR [288, 289] . Moreover, almost every patient that survived had a correctable cause [290] . Recent evidence shows that palliative care services were infrequently utilized in the care of patients with PH [287, 291, 292] . The care of patients with progressive disease should include a discussion of goals of care, potentially limiting aggressive therapy, and referral to palliative care when appropriate for the management of symptoms and potentially improve quality of life. PH and concomitant RVF present a diagnostic and therapeutic challenge in the ICU and have been associated with increased mortality. Prompt recognition is essential for the appropriate management in these patients. The use of biochemical markers and echocardiography may help in the diagnosis and have prognostic value, and invasive monitoring with PAC is likely necessary to monitor hemodynamics and therapeutic changes. Careful manipulation of RV preload is required as under-or overfilling of the RV will worsen its contractility. Pulmonary vasodilators have a profound effect on PVR and can be used to increase CO but co-administration of systemic vasopressors and restoration of cardiac output with the use of inotropes are usually required. Mechanical circulatory support is predominately being utilized as a bridge to transplant. Despite the advances in therapy that have improved the survival in patients with PH, realistic expectations should be discussed in the outpatient setting as patients who suffer cardiac arrest have very poor outcomes. Overall, more studies of RVF are required to improve overall outcomes of this disease. National Heart L, Blood Institute Working Group on C, Molecular Mechanisms of Right Heart F (2006) Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure Right ventricular structure is associated with the risk of heart failure and cardiovascular death: the Multi-Ethnic Study of Atherosclerosis (MESA)-right ventricle study The right ventricle and critical illness: a review of anatomy, physiology, and clinical evaluation of its function Myocardial dysfunction in septic shock Right ventricular dysfunction in septic patients Unsuspected right ventricular dysfunction in shock and sepsis Continuous wave Doppler determination of right ventricular pressure: a simultaneous Doppler-catheterization study in 127 patients Frequency and severity of tricuspid regurgitation determined by Doppler echocardiography in primary pulmonary hypertension Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy Two-dimensional assessment of right ventricular function: an echocardiographic-MRI correlative study Accuracy of echocardiographic right ventricular parameters in patients with different end-stage lung diseases prior to lung transplantation Pulsed Doppler tissue imaging of the velocity of tricuspid annular systolic motion; a new, rapid, and non-invasive method of evaluating right ventricular systolic function Clinical and prognostic relevance of echocardiographic evaluation of right ventricular geometry in patients with idiopathic pulmonary arterial hypertension Tricuspid annular displacement predicts survival in pulmonary hypertension Right heart function and scleroderma: insights from tricuspid annular plane systolic excursion Doppler echocardiographic index for assessment of global right ventricular function Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension Echocardiographic predictors of adverse bypass Comparison of inhaled and intravenous milrinone in patients with pulmonary hypertension undergoing mitral valve surgery Milrinone and nitric oxide: combined effect on pulmonary artery pressures after cardiopulmonary bypass in children Acute effects of levosimendan in experimental models of right ventricular hypertrophy and failure Effects of levosimendan on acute pulmonary embolism-induced right ventricular failure Effects of levosimendan on right ventricular afterload in patients with acute respiratory distress syndrome: a pilot study Effects of levosimendan versus dobutamine on pressure load-induced right ventricular failure Effects of levosimendan and milrinone on oxygen consumption in isolated guinea-pig heart Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial Safety and efficacy of a novel calcium sensitizer, levosimendan, in patients with left ventricular failure due to an acute myocardial infarction. A randomized, placebo-controlled, double-blind study (RUSSLAN) Levosimendan vs dobutamine for patients with acute decompensated heart failure: the SURVIVE Randomized Trial Phasic right coronary artery blood flow in conscious dogs with normal and elevated right ventricular pressures Humoral control of the pulmonary circulation The effect of phenylephrine and norepinephrine in patients with chronic pulmonary hypertension* Effect of dopamine versus norepinephrine on hemodynamics in septic shock. Emphasis on right ventricular performance Norepinephrine and phenylephrine effects on right ventricular function in experimental canine pulmonary embolism Hypotension in preterm infants with significant patent ductus arteriosus: effects of dopamine Dopamine effects on pulmonary artery pressure in hypotensive preterm infants with patent ductus arteriosus Pulmonary hemodynamic response to dopamine and dobutamine in hyperoxic and in hypoxic dogs