Cardiac catheterization in pulmonary arterial hypertension: Tips and tricks to enhance diagnosis and guide therapy

Abstract

Cardiac catheterization (CC) is essential for the diagnosis of pulmonary hypertension (PH), and for its characterisation. It allows distinction between pre- and post-capillary PH which, when integrated with other non-invasive data, facilitates classification into one of the 5 diagnostic groups defined by international PH guidelines. CC also provides valuable information for the risk stratification of patients with PH, guiding management and the type and intensity of treatment. Right heart catheterization is usually sufficient in PH practice, yet additional information can be acquired by extending the protocol to include left heart catheterization or provocation protocols.

This review provides a detailed overview of diagnostic CC as used in PH practice, including in patients with congenital heart disease, with an emphasis on fundamental concepts, tips and tricks and potential pitfalls.

Abbreviations

ABG

arterial blood gas

ASD

atrial septal defect

BPA

balloon pulmonary angioplasty

BSA

body surface area

CC

cardiac catheterization

CCB

calcium channel blocker

CHD

congenital heart disease

CHD-associated PH

congenital heart disease-associated pulmonary hypertension

CI

cardiac index

CO

cardiac output

CT

computed tomography

CTEPH

chronic thromboembolic pulmonary hypertension

Ea

arterial elastance

Ees

end-systolic elastance

FHVP

free hepatic venous pressure

IJVA

internal jugular venous access

IVC

inferior vena cava

L-R

left-right

LA

left atrium/left atrial

LPA

left pulmonary artery

LVEDP

left ventricular end-diastolic pressure

mPAP

mean PAP

MVO₂

mixed venous oxygen saturation

NO

nitric oxide

PA

pulmonary artery

PAH

pulmonary arterial hypertension

PaO₂

partial pressure of oxygen in arterial blood

PAP

pulmonary arterial pressure

PAPVR

partial anomalous pulmonary venous return

PAWP

pulmonary arterial wedge pressure

PH

pulmonary hypertension

PoPH

porto-pulmonary hypertension

PVR(I)

(indexed) pulmonary vascular resistance

Qp

pulmonary blood flow

Qs

systemic blood flow

Qp/Qs

ratio between pulmonary and systemic blood flow

RA

right atrium/right atrial

RHC

right heart catheterization

RPA

right pulmonary artery

RV

right ventricle/right ventricular

RVOT

right ventricular outflow tract

SaO₂

arterial oxygen saturation

SVC

superior vena cava

SVI

stroke volume index

TAPSE

tricuspid annular plane systolic excursion

US

ultrasound

VO₂

oxygen consumption

V/Q

ventilation/perfusion

WHVP

wedged hepatic venous pressure

1. Introduction

Invasive haemodynamic assessment is one of the oldest, yet most relevant investigations in cardiology. Cardiac catheterization (CC) was in use well before the advent of echocardiography and was the means of confirming diagnoses developed through detailed history taking, careful clinical examination, electrocardiography, and chest radiography. Despite major advances in imaging and other non-invasive diagnostic modalities over recent decades, CC has several indications in contemporary clinical practice. These include the reliable assessment of intracardiac pressures, detection and quantification of haemodynamic lesions, shunts, differentiating between causes of exercise intolerance and congestive heart failure, risk stratification and quantification of the response to treatment. Diagnostic CC, and in particular right heart catheterization (RHC), has received growing attention as a result of recent advances in the care of patients with pulmonary hypertension (PH), especially those with pulmonary arterial hypertension (PAH) or chronic thromboembolic PH (CTEPH). CC also retains a prominent role in congenital heart disease (CHD) practice.

From a technical point of view, diagnostic CC may appear straightforward, especially when compared to complex modern interventional procedures, yet it is often the case that few operators have maintained the expertise and rigour to acquire reliable and easily interpretable information, upon which clinical management relies. In this paper, we provide a detailed overview of diagnostic CC as used in PH practice, including in patients with CHD, with an emphasis on fundamental concepts, tips and tricks and potential pitfalls.

