Pulmonary arterial hypertension (PAH) is a progressive, symptomatic, and ultimately fatal disorder for which substantial advances in treatment have been made during the past decade . Despite advances in the management of PAH, the mortality rate remains excessive. Acute PAH, which may lead to refractory systemic arterial hypotension, severe hypoxemia, right ventricular (RV) dysfunction and failure, and ultimately result in cardiogenic and/or obstructive shock and death have always been neglected until serious complications have developed. Effective management requires timely recognition and accurate diagnosis of the disorder and appropriate selection among therapeutic alternatives. Despite progress in treatment, obstacles remain that impede the achievement of optimal outcomes . The pathophysiology, monitoring, and management of the acute pulmonary hypertension are reviewed in this article to highlight the importance and due management of it. The article also reviews established approaches to evaluation and treatment, with emphasis on the appropriate application of calcium channel blockers (CCBs), prostacyclin analogues, endothelin receptor antagonists (ETRAs), and phosphodiesterase 5 inhibitors.
Acute pulmonary arterial hypertension (PAH), which may complicate the course of many complex disorders, is always underdiagnosed and its treatment frequently begins only after serious complications have developed. Acute PAH is distinctive because they differ in their clinical presentation, diagnostic findings, and response to treatment from chronic PAH. The acute PAH may take either the form of acute onset of chronic PAH or acute PAH or surgery-related PAH. Significant pathophysiologic differences existed between acute and chronic PAH. Therapy of acute PAH should generally be aimed at acutely relieving right ventricular (RV) pressure overload and preventing RV dysfunction. There are three classes of drugs targeting the correction of abnormalities in endothelial dysfunction, which have been approved recently for the treatment of PAH: (1) prostanoids; (2) endothelin receptor antagonists; and (3) phosphodiesterase-5 inhibitors. The efficacy and safety of these compounds have been confirmed in uncontrolled studies in patients with PAH. Intravenous epoprostenol is suggested to serve as the first-line treatment for the most severe patients. In the other situations, the first-line therapy may include bosentan, sildenafil, or a prostacyclin analogue. Recent advances in the management of PAH have markedly improved prognosis.
Pathophysiology and Pathogenesis of Acute PAH
PAH is characterized by elevated pulmonary arterial pressure (PAP) and secondary RV failure. The definition of PAH used in clinical trials has been a mean pulmonary arterial pressure (mPAP) >25 mmHg at rest or >30 mmHg with exercise, a pulmonary capillary wedge pressure (PCWP) of <15 mmHg, and a pulmonary vascular resistance (PVR) of >3 Wood units, which has been attributed to the criteria for idiopathic PAH established by the National Institutes of Health Registry on Primary Pulmonary Hypertension (PPH) [3,4]. It is considered to be severe if mPAP >50 mmHg; of moderate severity, if mPAP 30–50 mmHg or mild, if mPAP <30 mmHg. Right heart failure is the most important consequence of PAH and remains a frequent cause of death in patients with PAH. Increased RV afterload leads to RV dilatation in most acute cases of PAH when there is not enough time for adaptive mechanisms (e.g., RV hypertrophy) to develop. Thus, RV dilatation or RV hypertrophy are the main features of the acute and chronic PAH, respectively.
The mechanisms of arterial PAH include vascular thromboembolism, endothelial dysfunction, hypoxic vasoconstriction, pulmonary vascular remodeling, smooth muscle proliferation with or without neointimal formation, and in situ thrombosis . Endothelial dysfunction with an imbalance between vasodilation and vasoconstriction, and between apoptosis and proliferation is thought to play a pivotal role in the development of chronic progressive PAH. Hypoxemic pulmonary vasoconstriction is an important determinant of arterial PAH in patients with respiratory disorders . In many types of PAH, production of endogenous vasodilators (nitric oxide [NO] and prostacyclin) is impaired and production of vasoconstrictors  (endothelin-1) is increased . This forms the pathophysiologic basis of common treatment strategies for arterial PAH, which attempt to achieve balance in key molecular pathways by increasing available NO and prostacyclin, or reducing the effects of endothelin-1.
Acute arterial PAH is characterized by a sudden increase in PAP. Mechanical obstruction with subsequent vasoconstriction characterizes acute PAH in pulmonary embolism (PE). In acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), both hypoxic pulmonary vasoconstriction and accumulation of intravascular fibrin and cellular debris contribute to subsequent vascular obliteration and PAH . Endotoxin plays a significant role in the development of PAH during sepsis. Multiple animal studies have shown that endotoxin can cause not only systemic hypotension, but also pulmonary biphasic hypertension, along with a decrease in compliance and an increase in resistance of respiratory system . Endotoxin-dependent hemodynamic and respiratory effects are mediated by excessive release of inflammatory mediators and imbalances in production of NO, prostanoids, and endothelin-1 (ET-1) . PAH in endotoxemia is characterized by constriction of proximal pulmonary arteries during the early phase followed by decreased compliance of the distal pulmonary vasculature .
Neurohormonal activation is an important factor in both acute and chronic RV failure. The consequence of sympathetic hyperactivity is an increase in PVR with impedance of flow, causing RV strain that impairs filling and causes RV volume and pressure overload. The RV dilates (and eventually hypertrophy can develop in chronic gradual pulmonary hypertension), encroaching on the left ventricle and decreasing preload, cardiac output, and coronary perfusion. Increased RV wall stress results in RV ischemia . Tricuspid regurgitation develops as a result of RV dysfunction and portends a poor prognosis . RV systolic dysfunction, severe tricuspid regurgitation, arrhythmias, and left ventricular dysfunction caused by ventricular interdependence may contribute to low cardiac output and hypotension in patients with pulmonary hypertension. Regardless of the underlying cause of PAH, the final common pathway for hemodynamic deterioration and death is cor pulmonale and RV failure. Among other clinically important adverse effects of right heart failure is the development of systemic venous hypertension leading to concomitant visceral organ congestion and dysfunction such as renal function impairment. The normal RV can acutely adapt to high flow, but is not able to tolerate any but very short acute high pressure load . The normal RV cannot acutely increase and sustain mean PAP >40 mmHg for more than a brief period of time .
The Causes of Arterial Pulmonary Hypertension
Multifactorial impairment of the physiologic balance can lead to vasoconstriction, vascular smooth muscle cell and endothelial cell proliferation/fibrosis, inflammation, remodeling, and in situ thrombosis. These are the likely mechanisms that lead to narrowing of the vessel followed by progressive increase in PVR and the clinical manifestations of PAH. The etiology of acute PAH is different from what of chronic (or persistent) PAH, but the pathogenesis of acute PAH is the same as of chronic (or persistent) PAH, which also includes endothelial injury in the pulmonary arterioles, vasoconstriction caused by reduced production of endogenous NO by the pulmonary endothelium, and thrombosis . Subsequently, major goal of the therapy is to avoid acute pulmonary vasoconstriction, halt the progression of vascular remodeling, and reverse the early vascular remodeling if possible.
Almost all diseases manifested as PAH can cause right heart failure: either as an acute condition, if the PAH develops acutely (as with sepsis/acute lung injury (ALI), PE, cardiac surgery, drug induced, etc.), or as a chronic condition, if arterial pulmonary hypertension is mainly chronic (as in chronic obstructive pulmonary disease (COPD), interstitial lung disease, sleep disorder breathing, chronic hypoventilation, PAH, chronic thromboembolic pulmonary hypertension(CTEPH), portopulmonary hypertension, etc.). PAH associated with various noncardiac etiological diseases (connective-tissue diseases, portal hypertension, HIV infection, consumption of anorectic agents) account for approximately 50% of cases of PAH. The acute PAH may take either the form of acute onset of chronic PAH or acute PAH or surgery-related PAH.
Acute Onset of Chronic Arterial PAH
Patients with preexisting PAH are particularly vulnerable to acute illnesses, which commonly result in rapid deterioration and even death . Besides idiopathic PAH, interstitial lung diseases, COPD, chronic hypoventilation and sleep disorder breathing, portopulmonary hypertension and chronic pulmonary thromboembolism are always accompany with chronic arterial PAH. On the basis of above-mentioned morbidities, multiple noncardiac predisposing factors can precipitate acute PAH onset and right heart failure, even leading to adverse outcome. These predisposing factors belong to several categories. In the pulmonary category, there are chronic hypoxia, and restrictive lung disease (with or w/o COPD), and decreased DLCO, and decreased pulmonary compensatory capacity. In the infection category, these are using of immunosuppressive, and disease modifying drugs for underlying disease, and malnutrition and overall decreased functional reserve. Patients with chronic PAH can rapidly deteriorate and usually die from progressive RV failure (49%), progressive respiratory failure (18%), or sudden cardiac death (17%).
