Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)

INTRODUCTION — Pulmonary hypertension (PH) is classified into five groups based upon etiology. Patients in the first group are considered to have pulmonary arterial hypertension (PAH), whereas patients in the remaining four groups are considered to have PH (table 1 and table 2 and table 3). In this topic, we discuss an overview of the treatment and prognosis of PAH. The treatment of PAH with PH-specific therapy; etiology and pathogenesis of PAH; and clinical manifestations, diagnosis and classification of PH are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy" and "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "The epidemiology and pathogenesis of pulmonary arterial hypertension (Group 1)".)

GENERAL MEASURES AND SUPPORTIVE THERAPY — Patients with group 1 PAH (table 1 and table 2 and table 3) should exercise as tolerated, receive routine vaccinations (figure 1), be counselled against smoking (and vaping), and maintain a normal body mass index. When indicated, they should also be treated with supportive measures including oxygen, diuretics, and anticoagulants. Patients should be additionally treated for any comorbidities known to be associated with or worsen PH. Females of childbearing age should be counselled regarding the risks of pregnancy including death and the potential teratogenic effects of medications; birth control can be prescribed accordingly.

General measures

Exercise and pulmonary rehabilitation — Patients with PAH should exercise regularly. Indications for referral to a pulmonary exercise rehabilitation program are extrapolated from the chronic obstructive pulmonary disease population, but the benefits appear to be similar [1-7].

●In a 2019 statement issued by the European Respiratory Society that reviewed 20 trials (784, mostly PAH patients), six of which were randomized trials, exercise training was consistently associated with improved exercise capacity, muscular function, quality of life, and, possibly, right ventricular function and pulmonary hemodynamics [6].

●In a 2023 meta-analysis of five randomized trials that included mostly patients with group 1 PAH, exercise programs ranging from 3 to 25 weeks resulted in improved exercise capacity (increase by 49 meters in the six-minute walk distance), peak oxygen uptake (increase 2.1 mL/kg/minute), and health-related quality of life [7].

The general benefits and risks of exercise and pulmonary rehabilitation are discussed separately. (See "The benefits and risks of aerobic exercise" and "Pulmonary rehabilitation".)

Vaccinations — PAH is considered a chronic disease, and, as such, patients should be immunized with all age-appropriate as well as influenza, coronavirus disease 2019 (COVID-19), and pneumococcal pneumonia vaccines (figure 1). (See "Standard immunizations for nonpregnant adults" and "Pneumococcal vaccination in adults".)

Counseling against smoking — For patients who smoke (cigarettes or other products), counseling should be provided. (See "Overview of smoking cessation management in adults".)

Nutrition — While there is no ideal PAH diet, it is reasonable to advise patients to follow a generally healthy diet and target a normal body mass index. (See "Healthy diet in adults" and "Malnutrition in advanced lung disease".)

Psychosocial support — Many patients experience fear, anxiety, and depression during the course of their illness, which is often most pronounced soon after diagnosis. Proactive psychosocial support from clinicians, chaplains, mental health and palliative care providers, and advocacy and support groups may help prevent debilitating mental health consequences. (See "Psychosocial issues in advanced illness" and "Palliative care for adults with nonmalignant chronic lung disease".)

Supportive therapy

Oxygen therapy — Oxygen should be administered to PAH patients with resting, exercise-induced, or nocturnal hypoxemia. However, data to support the value of oxygen in PAH patients are extrapolated from patients with hypoxemia from chronic obstructive pulmonary disease (table 4). In hypoxemic patients with chronic obstructive pulmonary disease, oxygen is associated with prolonged survival, but it is unknown whether the same benefit is extended to patients with PAH. (See "Stable COPD: Overview of management", section on 'Supplemental oxygen' and "Long-term supplemental oxygen therapy".)

Anticoagulation — While patients with group 1 PAH (table 1) were commonly anticoagulated in the past, in general, anticoagulation has fallen out of favor. Most experts agree that anticoagulation should be avoided in patients with systemic sclerosis (SSc) associated PAH since data in that population suggest a lack of benefit or potential harm. In all other patients, we suggest that anticoagulant therapy be administered on a case-by-case basis according to the clinician's assessment of the risks and benefits. In many cases, we only anticoagulate when other indications are present (atrial fibrillation, minipump use, thrombosis). Reflecting variable practice among centers are reports suggesting that following diagnosis, only 50 percent or less of those with group 1 PAH actually receive anticoagulation [8,9].