2. Indications for CC in PH and CHD practice

The following are common indications for performing CC for a patient within a PH, a CHD, or a transplant service:

• •Establishing the diagnosis of PH, differentiating between pre- and post-capillary haemodynamics and assisting in the correct allocation of patients within the International PH classification, which is essential for guiding management [1].
• •Identification and quantification of intracardiac shunts and their haemodynamic impact on the pulmonary circulation.
• •Assessment of candidacy for cardiac transplantation, with particular attention to pulmonary haemodynamics that, if abnormal, can become a contraindication to heart-only transplantation [2].
• •Assessment of haemodynamics in patients who had undergone cardiac transplantation, and who exhibit signs or symptoms suggestive of cardiac allograft rejection [3].
• •Quantification of valvular or vascular lesions, obstructive and regurgitant (e.g. valvular stenosis or regurgitation, aortic coarctation, peripheral pulmonary artery stenosis, cor triatriatum, pulmonary vein stenosis, pathway stenosis in the context of a previous Mustard procedure of transposition of the great arteries, or surgical conduit narrowing) and their impact on filling pressures, cardiac output (CO), and pulmonary haemodynamics.
• •Assessment of portal pressures, through the measurement of wedged hepatic venous pressure (WHVP) (e.g. when porto-pulmonary hypertension, PoPH, is suspected) [4].
• •Acute haemodynamic challenge with fluids, pulmonary vasodilators, temporary balloon occlusion of shunts, challenge with milrinone and/or sodium nitroprusside in certain instances of heart transplant assessment [5].
• •Assessment of exercise haemodynamics (exercise RHC).
• •Assessment of the effect of treatments (e.g. PAH therapies, previous CHD repair, valve repair or replacement) on haemodynamics, including PH.
• •Angiography to assess the coronary arteries or pulmonary circulation (e.g. in patients with CTEPH in preparation for pulmonary endarterectomy or balloon pulmonary angioplasty, BPA), and in the assessment of various types of CHD.

In PH practice, most patients only require RHC, with the addition of pulmonary angiography in CTEPH. Arterial access for left-heart catheterization is rarely required, unless:

• •Coronary angiography is needed, though low-risk patients with suspected coronary artery disease nowadays mainly undergo computed tomography (CT) coronary angiography and are referred to interventional cardiology for further assessment and treatment [6].
• •A reliable pulmonary arterial wedge pressure (PAWP) cannot be obtained and left ventricular end-diastolic pressure (LVEDP) is needed.
• •Left-sided congenital or other obstructive lesions are present (e.g. pulmonary vein stenosis, cor triatriatum sinister or mitral stenosis) and invasive assessment of their impact on haemodynamics is required. In these cases, the increase in the PAWP does not reflect an elevated LVEDP, as it is caused by a more proximal obstruction. Therefore, both PAWP through RHC and LVEDP from an arterial approach are required to measure the gradient.

3. A standardized RHC protocol

To promote standardization of the procedure, the RHC protocol should cover several requirements in different settings:

• •
  Pre-procedure:

  • o
    Review indications for the procedure and acquire informed written consent, after having explained to the patient the aim of the procedure, its steps, alternative investigations, potential complications, and the peri- and post-procedural management.
  • o
    Specific medication management, like bridging anticoagulation if necessary, interrupting metformin if medium contrast is expected or sodium-glucose cotransporter-2 (SGLT2) inhibitors if sedation/general anaesthesia is planned, or avoiding vasodilators and excessive use of diuretics which may falsely underestimate pulmonary pressures [7]. Notably, the management of anticoagulated patients around CC differs depending on whether arterial access may be needed.
• •
  Peri-procedure:

  • o
    View recent blood test results which should include full blood count, blood group, renal function when contrast is required, clotting profile for patients on anticoagulants, and β-HCG for women of child-bearing age.
  • o
    Use of a WHO checklist with briefing and debriefing for each case and also for the catheter session (see below).
  • o
    A patient-tailored approach regarding sedation, analgesia, intraprocedural discomfort prevention, choice of access route and need for oxygen (oxygen supplementation should be avoided unless not possible to do so).
• •
  Post-procedure:

  • o
    Care of access site, monitoring for adequate and stable haemostasis.
  • o
    Reestablishment of anticoagulation.
  • o
    Monitoring for other complications, especially in frail or older individuals, or in patients with significant comorbidities.
  • o
    Safe mobilisation and discharge planning.

The WHO checklist is a core set of safety checks, which should be carried out for all patients in surgical theatres and catheterization labs [8]. Its steps are summarized in Table 1.

Table 1.

WHO checklist.