Massive PE, sepsis, and ALI are the main causes of acute arterial PAH in the adult patient population . The onset of acute right heart failure as a complication of ALI and its more severe form ARDS is more gradual than in patients with massive PE. It usually occurs at least 48 h after the beginning of respiratory support . Evaluation of RV function by transesophageal echocardiography (TEE) in a group of 75 ARDS patients submitted to protective ventilation demonstrated 25% incidence of acute RV dysfuncion, with detrimental hemodynamic consequences associated with tachycardia. However, those changes in heart function were reversible in patients who recovered and did not increase mortality . Although the initial magnitude of pulmonary hypertension was not an indicator of mortality, PAP further increased in nonsurvivors, but not in survivors when followed for 7 days . Thus, development of PAH in ARDS patients seems to be a sign of poor prognosis. In a cohort of 352 ARDS patients, both mortality rate and incidence of right heart failure were related to the level of plateau pressure during mechanical ventilation. An interaction between plateau pressure and right heart failure was observed whereas odds ratio of dying for an increase in plateau pressure (from 18–26 to 27–35 cm H2O) in patients without right heart failure was 1.05 (P= 0.635), in contrast to odds ratio of 3.32 (P < 0.034) in patients with right heart failure . The implementation of low tidal volume ventilation in patients with ARDS has significantly lowered not only mortality (down to 32%), but also incidence of acute right heart failure in this patient population . In addition to being the major risk factor for ARDS development, sepsis itself can sometimes lead to severe acute arterial pulmonary hypertension .
In massive acute pulmonary embolism (APE), the increase of PVR depends on the thrombosis load and potentially on the pulmonary bed contraction caused by neurohormonal reaction. Plasma endothelin concentrations assessed on admission are not elevated in patients with APE and it does not play as important role in acute phase of increase of pressure in pulmonary arteries as in chronic pulmonary hypertension .
Development of ALI in the critically ill is associated with an array of abnormal interactions between the heart and lungs. Of these abnormalities, increased PVR is common and seems to indicate a worse prognosis than when PVR is normal. Increased pulmonary artery pressure, which follows ALI in humans, has been attributed to many factors. Early in ALI, PAH is secondary to an imbalance between the release of vasoactive mediators derived from arachidonic acid, endothelium-derived relaxing factor, and other metabolites. As ALI progresses, the combination of mechanical obstruction and severe regional hypoxic pulmonary artery vasoconstriction probably becomes the main factor responsible for PAH. In addition to these elements, in situ and peripherally derived thromboembolism can be seen in ALI, owing to diverse disturbances in the coagulation and fibrinolytic processes. The result is increased workload of the right ventricle, which is caused by increased afterload and may induce hemodynamic disturbances that culminate in overt RV failure. However, epidemiologic studies have demonstrated that death following ALI is more often the result of respiratory failure or sepsis. The absence of effective therapy for PAH in ALI might be explained by the pathophysiological and clinical course of the disease. A reasonable conclusion from the contributing elements cited above is that PAH complicating sepsis and trauma is simply a marker of the gravity of the systemic insult that leads to the development of ALI and probably not a separate process .
Acute pulmonary hypertension (PH) is a characteristic feature of the ARDS. The magnitude of PH has been shown to correlate with the severity of lung injury in patients with ARDS independently of the severity of associated hypoxemia and has an adverse prognostic significance. Early in the histopathological evolution of ARDS, pulmonary vasoconstriction, thromboembolism, and interstitial edema contribute to the development of PH, although pulmonary vascular remodeling probably occurs eventually . Many patients with severe ALI do not respond to NO inhalational therapy with alleviation of PAH and hypoxemia, so this treatment remains controversial .
During Gram-negative sepsis, endotoxin lipopolysaccharide (LPS) may activate host-inflammatory responses, resulting in the systemic inflammatory response syndrome and the adult respiratory distress syndrome. In cell culture systems, LPS activation of cellular responses may be potentiated by plasma proteins. In the isolated perfused rabbit lung, LPS administration markedly increases the pulmonary hypertensive response to subsequent administration of platelet-activating factor (PAF). Components of plasma—possibly LPS binding protein, and soluble CD14—potentiate the priming effect of endotoxin, resulting in an augmented pulmonary hypertensive response to PAF. Thus, plasma proteins decrease the threshold at which endotoxin primes the lung and may have a critical role in the pathogenesis of endotoxin-induced ALI . ALI is a common complication of gram-negative sepsis. Pulmonary hypertension and increased lung vascular permeability are central features of lung injury following experimental bacteremia. PAF is a prominent proinflammatory mediator during bacterial sepsis. E. coli bacteremia rapidly induces pulmonary hypertension stimulated by PAF and mediated at least in part by endothelin-1 and neutrophil activation and sequestration in the lung. Microvascular injury with leak is also mediated by PAF during E. coli bacteremia, but the time course of resultant hypoxemia and hemoconcentration is slower than that of pulmonary hypertension. The contribution of hypoxic vasoconstriction in exacerbating pulmonary hypertension in gram-negative sepsis is probably a late phenomenon .
In sepsis-caused acute PAH, studies demonstrated that the early acute rise in PAP is caused by thromboxane. The late sustained pulmonary hypertension of endotoxemia, on the other hand, appears to be mediated by endothelin. BMS182874, an endothelin receptor antagonist, blocks the effects of exogenously administered endothelins in chronically instrumented awake sheep. Pretreatment with BMS182874 significantly attenuated the early endotoxin-induced acute increase in PAP and completely blocked the late sustained pulmonary hypertension, while having no affect on the increases in thromboxane levels. BMS182874 shifts the dose response curve for U46619, a prostaglandin H2 analogue, to the right. BMS182874, in addition to functioning as an endothelium receptor antagonist, appears to counteract the action of thromboxane at the receptor level .
Surgery or Intervention-Related PAH
Some surgical interventions, in particular vascular, cardiac, and thoracic surgery may cause acute elevation of PAP either during the surgery or shortly after the intervention has been completed. This is particularly dangerous in patients with preexisting PAH, since even short periods of RV pressure overload can lead to profound decompensation with all negative hemodynamic consequences. Preexisting PAH is one of the major risk factors for morbidity and mortality in cardiothoracic surgery patients . PAH is a major determinant of perioperative morbidity and mortality in special situations such as heart and lung transplantation, pneumonectomy, and ventricular assist device placement . It is believed that an elevated PAP during and after surgery develops secondary-to-acute left heart failure/dysfunction or can be a consequence of pulmonary parenchymal and endothelial injury with activation of the systemic and pulmonary inflammatory response to cardiopulmonary bypass (CPB) circulation and/or ischemia reperfusion . Protamine-mediated acute PAH and RV failure in the perioperative period are common (1.78%) complications of CPB circulation during open heart operations . PAH can also develop later as a result of ARDS  or other complications (Sepsis, PE, etc.) not directly related to either surgery or anesthesia. Intraoperative management should include prevention of exacerbating factors such as hypoxemia, hypercarbia, acidosis, hypothermia, hypervolemia, and increased intrathoracic pressure; monitoring and optimizing RV function; and treatment with selective pulmonary vasodilators.
