Author: Abel P Wakai / Editor: Jason Kendall / Reviewer: Stewart McMorran / Codes: CAP6, HAP6 / Published: 19/01/2018 / Review Date: 19/01/2021
(i) Definition and classification
Pulmonary hypertension (PH) is an elevation in pulmonary vascular pressure that can be caused by an isolated increase in pulmonary arterial pressure or by increases in both pulmonary arterial and pulmonary venous pressures(1).
The World Health Organization (WHO) diagnostic classification of PH has 5 classes based on pathophysiology and aetiology (Box 1).
WHO Classification of Pulmonary Hypertension
- Pulmonary arterial hypertension
- Pulmonary venous hypertension
- Pulmonary venous hypertension associated with hypoxaemia (eg COPD)
- Pulmonary hypertension due to chronic thrombotic or embolic disease
- Miscellaneous causes (eg sarcoidosis and any extrinsic compression of pulmonary vessels, such as a tumour)
Pulmonary arterial hypertension (PAH) is the most widely studied class of PH. It refers to conditions that share common isolated elevations in pulmonary arterial pressure, namely: sporadic PAH, familial PAH and PAH associated with other diseases (e.g. collagen vascular disease and congenital systemic-to-pulmonary shunts), PAH associated with drugs and toxins (e.g. appetite suppressants such as fenfluramine, cocaine and amphetamines).
PAH is haemodynamically defined as a resting mean pulmonary arterial pressure greater than 25 mm Hg with a normal pulmonary capillary or left atrial pressure (<15 mm Hg)(1-3). PAH is suggested when an echocardiogram-derived estimate of pulmonary arterial systolic pressure exceeds 40 mm Hg at rest.
Pulmonary arterial hypertension is defined as a resting mean pulmonary arterial pressure greater than 25mmHg with a normal pulmonary capillary or left atrial pressure (<15mmHg).
Pulmonary arterial hypertension (PAH) is a rare but probably underestimated condition. No published data on the estimated prevalence of PH in developing countries is available. However, the prevalence of PH is thought to be much higher than reported in developing countries where diseases that may promote pulmonary vascular disease (schistosomiasis, sickle cell disease, human immunodeficiency virus infection, liver cirrhosis and congenital heart disease) are relatively common(4-6).
In Europe, the prevalence of PAH has been estimated at 15-60 subjects per million population with an annual incidence of 5-10 cases per million per annum
PAH affects women more commonly than men, and patients of all ages may develop the disease. The mean age at diagnosis has been reported at 36 to 50 years, with more recent series, and series including PAH related to other systemic diseases (particularly scleroderma), reporting older mean ages at diagnosis.
2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology and the European Respiratory Society;
Although there is a paucity of data-driven evidence regarding acute problems in PH, patients with known PH may present to the emergency department (ED) with a variety of acute problems related to this disease: pulmonary embolism, acute right heart failure, cardiac arrest, catheter-related sepsis and technical problems with intravenous catheters.
The emergency physician is in a strong position to consider the initial diagnosis in patients with previously undiagnosed PH, as long as there is a high index of suspicion in any patient presenting with breathlessness in the absence of an alternative cause of cardiorespiratory disease.
(i) At the cellular level
Several cellular mechanisms are implicated in the pathogenesis of PH(9) (see Box 2).
Cellular pathogenetic mechanisms in PH
- mutations in the bone morphogenetic protein receptor-2 (a member of the transforming growth factor-b family)
- allelic variations in the serotonin transporter (5-HTT),
- reduced bioavailability of endogenous nitric oxide
- alteration in the metabolism of cyclic nucleotides
- imbalance in the metabolism of prostanoids (prostacyclin and thromboxane A2)
- release of peptide mediators by the vascular endothelium (eg. endothelin-1)
(ii) Development of right heart failure:
Prolonged PH can lead to right heart failure due to sustained increases in pulmonary artery pressure and right ventricle (RV) afterload. Right ventricular function worsens in parallel to elevations of the pulmonary artery pressure. Chronic pressure overload stimulates the RV to hypertrophy over time. This hypertrophy, coupled with reduced contractility, causes a reduction in coronary blood flow to the RV myocardium, which can produce right ventricular ischaemia and dilation.
Right ventricular enlargement progresses to tricuspid annular dilation and regurgitation, and subsequent displacement of the inter-ventricular septum toward the left ventricle. Alterations in the left ventricle are then observed secondary to right ventricular overload. Left sided heart failure ensues, as evidenced by depressed left ventricular functional curves, and increased LV end diastolic and pulmonary capillary wedge pressures. The cascade that follows is a slippery slope that leads to increased RV end diastolic pressure, lower extremity oedema, increased jugular venous pressures, congestive hepatomegaly, decreased oxygenation, decreased tissue perfusion, and ultimately, cardiovascular collapse.
Patients with prolonged PH may present to the ED with acute right heart failure due to sustained increases in pulmonary artery pressure and right ventricle (RV) afterload.
The severity of PH can be clinically stratified according to World Health Organization (WHO) guidelines, a modification of the New York Heart Association (NYHA) functional classification(10,11) (see Box 3).