Effects of dopamine and dobutamine on hyperoxic and hypoxic pulmonary vascular tone in dogs Comparison of dopamine and norepinephrine in the treatment of shock Acute circulatory effects of dopamine in patients with pulmonary hypertension A blind, randomized comparison of the circulatory effects of dopamine and epinephrine infusions in the newborn piglet during normoxia and hypoxia Effects of epinephrine on right ventricular function in patients with severe septic shock and right ventricular failure: a preliminary descriptive study The effects of phenylephrine on right ventricular performance in patients with pulmonary hypertension Vasopressin-induced pulmonary vasodilation in rats Vasoconstrictor responses to vasopressor agents in human pulmonary and radial arteries: an in vitro study Intravenous arginine vasopressin for two pediatric cases of pulmonary hypertension after congenital heart surgery Arginine vasopressin is an ideal drug after cardiac surgery for the management of low systemic vascular resistant hypotension concomitant with pulmonary hypertension Comparative hemodynamic effects of vasopressin and norepinephrine after milrinone-induced hypotension in offpump coronary artery bypass surgical patients Vasopressin decreases pulmonary-to-systemic vascular resistance ratio in a porcine model of severe hemorrhagic shock Vasopressin as a rescue therapy for refractory pulmonary hypertension in neonates: case series Use of vasopressin after Caesarean section in idiopathic pulmonary arterial hypertension Vasopressin during spinal anesthesia in a patient with primary pulmonary hypertension treated with intravenous epoprostenol Effects of vasopressin on right ventricular function in an experimental model of acute pulmonary hypertension Hemodynamic effects of vasopressin, alone and in combination with nitroprusside, in patients with liver cirrhosis and portal hypertension Mechanisms of impaired cardiac function by vasopressin Direct cardiac effects of vasopressin and their reversal by a vascular antagonist Inhaled nitric oxide: a selective pulmonary vasodilator: current uses and therapeutic potential Nitric oxide and iron proteins Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension Inhaled nitric oxide selectively reverses human hypoxic pulmonary vasoconstriction without causing systemic vasodilation Inhaled nitric oxide for the adult respiratory distress syndrome Inhibitory effects of nitric oxide and interleukin-10 on production of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 in mouse alveolar macrophages Nitric oxide downregulates lung macrophage inflammatory cytokine production The initial response to inhaled nitric oxide treatment for intensive care unit patients with acute respiratory distress syndrome Inhaled nitric oxide for pulmonary hypertension after heart transplantation Inhaled nitric oxide for acute right-ventricular dysfunction after extrapleural pneumonectomy Successful perioperative utilisation of inhaled nitric oxide in mitral valve surgery Nitric oxide inhalation is useful in the management of right ventricular failure caused by myocardial contusion Hemodynamic effects of inhaled nitric oxide in right ventricular myocardial infarction and cardiogenic shock Nitric oxide inhalation is useful in the management of right ventricular failure caused by myocardial infarction Usefulness of nitric oxide inhalation for management of right ventricular failure after heart transplantation in patients with pretransplant pulmonary hypertension Pulmonary hypertension and right ventricular failure after heart transplantation: usefulness of nitric oxide Beneficial effects of inhaled nitric oxide in adult cardiac surgical patients Response to inhaled nitric oxide in patients with acute right heart syndrome Nitric oxide inhalation in the treatment of right ventricular dysfunction following left ventricular assist device implantation Inhaled nitric oxide for right ventricular dysfunction following cardiac transplantation Inhaled nitric oxide as salvage therapy in massive pulmonary embolism: a case series Inhaled nitric oxide in patients with pulmonary embolism Inhaled nitric oxide improves pulmonary functions following massive pulmonary embolism: a report of four patients and review of the literature Successful treatment of pulmonary hypertension with inhaled nitric oxide after pulmonary embolectomy Inhaled nitric oxide in a patient with severe pulmonary embolism Methemoglobinemia due to nitric oxide therapy in a child after cardiac surgery Methemoglobinemia: toxicity of inhaled nitric oxide therapy Inhaled nitric oxide therapy in adults epoprostenol analog for primary pulmonary hypertension Inhaled iloprost for severe pulmonary hypertension Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right-heart dysfunction, and refractory hypoxemia after cardiothoracic surgery Inhaled prostacyclin is safe, effective, and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery Intraoperative use of inhaled PGI(2) for acute pulmonary hypertension and right ventricular failure Inhaled prostacyclin, nitric oxide, and nitroprusside in pulmonary hypertension after mitral valve replacement Inhaled iloprost to control pulmonary artery hypertension in patients undergoing mitral valve surgery: a prospective, randomized-controlled