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):

DefinitePossible
AminorexCocaine
FenfluraminePhenylpropanolamine
Dexfenfluraminel-tryptophan
BenfluorexSt John’s wort
MethamphetaminesAmphetamines
DasatinibInterferon-α and -β
Toxic rapeseed oilAlkylating 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:

DefinitionsCharacteristicsClinical groups
Pre-capillary PHmPAP >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

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

CCC 700 6

Critical Care

Compendium

Chris is an Intensivist and ECMO specialist at the Alfred ICU in Melbourne. He is also the Innovation Lead for the Australian Centre for Health Innovation at Alfred Health and Clinical Adjunct Associate Professor at Monash University. He is a co-founder of the Australia and New Zealand Clinician Educator Network (ANZCEN) and is the Lead for the ANZCEN Clinician Educator Incubator programme. He is on the Board of Directors for the Intensive Care Foundation and is a First Part Examiner for the College of Intensive Care Medicine. He is an internationally recognised Clinician Educator with a passion for helping clinicians learn and for improving the clinical performance of individuals and collectives.

After finishing his medical degree at the University of Auckland, he continued post-graduate training in New Zealand as well as Australia’s Northern Territory, Perth and Melbourne. He has completed fellowship training in both intensive care medicine and emergency medicine, as well as post-graduate training in biochemistry, clinical toxicology, clinical epidemiology, and health professional education.

He is actively involved in in using translational simulation to improve patient care and the design of processes and systems at Alfred Health. He coordinates the Alfred ICU’s education and simulation programmes and runs the unit’s education website, INTENSIVE.  He created the ‘Critically Ill Airway’ course and teaches on numerous courses around the world. He is one of the founders of the FOAM movement (Free Open-Access Medical education) and is co-creator of litfl.com, the RAGE podcast, the Resuscitology course, and the SMACC conference.

His one great achievement is being the father of two amazing children.

On Twitter, he is @precordialthump.

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