Patients with increased (PVR) may experience acute pulmonary hypertension after heart transplantation. PAP or a transpulmonary gradient (TPG) >12 mmHg, is an established risk factor for mortality in heart transplantation. An increased PVR or an increased TPG is a risk factor for increased 3-day and 3-month mortality after heart transplantation (HTx). The reversibility of increased PVR or TPG under pharmacologic testing is supposed to indicate a decreased probability of RV failure/death after transplantation. PAPs greater than 50 mmHg, PVR greater than 6 Woods units, and TPG greater than 15 mmHg that are unresponsive to optimal vasodilators are contraindications to orthotopic heart transplantation. Therapies used to reduce PVR in the cardiac catheterization laboratory include high-flow oxygen; sublingual nitroglycerin; and intravenous inotropic agents, vasodilators, and selective pulmonary vasodilators. Systemic hypotension may be an undesirable side effect of vasodilators. Inhaled agents such as NO and prostacyclin are specific to the pulmonary vasculature and reduce PVR without causing systemic hypotension. All pharmacological therapies used to optimize pulmonary hemodynamics before transplantation can be used during transplantation in patients who are at high risk for acute RV failure and death after orthotopic heart transplantation because of elevated pulmonary hemodynamic values. Use of larger donor hearts for patients with elevated PVR and referral for heart–lung transplantation are potential treatment options .
Acute PAH occurring after CPB can be a cause of postoperative morbidity and mortality. Endogenous endothelin is a mediator of acute pulmonary hypertension occurring after cardiopulmonary bypass. Bosentan, a mixed endothelin antagonist completely prevented pulmonary hypertension after CPB and may, therefore, have therapeutic applications in the management of patients following cardiac surgery . Procedures using cardiopulmonary bypass and aortic cross-clamping are associated with a variable degree of ischemia/reperfusion of the lungs, leading to acute pulmonary hypertension (PHT). Pulmonary selectivity was demonstrated with sildenafil analog, because there were no similar changes in systemic vascular resistance (SVR) and no significant changes in systemic hemodynamics. Sildenafil analog (UK343–664), a PDE5 inhibitor, shows a promising role for managing the PVR increases that occur following CPB .
Absolute ethyl alcohol is used with increased frequency in the treatment of conditions such as percutaneous ablation of unresectable hepatic tumor, sclerotherapy of esophageal varices, ventricular septal ablation, and intravenous embolization of arteriovenous malformation. The postulated mechanism is severe pulmonary vasoconstriction due to the sudden passage of absolute ethyl alcohol into pulmonary circulation, causing acute pulmonary hypertention and RV strain. In patients at risk of sudden intravascular absorption of absolute ethyl alcohol, an increased level of awareness for acute PAH, together with prompt treatment of PAH with Sildenafil analogue or with a low dose of an NO-donor drug, will minimize the resk of cardiovascular decompensation and may be the treatment of such catastrophe .
Diagnosis and Monitoring of Patients with Acute PAH
Effective management requires timely recognition and accurate diagnosis of the disorder and appropriate selection among therapeutic alternatives. Since acute PAH are a life-threatening disorder, elevated pressure and resistance in the pulmonary vessels lead to progressive right heart failure which results in functional limitations and ultimately the death of most patients. Thus, the monitoring of RV function is of great importance. The assessment of PVR plays an important role in the diagnosis and management of PAH.
The broad availability of Doppler echocardiography has helped with (earlier) detection of PAH. Doppler echocardiography has become a popular screening tool for the diagnosis of PAH and in some clinical trials has been the only measure of the severity of the PAH in response to treatment . Echocardiography is the initial investigation of choice for noninvasive detection of PAH but measurement of PAP and cardiac output (CO) during right heart catheterization is mandatory to confirm the diagnosis. So PAH is usually recognized when the patient develops obvious signs of progressive RV failure, and during hemodynamic monitoring by echocardiogram or a pulmonary artery catheterization. In many cases, PAH remains undiagnosed and its treatment begins only after serious complications have developed. Timely assessment of PAP, CO, and PVR with the help of pulmonary artery catheterization and/or echocardiography is crucial for optimal management of patients with pulmonary hypertension.
One major disadvantage of the use of echocardiography as the diagnostic tool for evaluation of pulmonary hemodynamics is the lack of adequate assessment of transpulmonary blood flow and pulmonary venous pressures. Therefore, right-sided heart catheterization remains the current gold standard for diagnosis and vasoreactivity testing . As the gold standard for the diagnosis of pulmonary hypertension , pulmonary artery (PA) catheterization could provide direct measurement of the PAP. Besides direct measurement of the pulmonary hemodynamic parameters, it also provides useful information regarding response to vasodilator therapy. Analysis of mixed venous oxygen saturations during passage of the PA catheter on its way through the cardiac chambers can allow diagnosis of intracardiac shunts. A PCWP measurement reflects left ventricular end-diastolic (filling) pressure. PCWP <15 mmHg rule out left ventricular, valvular, and pulmonary venous diseases as possible causes of the pulmonary hypertension . In critical care settings, PA catheterization and monitoring is highly desirable in patients with severe PAH and in patients with progressive heart failure . It is important to emphasize that the thresholds required for diagnosis of severe chronic PAH are incompatible with life in patients with acute PAH and usually reflect worsening of preexisting chronic PAH.
Echocardiography is an important tool for diagnosing and determining the degree and clinical significance of PAH in critically ill patients [4,14].
It can noninvasively visualize cardiac anatomy and certain intracardiac shunts and valvular abnormalities, estimate right atrial and PAP, determine the severity of right and left ventricular dysfunction, wall motion abnormalities, and reveal other potential causes of PAH. In the absence of pulmonary outflow obstruction, pulmonary artery systolic pressure is equivalent to RV systolic pressure (RVSP), which can be calculated from measured systolic regurgitant tricuspid flow velocity and estimated right atrial pressure. Echocardiographic signs of significant PAH include RV dilation (D-shaped right ventricle) and its hypertrophy (in sustained cases), septal dyskinesia, and bowing into the left ventricle during late systole to early diastole, RV hypokinesis, tricuspid regurgitation, right atrial enlargement, and a dilated inferior vena cava [18,28,40]. Increased RV size combined with increased outflow resistance and reduced ejection fraction have been also described in acute right heart failure . A specific pattern of RV dysfunction in APE has been characterized by a severe hypokinesia of the RV mid-free wall, with normal contractions of the apical segment . TTE results were poorly predictive of the risk of death in patients who developed acute right heart failure . However, definition of the acute right heart failure as RV end-diastolic area/left ventricular end-diastolic area (RVEDA/LVEDA) ratio in the long axis greater than 0.6 associated with septal dyskinesia in the short axis could be used to stratify the severity of the condition [16,42]. TEE is more accurate and sensitive in critically ill patients than TTE, especially in acute diseases such as PE when acute pulmonary hypertension is highly suspected [43,44]. Determination of pulmonary artery systolic pressure by Doppler echocardiography (based on the pressure gradient between the right ventricle and right atrium) or by right heart catheterization is useful in evaluating the severity and prognosis of cardiac disease . PVR is an important hemodynamic variable in the management of patients with acute PAH. Doppler echocardiography could provide Doppler variables of time-velocity integral of RV outflow pulmonary artery flow and peak tricuspid regurgitant pressure gradient (TRPG). The TRPG/TVI ratio provides a reliable estimation of PVR over a wide range in patients with PAH with various underlying causes.  The noninvasive index of systolic pulmonary arterial pressure (SPAP) to heart rate (HR) times the RV outflow tract time-velocity integral (TVI [RVOT]) (SPAP/[HR × TVI [RVOT]) provides clinically useful estimations of PVR in PAH. The index of SPAP/(HR × TVI [RVOT]) provides useful estimations of PVRI in patients with PAH .
Recent advances in magnetic resonance imaging (MRI) technology have led to the development of techniques for noninvasive assessment of cardiovascular structure and function, including hemodynamic parameters in the pulmonary circulation, which are superior in their identification of RV morphologic changes. These advantages make cardiac MRI an attractive modality for following up and providing prognoses in patients with PAH. Over the coming decade, it can be anticipated that continued improvements in MRI image acquisition, spatial and temporal resolution, and analytical techniques will result in improved understanding of PAH pathophysiology, diagnosis, and prognostic variables, and will supplement, and may even replace, some of the invasive procedures currently applied routinely to the evaluation of PAH . Cardiac MRI has several advantages over other imaging methods. The use of cine acquisition techniques allows precise description of characteristic volumetric and functional variables, such as RV volumes, muscle mass, stroke volume, ejection fraction, or cardiac output. Impaired RV contractility and function have also been assessed using measures like ventricular septal bowing and pressure–volume loops. MRI investigations have been performed to monitor medical treatment, and the improvement in well-established prognostic factors, such as the 6-min walk, were correlated with measures of RV function. Flow-derived parameters of the pulmonary arteries (such as peak velocity, acceleration time and volume, or pulmonary flow profile) are available using velocity-encoded imaging, and may detect early signs of remodeling. Additionally, magnetic resonance angiography is a promising new tool to visualize pulmonary perfusion and to diagnose CTEPH .