	Morning team brief	Time out	Sign out	Debrief
When?	Beginning of day	When patients enter the catheter lab	End of procedure	End of the day
What?	•Members' introduction •Patient list overview • Equipment assessment: - vascular access devices - diagnostic catheters - blood gas and saturation analysers - reversibility agents - metabolic systems - exercise/fluid challenge	•Confirmation of patient's identity •Confirmation of the intended procedure •Other pre-procedural checks (e.g. allergies, pregnancy test etc.)	• Post-procedural instructions to the ward team regarding: - access-site care - need for vital sign monitoring - reinitiation of anticoagulation - plans for ward review - plans for discharge	•List overview •What went well? • What went wrong, what can be improved: - complications - lack of equipment - staffing issues - delays
Why?	•Avoid miscommunication •Avoid delays and incomplete investigation •Enhance team performance	•Perform the right procedure in the right patient •Avoid complications •Avoid or prepare for adverse events	•Manage patients effectively	•Identify areas of improvement •Drive change

4. RHC steps and acquisition of pressures and saturations

4.1. Vascular access

Venous access depends on operator preference and anatomical characteristics, procedural needs, and anticoagulation status. Femoral, neck or arm access can be used interchangeably, with pros and cons for each:

• •Femoral access is more familiar to cardiologists and allows access with larger sheaths/catheters, or multiple catheters (e.g. when assessing tricuspid stenosis or performing temporary balloon occlusion of an atrial septal defect, ASD). However, femoral access carries the risk of accidental arterial puncture, which is reduced if ultrasound (US) guidance is used. Manipulation of balloon-tipped or other catheters towards the pulmonary arteries (PAs) can be more laborious compared to upper body access, often requiring the use of a hydrophilic guide. For this reason and for the risk of arterial puncture, fluoroscopy is essential when choosing this approach. A couple of hours of bed rest are typically needed before mobilisation, after a RHC from this approach.
• •Internal jugular venous access (IJVA) is more familiar to intensivists and provides a cleaner large access, with easy advancement of the catheter to the PAs. It can be performed at patients' bedside, with no requirement of ionizing radiations. It does also carry the risk of accidental arterial puncture which, unlike the femoral access, is not as easily compressible and can rarely lead to significant complications. However, this risk is low in experienced hands and with the use of US guidance. Mobilisation after the RHC is easier compared to a femoral approach.
• •Venous access through the arm is increasingly used and can either be through the cephalic or basilica vein, with US guidance (especially for the latter). Like IJVA, catheter advancement to the PAs is typically straightforward. Arm access may limit the size of catheter used, making it less feasible in case of short stature/low body surface area (BSA), though sheaths up to 7F for basilica access and 6F for cephalic access are typical. A hydrophilic wire and the use of fluoroscopy may be needed for overcoming tortuous anatomy in the shoulder region, especially with cephalic access. Additionally, a venogram may be performed in case of difficulty in advancing the catheter. Therefore, this approach may not be suitable if there are contraindications to the use of contrast media (e.g. allergy, chronic kidney disease).

4.2. Difficulties in reaching the pulmonary arteries and other structures

Difficulties are often encountered during RHC when advancing a catheter towards the pulmonary circulation and include:

• •Catheters inserted through the femoral access can often enter collateral veins, especially in the pelvic area. Attention is required to avoid injury (through excessive force or inflation of a balloon in a small vessel) or kinking of the catheter and the creation of a large loop that may be difficult to straighten. When smaller catheter loops are formed, these can be straightened in the right atrium (RA), often with the help of a wire, avoiding the formation of knots. A looped catheter should not be pulled back to the sheath without fluoroscopy, to avoid kinks that may make catheter removal difficult or traumatic.
• •Catheters inserted from the arm may become stuck at shoulder level (e.g. where the cephalic vein drains into the subclavian vein, or within collaterals). Moreover, the catheter may take a route towards the head rather than the heart. Fluoroscopic guidance and the use of a hydrophilic guidewire may easily overcome such issues. Injection of a small amount of contrast through the catheter can clarify the anatomy, when needed.
• •Access to the inferior vena cava (IVC) for saturation sampling or WHVP can be difficult when using an upper body approach. This problem can be easily overcome by advancing a guidewire while keeping the catheter within the superior vena cava (SVC).
• •SVC access for saturation sampling is recommended to obtain a reliable mixed venous oxygen saturation (MVO₂) and for excluding shunts (e.g. sinus venosus ASD ± partial anomalous pulmonary venous return (PAPVR) to the SVC). Balloon-tipped catheters advanced from a femoral access require careful manipulation in the RA with, typically, anticlockwise rotation to align the catheter to the SVC (as opposed to clockwise when wishing to advance towards the right ventricle).
• •The most difficult step for achieving PA access from a femoral approach involves advancing the catheter from the right ventricular (RV) inlet towards the RV outflow tract (RVOT). This can be achieved by inflating the balloon and gentle clockwise rotation of the catheter to align with the RVOT. Alternatively, a careful loop can be created in the RA, in such a way that the tip of the catheter points towards the RVOT as soon as it enters the RV. In both instances, a guidewire can be used to either provide more support (“body”) and straighten the tip of the catheter, or be carefully advanced ahead of the catheter, avoiding injury to the tricuspid valve or RV and monitoring for ventricular arrhythmia.
• •Balloon-tipped catheters advanced through an upper body access preferentially enter the right PA. If the left PA (LPA) needs to be accessed (e.g. for obtaining alternative PAWP measurements), the catheter should be placed in the RVOT or proximal PA and a wire can be used that will typically advance towards the LPA. Femoral access usually results in LPA access.