In the past, the practice of anticoagulation was based upon the increased risk for intrapulmonary vascular thrombosis and venous thromboembolism in patients with PAH, the observation that even a small thrombus can produce hemodynamic collapse in those with a compromised pulmonary vascular bed, and early studies that suggested a mortality benefit [8,10-12]. However, much of those data were flawed and evidence from registry-based studies has since reported conflicting outcomes in patients with idiopathic PAH (IPAH) and potential harm in those with SSc-PAH:

●A 2018 systematic review of 12 nonrandomized studies reported that while mortality was reduced by anticoagulation (hazard ratio [HR] 0.73, 95% CI 0.57-0.93), most of the benefit was seen in patients with IPAH (HR 0.73, 95% CI 0.56-0.95). In contrast, no benefit was seen in connective tissue disease (CTD) related PAH (HR 1.16, 95% CI 0.58-2.32) and the risk of death was increased in patients with SSc-PAH (HR 1.58, 95% CI 1.08-2.31) [13]. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis", section on 'Pulmonary arterial hypertension-related (supportive therapies)'.)

●In the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA), anticoagulation was associated with an improved three-year survival in patients with IPAH compared with those who had other forms of PAH (mostly CTD-associated PAH; HR 0.79, 95% CI 0.66-0.94) [8]. In a post-hoc analysis of those with SSc-PAH, there was a nonsignificant trend towards worse survival among those taking anticoagulants compared with patients not on anticoagulant therapy (three-year survival 62 versus 74 percent; HR 1.82, 95% CI 0.94-3.54).

●In the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL), there was no survival advantage associated with warfarin use in patients with IPAH compared with matched warfarin-naïve PAH controls, even when adjusted for disease severity [9]. However, a 50 percent increase in mortality (mostly from progressive disease) was reported in SSc-PAH patients receiving warfarin when compared with PAH patients who were not anticoagulated.

When anticoagulation is chosen as a treatment strategy for PAH, warfarin is the anticoagulant of choice, with a therapeutic goal of an international normalized ratio of approximately 2. Many centers in the United States target a range of 1.5 to 2.5 with no bridging for temporary interruptions, while many European centers target a range of 2 to 3 with bridging anticoagulant for interruptions. Experience is limited with direct oral anticoagulants (DOACs; ie, direct thrombin or factor Xa inhibitors). One retrospective study of 366 patients with PAH reported that one-half had at least one of the three major risk factors for bioaccumulation of DOACs (eg, severe renal insufficiency), such that we mainly administer DOACs in those with proven indications [14]. (See "Warfarin and other VKAs: Dosing and adverse effects" and "Perioperative management of patients receiving anticoagulants" and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

The type of PAH may alter the risk of bleeding on anticoagulation with higher events being reported in patients with CTD-PAH compared with other forms of PAH. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis", section on 'Pulmonary arterial hypertension-related (supportive therapies)'.)

Patients with PH frequently have other risk factors for thromboembolism that may warrant anticoagulation (eg, atrial fibrillation, severe left heart failure). Anticoagulation for these conditions should be assessed independently and are discussed elsewhere. (See "Atrial fibrillation in adults: Use of oral anticoagulants" and "Antithrombotic therapy in patients with heart failure" and "Overview of the treatment of proximal and distal lower extremity deep vein thrombosis (DVT)" and "Treatment, prognosis, and follow-up of acute pulmonary embolism in adults".)

Diuretics (treatment of chronic right heart failure) — Patients with chronic fluid retention from pulmonary hypertension (PH) related right ventricle (RV) failure may benefit from diuretics (typically loop diuretics). Diuretics diminish hepatic congestion, peripheral edema, and pleural effusions and may be of particular benefit in those in whom interventricular septal deviation from elevated RV pressure impairs left ventricle output. However, caution should be exercised so that diuresis does not result in volume depletion with associated hypotension, which can precipitate an acute PH crisis. (See "Right ventricular myocardial infarction", section on 'Treatment'.)

Most diuretic is administered orally in the chronic setting. However, intravenous diuresis may be useful in the acute setting, the details of which are discussed below. (See 'Management of acute pulmonary hypertensive crisis' below.)

Occasionally, for patients in whom diuretics are ineffective for the treatment of fluid overload (eg, cardiorenal syndrome in patients with severe PAH), ultrafiltration may be beneficial.

Treatment of comorbidities or associated etiology — Any condition known to be associated with the patient's PAH should be treated (eg, scleroderma, human immune deficiency disorder, schistosomiasis), drugs or toxins known to worsen or induce PH should be discontinued, and therapy for any underlying pulmonary or cardiac disorder should be optimized. There are no data that suggest treatment of the primary disorder leads to improvement or reversal of PH, but it is likely that treatment offsets any potential contribution that a comorbidity may have to PAH deterioration. (See "Pulmonary arterial hypertension associated with human immunodeficiency virus", section on 'General measures' and "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis", section on 'Systemic sclerosis-related (immunosuppressants)' and "Schistosomiasis: Epidemiology and clinical manifestations", section on 'Pulmonary complications'.)

