Pulmonary Hypertension: Pathophysiology and Manipulation of Pulmonary Vascular Resistance

Definition and Haemodynamic Classification

• Pulmonary hypertension (PH) is defined as a resting mean pulmonary artery pressure (mPAP) > 20 mmHg measured by right heart catheterisation.
• Understanding the normal pulmonary haemodynamic profile is essential before considering pathological deviation.

Normal Pulmonary Vascular Pressures

• The pressure gradient driving flow across the pulmonary circulation is only approximately 9 mmHg (mPAP minus pulmonary venous pressure), illustrating how the pulmonary circuit is a low-resistance, high-compliance system.
• The PAOP (wedge pressure) is typically 2-3 mmHg higher than true left atrial pressure.

Pulmonary Vascular Resistance Formula

$$PVR = \frac{mPAP - PAOP}{CO} \times 80$$

• Where PVR is expressed in dyn·s·cm$^{-5}$ (normal ~100-200 dyn·s·cm$^{-5}$), CO is cardiac output in L/min, and pressures are in mmHg.
• The transpulmonary gradient (TPG = mPAP − PAOP) is often a more clinically meaningful index, as it is less confounded by elevated left-sided filling pressures.

Pathophysiology of Pulmonary Hypertension

Vascular Tone and Vasoconstriction

• The pulmonary vasculature is a dynamically regulated, compliant circuit.
• Normal vascular tone is maintained by a balance between vasodilatory mediators (nitric oxide, prostacyclin) and vasoconstrictive mediators (endothelin-1, thromboxane A2, serotonin).
• In PH, this balance shifts towards vasoconstriction and vascular remodelling.

The NO-cGMP Pathway

Nitric oxide (NO) is a key endogenous pulmonary vasodilator synthesised in endothelial cells. Its mechanism:

1. NO diffuses into vascular smooth muscle cells
2. Activates soluble guanylyl cyclase (sGC) → converts GTP to cyclic GMP (cGMP)
3. Elevated cGMP activates protein kinase G → smooth muscle relaxation and vasodilation

• In health, cGMP is degraded by phosphodiesterase type 5 (PDE5), which is enriched in the pulmonary vascular bed relative to the systemic circulation.
• In PH, endothelial dysfunction leads to reduced NO bioavailability, decreased cGMP signalling, and unopposed vasoconstriction.

The Endothelin Pathway

Endothelin-1 (ET-1), a potent vasoconstrictor and mitogen, acts via $ET_A$ and $ET_B$ receptors on pulmonary vascular smooth muscle. In PH, ET-1 levels are elevated and contribute to:

• Vasoconstriction
• Vascular smooth muscle hypertrophy and proliferation
• Vascular remodelling

$ET_B$ receptor effects predominate in the clinical context, and antagonism reduces pulmonary artery pressure.

Vascular Remodelling

Beyond vasoconstriction, chronic PH involves structural changes:

• Smooth muscle hypertrophy and intimal proliferation in arterioles
• Adventitial fibrosis
• In-situ thrombosis
• Formation of plexiform lesions (characteristic of severe idiopathic PAH)

These structural changes render some component of elevated PVR irreversible, differentiating "reactive" (vasoreactive) from "fixed" PH.

Hypoxic Pulmonary Vasoconstriction (HPV)

• Unique to the pulmonary circulation, HPV is a protective reflex redirecting blood away from poorly ventilated alveoli to preserve V/Q matching.
• Unlike systemic vessels, pulmonary arterioles constrict in response to alveolar hypoxia.
• Chronic hypoxia (e.g. COPD, altitude) causes sustained HPV, vascular remodelling, and progressive PH.
• This can be compounded by hypercapnia and acidosis, which are independent pulmonary vasoconstrictors.

Classification (WHO Groups)

Right Ventricular Consequences

Progressive elevation in PVR imposes afterload on the right ventricle (RV). The thin-walled RV is poorly adapted to acute pressure overload:

• Acute massive increase → acute RV failure, reduced RV stroke volume, septal shift → LV underfilling → cardiovascular collapse
• Gradual rise → RV hypertrophy, dilation, and eventual failure
• Elevated mPAP propagates to elevated right atrial pressure and systemic venous hypertension.
• If pulmonary artery pressures rise gradually, the RV may adapt through remodelling but will ultimately fail.
• Acute decompensation is common perioperatively.