Biomarker May Serve as Tools for the Diagnosis of Acute PAH
The most useful biochemical biomarker available to date may be brain natriuretic peptide (BNP) (and/or N-terminal prohormone brain natriuretic peptide), which can inform on the pressure load on the right ventricle and has prognostic value [50,51]. A reduction in circulating BNP levels should accompany the response to an effective treatment. There is increasing recognition of the importance of maintaining RV function in pulmonary hypertension, but the primary goal is to retard and regress the pulmonary vascularpathology. As such, BNP levels give limited information about the response of patients with pulmonary hypertension to treatment. Elevated BNP is an important prognostic indicator and correlates strongly with PVR, cardiac output, and functional status in patients with PAH . A high level of plasma BNP, and in particular, a further increase in plasma BNP during follow-up, may have a strong, independent association with increased mortality rates in patients with PAH . However, the significance of measuring BNP level in patients with PAH in the acute setting remains to be defined. N-terminal pro-BNP (NT-proBNP) is a byproduct of the BNP that was shown to be of prognostic value in pulmonary hypertension (PH). The role of NT-proBNP in PH has to be determined, especially under the influence of renal impairment that might lead to an accumulation of the peptide, and may be a sign of increased mortality per se. However, NT-proBNP could be superior to BNP as a survival parameter in PH because it integrates hemodynamic impairment and renal insufficiency, which serves as a sign of increased mortality per se.
Serum troponin may be elevated in patients with pulmonary hypertension and has been associated with RV overdistension and/or ischemia. Troponin I leak due to acute RV strain from PE has been well studied, and may predict mortality [55,56].
Management of Acute PAH
Recently published data addressing certain molecular mechanisms for pathogenesis of PAH have led to the successful therapeutic interventions. This review will focus on the common and critical molecular pathways including genetic basis of the development of PAH that on the whole may be new targets for therapeutic interventions. For the acute PAH, conventional therapy includes right fluid management, ventilation management and nonspecific drugs (oxygen, warfarin, diuretics). The following three classes of drugs targeting the correction of abnormalities in endothelial dysfunction have been approved recently for the treatment of PAH: (1) prostanoids; (2) endothelin receptor antagonists; and (3) phosphodiesterase-5 inhibitors. The efficacy and safety of these compounds have been confirmed in uncontrolled studies in patients with PAH. Intravenous epoprostenol is the first-line treatment for the most severe patients. In the other situations, the first-line therapy may include bosentan, sildenafil, or a prostacyclin analogue. Recent advances in the management of PAH have markedly improved prognosis. The endothelin-1 receptor antagonist bosentan, the phosphodiesterase-5 inhibitor sildenafil, and prostanoids have been shown to improve symptoms, exercise capacity, and hemodynamics. Intravenous prostacyclin (PGI2) is the first-line treatment for the most severely affected patients . The evolution of therapy from vasodilators to antiproliferative agents reflects the advancement in the understanding of the mechanisms mediating PAH .
RV failure may result from a newly developed disease (e.g., as a consequence of ARDS or of severe pulmonary embolism) or of already present pulmonary hypertension (PHT). There is as yet no generally recognized definition of acute or chronic RV failure. The particular clinical picture and the associated hemodynamics determine this condition. RV failure in the course of PHT represents a great challenge in clinical and intensive care practice. Once the vicious circle of right heart failure is reached an optimal balance has to be found between preload and afterload. In addition to optimizing blood volume, positive inotropic drugs (e.g., dobutamine) are available to maintain systemic blood pressure. Furthermore, an increase in RV contractility by inodilators is aimed at. The central goal in the treatment of right heart failure as part of PHT is to lower PVR and thus decrease RV afterload. However, it is very difficult to break the vicious circle involved in the acute right heart syndrome; it must be the primary aim of treatment to recognize as early as possible any worsening of PHT and prevent acute right heart failure. Lung transplantation or surgical atrioseptostomy may represent possible ultimate therapeutic options for patients with PHT .
General Management Principles
Right fluid management is the basis for recovery of acute PAH. In patients with PAH, RV dysfunction/failure can reduce LV filling and lead to cardiogenic shock. Patients with cardiogenic shock secondary to RV dysfunction usually have a very high (>20 mmHg) RV filling pressure . In addition to decreased RV contractility and cardiac output, RV dilatation can further limit LV filling via ventricular interdependence, which causes shifting of the interventricular septum toward the LV cavity. The challenge in fluid management in those patients is to find the optimal RV preload necessary to avoid the detrimental effects of ventricular interdependence on LV function. Hemodynamic monitoring of patients with RV failure due to acute RV myocardial infarction showed that cardiac and stroke indexes increased and the RV reached its maximum stroke work index when the filling pressure was 10–14 mmHg. These values may be regarded as the optimal level of RV filling pressure in patients with RV infarction . There are no data on optimal RV filling pressure in patients with RV dysfunction secondary to acute PAH.
Right ventilation management is another important basis for recovery of acute PAH. It was found that controlled ventilation altered RV function primarily by increasing RV afterload during the lung inflation period . Transpulmonary pressure (and related tidal volume), but not airway pressure itself, was the main determinant factor of RV afterload during mechanical ventilation . This supports a low-volume strategy in ARDS, recommended as a protective measure for lung parenchyma, which might also represent a protective measure for the RV and pulmonary circulation . Frequency of acute right heart failure in ARDS patients declined from 61% to 25% over the last 15–30 years, which could be explained in part by fundamental alterations in respiratory support and implementation low tidal volume ventilation . Lower incidence of acute right heart failure in ARDS patients was associated with lower (less than 27–30 mmHg) plateau pressure .
RV systolic function was generally negatively affected by end-expiratory pressure (PEEP) in ARDS patients undergoing mechanical ventilation. In those patients PEEP titration significantly affected RV outflow impedance, the lowest values of which was associated with the achieved better total quasi-static lung compliance (calculated by dividing tidal volume by the difference between plateau and end-expiratory airway pressures) . This suggests that lung hyperinflation along with either inadequate or excessive PEEP can significantly reduce RV systolic function and cardiac output. On the other hand, in an experimental study on healthy animals, the open lung concept ventilation resulted in significantly improved lung aeration with no negative effect on RV afterload or LV afterload. This is possibly explained by a loss of hypoxic pulmonary vasoconstriction due to alveolar recruitment. The reductions in the CO and in the mean PAP were the consequences of a reduced preload . A clinical study in patients after cardiac surgery found no evidence that ventilation according to the open lung concept affects RV afterload .
Hypercapnia has been shown to induce pulmonary hypertension in animal models. Study on healthy volunteers revealed that human pulmonary vascular responses to hypercapnia and hypocapnia consist, respectively, of constriction and dilatation that take 1.5–2 h to reach a steady level. The time courses for recovery in eucapnia are similar. Hypercapnia generated a rise in cardiac output by changing heart rate; hypocapnia produced a fall in cardiac output by changing stroke volume. The finding of marked vasodilatation in response to hypocapnia demonstrates that there is normally a substantial vascular tone in the human pulmonary circulation .
Treatment with 100% oxygen is a selective pulmonary vasodilator in patients with sustained pulmonary hypertension, regardless of primary diagnosis, baseline oxygenation, or RV function . In patients with ALI vascular response to oxygen was different and administration of 100% O2 worsened intrapulmonary shunt possibly secondary to collapse of unstable alveolar units with very low ventilation-perfusion (V A/Q) ratios. This is in contrast to administration of 100% O2 to patients with COPD, in whom only the dispersion of the blood flow distribution was changed, suggesting release of hypoxic pulmonary vasoconstriction . Optimal supplemental oxygen management is an integral component of pulmonary hypertension therapy .