Birth control — Clinicians should inform females of childbearing age with PAH that pregnancy can increase the risk of worsening pulmonary vascular hemodynamics, precipitate acute cardiovascular collapse and death, and result in fetal hypoxemia. There are no known factors that reliably predict risk but severe PAH or rapidly declining disease may imply limited ability to tolerate worsening disease. In addition, for females on medication, select PH-specific drugs (endothelin receptor antagonists and riociguat) are known to be teratogenic. Because of the risks, many females with PAH choose to avoid pregnancy and clinicians should advise suitable birth control measures. In general, estrogen-containing contraceptives should be avoided since estrogen is thought to play a role in the pathogenesis of PAH. Dual barrier protection (eg, drug-eluting intrauterine devices [IUDs]) is often prescribed in those who are taking teratogenic PH-specific medications. Females should be counseled that distributors of PH-specific medications will typically not dispense unless females undergo monthly pregnancy testing. In general, a negative pregnancy test is required prior to treatment, monthly during treatment, and at one month after discontinuation of treatment.

Contraceptive counseling is an active part of patient care since pregnancy in females with PAH is associated with increased maternal and fetal risks, including high risk of maternal death [15-17]. There are many variables that impact contraceptive choice, including method efficacy, duration of action, presence of hormones, and need for daily maintenance (table 5). Females with PAH have additional concerns including the impact of the contraceptive on their disease, presence of other medical disorders, and anticipated time course of their illness, all of which must be balanced against the very significant risks associated with an unintended pregnancy among PAH patients. Both the World Health Organization and the United States Centers for Disease Control and Prevention provide tables of medical eligibility criteria for contraceptive use in females with various characteristics and medical disorders. Clinicians should also consider the contraceptive needs of transgender men and gender nonbinary persons. (See "Contraception: Counseling and selection".)

There is no consensus on the optimal contraceptive method for patients with PAH [18,19]. While the patient ultimately selects their method, we take the following approach:

●Long-acting reversible contraceptives (LARC) – For females who desire the most effective or durable contraception, we discuss LARC methods, including the copper IUD, levonorgestrel-releasing IUDs, and etonogestrel implant (figure 2). These methods have failure rates of less than 1 percent, do not require daily or monthly patient action, and last from 3 to 10 years, depending on the device. LARC methods are similar in efficacy to sterilization but have no surgical risk. However, for females who do not desire future fertility, surgical sterilization (male or female) is a reasonable option.

LARC methods can be used in most females with PAH, regardless of disease severity. For females at increased risk of arterial or venous thromboembolic events, IUDs do not increase the risk. There is no evidence that IUDs increase the risk of infection [20,21]. As the risk of thromboembolic events in users of the etonogestrel implant is controversial, we avoid the etonogestrel implant in females at increased risk of thromboembolism who are candidates for, and amenable to, other options. For patients receiving anticoagulation therapy, the concern is less and the implant may be reasonable. Contraceptive selection and the attributes of various contraceptive methods are presented separately:

•(See "Contraception: Counseling and selection".)

•(See "Intrauterine contraception: Background and device types".)

•(See "Intrauterine contraception: Candidates and device selection".)

•(See "Contraception: Etonogestrel implant".)

•(See "Overview of female permanent contraception".)

•(See "Vasectomy".)

●Hormonal contraceptives – For patients who do not find LARC methods acceptable, we discuss depot medroxyprogesterone acetate (DMPA) injections, progestin-only oral pills, and combined estrogen-progestin products (oral pills, transdermal patch, and vaginal rings). Although not as effective as LARC, these methods are highly effective when used correctly and consistently but require regular action on the part of the user (figure 2). Progestin-only methods are preferred as they are not associated with an increased risk of thromboembolism. In general, we avoid estrogen-containing products because of the potential increased risk of thromboembolism, although this risk may be acceptable, if the patient is taking anticoagulant medication.

•DMPA – DMPA is a highly effective contraceptive that has the advantage of every-13-weeks dosing. However, the absolute risk of thromboembolism has been debated because of evidence suggesting changes in lipid metabolism. DMPA does not alter coagulation factors or blood pressure. For patients who decline the LARC methods or prefer this method, the high efficacy generally balances the theoretical risk.

-(See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits".)

-(See "Depot medroxyprogesterone acetate (DMPA): Formulations, patient selection and drug administration".)

•Progestin-only pills (POPs) – Norethindrone POPs can be taken by females with PAH, including those with increased risk for thromboembolism or who have hypertension. However, POPs with norethindrone must be taken at the same time of the day for full effect and are less effective than DMPA or combined estrogen-progestin contraceptives. For patients who wish to use norethindrone POPs, combined use with a male or female condom will lower the risk of unintended pregnancy. As the thromboembolic risks of the drospirenone and desogestrel POPs may be higher than for norethindrone, we do not advise these for PAH patients. (See "Contraception: Progestin-only pills (POPs)".)

•Combined estrogen-progestin contraceptives – Combined estrogen-progestin contraceptives include oral pills, a transdermal patch, and vaginal rings. Specific to females with PAH, these methods are avoided if other modalities are available and acceptable to the patient. One major concern is that estrogen-containing contraceptives also increase the risk of both cardiovascular and venous thromboembolic events, to which PAH patients are already vulnerable. In addition, combined hormonal contraception is generally avoided in females with hypertension, even if the disease is adequately controlled by medication [22,23]. (See "Combined estrogen-progestin contraception: Side effects and health concerns".)