5. Acquisition and interpretation of pressures and saturations

5.1. Pressures

Pressure measurements should always be preceded by careful zeroing of transducers at mid-chest level (Fig. 1). Right atrial (RA) pressures should identify the mean and all components of the waveform, including the a and v waves (Fig. 2). A very low mean RA pressure usually reflects dehydration or an incorrect zeroing (e.g. transducer higher than the chest). Increased mean RA pressure in patients with PH typically reflects RV dysfunction and raised RV end-diastolic pressure. A prominent a wave is often present, while a prominent v wave is not uncommon when significant tricuspid regurgitation has developed. Additional information can be acquired by examining the x and y descents (e.g. RV restriction).

Fig. 1.

Transducer setup. Impact of transducer height on pressure readings. The transducer should be zeroed at midthoracic level, halfway between the anterior sternum and the bed surface. If the transducer is placed too high, the pressures measured at the level of the mid-chest will be falsely lower. Conversely, if the transducer is placed too low, the pressures measured at the mid-chest level will be falsely higher.

Fig. 2.

Right atrial pressure waveform. a – Atrial systole. c – Closure of tricuspid valve. x – Downward movement of the tricuspid valve. v - Rapid filling of the right atrium. y – Opening of the tricuspid valve.

The most relevant RV pressure values are the peak systolic and end-diastolic (Table 2). The former should be similar to systolic PA pressure (in the absence of pulmonary stenosis) and the latter should be similar to mean RA pressure (Fig. 3). The mean RA pressure and RV end-diastolic pressure are important parameters in PH, especially when associated with severe heart failure, as they provide important information on RV preload.

Table 2.

Normal values for pressures measured during cardiac catheterization.

Parameter	Normal values	Notes
Central venous pressure	2–6 mmHg	Influenced by state of hydration
Right atrial (RA) pressure, mean	≤6 mmHg	Influenced by state of hydration
Right ventricular (RV) pressure
Systolic	≤30 mmHg
End-diastolic	≤8 mmHg
Pulmonary artery pressure
Systolic	≤30 mmHg
Mean	≤20 mmHg	Ideally taken at end-expiratory unless large respiratory swing
Diastolic	≤12 mmHg
Pulmonary artery wedge pressure (PAWP)	≤12 mmHg	≤15 mmHg for precapillary PH Influenced by state of hydration Consider fluid challenge if ≤ 15 mmHg but clinical suspicion of left ventricular (LV) diastolic dysfunction
Left atrial (LA) pressure, mean	≤12 mmHg	Preferred when ASD is present
LV end-diastolic pressure	≤12 mmHg	Required when no reliable PAWP or LA pressure can be obtained
Pulmonary vascular resistance (PVR)	≤2 WU
PVR indexed (for average BSA 1.7 m2)	≤3.5 WU x m2
Cardiac Output (CO)	4–8 L/min
Cardiac Index (CI)	2.5–4 L/min/m2
Mixed venous (MV) saturation	65–80 %	When low it suggests low CO If pulmonary artery saturations>75 %, perform serial oximetry to exclude a step-up from MV to pulmonary artery, if not doing so already

Most values are influenced by the status of hydration of the patient, especially central venous pressure, RA pressure, and LA pressure/PAWP.

WU = Wood units.

Fig. 3.

Right ventricular and pulmonary artery pressure waveforms. IVC= Isovolumic contraction. IVR = Isovolumic relaxation.

PAWP is a surrogate of left atrial (LA) pressure. Direct LA pressure cannot usually be obtained unless an ASD is present. PAWP involves the use of a balloon-tipped end-hole catheter (Swan-Ganz). With the balloon inflated in a large PA, the catheter is advanced until it wedges into a smaller PA branch. This generates a “static column of blood” in that vessel, which extends across the respective arterioles, capillaries and venules into the larger pulmonary veins where blood ceases to be static thanks to the return from other lung segments. As the pressure inside a static fluid is the same in all directions, the pressure measured at the tip of the catheter reflects the pressure in the pulmonary vein draining that lung segment. Thus, the pressure measured at the tip of the catheter is equivalent to the LA pressure, unless a pulmonary venous stenosis is present (Fig. 4).