Patients with chronic pulmonary hypertension usually have multiple predisposing factors, which make them more vulnerable to acute conditions and explain decreased ability to survive acute illness . Tighter monitoring combined with early diagnosis and appropriate intervention increases the chance of survival. Treatment strategies for such patients should be generally directed at rapid reversal of the precipitating condition as well as at relieving RV pressure overload and maintaining systemic pressure for coronary and end-organ perfusion. Unlike patients with acute pulmonary hypertension , patients who develop acute pulmonary hypertension on top of preexisting pulmonary hypertension can generate higher PAP and also require higher RV preload (because of RV hypertrophy). Therapy for acute massive PE with associated hemodynamic instability or cardiogenic/obstructive shock aims at urgently relieving mechanical obstruction of the pulmonary circulation by either pharmacologic thrombolytic or by surgical or catheter thrombectomy (or mechanical clot disruption) [46,71,72]. Patients with massive PE but without hemodynamic instability are less likely to benefit from thrombolytic therapy. The time the resolution of RV dilatation, which usually takes between 10 and 20 days, is hastened by thrombolytic therapy . The therapy of acute pulmonary hypertension in patients with sepsis and ARDS is generally aimed at optimizing gas exchange and minimizing ventilator-induced lung injury. Inhaled pulmonary vasodilators are sometimes used in order to prevent or relieve acute right heart failure.
A number of vascular mediators have been implicated in the pathophysiology of PAH, including prostacyclin, thromboxane A2, endothelin-1, and NO . Various treatments approved by the United States Food and Drug Administration for the management of PAH target three of the many pathways implicated in the development of PAH: prostacyclin-, endothelin-1 (ET-1), and nitric oxide-mediated pathways.
Over the last decade, treatment of PPH has gained major progress through medication such as analogue of prostacyclin (Epoprostenol ) and dual antagonist of endothelin receptor (Bosentan ), or inhibitors of phosphodiesterase (Milrinone and Sildenaphil). All of these medicines have proven highly clinically effective.
Pulmonary emb basis H of non-cardiac etiologyervention such as Inhaled Nitric oxide (iNO) is a potent vasodilator that dilates pulmonary vasculature in ventilated lung areas, thereby improving ventilation/perfusion (V/Q)match and oxygenation, and reducing PAP  and RV oxygen demand . This improves cardiac performance without altering RV contractility  and cardiac output in hemodynamically stable patients with a variety of causes of pulmonary hypertension [79,80]. Multiple studies on utilization of the iNO in ARDS patients showed improved oxygenation for 24–48 h, variable improvement in MPAP  and no significant impact on the duration of ventilatory support or mortality in this patient population [82,83]. A combination of iNO and other interventions, such as positive end-expiratory pressure and prone positioning, yielded beneficial and additive effects on arterial oxygenation . iNO has been successfully used and associated with improved outcomes in critically ill postoperative patients, who developed severe PAH or RV failure .
Because iNO is a selective pulmonary vasodilator without significant effects on systemic blood pressure, reductions in PAP is the result of the pulmonary vasodilatory response. A combination treatment of iNO with other pulmonary vasodilators (milrinone, sildenafil, etc.) has been used in management of acute pulmonary hypertension in different conditions. [85,86] iNO treatment is associated with multiple side effects including methemoglobinemia [56,87] and NO2 formation . Abrupt withdrawal of nitric oxide has been associated with rebound pulmonary hypertension, significant drop in PaO2, and life-threatening hemodynamic deterioration [68,88]. Close monitoring and gradual discontinuation are important to prevent and detect rebound pulmonary hypertension.
Prostaglandin E1 and prostacyclin both produce significant pulmonary vasodilatation and can lower PVR. Both possess antithrombotic, antiproliferative, and antiinflammatory properties. In patients with chronic severe PAH, intravenous prostacyclin is highly effective and associated with a significant survival benefit [89,90]. Prostacyclin, subcutaneous or intravenous treprostinil, intravenous PGE1, and other prostanoids have relatively long half-lives and can significantly affect systemic hemodynamics. This feature limits their use in critically ill or hemodynamically unstable patients. PGI2 in combination with norepinephrine and dopamine was effective in the treatment of protamine-mediated acute PAH and RV failure in the setting of open heart surgery . Prostacyclin and its analogs (iloprost and treprostinil) in inhaled forms are as effective as intravenous forms in patients with chronic PAH . Inhaled prosaglandins have been used to treat severe sustained pulmonary hypertension and intractable hypoxia, but were associated with systemic hypotension . Inhaled iloprost effectively decreased PAP and improved RV performance immediately after separation from CPB . Inhaled iloprost was effective in the treatment of acute RV dysfunction in the setting of preexisting PAH in heart transplant recipients during weaning from CPB circulation and was not associated with significant systemic side-effects. Despite the observation that RV ejection fraction increased on inhaled NO, but not with PGI2, both inhaled NO and PGI2 aerosol showed beneficial effects on RV performance and may prove helpful in the treatment of acute PAH . Inhaled prostacyclin showed different effect on oxygenation and pulmonary hemodynamics in patients presenting with primary pulmonary ARDS (reduction in PaO2/FIO2) compared with extrapulmonary cause of ARDS (increase in PaO2/FIO2 along with a decrease in mean pulmonary artery pressure) . In a comparative trial in patients with PAH, both inhaled and infused prostacyclin had profound effects on pulmonary hemodynamics, almost equipotently reducing PVR, whereas only inhaled prostacyclin significantly reduced PAP . Inhalation of iloprost in patients with severe PH associated with lung fibrosis resulted in the same degree of reduction of PVR as intravenous prostacyclin, only inhaled iloprost preserved gas exchange .
PGI2 is a recommended first-line therapy for unstable patients in NYHA functional class IV [97,98,99]. How prostacyclin improves cardiac output in right-heart failure in conjunction with pulmonary hypertension has been evaluated in a dog model of acute afterload-induced RV failure . In this model, prostacyclin improved right ventriculoarterial coupling and increased cardiac output by decreasing pulmonary arterial resistance, because of vasodilating effects, without a detectable effect on contractility. It is likely that clinical RV failure in human PAH might be due to aggravated right ventriculoarterial decoupling, and eventually a decrease in right ventricle contractility. These observations provide a rationale for inotropic interventions added to prostacyclin therapy in patients with PAH who present with RV decompensation .
Continuous intravenous epoprostenol improves exercise capacity, hemodynamics, and survival in IPAH and is the preferred treatment option for the most critically ill patients. Treprostinil, a prostanoid, may be delivered via either continuous intravenous or subcutaneous infusion. Iloprost is a prostanoid delivered by an adaptive aerosolized device 6 times daily.
Phosphodiesterase inhibitor Sildenafil is a selective inhibitor of phosphodiesterase type 5 with sustained pulmonary vasodilatatory effect. Sildenafil lowers PVR and PAP and increases CO in patients with different forms of chronic PAH [101,102] including patients with PAH secondary to congestive heart failure . This effect is mainly achieved by balancing pulmonary and systemic vasodilation. In patients, after coronary artery bypass graft surgery, sildenafil may improve myocardial perfusion, reduce platelet activation, and potentially reduce early graft occlusion . In the chronic setting, it is highly effective both alone and in combination with other pulmonary vasodilators: epoprostenol , iloprost [106,107], BNP  and iNO . Although mostly used in patients with chronic PAH and in hemodynamically stable patients sildenafil possesses multiple features that could be effective in treatment of critically ill patients with severe RV dysfunction related to secondary PAH . Its ability to augment and prolong the hemodynamic effects of other pulmonary vasodilators has been successfully used to minimize rebound pulmonary hypertension after iNO discontinuation [110,111,112], weaning from intravenous vasodilators in patients after cardiac surgery  as well as in chronic PAH therapy . Experimental evaluation of the inhaled and intravenous sildenafil administration showed similar effects on pulmonary endothelium-dependent relaxation, overall hemodynamic profile, and oxygenation after cardiopulmonary bypass. Both administration routes prevented a significant increase in mPAP without severe systemic hypotension . Its chronic administration has been shown to improve exercise capacity, World Health Organization functional class, and hemodynamics in patients with symptomatic PAH. Sudden cessation of sildenafil monotherapy, in patients with PAH, carries with it a significant and unpredictable risk of rapid clinical deterioration. It is recommended that if sildenafil needs to be ceased, it would be more prudent to consider concurrent vasodilator therapy before the gradual cessation of sildenafil . Pilot study suggested beneficial effects in favor of sildenafil in several secondary endpoints at both 3 months and 12 months .