●Pericoital or barrier contraceptives – For females who desire only a coital-dependent method of contraception, we discuss use of diaphragm with spermicide or the contraceptive sponge. A major concern with these methods is the typical-use first-year pregnancy rates range from 12 to 24 percent (figure 2) [24]. However, for contraceptive sponge users, contraceptive efficacy varies based on parity, with typical-use first-year pregnancy rates of 12 percent for nulliparous females and 27 percent for parous females. Combined use of these methods with male or female condoms can reduce the unintended pregnancy rate. Other coital-dependent contraceptives, including the cervical cap and spermicide alone, have unacceptably high unintended pregnancy rates (20 to 30 percent) and are therefore not advised for females who desire to avoid pregnancy. (See "Pericoital (on demand) contraception: Diaphragm, cervical cap, spermicides, and sponge".)

Of note, we advise consistent condom use (male or female) for all patients at risk of acquiring a sexually transmitted infection. However, the high unintended pregnancy rates make these suboptimal for use on their own.

●Emergency contraception (EC) – We counsel patients about the options and availability of EC. While regular use of EC as a sole contraceptive method is not advised, these methods can be used after intercourse when no contraception was employed (ie, unprotected intercourse), a method was used imperfectly (ie, a condom slipped or broke, pills or injection was missed), or sex was forced without use of contraception. The most effective EC is the copper IUD, which is compatible with PAH. Oral options include ulipristal acetate, levonorgestrel, and mifepristone (not available in the United States). The selection and use of these agents are presented in detail separately. (See "Emergency contraception".)

●Sterilization – For patients who desire a highly effective method of contraception and who do not want a medical option, sterilization is an option, although the risk of precipitating an acute PH crisis needs to be accepted by the patient. (See "Overview of female permanent contraception".)

Altitude and air travel — Patients with exposure to high altitude or patients planning air travel should continue their routine PAH medications. Supplemental oxygen (2 to 4 L per minute) can also be administered to maintain oxygen saturations above 90 percent. Assessment of patients for air travel and the effects of high altitude are discussed separately. (See "Assessment of adult patients for air travel", section on 'Pulmonary' and "Evaluation of patients for supplemental oxygen during air travel" and "High-altitude illness: Physiology, risk factors, and general prevention" and "Approach to patients with heart disease who wish to travel by air or to high altitude".)

PULMONARY HYPERTENSION-SPECIFIC THERAPY — Pulmonary hypertension (PH) specific therapy is directed at the PH itself. All patients with PAH should be evaluated by a PAH specialist for PH-specific therapy, the details of which are discussed separately. (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

SPECIAL POPULATIONS

Pregnancy — Females with PAH should be counseled regarding the risk of pregnancy (worsening pulmonary vascular hemodynamics, acute cardiovascular collapse and death from right ventricular failure, and fetal hypoxemia). For females who choose to become pregnant (or develop pulmonary hypertension [PH] when pregnant), we advocate an individualized risk-based approach with shared decision-making and co-management with PAH and maternal fetal medicine specialists.

●Maternal-fetal risk – Several issues may arise during pregnancy including worsening shortness of breath, progressive PH, hypoxemia, and acute cardiovascular collapse and death. The first 24 to 36 hours after delivery is the time of greatest risk and death.

It is unknown whether the risk of fetal abortion is increased but fetal hypoxemia may be an issue in those with maternal hypoxemia from PAH. There are some data that fetal demise is increased [25,26]. Also, chronic maternal hypoxemia would be expected to increase the risk for fetal growth restriction. Pregnant females with PAH should also be counseled about the risk of congenital anomalies and offered first- and second-trimester ultrasound examination to screen for fetal anomalies. (See "Prenatal genetic evaluation of the fetus with anomalies or soft markers".)

●PH-specific therapy – In general, it is felt that the effects of untreated PAH are potentially worse than continuing treatment, although adjustments may need to be made in the medication class and/or dosing. For example, the PH-specific medications, endothelin receptor antagonists (bosentan, ambrisentan, macitentan) and guanylate cyclase stimulants (riociguat) should be discontinued since they are absolutely contraindicated in pregnancy due to their known teratogenicity. In most cases, patients are treated with a parenteral prostanoid. Right heart catheterization (RHC) may be performed if a clinical decision depends upon the information gained from RHC but interpretation can be challenging due to the increased volume and cardiac output associated with pregnancy.

●Delivery – While there is no consensus, the choice of delivering by cesarean or vaginally (with or without regional anesthesia and instrumental assistance) should be individualized. We advise delivery in settings where anesthesia and assistance are available; assisted vaginal delivery is often the preferred option, provided that there are no other indications for cesarean section. Perioperative management of PAH patients is discussed separately. (See "Anesthesia for noncardiac surgery in patients with pulmonary hypertension or right heart failure".)