Functional Assessment in PH (WHO guidelines)
- Class I – Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain or near syncope.
- Class II – Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain or near syncope.
- Class III – Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain or near syncope.
- Class IV – Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity.
Severe exercise limitation (World Health Organization [WHO] class IV), near syncope, syncope, or lower extremity oedema suggest advanced PH and require urgent referral to a specialist unit for evaluation.
The symptoms of PH are non-specific. Progressive dyspnoea and fatigue that cannot otherwise be explained are the most common symptoms of PH. Although PH remains an uncommon cause of dyspnoea, a thorough evaluation of any patient presenting to the ED with dyspnoea in the absence of an alternative cause of cardiorespiratory disease is warranted (Box 4).
A problem-focused history in a patient presenting with dyspnoea in the absence of an alternative cause of cardiorespiratory disease should include the following
- the type and level of activity associated with dyspnoea;
- timing of symptom onset and progression;
- associated symptoms, including chest pain, palpitations, lower extremity oedema, near syncope, syncope and fatigue;
- thorough review of cardiac, respiratory, rheumatological, neurological and haematological systems;
- family history of PH.
(ii) Physical examination
Findings on physical examination may suggest PH, or the presence of underlying conditions associated with PH (Box 5). Signs of impaired right heart function are indicative of more severe PH.
Physical signs suggestive of PH
- accentuated pulmonary component of the second heart sound
- jugular venous distension with elevated A waves
- right-sided S4
- right ventricular heave
- parasternal lift
- tricuspid regurgitation murmur
- lower extremity oedema
The most consistent finding in patients with PH is an increased pulmonary component of the second heart sound (P2).
PH should be considered in all patients presenting with dyspnoea in the absence of an alternative cause of cardiorespiratory disease.
Figure 1 demonstrates an ED-based diagnostic approach to a patient suspected of having pulmonary hypertension. In the ED, investigational tools for PH are generally limited to venous and arterial blood assays, electrocardiography (Box 6) and chest radiography (Box 7). If PH is suggested after these initial investigations, the best screening investigation to confirm the diagnosis and determine referral to a specialist is echocardiography.
Figure 1. An ED diagnostic approach to the patient with suspected PH
Electrocardiographic features of PH
- right ventricular hypertrophy
- right-axis deviation
- right ventricular strain
- right atrial enlargement
Approximately 13% of patients with PH have normal ECGs(12).
XR features of PH
- enlarged main and hilar pulmonary arterial shadows (>17 mm) with attenuation of peripheral vascular markings (pruning)
- anterior displacement of the right ventricle into the retrosternal space on the lateral view and a globular heart (suggests RV dilation or hypertrophy)
- linear calcification of the right pulmonary artery (indicates severe longstanding PH)
- presence of underlying conditions (eg COPD and interstitial lung disease) associated with the development of PH
- While ECG and chest radiography are often abnormal at presentation, the sensitivity of these investigations is such that normal appearances do not exclude PH.
- Doppler echocardiography is the best screening investigation for PH.
Management of the acutely ill patient with PH should include careful evaluation for secondary causes of decompensation (such as a low-grade line infection or pulmonary thromboembolism). The management approach can be broadly divided into two stages: immediate ED management and subsequent or specialist management (Table 1 and list 8).
(i) Immediate ED management
Table 1. Immediate ED management
|Hypoxaemia||supplemental oxygen |
(controversial in patients with Eisenmenger syndrome(13))
|Arrhythmias||beta blockerscalcium channel blockersdigoxin|
|Volume overload||diureticsinotropes or vasopressors|
|Acute right heart failure||spironolactonedigoxinsearch for underlying precipitant|
|Cardiac arrest||advanced life support |
(resuscitation while searching for underlying precipitant)
|Technical intravenous catheter and pump problems||prompt restoration of intravenous therapy|
|Catheter-related infection||prompt blood culturesempiric initiation of appropriate antibiotic therapy|
|Bleeding in warfarinised PH patients||avoidance of unnecessary punctures (e.g. arterial blood gas sampling)correct INRsearch and correct underlying cause (e.g. drug interaction)|
For patients who are volume overloaded at presentation, diuresis, even against the background of marginal cardiac output and low blood pressure, may be required(8). In a subset of patients, support with inotropes or vasopressors is necessary: animal data suggest a better haemodynamic response with sympathomimetic agents such as dobutamine, noradrenaline, and dopamine rather than vasopressin or phenylephrine; milrinone also has favourable effects on cardiac output but may lead to excessive hypotension(8,14-17).
Diuretics are indicated for right ventricular volume overload(1). However, rapid and excessive diuresis may precipitate systemic hypotension and renal insufficiency(1). Spironolactone, an aldosterone antagonist that is of benefit in patients with left-heart failure, is also used to treat right-heart failure(1). Although not extensively studied in PAH, digitalis is sometimes used for refractory right ventricular failure(18). In addition, atrial flutter or other atrial dysrhythmias often complicate late-stage right-heart dysfunction, and digoxin may be useful for rate control(1).