Fig. 4.

Measurement of wedge pressure and impact of obstruction. Impact of fixed obstruction and stenosis on wedge pressure measurement. The inflated balloon into a small PA branch generates a static column of blood across arterioles, capillaries and venules. Stenoses within the static column of blood (wide white arrow) cannot be detected by the PAWP. Conversely, stenoses in larger pulmonary veins (thin black arrow) do have an impact on wedge pressure.

Understanding the principle behind PAWP is important for avoiding pitfalls. Stenoses within the static column of blood (e.g. at the level of the pulmonary venules, as in pulmonary veno-occlusive disease) cannot be detected by the PAWP, which only reflects pressure in the larger pulmonary veins. Partial occlusion (a partially wedged balloon) will allow pressure from the PA to reach the tip of the catheter, overestimating LA pressure. It is important to observe the pressure waveform change as the catheter is moved from the PA to the PAWP position, obtaining the expected waveforms described for the RA.

Over-wedging is a phenomenon commonly observed, where the pressure rises when the balloon wedges, often to pressures higher than those of the PA. In such cases, partial release of the balloon may help obtain an adequate waveform.

It is important never to pull the catheter back while the balloon is inflated, especially in the wedge position where damage to the vessel can be catastrophic (e.g. causing rupture and haemoptysis). The same is true for the tricuspid valve, which can be damaged by forceful withdrawal of an inflated balloon.

Significant respiratory variation can be observed in both the RA and LA pressures, and occasionally in pulmonary arterial pressure (PAP) in patients with significant lung disease or obesity. Guidelines recommend measurement of pressures, especially PAWP, at end expiration without breath-holding, ideally averaging over ≥4 respiratory cycles. When excessive variability is observed or values appear implausible, it is recommended to measure LV end-diastolic pressure (if left heart access possible). Many centres do, in such cases, use the electronic mean (e.g. ignoring the respiratory cycle), though there is a risk of underestimating PAWP [1,9].

It is recommended that non-invasive aortic pressure and saturation (pulse oximetry) are documented since they cannot be measured invasively unless arterial access (or puncture) is obtained.

5.2. Oxygen saturations

Serial oximetry is recommended during RHC and should typically include measurements from the high and low SVC, IVC, mid-RA, RV, and PA. Oxygen saturation is used for:

• •Estimating MVO₂, typically calculated as (3xSVC + IVC)/4. This formula supports the notion that SVC saturation carries a far greater weight in determining MVO₂ compared to the IVC, which is why many experts use SVC saturation alone.
• •Detecting and quantifying shunts. A “step-up” in saturations should be investigated as a sign of a left-right (L-R) shunt. The shunt fraction, i.e. the ratio between pulmonary and systemic blood flow (Qp/Qs), is assessed using the following formula:

$$\frac{\mathit{Q}\mathit{p}}{\mathit{Q}\mathit{s}}=\frac{\left({\mathit{A}\mathit{o}\mathit{O}}_{\mathbf{2}}–{\mathit{M}\mathit{V}\mathit{O}}_{\mathbf{2}}\right)}{\left({\mathit{P}\mathit{V}\mathit{O}}_{\mathbf{2}}-{\mathit{P}\mathit{A}\mathit{O}}_{\mathbf{2}}\right)}$$

where AoO₂₌ systemic arterial saturation, PAO₂ = saturation in the PA, and PVO₂ = saturation in the pulmonary veins.

• •Calculation of cardiac output (CO) with the Fick principle, using the formula below:

$$\mathit{C}\mathit{O}=\frac{{\mathit{V}\mathit{O}}_{\mathbf{2}}}{\left(\mathit{C}\mathit{a}–\mathit{C}\mathit{v}\right)}$$

where VO₂ = (resting) oxygen consumption, C_a = systemic arterial oxygen content, and C_v=mixed venous oxygen content.