●Breastfeeding – Some PH-specific medications can be found in breast milk (LactMed). Although anecdotal cases report successful breastfeeding while on sildenafil, treprostinil, and bosentan, the data are weak and, in general, we do not advise it [27,28].

There is a paucity of data to support these findings. In general, they suggest that pregnancy in patients with PAH is a risky. However, in patients with well-controlled mild disease who are closely monitored by experts in the management of PAH and pregnancy, a good outcome generally can be achieved:

●A retrospective review of 49 pregnant females with PH (30 had World Health Organization group 1 PAH) from four major academic medical centers in the United States reported a mortality of 16 percent (eight females). Seven of the eight deaths occurred in females with group 1 PAH; six of whom had severe PH (defined as mean pulmonary artery pressure ≥50 mmHg) [29]. Three deaths occurred following pregnancy termination procedures and five deaths occurred postpartum, four in those who delivered by cesarean section compared with one who delivered vaginally. There were no neonatal deaths. Seventy-three percent of females with severe PH received advanced therapies for pulmonary hypertension including vasopressors, inotropes, pulmonary vasodilators, and extracorporeal membrane oxygenation (ECMO).

●In another retrospective single-center series of 25 pregnancies in 16 patients with PAH over a 12-year period, 13 patients had a total of 17 successful pregnancies with 18 healthy newborn infants [30]. There were five spontaneous abortions and three terminations. One patient who became pregnant in the accelerated phase of PAH progression required acute ECMO and was successfully transplanted, while another temporarily required ECMO after an emergency caesarian section following the development of a febrile illness at the end of the pregnancy. Over one-third developed progressive PAH within 9 to 22 months after delivery that responded to PAH-specific medication; although not conclusive, the relatively long interval between delivery and clinical worsening suggested that pregnancy was not a triggering factor. By the end of the study period, all offspring were well with no apparent deficits noted during development. (See 'Management of acute pulmonary hypertensive crisis' below.)

Surgical or periprocedural care — Patients with PAH, and particularly those with significant right ventricular dysfunction, are at high risk of complications and death when undergoing anesthesia or sedation for major surgery and procedures including intubation and mechanical ventilation [31-33]. The perioperative course can be complicated by hemodynamic instability resulting in severe hypoxemia, acute right heart failure/circulatory collapse, and death, most often precipitated by systemic hypotension from induction medications [34]. In addition, medication-related complications can increase surgical risk of bleeding (eg, anticoagulants and prostanoids). Risk assessment and management of patients with PH perioperatively or periprocedurally should be performed with the assistance of a specialist in PH and sedation/anesthesia, the details of which are discussed separately. (See "Anesthesia for noncardiac surgery in patients with pulmonary hypertension or right heart failure".)

MANAGEMENT OF ACUTE PULMONARY HYPERTENSIVE CRISIS — Acute pulmonary hypertensive (PH) crisis is a potentially fatal complication of PAH. It is manifested by a rapid rise in pulmonary vascular resistance leading to acute right heart failure, inadequate cardiac output, and shock.

Triggers include surgery/anesthesia, acute lung disease (eg, pneumonia), fever, hypovolemia, or interruption of prostanoid infusion. Although an acute PH crisis can occur when oral medications are disrupted, it is less common and may be slower in onset [35].

At risk patients are those with suprasystemic pulmonary artery pressure (PAP; ie, greater than that of the systemic circulation) and right ventricular (RV) dysfunction. Patients receiving PH-specific medication for PAH should be counseled and educated regarding this complication; medication-alert bracelets may also help identify and prevent this risk.

General principles of management of PH crises include:

●Expertise – Patients with acute PH crisis are best managed in a center with expertise since management is challenging and mortality is high. For example, for those in whom temporary disruption was the cause of the crisis, resumption of PH-specific medication under the supervision of a PH expert is typically indicated. In contrast, increasing PH-specific medication during hypoxemic respiratory failure from pneumonia could be harmful. For those in whom PH-specific medication is being considered, we have found that the slow initiation and titration of intravenous prostacyclin (ideally under hemodynamic monitoring) is, by far, the most effective approach to management, particularly when low systemic blood pressure is due to a severely reduced cardiac output (eg, less than 2 L/minute).

●Provision of oxygen – The provision of oxygen rather than increasing medications is particularly important in crises precipitated by a temporary reversible condition such as pneumonia. In some cases, mechanical ventilation or extracorporeal membrane oxygenation (ECMO) may be used to buy time for the inciting process to improve or for initiation of medication; rarely, ECMO is used as a bridge to lung transplantation. In some patients, inhaled nitric oxide can be administered for severe or refractory hypoxemia due to PAH. (See "Overview of initiating invasive mechanical ventilation in adults in the intensive care unit" and "Extracorporeal life support in adults in the intensive care unit: Overview" and "Inhaled nitric oxide in adults: Biology and indications for use", section on 'Patients with underlying pulmonary hypertension'.)