(ii) Subsequent specialist management
Because of the expertise required, specialist centres prefer to initiate administration of the drugs outlined in Box 8(1). Regarding subsequent (specialist) management, there has been recent interest in using a combination of drugs with different mechanisms of action for the management of PH. For example, phosphodiesterase inhibitors may enhance and prolonged the effects of prostanoids(1).
Similar to drug treatment of essential hypertension and cancer, combination drug therapy potentially enhances drug efficacy and may permit individual drugs to be used at lower doses, minimizing drug toxicity(1). Regarding the interventional and surgical therapies for PH, atrial septostomy is generally used as a palliative procedure or as a stabilizing bridge to lung transplantation when advanced medical therapy is not available (e.g. in developing countries)(19,20).
Subsequent (specialist) management
- vasodilator testing and calcium-channel blockers
- endothelin-receptor antagonists
- interventional and surgical therapies (eg atrial septostomy, lung transplantation)
- Diuretics are indicated to reduce fluid retention in patients with PH;
- Acute arrhythmias require prompt management with the aim of restoring sinus rhythm and preventing recurrence of the arrhythmia;
- Digoxin may be beneficial in heart failure due to PH, and should be considered in patients in sinus rhythm who remain symptomatic on medical therapy;
- Establishing the diagnosis and aetiology requires early referral to a specialist PH unit;
- If possible, all patients should be seen by a consultant in cardiology or respiratory medicine before referral to a designated centre.
Prognosis & Followup strategies
The main pitfall in the ED management of PH is not maintaining a high index of suspicion in the patient presenting with dyspnoea in the absence of an alternative cause of cardiorespiratory disease.
A patient with PH may present with symptoms that are very common in ED patients (e.g. dyspnoea, fatigue, chest pain, near syncope or syncope). The emergency physician should consider PH in the differential diagnosis for these symptoms. For example, a patient who presents to the ED with chest pain may be having an acute myocardial infarction for which sublingual glyceryl trinitrate (GTN) is appropriate; however if a patient with chest pain also has RV failure as a complication of PH, sublingual GTN may cause catastrophic hypotension and may be contraindicated.
It will be important for the emergency physician to distinguish RV failure from LV failure. A chest x-ray and ECG will normally suffice in the right clinical context to make this distinction. Identifying acute right heart failure is important since the emergency physician may find a treatable cause eg. acute pulmonary embolism.
Sublingual glyceryl trinitrate may be contraindicated in patients with chest pain associated with decompensated right ventricular failure due to PH.
MedicoLegal and other considerations
Grade of recommendation: D; Level of evidence: 5
- PH should be considered in all patients presenting with dyspnoea in the absence of an alternative cause of cardiorespiratory disease(21).
- While ECG and chest radiography are often abnormal at presentation, the sensitivity of these investigations is such that normal appearances do not exclude PH(21).
- Doppler echocardiography is the best screening investigation for PH(21).
- Diuretics are indicated to reduce fluid retention in patients with PH(21).
- Digoxin may be beneficial in heart failure due to PH, and should be considered in patients in sinus rhythm who remain symptomatic on medical therapy(21).
- Acute arrhythmias require prompt management with the aim of restoring sinus rhythm and preventing recurrence of the arrhythmia(21).
- Establishing the diagnosis and aetiology requires early referral to a specialist PH unit(21).
- If possible, all patients should be seen by a consultant in cardiology or respiratory medicine before referral to a designated centre(21).
- Sublingual glyceryl trinitrate may be contraindicated in patients with chest pain associated with decompensated right ventricular failure due to PH(21).
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- Sandoval J, Aguirre JS, Pulido T, Martinez-Guerra ML, Santos E, Alvarado P, et al. Nocturnal oxygen therapy in patients with the Eisenmenger syndrome. Am J Respir Crit Care Med 2001;164:682-7.
- Acosta F, Sansano T, Palenciano CG, et al. Effects of dobutamine on right ventricular function and pulmonary circulation in pulmonary hypertension during liver transplantation. Transplant Proc 2005;37:3869-70.
- Hirsch LJ, Rooney MW, Wat SS, et al. Norepinephrine and phenylephrine effects on right ventricular function in experimental canine pulmonary embolism. Chest 1991;100:796-801.
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- Rich S, Seidlitz M, Dodin E, Osimani D, Judd D, Genthner D, et al. The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension. Chest 1998;114:787-92.
- Rothman A, Sklansky MS, Lucas VW, et al. Atrial septostomy as a bridge to lung transplantation in patients with severe pulmonary hypertension. Am J Cardiol 1999;84:682-6.
- Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe primary pulmonary hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment. J Am Coll Cardiol 1998;32:297-304.
- National Pulmonary Hypertension Centres of the UK and Ireland. Consensus statement on the management of pulmonary hypertension in clinical practice in the UK and Ireland. Thorax 2008;63 Suppl 2:ii1-ii41.
- 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The joint task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology and the European Respiratory Society; European Heart Journal, vo. 37, issue 1, 1 Jan 2016, pages 67-119