CCBs were introduced for the treatment of hypertension in the 1980s . CCBs have been used in hemodynamically stable patients with PAH who demonstrated pulmonary vascular response to acute vasodilator challenge . There are no studies of CCBs in critically ill patients with acute PAH. Acute administration of nifedipine did not cause pulmonary vasodilation, and in contrast led to increased RVEDP and decreased RV contractility . Prolonged half-life and negative inotropic effects, which may precipitate fatal worsening of RV failure, limit the use of CCBs in treatment of acute pulmonary hypertension. Treatment with high doses of CCBs has been shown to have a sustained beneficial effect in a very small subset of patients with severe idiopathic PAH who demonstrated an acute fall in PAP in response to a pulmonary vasodilator . The empirical use of CCBs is discouraged because of the risks of systemic hypotension and impaired right-sided heart function . Consequently, the current recommendations for the treatment of PAH propose that the acute response of the pulmonary circulation to a pulmonary vasodilator should be used as the basis for selecting patients for high-dose CCB treatment . A retrospective analysis of 557 patients with IPAH showed that only 13% of patients displayed vasoreactivity, as defined by a decrease of more than 20% in both mPAP and PVR. Of the patients displaying vasoreactivity, only about half benefited from treatment with long-term CCBs. Patients who benefited from these medications tended to have had a more profound short-acting vasodilator response during invasive testing .
ETRAs basic research in vascular biology has implicated endothelin-1 (ET-1) and its receptors (ETA and ETB) in diverse preclinical models of PAH, and ET-1 has been shown to contribute significantly to PAH in human patients . The introduction of ETRAs to clinical medicine has substantially expanded therapeutic approach toward severe PAH . Bench-to-bedside scientific research has shown that endothelin-1 (ET-1) is overexpressed in several forms of pulmonary vascular disease and may play an important pathogenetic role in the development and progression of PAH. Endothelin receptor antagonism has emerged as an important therapeutic approach in PAH.
Oral ETRAs improved exercise capacity, functional status, pulmonary hemodynamics, and delayed the time to clinical worsening in several randomized placebo-controlled trials. Two ETRAs are currently approved by the US Food and Drug Administration: bosentan, a dual ETRAs for patients with class III and IV PAH, and ambrisentan, selective ETRAs for patients with class II and III PAH. Sitaxsentan, another selective ETRAs, has been approved in Europe, Canada, and Australia . ET receptors (ET[A] and ET[B]) have different densities and distributions throughout the body and are dynamically regulated, such that blockade of ET(A) and ET(B) receptors may have different results in normal versus pathological conditions. Although differences in biological effects can be found in studies of isolated cells, blood vessels and animal models, clinical treatment studies have not identified clear differences in efficacy among the various ETRAs. The main differences appear to be in safety profiles, with a greater frequency of serum liver function abnormalities occurring with the available dual ET(A)/ET(B) antagonist, and possibly higher rates of peripheral edema noted with selective ET(A) agents .
Bosentan, a dual endothelin receptor antagonist, is indicated for the treatment of patients with PAH. Following oral administration, Bosentan attains peak plasma concentrations after approximately 3 h. The terminal half-life after oral administration is 5.4 h and is unchanged at steady state. Steady-state concentrations are achieved within 3–5 days after multiple-dose administration, when plasma concentrations are decreased by about 50% because of a 2-fold increase in clearance, probably due to induction of metabolizing enzymes. The pharmacokinetics of bosentan is dose proportional up to 600 mg (single dose) and 500 mg/day (multiple doses). The pharmacokinetics of bosentan in pediatric PAH patients are comparable to those in healthy subjects, whereas adult PAH patients show a 2-fold increased exposure. Severe renal impairment (creatinine clearance 15–30 mL/min) and mild hepatic impairment (Child–Pugh class A) do not have a clinically relevant influence on the pharmacokinetics of bosentan. Bosentan should generally be avoided in patients with moderate or severe hepatic impairment and/or elevated liver aminotransferases. In healthy subjects, bosentan doses >300 mg increase plasma levels of endothelin-1. In a pharmacokinetic-pharmacodynamic study in PAH patients, the hemodynamic effects lagged the plasma concentrations of bosentan . An open-label study suggests a beneficial effect of bosentan therapy not only on pulmonary hemodynamics, but also on quality of life and exercise capacity for patients with severe CTEPH .
Sitaxsentan is the first oral ETRA with high selectivity for the endothelin-A (ET [A]) receptor to be approved for clinical use by regulatory agencies in Europe for the treatment of PAH. Sitaxsentan therapy appears safe and efficacious for patients with PAH; reductions in mortality and the risk for clinical worsening events provide support for durability of efficacy at 1 year . Clinical trials have shown it to be well tolerated and to improve exercise tolerance, functional class, and pulmonary hemodynamics in PAH, results which appear to be at least as good as those for the mixed ETRA bosentan. Importantly, compared to bosentan, Sitaxsentan has a lower incidence of liver toxicity and no interaction with sildenafil .
Ambrisentan is the second selective endothelin-A receptor antagonist to be licensed in Europe, and the first in the United States, for the management of PAH. It has been shown to be clinically effective in improving exercise tolerance and functional class. Furthermore, ambrisentan is well tolerated and associated with low rates of liver toxicity and minimal interactions with other medicines commonly used to treat PAH. Overall, current data support a role for ambrisentan in the management of PAH. However, the results of longer-term follow-up studies are still required to fully assess efficacy and safety . Ambrisentan has been shown to be an effective ETRAs in patients with PAH, at the same time, a significant advantage of ambrisentan is the lack of any clinically important drug interactions with warfarin and sildenafil, which are frequently used by patients being treated for PAH .
Platelet-derived growth factor (PDGF) has the ability to induce the proliferation and migration of smooth muscle cells and fibroblasts, and PDGF and its receptors are overexpressed in human and experimental PAH . Novel therapeutic agents, such as imatinib mesylate, inhibit several tyrosine kinases, including PDGF receptors α and β. Imatinib has been demonstrated to reverse pulmonary vascular remodeling in animal models of pulmonary hypertension. Four cases of clinical and hemodynamic improvements have also been reported in human PAH[134,135,136]. Concerns have arisen about the cardiac safety of tyrosine kinase inhibitors, especially in patients with preexisting cardiac conditions [137,138]. Safety and efficacy of tyrosine kinase inhibitors are currently being evaluated in multicenter randomized trials. Imatinib, as a selective antagonist of the platelet-derived growth factor receptor, was effective in the case of a single patient with severe treatment-refractory familial PAH , suggesting that such antiproliferative drugs may reverse pulmonary vascular remodeling, thus alleviating PAH.
A significant venodilator effect of nitroglycerine decreases RV preload leading to adverse consequences in patients with right heart failure. Inhaled nitroglycerin may be a safer therapeutic option leading to a significant reduction in both mean PAP and PVR in patients after mitral valve operations without reducing systemic mean arterial pressure . Intravenous adenosine is a pulmonary vasodilator with a very short half-life (6–10 seconds) and can be effective for short term lowering PVR . In the setting of acute PAH, adenosine infusion may help lower PAP without lowering systemic arterial pressure and reverse the clinical state of shock by achieving pulmonary vasodilatation . However, higher doses (70 mg/kg per min to 100 mg/kg per min) cause systemic vasodilatation . Adenosine is used to treat persistent pulmonary hypertension of the newborn [143,144]. Treatment with the use of vasoactive intestinal peptide also may elicit beneficial effects in PAH and warrants further investigation .
Critically ill patients with associated acute pulmonary hypertension frequently develop profound and refractory systemic arterial hypotension. In cases with severe acute arterial pulmonary hypertension (e.g., massive PE), relieving the acute obstruction (either mechanically or with pulmonary vasodilators) of the pulmonary circulation can successfully resolve systemic arterial hypotension. In acute pulmonary hypertension associated with decreased cardiac contractility and/or SVR, the use of vasopressors with or without pulmonary vasodilators is necessary to maintain coronary and end-organ perfusion. Progression of RV failure should be always considered in the management plan. Cases of severe acute PAH combined with heart failure and systemic arterial hypotension require tight hemodynamic monitoring and aggressive treatment with combinations of pulmonary vasodilators, inotropic agents, and systemic arterial vasoconstrictors. The choice of vasopressor and inotropes in patients with acute pulmonary hypertension should take into consideration their effects on PVR and cardiac output when used alone or in combinations with other agents, and must be individualized based on individual patient response.