C_a is calculated as:

$$\mathit{C}\mathit{a}=\mathbf{1.36}\times \left[\mathit{H}\mathit{b}\right]\times \left(\frac{{\mathit{S}\mathit{a}\mathit{O}}_{\mathbf{2}}}{\mathbf{100}}\right)+\mathbf{0.003}\times {\mathit{P}\mathit{a}\mathit{O}}_{\mathbf{2}}$$

C_v is calculated as:

$$\mathit{C}\mathit{v}=\mathbf{1.36}\times \left[\mathit{H}\mathit{b}\right]\times \left(\frac{{\mathit{M}\mathit{V}\mathit{O}}_{\mathbf{2}}}{\mathbf{100}}\right)+\mathbf{0.003}\times {\mathit{P}\mathit{v}\mathit{O}}_{\mathbf{2}}$$

where PaO₂ = partial pressure of oxygen in arterial blood (mmHg), SaO₂ = arterial oxygen saturation (%), PvO2 = mixed venous oxygen tension (mmHg).

Aortic saturations can be invasively measured through an arterial blood gas (ABG) analysis; in practice, however, non-invasive methods such as plethysmography are often preferred.

Attention is needed in the interpretation of saturations in patients receiving supplemental oxygen during RHC. An FiO₂ >0.3 is likely to result in oxygen being dissolved in the blood, which should be taken into account in the Fick calculations by measuring PaO₂. Even though it is recommended that PaO₂ is measured in such cases, it is recognized that the above formula gives a low relative importance to it (i.e. multiplying PaO₂ measured in mmHg by 0.003). Perhaps more importantly, supplemental oxygen typically causes an artificial rise in oxygen saturations “across the board”, making interpretation of shunt fraction difficult.

5.3. Quantification of pulmonary blood flow and calculation of pulmonary and systemic vascular resistance

A fundamental component of the RHC is the calculation of CO. The term CO should be clarified in patients with intracardiac shunts, in whom the systemic (Qs) and pulmonary blood flow (Qp) differ. Moreover, it is essential to remember that, in the presence of shunts, the methods for calculating “CO” described below, measure Qp, not Qs. Finally, Qp, not Qs is the denominator in the formula for calculating pulmonary vascular resistance (PVR), an obvious but often confusing point for inexperienced operators.

The following methods can be used in the catheter lab to calculate Qp:

• •The Fick method, which can be direct or indirect. When applied to the lungs, the Fick principle is based on the concept that, if one can measure the changes in oxygen content between the PA and pulmonary veins and knows the amount of oxygen the patient is consuming per minute (VO₂), they can calculate the pulmonary blood flow (Qp). The formula for calculating oxygen concentration was described above and requires measurement of haemoglobin concentration, oxygen saturations in the PA and pulmonary veins (non-invasive aortic saturations are typically used in the absence of a right-left shunt), and PaO₂ if FiO₂ >0.3. VO₂ can either be measured by metabolic analysers (direct Fick) or extracted from nomograms (indirect Fick). The former is far more accurate than the latter because it relies on direct measurement rather than an estimate of VO_2. [10] To reduce the possibility of error, nomogram-based estimates should be avoided especially, in case of severe obesity or temporary/permanent metabolic disorders, e.g. hypo/hyperthyroidism, burns or sepsis. If direct Fick is unavailable in the catheter lab, it may be reasonable to consider the baseline value of VO2 from a recent cardiopulmonary exercise test.
• •Thermodilution consists in injection of cold saline in the proximal port of a dedicated Swan-Ganz catheter, with a thermistor at the tip detecting changes in temperature. In patients with a high pulmonary blood flow, the temperature change measured at the tip of the catheter will happen fast, much faster than in patients with a low CO. Severe tricuspid regurgitation has been shown to affect the accuracy of thermodilution, underestimating CO by an amount that is proportional to the level of CO and the severity of regurgitation. This is because, with tricuspid regurgitation, a significant proportion of the thermal indicator (cold saline) joins the regurgitant flow and results in a spuriously flatter and more prolonged thermodilution curve [11]. This method is deemed more accurate than indirect Fick, but less accurate than direct Fick. Moreover, thermodilution should not be used in patients with shunt, as it assumes a closed circuit between the site of injection and the thermistor.
• •Hybrid labs allow simultaneous invasive pressure measurement with calculation of Qp, Qs and shunt fraction by cardiac magnetic resonance (CMR). This method is considered very reliable, and allows accurate estimates in patients with a low Qp and in patients with complex anatomy or multiple sources of Qp [12]. However, it is expensive and not widely available.

The calculation of PVR is one of the most important targets of invasive haemodynamic assessment. This is calculated as:

$$\mathit{P}\mathit{V}\mathit{R}=\frac{\mathit{m}\mathit{P}\mathit{A}\mathit{P}-\mathit{m}\mathit{P}\mathit{A}\mathit{W}\mathit{P}}{\mathit{Q}\mathit{p}}\left(\mathit{W}\mathit{U}\right)$$

where mPAP = mean PAP, WU= Wood Units.