●Provision of advanced life support for cardiac arrest associated with PH-advanced cardiac life support protocols are provided separately. (See "Advanced cardiac life support (ACLS) in adults".)

●Avoidance of hypovolemia/hypervolemia – Assessing and managing fluid status can be difficult. While some patients require gentle fluid resuscitation, other require intravenous diuresis; the latter is often given as a bolus dose, although a continuous infusion may be better tolerated hemodynamically in those with borderline low blood pressure. A right heart catheter or other hemodynamic tools may be needed to guide fluid management, although their interpretation in patients with PAH may be challenging. (See "Pulmonary artery catheters: Insertion technique in adults" and "Pulmonary artery catheterization: Interpretation of hemodynamic values and waveforms in adults" and "Pulmonary artery catheterization: Indications, contraindications, and complications in adults" and 'Diuretics (treatment of chronic right heart failure)' above and "Novel tools for hemodynamic monitoring in critically ill patients with shock".)

●Provision of mechanical ventilation support – The principles of mechanical ventilation are similar to patients who do not have PAH. (See "Extracorporeal life support in adults in the intensive care unit: Overview".)

●Administer inotropic and/or vasopressor support – Vasopressors may be needed for systemic blood pressure support, particularly when prostacyclin is being titrated upward. Use of inotropic agents, which are sometimes administered in the acute setting, can be challenging due to their altered hemodynamic effects on pulmonary vascular resistance. Dobutamine and milrinone are the most widely used agents, while experience with levosimendan is limited and is less widely available.

All of the agents increase RV contractility, as well as decrease RV afterload by inducing pulmonary vasodilation, a feature that may be enhanced by inhaled nitric oxide or inhaled epoprostenol [36,37].

The primary side effects of intravenous inotropic agents are tachycardia and systemic hypotension. The hypotension induced by these agents generally occurs at low doses and then resolves as the dose is increased. Since most patients are hypotensive when the inotropic agent is initiated, we first increase systemic blood pressure by administering norepinephrine by continuous infusion and then begin the inotropic agent. As we adjust the dose of the inotropic agent, we attempt to lower the dose of norepinephrine so that the patient is left receiving the inotropic agent alone. If this is not possible, adding phenylephrine or vasopressin to norepinephrine is appropriate [38]. (See "Use of vasopressors and inotropes".)

Prognosis following acute crisis is poorly studied. In one retrospective study, mortality at three months was high (31 percent) and continued to rise following that (one year [41 percent]; five years [66 percent]), although rates were lower among those younger than 50 years of age [39]. Another retrospective study reported an in-hospital mortality rate of 41 percent [40]; those with a high risk assessment predicted mortality (table 6). (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy", section on 'High- versus low-/intermediate-risk multiparameter risk assessment models'.)

MANAGEMENT OF ARRHYTHMIAS — Patients with PAH may develop rhythm disturbances, particularly, supraventricular tachycardia (SVT), atrial flutter, and atrial fibrillation. Bradycardia from acute right ventricular (RV) dilatation may also occur. One retrospective study reported a prevalence of 37 percent for conduction disease in patients with idiopathic PAH [41]. The principles of management are generally similar to patients who do not have PAH. However, aggressive and early management including rate control, cardioversion, and ablation are particularly important since the tolerance for rhythm disturbances is low in PAP due to worsening of pulmonary hemodynamics and risk of precipitating an acute PH crisis. (See "Overview of the acute management of tachyarrhythmias" and "Atrial fibrillation: Overview and management of new-onset atrial fibrillation".)

While digoxin therapy may have inotropic value in patients with group 3 pulmonary hypertension (PH) due to chronic obstructive pulmonary disease who have biventricular failure [42], data to support its use in patients with group 1 PAH for this purpose are nonexistent. Nonetheless, it is sometimes used as a heart rate control measure in patients with SVT. Verapamil is preferred for multifocal atrial tachycardia, unless there is concurrent left ventricular failure, in which case beta blockers are preferred. However, we advise caution with beta blockade use since adverse effects on pulmonary hemodynamics is not unusual. For maintenance of sinus rhythm following chemical cardioversion of atrial fibrillation, some experts prefer to use amiodarone or dofetilide due to their limited adverse effects on pulmonary hemodynamics when compared with other agents.

PROGNOSIS

Natural history — Left untreated, PAH is progressive and sometimes fatal. Without therapy, the prognosis of patients in group 1 PAH is poor. Data from the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL registry) reported that following diagnosis, patients with PAH had a one-year survival rate of 85 percent, three-year survival rate of 68 percent, five-year survival rate of 57 percent, and seven-year survival rate of 49 percent [43].