trial Inhaled iloprost controls pulmonary hypertension after cardiopulmonary bypass Treatment with epoprostenol of pulmonary arterial hypertension following mitral valve replacement for mitral stenosis A prospective, randomized, crossover pilot study of inhaled nitric oxide versus inhaled prostacyclin in heart transplant and lung transplant recipients The use of inhaled aerosolized prostacyclin (IAP) in the treatment of pulmonary hypertension secondary to pulmonary embolism Are inhaled vasodilators useful in acute lung injury and acute respiratory distress syndrome? Aerosolized prostacyclin for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) A review of inhaled nitric oxide and aerosolized epoprostenol in acute lung injury or acute respiratory distress syndrome Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study Bosentan therapy for pulmonary arterial hypertension Riociguat for the treatment of pulmonary arterial hypertension The influence of hydrogen ion concentration and hypoxia on the pulmonary circulation Response of the pulmonary vasculature to hypoxia and H ? ion concentration changes Right ventricular performance during increased afterload impaired by hypercapnic acidosis in conscious dogs Right ventricular response to hypercarbia after cardiac surgery Cardiopulmonary interactions during mechanical ventilation in critically ill patients Reevaluation of hemodynamic consequences of positive pressure ventilation: emphasis on cyclic right ventricular afterloading by mechanical lung inflation Jardin F (1999) Cyclic changes in right ventricular output impedance during mechanical ventilation Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome Is there a safe plateau pressure in ARDS? The right heart only knows Right ventricular failure in acute lung injury and acute respiratory distress syndrome Acute cor pulmonale in acute respiratory distress syndrome submitted to protective ventilation: incidence, clinical implications, and prognosis Pulmonary vascular dysfunction is associated with poor outcomes in patients with acute lung injury Prevalence and prognosis of cor pulmonale during protective ventilation for acute respiratory Why protect the right ventricle in patients with acute respiratory distress syndrome? Prone positioning unloads the right ventricle in severe ARDS Prone positioning in severe acute respiratory distress syndrome Cardiac function and haemodynamics during transition to high-frequency oscillatory ventilation Right ventricular function during high-frequency oscillatory ventilation in adults with acute respiratory distress syndrome High-frequency oscillation for acute respiratory distress syndrome High-frequency oscillation in early acute respiratory distress syndrome Incidence and clinical relevance of supraventricular tachyarrhythmias in pulmonary hypertension Hemodynamic importance of systolic ventricular interaction, augmented right atrial contractility and atrioventricular synchrony in acute right ventricular dysfunction Hemodynamic benefit of atrial pacing in right ventricular myocardial infarction Reversibility of hypotension and shock by atrial or atrioventricular sequential pacing in patients with right ventricular infarction Right ventricular infarction, bradyarrhythmias, and cardiogenic shock: importance of atrial or atrioventricular sequential pacing Sinus arrest in diaphragmatic myocardial infarction: treatment of power failure with atrial pacing Atrial pacing in the management of right ventricular infarction Cardiac resynchronization therapy: a novel adjunct to the treatment and prevention of systemic right ventricular failure Electrical resynchronization: a novel therapy for the failing right ventricle Post-transplant survival after lowering fixed pulmonary hypertension using left ventricular assist devices Does pretransplant left ventricular assist device therapy improve results after heart transplantation in patients with elevated pulmonary vascular resistance? Reversibility of fixed pulmonary hypertension in left ventricular assist device support recipients Normalization of high pulmonary vascular resistance with LVAD support in heart transplantation candidates Implantable left ventricular assist device for treatment of pulmonary hypertension in candidates for orthotopic heart transplantation-a preliminary study Left ventricular assist devices decrease fixed pulmonary hypertension in cardiac transplant candidates Right side of heart failure Biventricular VAD versus LVAD for right heart failure Right ventricular dysfunction in patients with acute inferior MI: role of RV mechanical support Mechanical support for isolated right ventricular failure in patients after cardiotomy Temporary percutaneous right ventricular support using a centrifugal pump in patients with postoperative acute refractory right ventricular failure after left ventricular assist device implantation Experience with right ventricular assist devices for perioperative right-sided circulatory failure Outcome of unplanned right ventricular assist device support for severe right heart failure after implantable left ventricular assist device insertion Right ventricular failure following heart transplantation-recovery after extended mechanical support Life-threatening right ventricular