Pulmonary Hypertension

OVERVIEW

Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical conditions and can complicate many cardiovascular and respiratory diseases (Galie et al, 2019).

• Pulmonary arterial hypertension (PAH) is traditionally defined as an increase in mean pulmonary arterial pressure (PAPm) ≥25 mmHg at rest as assessed by right heart catheterization (RHC) (Galie et al, 2019)
  • Recently it has been proposed to include pulmonary vascular resistance (PVR) ≥3 Wood Units (WU) into the definition of pre-capillary PH associated with mPAP >20 mmHg, irrespective of aetiology (Galie et al, 2019)
  • normal PAPm at rest is 14+3 mmHg with an upper limit of normal of approximately 20 mmHg (97.5th percentile) (Simmonaeu et al, 2019)
• PH on exercise is not well defined and should not be used for diagnosis

In many cases PH is an incurable, chronic and progressive disease

• therapy is focussed on symptomatic relief and delaying progression
• lung transplantation is a potential option for refractory PH

CLASSIFICATION AND CAUSES

PH is classified by the World Symposia on Pulmonary Hypertension (WSPH) into 5 groups, with distinct clinical, haemodynamic, pathological, and therapeutic characteristics (Simmonaeu et al, 2019).

1. Pulmonary arterial hypertension

• 1.1 Idiopathic
• 1.2 Heritable
  • 1.2.1 BMPR2 mutation
  • 1.2.2 Other mutations
• 1.3 Drugs and toxins induced
• 1.4 Associated with:
  • 1.4.1 Connective tissue disease
  • 1.4.2 HIV
  • 1.4.3 Portal hypertension
  • 1.4.4 Congenital heart disease (subgroups: Eisenmenger syndrome, left-to-right shunts, coincidental or small defects and post-operative/closed defects)
  • 1.4.5 Schistosomiasis
• 1.5 PAH long-term responders to calcium channel blockers
• 1.6 PAH with overt features of venous/capillaries involvement (pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH))
• 1.7 Persistent PH of the newborn syndrome

2. Pulmonary hypertension due to left heart disease

• 2.1 Left ventricular systolic dysfunction
• 2.2 Left ventricular diastolic dysfunction
• 2.3 Valvular disease obstruction and congenital cardiomyopathies
• 2.4 Congenital/ acquired left heart inflow/ outflow tract obstruction and congenital cardiomyopathies
• 2.5 Congenital /acquired pulmonary veins stenosis

Pulmonary hypertension due to lung diseases and/or hypoxia

• 3.1 Chronic obstructive pulmonary disease
• 3.2 Interstitial lung disease
• 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern
• 3.4 Sleep-disordered breathing
• 3.5 Alveolar hypoventilation disorders
• 3.6 Chronic exposure to high altitude
• 3.7 Developmental lung diseases (Web Table III)

4. Chronic thromboembolic pulmonary hypertension and other pulmonary artery obstructions

• 4.1 Chronic thromboembolic pulmonary hypertension
• 4.2 Other pulmonary artery obstructions
  • 4.2.1 Angiosarcoma
  • 4.2.2 Other intravascular tumors
  • 4.2.3 Arteritis
  • 4.2.4 Congenital pulmonary arteries stenoses
  • 4.2.5 Parasites (hydatidosis)

5. Pulmonary hypertension with unclear and/or multifactorial mechanisms

• 5.1 Haematological disorders: chronic haemolytic anaemia, myeloproliferative disorders
• 5.2 Systemic and disorders: sarcoidosis, pulmonary histiocytosis, neurofibromatosis, glycogen storage disease, Gaucher disease
• 5.3 Others: fibrosing mediastinitis, chronic renal failure (with/without dialysis),
• 5.4 Complex congenital heart disease

Simonneau et al (2019) identify the following drugs and toxins associated with PAH (group 1.3):

Definite	Possible
Aminorex	Cocaine
Fenfluramine	Phenylpropanolamine
Dexfenfluramine	l-tryptophan
Benfluorex	St John’s wort
Methamphetamines	Amphetamines
Dasatinib	Interferon-α and -β
Toxic rapeseed oil	Alkylating agents
	Bosutinib
	Direct-acting antiviral agents against hepatitis C virus
	Leflunomide
	Indirubin (Chinese herb Qing-Dai)

PATHOPHYSIOLOGY

Cardiac causes

• LA or LV disease -> ↑ LA pressure -> ↑ pulmonary venous pressure -> ↑ PAP -> ↑PVR
• L to right shunt will also cause high PVP

Respiratory causes

• hypoxic vasoconstriction increases pulmonary hypertension

Which leads to:

• vasoconstriction
• altered vascular endothelium and smooth muscle function
• cellular remodelling
• increased vascular contractility
• lack of relaxation in response to various endogenous vasodilators
• fibrosis of vascular tissue

DIAGNOSIS

Right heart catheterization is the gold standard investigation for diagnosis. Haemodynamic definitions of PH, from Simmonaeu et al, (2019), are:

Definitions	Characteristics	Clinical groups
Pre-capillary PH	mPAP >20 mmHg PAWP ≤15 mmHg PVR ≥3 WU	1, 3, 4 and 5
Isolated post-capillary PH (IpcPH)	mPAP >20 mmHg PAWP >15 mmHg PVR <3 WU	2 and 5
Combined pre- and post-capillary PH (CpcPH)	mPAP >20 mmHg PAWP >15 mmHg PVR ≥3 WU	2 and 5

Severity

• Mild = 20-40mmHg
• Moderate = 41-55mmHg
• Severe = > 55mmHg

Functional assessment

• I – no limitation on physical activity (no SOB, fatigue, chest pain or syncope)
• II – minimal limitation of physical activity (comfortable @ rest, but develop symptoms on normal physical activity)
• III – marked limitation of physical activity (comfortable @ rest but symptoms on less than normal activity)
• IV – unable to perform any physical activity, RHF, symptoms @ rest

ASSESSMENT

History

• Non-specific
  • progressive dyspnea (initially exertional)
• fatigue
• weakness
• chest pain (like angina)
• syncope or pre-syncope
• cough
• Symptoms of underlying causes (e.g. collagen disease, valve pathology, VTE, OSA, alcohol consumption, chronic respiratory disease)
• Progressive right heart failure occurs later or in accelerated disease
• Rarely
  • haemoptysis
  • Ortner’s syndrome/hoarseness (unilateral vocal chord paralysis)
  • arrhythmias

Examination

• prominent ‘a’ wave
• augmented P2 heart sound (palpable in severe cases)
• right heart failure – increased JVP and jugular distention (large V waves), hepatojugular reflux, parasternal heave (RV lift), tricuspid or pulmonary regurgitant murmur, S3 gallop, hepatomegaly, ascites, splenomegaly, peripheral oedema
• other signs of CHF
• hypoxaemia

INVESTIGATIONS

Bedside

• ECG
  • A normal ECG does not exclude PH
  • Findings may include: RVH, RAD, p-pulmonale, tall R waves in V1, right ventricular strain
• ABG (hypoxia, acidosis, lactate)

Laboratory

• Cardiac biomarkers (N-terminal pro-brain natriuretic peptide/brain natriuretic peptide, troponin)
• Electrolytes and renal function (estimated glomerular filtration rate, urea, uric acid)
• Liver function (aminotransferases, bilirubin)
• Inflammation/infection (C-reactive protein, procalcitonin)
• Tissue damage or hypoxia (blood gases, lactate)
• Screening for connective tissue disease (CTD), hepatitis and HIV

Imaging

• Echocardiography
  • estimation of PAP (less accurate than right heart catheterisation)
  • Right and left ventricle function, valve function, pericardial effusion
  • Rule out other conditions mimicking right ventricular failure, such as pericardial tamponade
• V/Q scan or CTPA: suspected pulomnary embolism
• high resolution CT: parenchymal disease suspected
• CXR – RVH on lateral (loss of retrosternal space), prominent pulmonary vasculature

Special tests

• iNO provocation test: if lowers PA pressure -> Ca2+ antagonists may be helpful
• pulmonary function tests and DLCO: mild restrictive disease is common; DLCO <60% in pulmonary venous disease
• Cardiopulmonary exercise testing (CPET) (severity of exercise limitation and prognosis)
• Right heart catheterisation (considered mandatory for diagnosis of PH)

MANAGEMENT

Resuscitation

• CPR is often not appropriate in patients with severe PH, endeavour to address goals of care early
• Address life threats by attempting to:
  • optimize PAP
  • optimise RV preload
  • decrease RV afterload
  • avoid RV ischaemia and failure

Specific therapy

• treat underlying cause
  • e.g. pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension (CTEPH)
• treatments for PH:
  • prostanoids (e.g. epoprostenol/ prostacyclin)
  • phosphodiesterase type 5 inhibitors (e.g. sildenafil)
  • endothelin receptor antagonists (e.g. bosentan)
• refer/ consider if appropriate candidate for lung transplantation