Overall prognosis — National surveillance data reported that mortality rates from pulmonary hypertension (PH) have increased from 5.2 to 5.4 per 100,000 over a 22 year period (1980 to 2002), with the greatest increase reported in Black individuals and females [44]. In general, in the absence of therapy, those with group 1 PAH have worse survival than groups 2 through 5 (table 1).

In the era of PH-specific therapy, the prognosis of PAH may be improving and comparable or better than other forms of PH. In the Giessen Pulmonary Hypertension Registry, patients with chronic thromboembolic PH (CTEPH) had the best one-, three-, and five-year survival rates of 89, 77, and 67 percent, respectively [45]. Patients with chronic lung disease associated PH (group 3) had worse survival at one year (80 versus 88 percent), three years (52 versus 72 percent), and five years (38 versus 59 percent) compared with group 1 PAH. Patients with group 2 PH had similar survival rates to those with PAH.

Prognosis varies among the etiologies of group 1 PAH. Patients with associated forms of PAH (eg, portopulmonary hypertension, systemic sclerosis-related PAH) generally have a worse prognosis compared with idiopathic PAH (IPAH). An exception is patients with PAH due to Eisenmenger's syndrome, who have a better prognosis than patients with IPAH [46]. A retrospective study of patients with methamphetamine-induced PAH reported a doubling in the risk of death when compared with IPAH patients [47]. The prognosis of patients with disease-associated PAH is discussed in the following sections:

●Systemic sclerosis (see "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Definition, risk factors, and screening")

●Human immunodeficiency virus (see "Pulmonary arterial hypertension associated with human immunodeficiency virus", section on 'Prognosis')

●Portopulmonary hypertension (see "Portopulmonary hypertension", section on 'Prognosis')

●Congenital heart disease (see "Pulmonary hypertension in adults with congenital heart disease: General management and prognosis", section on 'Prognosis')

●Schistosomiasis (see "Schistosomiasis: Epidemiology and clinical manifestations", section on 'Pulmonary complications')

●Pulmonary veno-occlusive disease (see "Treatment and prognosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis in adults", section on 'Prognosis')

●Pulmonary hypertension of the newborn (see "Persistent pulmonary hypertension of the newborn (PPHN): Management and outcome", section on 'Outcome')

Prognostic factors — Data from prospective trials have described factors that portend a poor prognosis in patients with PAH [43,44,48-71]. While these factors indicate poor prognosis when PAH is newly diagnosed, some may not be reliable for ongoing assessment of prognosis during follow-up [70].

Factors associated with poor prognosis include [43,44,48-73]:

●Age >50 years and male sex – Increased age and male sex are frequently cited as factors that are associated with worse survival. The worse prognosis in older patients may reflect the presence of multifactorial disease or the presence of comorbidities that impact survival.

•A registry in the United Kingdom and Ireland of patients with PAH diagnosed between 2001 and 2009 found that individuals over 50 years had worse survival at one year (90 versus 95 percent), three years (76 versus 91 percent), five years (57 versus 87 percent), and seven years (44 versus 75 percent) compared with patients less than 50 years of age [74].

•Data from the REVEAL registry found that, among individuals with PAH who were older than 60 years, males had a lower two-year survival than females (64 versus 78 percent; hazard ratio 1.67, 95% CI 1.3-2.2) [43]. In contrast, there was no difference in survival among males and females with PAH who were 60 years or younger (84 versus 86 percent).

●Severe PAH – Severe PAH is evidenced by the World Health Organization (WHO) functional class III or IV (table 7), failure to improve to a lower WHO functional class during treatment, and indices of right ventricle dysfunction including:

•Echocardiographic findings of a pericardial effusion, large right atrial size, elevated right atrial pressure, or septal shift during diastole

•Poor right ventricular contractile reserve determined by an increase in pulmonary artery systolic pressure of <30 mmHg with exercise during stress echocardiography

•Low right ventricle fractional area change and oxygen pulse during exercise on stress echocardiography

•Low right ventricular ejection fraction <25 percent on planar radionuclide angiography

•Increased N-terminal pro-brain natriuretic peptide level (NT-proBNP)

•Prolonged QRS duration

•Supraventricular arrhythmia (eg, persistent atrial fibrillation or atrial flutter)

Patients with severe PAH or right heart failure die sooner without treatment (usually within one year) than patients with mild PAH or no right heart failure. Patients with IPAH and a mean right atrial pressure ≥20 mmHg have a median survival of approximately one month [75].

●Others – Other factors associated with poor outcome include:

•Decreased pulmonary arterial capacitance (ie, the stroke volume divided by the pulmonary arterial pulse pressure)

•Hypocapnia

•Comorbid conditions (eg, chronic obstructive pulmonary disease, diabetes)

•PAH associated with connective tissue disease

•Selective serotonin reuptake inhibitors

•Low von Willebrand factor levels

•Bone morphogenetic protein receptor type 2 (BMPR2) mutations

•Carriers of the RNF213 variant

•Episode of acute PH crisis

•Mechanical ventilation

Circulating factors, such as hepatoma-derived growth factor, remain investigational as a potential biomarker or predictor of prognosis [76].