It is integral to differentiating between pre-capillary and post-capillary PH, grading the severity of pulmonary vascular disease, and deciding on the operability of CHD with a L-R shunt. The definition of a normal PVR has changed over time, and so has the PVR cutoff for defining operability. Currently, a normal PVR is defined as ≤2 WU, while patients with a PVR <5 WU and a L-R shunt causing volume overload should be considered for repair [1,13].

Indexed PVR (PVRI) is commonly used to account for body habitus and is particularly relevant to paediatric practice. A common pitfall in calculating PVRI when PVR and BSA are known, is to divide PVR by BSA instead of multiplying it. Indeed, PVRI is measured as WU x m².

$$PVRI=\frac{mPAP-mPAWP}{CI}=\frac{mPAP-mPAWP}{\frac{CO}{BSA}}=\frac{mPAP-mPAWP}{CO}\times BSA$$

$$\text{Hence}:\mathit{P}\mathit{V}\mathit{R}\mathit{I}=\mathit{P}\mathit{V}\mathit{R}\times \mathit{B}\mathit{S}\mathit{A}\left(\mathit{W}\mathit{U}\times {\mathit{m}}^{\mathbf{2}}\right)$$

By using PVRI, we multiply PVR by the BSA, thus giving a greater weight to a raised PVR in larger individuals. A smaller individual is expected to have a smaller total cross-sectional area of their pulmonary vascular bed. For example, an estimated PVR of 5 WU in a large individual is more likely to reflect pulmonary vascular disease than in a small child in whom the PVR is expected to be higher due to their small size. Debate is ongoing between experts on whether PVR or PVRI should be used in the adult population, and whether indexing provides additional clinical value. The latest ACHD ESC guidelines have removed PVRI from the definition of operability [13].

It is noteworthy that PVR was previously not part of the diagnosis of pre-capillary PH in the international guidelines but was reintroduced in 2015. This is likely due to concerns regarding accuracy in calculating PVR, mainly its denominator i.e. CO (Qp), which remains an important source of error.

5.4. Additional procedures

Beyond the baseline haemodynamics measured during RHC, provocation tests are often used and provide a more comprehensive understanding of the condition.

5.4.1. Vasoreactivity testing

Pulmonary vasoreactivity testing is a crucial diagnostic tool used to determine the nature of the increased PVR observed at baseline. By using pulmonary vasodilators in the catheter lab, one can differentiate between vasoconstriction versus fixed/structural obstruction. Inhaled NO and inhaled iloprost are the most commonly used vasodilators for this purpose. Although more technically demanding, intravenous epoprostenol can also be used [1].

Vasoreactivity testing is mandated in idiopathic, heritable, or drug-induced PAH. A positive vasoreactive response in this setting is defined as a reduction in mPAP by at least 10 mmHg, leading to an absolute value of ≤40 mmHg, with a stable or increasing CO. Patients who show a positive vasoreactivity response should be offered treatment with calcium channel blockers (CCBs) at large doses, followed by repeated RHC [14]. Unfortunately, such a favourable response to CCBs is only observed in a minority of patients, with even fewer exhibiting a satisfactory long-term response [15]. Vasoreactivity testing is not recommended in PAH other than in idiopathic, heritable, and drug-induced PAH, and should be avoided in cases of suspected or confirmed pulmonary veno-occlusive disease or group 2 PH (risk of acute pulmonary oedema) [1].

In the past, vasoreactivity testing was a standard component of the operability assessment in CHD-associated PH (CHD-PH). However, current guidelines do not routinely recommend acute vasoreactivity testing in this population, due to the lack of prospective data on its utility for evaluating operability and the normalization of PVR after repair [13]. A vasoreactive response also appears to hold prognostic value in patients with Eisenmenger syndrome receiving PAH targeted therapy, but has not entered clinical practice [16].

5.4.2. Assessing for occult post-capillary PH: fluid challenge

An important step in the haemodynamic assessment of PH is distinguishing between pre- and postcapillary physiology. Small deviations in PAWP can make the difference between a pre or postcapillary diagnosis and substantially influence management decisions. In this setting, euvolemia is desirable, yet patients undergoing CC are often dehydrated, having been kept nil by mouth for several hours, leading to a falsely low measurement of PAWP. It is, therefore, important to unmask postcapillary PH using fluid challenge in patients with a relevant risk factor, such as older age, type 2 diabetes, hypertension, obesity, etc. [17,18].