Dobutamine is predominantly a β1-adrenergic agonist, with weak β2 activity, and α1 selective activity, although it is used clinically in cases of cardiogenic shock for its β1 inotropic effect in increasing heart contractility and cardiac output. At doses of 1–5 μg/kg per min dobutamine decreased PVR, lowered MAP and slightly increased cardiac output ; at doses of 5–10 μg/kg per min, dobutamine caused significant tachycardia and systemic hypotension without improving PVR [142,147]. Administration of dobutamine augments myocardial contractility and reduces left ventricular afterload. It can cause systemic hypotension in some patients because of peripheral vasodilatory effects, which may require use of norepinephrine or other peripheral vasoconstrictors to maintain appropriate systemic perfusion pressures. In combination with inhaled NO dobutamine administration had additive effects on pulmonary circulation , increased cardiac performance, and improved oxygenation  with no effect on systemic hemodynamics. In an animal model of acute RV failure secondary to acute PAH, dobutamine was superior to norepinephrine in improving RV function by optimizing pulmonary vasodilation, decreasing PA resistance and elastance, and increasing RV contractility . An arterial catheter should be placed as soon as possible in patients with septic shock. Vasopressors are indicated to maintain mean arterial pressure of <65 mmHg, both during and following adequate fluid resuscitation. Norepinephrine or dopamine is the vasopressor of choice in the treatment of septic shock. Norepinephrine may be combined with dobutamine when cardiac output is being measured. Epinephrine, phenylephrine, and vasopressin are not recommended as first-line agents in the treatment of septic shock. Vasopressin may be considered for salvage therapy. Low-dose dopamine is not recommended for the purpose of renal protection. Dobutamine is recommended as the agent of choice to increase cardiac output but should not be used for the purpose of increasing cardiac output above physiologic levels .
Norepinephrine acts as a drug that will increase blood pressure by its prominent increasing effects on the vascular tone from α-adrenergic receptor activation. The resulting increase in vascular resistance triggers a compensatory reflex that overcomes its direct stimulatory effects on the heart, called the baroreceptor reflex, which results in a drop in heart rate called reflex bradycardia. Norepinephrine has significant inotropic effects and produces vasoconstriction. It is widely used in critical care settings to treat hemodynamically unstable patients. In addition to positive effects on cardiac output and systemic arterial pressure, norepinephrine increases PVR and worsens PAH . However, norepeinephrine is superior to phenylephrine in restoring systemic arterial pressure, decreasing PVR, augmenting RV myocardial blood flow and improving cardiac output in animal model of acute PE . Alfa-adrenergic stimulation can cause a disproportionate rise in PVR , which is implicated in the development of acute PAH in critical illnesses. Besides disproportional increase in PVR, phenylephrine also causes bradycardia  with detrimental consequences on pulmonary and systemic hemodynamic. The effects of phenylephrine and norepinephrine in the treatment of systemic hypotension were evaluated in patients with chronic PAH who developed systemic hypotension following induction of anesthesia. In contrast to phenylephrine, norepinephrine decreased the ratio of PAP to systemic blood pressure without a change in cardiac index. Thus, norepinephrine has been considered to be preferable to phenylephrine for the treatment of hypotension in patients with chronic PAH . There are growing data on successful combination of norepinephrine and selective pulmonary vasodilators in the treatment of patients with acute and chronic pulmonary hypertension . In a small animal study of sepsis-induced pulmonary hypertension, epinephrine infusion increased SVR and cardiac output and lowered PVR .
Dopamine is a sympathomimetic catecholamine that exhibits alpha adrenergic, beta adrenergic, and dopaminergic agonism. Dopamine produces dose-dependent dopaminergic, beta- and alpha- adrenergic effects on cardiac output and vascular tone. Low dose: 2–5 μg/kg per min. Little effect was seen on heart rate or cardiac output. Increased blood flow accompanied by increased urine output. Intermediate doses: 5–15 μg/kg per min. An increase in cardiac contractility and cardiac output results in increased normal blood flow and heart rate. High dose: 15 μg/kg per min. Alpha-adrenergic effects begin to dominate: increased systemic and PVR. Decrease in normal perfusion. In patients with chronic PAH dopamine, infusion led to increased heart rate, mPAP, aortic mean pressure, and cardiac index with concomitant fall of SVR . Administration of dopamine, similar to epinephrine, is associated with high risk of tachyarrhythmia, with potentially fatal consequences in patients with severe pulmonary hypertension .
Isoproterenol's effects on the cardiovascular system relate to its actions on cardiac β1 receptors and β2 receptors on skeletal muscle arterioles. Isoproterenol has positive inotropic and chronotropic effects on the heart. In skeletal muscle arterioles, it produces vasodilatation. Its inotropic and chronotropic effects elevate systolic blood pressure, while its vasodilatory effects tend to lower diastolic blood pressure. Isoproterenol has positive inotropic and chronotropic effect, which in therapeutic doses increases cardiac output and produces pulmonary and peripheral vasodilation. As a pulmonary vasodilator, isoproterenol is one of the preferred inotropic agents in heart transplantation patients with elevated PVR. The dosage of isoproterenol should be reduced gradually because PVR may return quickly to elevated baseline levels after discontinuation of this drug . In animals with acute PAH, administration of isoproterenol did not reduce PAP, and instead produced significant tachycardia and was associated with arrhythmias .
Vasopressin is derived from a preprohormone precursor that is synthesized in the hypothalamus and stored in vesicles at the posterior pituitary. Vasopressin is an endogenous peptide hormone with weak nonadrenergic vasopressor effect on the systemic vasculature and an ability to produce NO-mediated selective pulmonary vasodilation . In healthy animals, a linear relationship was observed between vasopressin levels and systemic vascular resistance. However, vasopressin did not affect PVR or any vascular compliance . It was very effective (at dose of 0.1 U/min) in treating refractory low SVR hypotension concomitant with pulmonary hypertension in postoperative patients . Experimental data on use of vasopressin in acute pulmonary hypertension are controversial: In one setting of acute pulmonary vasoconstriction vasopressin infusion produced significant pulmonary vasodilation . Use of high dose of vasopressin (1.16 units/kg per hour) in another animal model of acute pulmonary hypertension led to increased PVR and decreased cardiac output with a decrease in RV contractility, leading the authors to cautioning against its use when RV function is compromised .
Patients with advanced RV failure who have not benefited from pharmacologic treatment and who have arterial oxygen saturations within an acceptable range should be considered for percutaneous balloon atrial septostomy [163,164]. Atrial septostomy has been developed as an alternative/bridge treatment and applied in patients with lack of response to medical therapy in the absence of other surgical treatment options. It has a substantial morbidity and mortality in critically ill patients with severe RV failure . With growing experience, procedure-related death rates have been reduced to 5.4%, and the most suitable patient group has been identified among patients with a mean right atrial pressure between 10 and 20 mmHg . Acute right heart failure after orthotopic heart transplantation was successfully managed by decompression of the RV through the patent foramen ovale of the donor heart and inhalation of iloprost . Both pericardiectomy and creation of atrial septal defects have been used in extreme cases of acute RV failure secondary to acute MI . Decompression of the RV through the septostomy may potentially be an effective alternative in the management of severe acute pulmonary hypertension. The defect could be subsequently closed using a transcatheter septal occlusion device, after the patient's condition has been stabilized. It has been observed that patients with PPH who have a patent foramen ovale have a better survival rate than patients with an intact septum. In an effort to create the more favorable condition of intraatrial communication, the technique of atrial septostomy for congenital cardiac defects such as transposition of the great arteries has been applied to patients with severe pulmonary hypertension and right heart failure. This also has been utilized as a bridge to lung transplantation for patients with severe PPH .