Management of PH with right heart failure

• avoid intubation and positive pressure ventilation (including NIV) if possible
• optimise fluid status
  • usually requires fluid removal to prevent RV distention compromises LV function
    • diuretics (e.g. frusemide)
    • Renal replacement therapy
• decrease RV afterload, options include:
  • inhaled nitric oxide (iNO)
    • e.g. via high flow nasal prongs, NIV, or if intubated
    • 20-40ppm
    • doesn’t tend to cause systemic hypotension as inactivated when bound to Hb
  • prostacyclin
    • inhaled: 50mcg in saline nebulised every hour OR 50ng/kg/min nebulised into inspiratory limb
    • intravenous: 4-10ng/kg/min
  • other PH medications (e.g. oral phosphodiesterase type 5 inhibitors and endothelin receptor antagonists)
• optimise cardiac output using inotropes, eg:
  • milrinone
  • dobutamine
• optimise blood pressure with vasopressors:
  • noradrenaline if low dose (may exacerbate pulmonary hypertension at higher doses)
  • vasopressin (appears to spare the pulmonary circulation better than noradrenaline)
• if realistic options, consider VA ECMO (or temporary RVAD) – ideally in an awake, non-intubated, spontaneously breathing patient – as bridge to:
  • lung transplantation
  • recovery

Supportive care and monitoring

• Routine ICU level monitoring (T, ECG, invasive BP, SpO2, RR, CVP, ETCO2 if intubated)
• Complex cases may be managed with pulmonary artery catheterisation
• Where possible avoid factors that exacerbate pulmonary hypertension and right heart failure including:
  • hypoxia (e.g. SpO2 <90%)
  • acidaemia (including hypercapnia)
  • raised intrathoracic pressure (e.g. high PEEP)
  • hypothermia
  • dysrhythmias
  • infection (consider gut translocation in right heart failure)
  • VTE
  • pain
  • anaemia
• Consider transition to comfort measures if not responsive to standard therapies and not a candidate for lung transplantation (and ECMO)
• Multi-disciplinary team approach

References

LITFL

• CCC — Pulmonary Hypertension Echocardiography
• Paul Young’s ICU Mind Maps — Pulmonary Hypertension (pdf)
• Wiesbauer F. Hypertension. Medmastery

Journal articles

• Bassily-Marcus AM, Yuan C, Oropello J, Manasia A, Kohli-Seth R, Benjamin E. Pulmonary hypertension in pregnancy: critical care management. Pulmonary medicine. 2012:709407. 2012. [pubmed] [free full text]
• Galiè N, McLaughlin VV, Rubin LJ, et al. An overview of the 6th World Symposium on Pulmonary Hypertension. Eur Respir J 2019;53:1802148. 10.1183/13993003.02148-2018 [PMC free article] [PubMed]
• Gille J, Seyfarth HJ, Gerlach S, Malcharek M, Czeslick E, Sablotzki A. Perioperative anesthesiological management of patients with pulmonary hypertension. Anesthesiology research and practice. 2012:356982. 2012. [pubmed] [free full text]
• Hoeper MM, Benza RL, Corris P, et al. . Intensive care, right ventricular support and lung transplantation in patients with pulmonary hypertension. Eur Respir J 2019; 53: 1801906. [PMC free article] [PubMed] 
• Hill NS, Roberts KR, Preston IR. Postoperative pulmonary hypertension: etiology and treatment of a dangerous complication. Respiratory care. 54(7):958-68. 2009. [pubmed] [free full text]
• McCann C, Gopalan D, Sheares K, Screaton N. Imaging in pulmonary hypertension, part 1: clinical perspectives, classification, imaging techniques and imaging algorithm. Postgraduate medical journal. 88(1039):271-9. 2012. [pubmed] [free full text]
• McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: A report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: Developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009;119:2250–94. [PubMed] 
• Price LC, Wort SJ, Finney SJ, Marino PS, Brett SJ. Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. Critical care (London, England). 14(5):R169. 2010. [pubmed] [free full text]
• Price LC, McAuley DF, Marino PS, Finney SJ, Griffiths MJ, Wort SJ. Pathophysiology of pulmonary hypertension in acute lung injury. American journal of physiology. Lung cellular and molecular physiology. 302(9):L803-15. 2012. [pubmed] [free full text]
• Simonneau G, Montani D, Celermajer DS, et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur Respir J 2019;53:1801913. 10.1183/13993003.01913-2018 [PMC free article] [PubMed]
•  Vonk Noordegraaf A, Chin KM, Haddad F, et al. . Pathophysiology of the right ventricle and of the pulmonary circulation in pulmonary hypertension: an update. Eur Respir J 2019; 53: 1801900. [PMC free article] [PubMed]