Monitoring of Pulmonary Haemodynamics

Pulmonary Artery Catheter (PAC)

The Swan-Ganz catheter remains the gold standard for direct measurement of pulmonary haemodynamics. It allows measurement of:

• mPAP and its components
• PAOP (estimate of LAP/LVEDP)
• Cardiac output (thermodilution)
• Derived PVR and SVR
• Limitations include procedural risks and the recognition that PAOP may not accurately reflect LVEDP in certain conditions (e.g. PEEP creating zone 1/2 conditions, mitral regurgitation, pulmonary veno-occlusive disease, pulmonary arterial hypertension itself where PADP > PAOP).
• The transpulmonary gradient (mPAP, PAOP) better reflects intrinsic pulmonary vascular disease, distinguishing pre-capillary from post-capillary PH.

Additional Monitoring Modalities

• Transoesophageal echocardiography (TOE): dynamic RV assessment, septal geometry, RV/LV ratio, pericardial effusion, volume status
• Transthoracic echo: estimated RVSP from tricuspid regurgitation jet ($4v^2$), RV hypertrophy/dilation
• Central venous pressure: crude marker of RV filling; elevated in RV failure

Methods to Manipulate Pulmonary Vascular Resistance

• Strategies to reduce PVR exploit the molecular pathways governing pulmonary vascular tone.
• Both pharmacological and physiological approaches are available to the anaesthetist.

Ventilatory and Physiological Strategies

Optimising ventilation is the most immediately accessible tool for the anaesthetist managing elevated PVR intraoperatively.

• Avoiding hypercarbia, hypoxia, acidosis, hypothermia, and pain are foundational.
• The relationship between lung volume and PVR is U-shaped: PVR is lowest at FRC because alveolar vessels are not compressed (over-inflation) and extra-alveolar vessels are not compressed (under-inflation).

Pharmacological Approaches: Pulmonary Vasodilators

Inhaled Nitric Oxide (iNO)

Mechanism: NO activates sGC in pulmonary vascular smooth muscle → elevated cGMP → vasodilation. Being inhaled, NO selectively dilates vessels in ventilated lung units, this is the key advantage:

• Redistributes blood flow from poorly ventilated (low V/Q) to well-ventilated areas
• Improves V/Q matching and oxygenation
• Minimal systemic effect as NO is rapidly inactivated by haemoglobin upon reaching the systemic circulation

Clinical indications: Neonatal hypoxic respiratory failure with PH, severe PAH, acute RV failure post-cardiac surgery, bridge to transplantation.

• Toxicity: Methemoglobinaemia (particularly at high doses or prolonged use).
• Abrupt discontinuation may cause rebound pulmonary vasoconstriction.

PDE5 Inhibitors (Sildenafil, Tadalafil)

• Mechanism: Inhibit PDE5 → prevent breakdown of cGMP → potentiate endogenous NO signalling.
• The relative enrichment of PDE5 in the pulmonary vasculature (versus systemic) accounts for their relative pulmonary selectivity.

Effect: Pulmonary vasodilation, reduction of mPAP and PVR, improved RV function.

• Administration: Oral.
• Onset minutes to hours (sildenafil faster onset).

Toxicity: Systemic hypotension (particularly combined with nitrates or iNO), priapism.

• Perioperative relevance: Patients with established PH are often already on sildenafil.
• Continuation perioperatively is important; oral absorption may be unreliable post-cardiac surgery and IV formulations or iNO may be needed.

sGC Stimulators (Riociguat)

• Mechanism: Directly stimulates soluble guanylyl cyclase (independently of NO), increasing cGMP production.
• Works even where endogenous NO is deficient.

Effect: Smooth muscle relaxation, pulmonary vasodilation.

• Toxicity: Hypotension, GI disturbance.
• Contraindicated with PDE5 inhibitors (synergistic hypotension) and nitrates.

Endothelin Receptor Antagonists (Bosentan, Ambrisentan, Macitentan)

• Mechanism: Competitively antagonise $ET_A$ and $ET_B$ receptors, with $ET_B$ effects predominating clinically → reduced PA pressure.
• May also slow vascular remodelling associated with chronic hypoxia.