Cause of death — The main cause of death in patients with PAH is thought to be right heart failure with cardiopulmonary collapse, either due to an acute precipitant or severe PAH (see 'Management of acute pulmonary hypertensive crisis' above). However, in the era of pulmonary hypertension (PH) specific medications, deaths due to cardiopulmonary collapse may be declining. While early studies in the 1990s reported a high prevalence (73 to 84 percent) of death from circulatory collapse due to right heart failure, analyses done during the era of PAH-specific therapies report lower rates (44 to 50 percent), suggesting that although right heart failure and circulatory collapse remain important causes of death in patients with PAH, it may be declining with evolving trends in therapy [77,78]. Supporting this finding, we find that it is not uncommon to have success treating PAH in patients with systemic sclerosis (SSc) or liver disease for example, only to have patients then die of other SSc-related complications or progression of their cirrhosis. A multicenter prospective study is required to establish the true prevalence of conditions that contribute to death in patients with PAH.

Patients with PAH who experience cardiac arrest rarely survive. In a retrospective study of 132 patients with PAH who required cardiopulmonary resuscitation (CPR) for circulatory arrest, CPR was unsuccessful in 80 percent and only 6 percent survived more than 90 days without residual neurologic deficit [79].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pulmonary hypertension in adults".)

SUMMARY AND RECOMMENDATIONS

●Classification – The World Health Organization (WHO) classifies patients with pulmonary hypertension (PH) into five groups based upon etiology. Patients in the first group are considered to have pulmonary arterial hypertension (PAH), whereas patients in the remaining four groups are considered to have PH (table 1 and table 2 and table 3). (See 'Introduction' above.)

●General measures – Patients with PAH should exercise as tolerated, receive routine vaccinations (figure 1), be counselled against smoking (and vaping), and maintain a normal body mass index. (See 'General measures and supportive therapy' above.)

•When indicated, patients should also receive psychosocial support and be treated with supportive measures including oxygen (eg, resting, exercise-induced, or nocturnal hypoxemia (table 4)) and diuretics (eg, fluid overload from right heart failure). (See 'Psychosocial support' above and 'Oxygen therapy' above and 'Diuretics (treatment of chronic right heart failure)' above.)

•In general, anticoagulation has fallen out of favor; most experts agree that anticoagulation should be avoided in patients with systemic sclerosis (SSc) associated PAH due to a lack of benefit or potential harm; in the remaining groups of patents with PAH, we suggest that it be administered on a case-by-case basis according to the clinician's assessment of the risks and benefits. (See 'Anticoagulation' above.)

•Patients should be additionally treated for any comorbidities known to be associated with or worsen PH. Females of childbearing age with PAH should be informed of the increased maternal and fetal risk of pregnancy, and birth control should be prescribed accordingly. (See 'Treatment of comorbidities or associated etiology' above.)

●PAH management – Patients with PAH should be evaluated by a PAH specialist for PH-specific therapy (ie, therapy that is directed at the PH itself). (See "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

●Special populations – For females with PAH who choose to become pregnant, co-management with PAH and maternal fetal medicine specialists is advised. PH-specific therapy should be continued during pregnancy; most patients are managed with a parenteral prostanoid, typically epoprostenol. For patients undergoing sedation or anesthesia for surgery or a procedure including mechanical ventilation, the assistance of a specialist in PH and sedation/anesthesia are appropriate so that acute cardiovascular collapse can be avoided by induction medications. (See 'Special populations' above and "Anesthesia for noncardiac surgery in patients with pulmonary hypertension or right heart failure".)

●Acute PH crisis – Acute PH crisis is a potentially fatal complication of PAH, particularly in patients who have severe PAH as evidenced by suprasystemic pulmonary artery pressure and right ventricular dysfunction. Management may involve oxygenation and advanced cardiac life support measures (including extracorporeal membrane oxygenation), careful fluid balance management, mechanical ventilation, and/or inotropic and vasopressor support. (See 'Management of acute pulmonary hypertensive crisis' above.)

●Management arrythmias – For patients with PAH who develop rhythm disturbances, (eg, supraventricular tachycardia, atrial flutter, and atrial fibrillation), aggressive and early management including rate control, cardioversion, and ablation are important to avoid worsening of pulmonary hemodynamics and precipitation of an acute PH crisis. (See 'Management of arrhythmias' above.)

●Prognosis – PH-specific therapy may improve PAH-associated mortality. Factors associated with poor prognosis include age older than 50 years, male sex, severe PAH as evidenced by WHO functional class III or IV (table 7), failure to improve to a lower WHO functional class during treatment, and indices of right ventricle dysfunction, as well as other factors including connective tissue disease-associated PAH and comorbid conditions. Approximately one-half of patients die from circulatory collapse from right heart failure. (See 'Prognosis' above.)