failure in pulmonary hypertension: RVAD or ECMO? Early biventricular assist device use in children: a single center review of 31 patients Extracorporeal membrane oxygenation is superior to right ventricular assist device for acute right ventricular failure after heart transplantation Exacerbation of underlying pulmonary disease in pregnancy Pulmonary hypertension in pregnancy Outcome of pulmonary vascular disease in pregnancy: a systematic overview from 1978 through 1996 Has there been any progress made on pregnancy outcomes among women with pulmonary arterial hypertension? Primary pulmonary hypertension in pregnancy; a role for novel vasodilators Swan-Ganz catheter-induced severe complications in cardiac surgery: right ventricular perforation, knotting, and rupture of a pulmonary artery Pregnancy and primary pulmonary hypertension: successful outcome with epoprostenol therapy Pulmonary hypertension in pregnancy: treatment with pulmonary vasodilators Favorable outcome of pregnancy with an elective use of epoprostenol and sildenafil in women with severe pulmonary hypertension Inhaled nitric oxide for primary pulmonary hypertension in pregnancy Inhaled nitric oxide therapy in pregnancy complicated by pulmonary hypertension Use of inhaled nitric oxide for emergency Cesarean section in a woman with unexpected primary pulmonary hypertension Frequency and clinical implications of increased pulmonary artery pressures in liver transplant patients Portopulmonary hypertension Portopulmonary hypertension and right heart failure in patients with cirrhosis Portopulmonary hypertension: a consequence of portal hypertension The prevalence and the impact of portopulmonary hypertension on postoperative course in patients undergoing liver transplantation Initial experience using continuous intravenous treprostinil to manage pulmonary arterial hypertension in patients with end-stage liver disease Treatment with sildenafil and treprostinil allows successful liver transplantation of patients with moderate to severe portopulmonary hypertension Successful use of continuous intravenous prostacyclin in a patient with severe portopulmonary hypertension Oral vasodilator therapy in patients with moderate to severe portopulmonary hypertension as a bridge to liver transplantation Safety and efficacy of ambrisentan for the treatment of portopulmonary hypertension Ambrisentan improves exercise capacity and symptoms in patients with portopulmonary hypertension Sildenafil treatment for portopulmonary hypertension Sildenafil monotherapy in portopulmonary hypertension can facilitate liver transplantation Precapillary pulmonary hypertension; its relationship to pulmonary venous hypertension Pulmonary hypertension in heart failure: epidemiology, right ventricular function and survival Selection of cardiac transplantation candidates in 2010 Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension Comparative effectiveness of sildenafil for pulmonary hypertension due to left heart disease with HFrEF Effects of sildenafil on invasive haemodynamics and exercise capacity in heart failure patients with preserved ejection fraction and pulmonary hypertension: a randomized controlled trial Specifics of inhaled iloprost pharmacodynamics in patients with severe left ventricular systolic dysfunction Iloprost improves hemodynamics in patients with severe chronic cardiac failure and secondary pulmonary hypertension Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure? Clinical and hemodynamic effects of bosentan dose optimization in symptomatic heart failure patients with severe systolic dysfunction, associated with secondary pulmonary hypertension-a multi-center randomized study Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the EndothelinA Receptor Antagonist Trial in Heart Failure (EARTH): randomised, double-blind, placebo-controlled trial Effects of tezosentan on symptoms and clinical outcomes in patients with acute heart failure: the VERITAS randomized controlled trials Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock Pulmonary hypertension due to left heart disease The end-of-life experience for a cohort of patients with pulmonary arterial hypertension Prognostic factors and outcomes of patients with pulmonary hypertension admitted to the intensive care unit Efficacy of CPR in a general Outcome after cardiopulmonary resuscitation in patients with pulmonary arterial hypertension Physician attitudes toward palliative care for patients with pulmonary arterial hypertension: results of a cross-sectional survey Symptom burden, quality of life, and attitudes toward palliative care in patients with pulmonary arterial hypertension: results from a cross-sectional patient survey Right ventricular function in cardiovascular disease, part I: anatomy, physiology, aging, and functional assessment of the right ventricle Assessment of right ventricular function using two-dimensional echocardiography Longitudinal but not circumferential deformation reflects global contractile function in the right ventricle with open pericardium Prognostic value of right ventricular longitudinal peak systolic strain in patients with pulmonary hypertension Outcome prediction by quantitative right ventricular function assessment in 575 subjects evaluated for pulmonary hypertension