Route: Oral.

Perioperative relevance: Significant hepatotoxicity and drug interactions (CYP450); continue perioperatively as abrupt cessation may precipitate PH crisis.

Prostanoids (Epoprostenol, Iloprost)

• Though not detailed in the available context, prostacyclin analogues are important agents: they activate adenylyl cyclase → increased cAMP → smooth muscle relaxation and antiproliferative effects.
• Epoprostenol (IV) and inhaled iloprost are used for severe PAH.

Calcium Channel Antagonists

• At lower doses, calcium channel blockers (nifedipine, diltiazem, amlodipine) reduce PVR in vasoreactive patients (identified by acute vasoreactivity testing at right heart catheterisation).
• At doses required for anti-PH effect, significant negative inotropy can worsen RV failure, a critical limitation in decompensated disease.

Pulmonary Vasoconstrictors

• Sympathomimetics with α-receptor activity (noradrenaline, phenylephrine, metaraminol) affect pulmonary and systemic vessels with similar potency.
• Vasopressin is notable for having no significant pulmonary vasoconstrictive effect while increasing systemic vascular resistance, making it potentially useful to maintain coronary perfusion pressure to the RV (which depends on the SVR-mPAP gradient) without worsening PH.
• This is an important nuance in managing RV failure complicating PH.

Anaesthetic Implications and Perioperative Management

Risk Stratification

PH carries significant perioperative risk:

• mPAP > 35 mmHg or PVR > 400 dyn·s·cm$^{-5}$ significantly elevates mortality
• RV function and reserve are the key determinants of outcome
• Classification (Group 1-5) guides management, particularly the distinction between pre-capillary (high TPG) and post-capillary (elevated PAOP, Group 2) disease

Goals of Anaesthetic Management

Specific Intraoperative Strategies

• Supplemental oxygen throughout; target $SpO_2$ > 94% to avoid HPV
• Avoidance of hypercarbia: controlled ventilation with normocarbia, avoid breath-holding and airway obstruction
• Adequate analgesia and depth: pain and light anaesthesia → sympathetic activation → PVR rise
• Lung-protective ventilation: tidal volumes 6-8 mL/kg IBW, PEEP titrated to FRC
• Continuation of pre-existing PH therapies: sildenafil, bosentan, epoprostenol, never abruptly cease
• Inhaled NO: available for acute intraoperative PH crisis (5-40 ppm), particularly post-cardiac surgery; monitor for methaemoglobinaemia
• Vasopressors: vasopressin preferred to maintain SVR without worsening PVR; noradrenaline may be used but raises both SVR and PVR
• Inotropes: dobutamine or milrinone (a PDE3 inhibitor with pulmonary vasodilatory properties) to support RV contractility

Crisis Management: Acute RV Failure / PH Crisis

An acute PH crisis (sudden mPAP spike, RV failure, cardiovascular collapse) is a perioperative emergency:

1. 100% oxygen: immediately reduces HPV contribution
2. Correct acidosis: hyperventilation, sodium bicarbonate if severe
3. Inhaled NO: immediate pulmonary vasodilation without systemic hypotension
4. Vasopressin/noradrenaline: restore RV coronary perfusion pressure (SVR > mPAP)
5. Inotropic support: milrinone, dobutamine for RV contractility
6. Consider ECMO: venoarterial ECMO as rescue if refractory; note ECMO itself does not reduce pulmonary vascular pressures
7. Avoid escalating PEEP: increases PVR

Monitoring Considerations

In patients with significant PH undergoing major procedures:

• Arterial line mandatory for continuous blood pressure and ABG monitoring
• Consider PAC (or TOE) for complex cases involving cardiac surgery or acute RV failure
• TOE provides real-time RV assessment, septal position (D-sign), volume status
• PAOP interpretation requires caution: PEEP may create zone 1-2 conditions leading to overestimation of PAOP; TPG more reliable in distinguishing pre- from post-capillary disease in the setting of PAH

The understanding that the pulmonary vasculature is highly responsive to physiological and pharmacological manipulation, particularly through the NO-cGMP-PDE5 pathway and endothelin axis, underpins rational perioperative management of this high-risk patient group.