Mechanical Support Devices
Cardiac surgical patients who do not respond to medical therapy may be candidates for mechanical support with a RV assist device. In cases of acute right heart failure after heart transplantation, mechanical circulatory support systems, such as RV assist devices, extracorporeal membrane oxygenation, femoral vein-to-femoral artery roller, or centrifugal pumps, may facilitate hemodynamic stability until the transplanted heart has recovered, or until a new heart has been found for retransplantation . They possibly could be successfully applied in other cases of potentially reversible acute PAH and right heart failure. Intraaortic balloon counterpulsation (IABP) has long been the mainstay of mechanical therapy for cardiogenic shock. Not every patient has a hemodynamic response to IABP . However, in patients with acute PAH and RV failure associated with systemic hypotension, it could improve coronary and peripheral perfusion and augment LV performance with an acute decrease in afterload . Severe pulmonary hypertension refractory to medical treatment is a contraindication to orthotopic heart transplantation in most centers. A study supports that LVAD support and continuous nonpulsatile mechanical unloading of the left ventricle can reverse medically unresponsive pulmonary hypertension and render patients eligible for orthotopic heart transplantation . Mechanical support using an implantable LVAD is a very efficient approach with an acceptable risk to treat severe pulmonary hypertension in end-stage heart failure patients before heart transplantation. Adequate reduction of PVR can be expected within 3–6 months. Subsequent heart transplantation is associated with a good outcome . Severely elevated PVR is a relative contraindication to orthotopic heart transplantation. A potential novel strategy to reverse elevated PVR may be implantation of a chronic left ventricular assist device (LVAD) with subsequent left ventricular unloading. Patient underwent placement of biventricular assist devices and subsequently could experience a marked reduction of PVR, ultimately enabling successful heart transplantation .
Fixed pulmonary hypertension in cardiac transplant candidates can be lowered using LVADs. The posttransplant survival of these patients is uncertain as pulmonary hypertension may reappear, possibly affecting posttransplant survival. LVAD therapy lowers fixed pulmonary hypertension in cardiac transplant candidates with fixed pulmonary hypertension. Thereafter, long-term posttransplant survival is comparable to cardiac transplant recipients without pulmonary hypertension . Elevated PVR in heart transplant candidates can be reduced using a LVAD, and LVAD is proposed to be the treatment of choice for candidates with PH. Pretransplant LVAD therapy reduces an elevated PVR in heart transplant recipients, but there was no statistically significant difference in posttransplant survival in patients with PH with, or without LVAD therapy . Acute RV failure after cardiac surgery occurring in the first postoperative hours is associated with a bad prognosis. We have used a centrifugal pump either for left, right, or biventricular assistance. However, the use of this device for pure RV assistance is rare. We report a 30-year-old female undergoing a mitral valve replacement and a 42-year-old male undergoing a cardiac transplantation, who had a successful RV assistance using a centrifugal pump, due to a failing right ventricle, as the result of insufficient myocardial protection and severe pulmonary hypertension. These two cases illustrate the value of the mechanical ventricular assist device for the treatment of right heart failure .
The Management of Renal Impairment Due to PAH
Renal blood flow is the main factor determining GFR glomerular filtration rate in patients with cardiac dysfunction. Venous congestion, characterized by an increased Right Atrial Pressure, adjusted for RBF is also related to GFR. Treatment to preserve GFR should not only focus on improvement of renal perfusion, but also on decreasing venous congestion .
Combined Therapy Approach
Combination therapy using drugs with different mechanisms of action to maximize clinical benefit is an emerging therapeutic option in PAH [179,180,181,182]. The choice of drug depends on a variety of factors including accessibility, approval status, and patient's preferences . The use of combinations of targeted oral therapies for the treatment of PAH is becoming increasingly commonplace, and benefits of early diagnosis and treatment of PAH recently have become apparent [184,185]. The situations and corresponding treatment combinations could be but not limit to as follows:
- 1Protamine-mediated acute PAH and RV failure in the setting of open heart surgery. PGI2 in combination with norepinephrine and dopamine was effective .
- 2Acute and chronic pulmonary hypertension and systemic hypotension. Combination of norepinephrine and selective pulmonary vasodilators should be adopted.
- 3Severe pulmonary hypertension leading to impaired RV function presented in ARDS. The combination of iNO and intravenously administered prostacyclin (i.v. PGI2) might be more useful than either drug alone .
- 4Severe pulmonary hypertension. iNO therapy alone or in combination with a PDE5 inhibtor could be a therapeutic alternative .
- 5Long-term treatment of PAH and CTEPH patients. The combination of sildenafil and inhaled treprostinil was well tolerated and induced additive, pulmonary selective vasodilatation in pulmonary hypertension patients .
- 6In combination with iNO, milrinone produced additive pulmonary vasodilatation in animal model of acute pulmonary hypertension. A combination of milrinone and sildenafil led to more effective pulmonary vasodilation and increased RV contractility, without additional systemic vasodilatation in an animal model. Cardiac output and RV performance were significantly improved after milrinone or both drugs combined, but not with sildenafil alone.
- 7The combination of PDE3 inhibitor and PDE4 inhibitor: Milrinone and sildenafil are effective pulmonary vasodilators, with independent action and additive effect. Both drugs combined, achieved a better hemodynamic profile, with greater pulmonary vasodilatation and increased contractility but without additional systemic vasodilatation. The systemic hemodynamic profile (systemic vasodilation, cardiac output, RV dP/dT) is improved with milrinone but not with sildenafil .
- 8Bosentan has not been studied in acute care settings. Currently, the only possible implication of Bosentan in critically ill patients would be weaning or conversion from inhaled or intravenous pulmonary vasodilators to oral medication (Bosentan), but ET blockers are probably not a good option for acute PAH due to ARDS. Some study investigating the combination of Bosentan and prostacyclin analogue showed clinical improvement. Additional Bosentan therapy may also reduce the epoprostenol dose and therefore decrease its side effects.
- 9PAH patients with NYHA II–IV symptoms. A nonrandomized, uncontrolled trial in reported the effectiveness of bosentan monotherapy followed by the addition of sildenafil and/or inhaled iloprost .
- 10Acute PAH after heart transplantation: Superimposed acute RV dysfunction in the setting of preexisting pulmonary hypertension is a nearly fatal complication after heart transplantation. The optimal treatment modality remains a matter of debate. Recently, sildenafil citrate, in combination with iNO, has gained popularity and was proved safe and effective in the treatment of acute PAH after heart transplant .
Suggestions of Interventions for Acute PAH
No current treatment approach to PAH provides a cure. Rather, treatment goals are to reduce PVR, PAP, and symptoms and to increase patient activity and longevity. With an increasing number of pharmacologic treatment options available, the decision regarding when and how to use such treatment have taken on added complexity and importance. Although head-to-head comparative trials of available medications are not available, most experienced investigators and clinicians agree that patients with more advanced PAH should be treated initially with parenteral prostacyclin analogues, especially in the setting of RV failure. PDE5 inhibitors or ETRAs are reasonable initial therapies for patients who have mild-to-moderate PAH (i.e., WHO functional class II or III) or for patients who are not candidates for more invasive therapies. Conversely, intravenous therapies with a prostacyclin analogue should be considered as first-line therapy for patients with severe symptoms (WHO functional class IV) or for patients whose disease progresses on less invasive therapy. Use of inhaled iloprost and subcutaneously administered treprostinil allows for the administration of an effective prostacyclin analogue without some of the risks associated with continuous intravenous infusion. However, when inhaled or delivered subcutaneously, these agents appear to be less efficacious than when delivered via the parenteral route and may not be well tolerated by the patient. Interventional procedures such as atrial septostomy and lung transplantation are indicated in patients with advanced NYHA class III and IV symptoms and refractory to available medical treatment.
Patients who respond to an acute trial of a vasodilator may be treated with oral CCB, whereas oral therapies such as sildenafil and bosentan have been effective in patients with mild-to-moderate symptoms. Infusions of the prostacyclin analogues epoprostenol and treprostinil appear to be the treatment of choice for moderate-to-severe PAH, and agents with alternate routes of delivery such as inhaled iloprost may be advantageous in adjunctive roles. Future trials that focus on the long-term effects of currently available agents, as well as on combination therapy, are needed .
In patients at risk of sudden intravascular absorption of absolute ethyl alcohol, an increased level of awareness for acute PAH, together with prompt treatment of PAH with Sildenafil analogue or with a low dose of an NO-donor drug, will minimize the risk of cardiovascular decompensation and may be the treatment of such catastrophe.
Conflict of Interest
The authors have no conflict of interest.