Fluid challenge is performed through infusion of normal saline, for a total of 500 mL (7–10 mL/kg) over 5–10 min. It is considered “positive” if PAWP rises to ≥18 mmHg. This can have therapeutic implications, as PAH therapies can be detrimental by markedly increasing PAWP and causing pulmonary congestion in patients with occult diastolic dysfunction of the LV.

5.4.3. Exercise right heart catheterization

The primary indication for exercise testing during CC is the investigation of dyspnoea of unknown aetiology, or of symptoms that are disproportionate to the severity of the underlying cardiac or pulmonary condition. In fact, physical activity may worsen or unmask underlying pathologies (e.g. mitral insufficiency, diastolic LV dysfunction, respiratory conditions), causing a pathological rise in PAP or PAWP.

Exercise RHC uses stationary cycle ergometers set on the catheterization lab table. While standardized protocols for this procedure are lacking, a dynamic form of exercise is recommended, avoiding isotonic arm exercises. For achieving a steady-state oxygen uptake, it is advisable to maintain a duration of 3 min per stage. Parameters such as PAP, PVR, and cardiac index (CI) should be assessed at each exercise stage, though accurate measurements require expertise. RAP, MVO₂, SaO₂, and arteriovenous oxygen difference should be measured at rest and at peak exercise. Subsequently, calculations for mPAP/CO and PAWP/CO slopes can be derived [19]. The physiological augmentation of CO and mPAP during exercise is reflected in the slope of mPAP/CO that should not exceed 3 mmHg/L/min. A higher slope delineates exercise-induced PH [1]. A PAWP/CO slope >2 mmHg/L/min during exercise CC is useful for unmasking postcapillary PH [20].

In skilled hands, exercise RHC poses no additional risk of complications compared to resting RHC and cardiopulmonary exercise testing, and should, therefore, be integrated into routine clinical practice for evaluating patients suspected of having exercise-induced PH or occult post-capillary PH. Expertise is, however, required for acquiring high-quality, interpretable data during exercise.

5.4.4. RV-PA coupling

RV-PA coupling highlights the RV's capacity to adapt to the increased afterload [21]. In PH, the RV initially adapts to increased afterload following a “homeometric adaptation” with concentric hypertrophy, which allows CO, ejection fraction and exercise capacity to be maintained. If the afterload increases further, there is a transition towards a maladaptive state, causing RV dilatation, and eventually dysfunction (“heterometric adaptation”) [22].

Standard CC is unable to provide reliable information regarding RV-PA coupling. This requires special catheters for recording pressure-volume (PV) loops and measuring the ratio of end-systolic elastance/arterial elastance (Ees/Ea). Ees represents RV contractility, whereas Ea is a surrogate of afterload (end-systolic pressure/stroke volume). The ideal Ees/Ea ratio is thought to be between 1.5 and 2.0 [23,24]. Description of PV loops and elastance, which remain research tools, are beyond of the scope of this paper.

Recently, the ratio of TAPSE/systolic PAP on echocardiography has been shown to be associated with invasively measured Ees/Ea [25].

5.4.5. Pulmonary angiography in chronic thromboembolic PH (CTEPH)

CTEPH is one of the most common types of PH, characterized by the persistence of organised thromboembolic material obstructing the PAs several months or years after acute pulmonary embolism. CTEPH often coexists with group 2 PH, i.e. a postcapillary PH component, which is associated to a worse prognosis [26].

When CTEPH is suspected on a ventilation/perfusion (V/Q) scan, pulmonary angiography should be considered during RHC, and interpreted in conjunction with data from non-invasive modalities.

Digital subtraction angiography is preferred in this setting, as it requires less contrast than conventional angiography and allows better detection of stenotic or obstructive lesions in the pulmonary arterial tree. Typical angiographic findings associated with CTEPH result from the organization and recanalization processes of vessels with persistent clots, and include irregularities in vessel wall contour, constricted vessel bands, web-like formations within vessel lumens, early vanishing of vessels, and ‘pouch’ defects [27]. While non-invasive techniques may provide valuable information, pulmonary angiography remains essential when contemplating surgical (pulmonary endarterectomy) or percutaneous (BPA) treatment.

5.4.6. RHC in suspected portopulmonary hypertension (PoPH)

PoPH is a pulmonary vascular complication related to advanced liver disease. In case of clinical and echocardiographic suspicion of PH and a clinical history or suspicion of portal hypertension, RHC should be performed and should include measurement of WHVP [1].

WHVP is an indicator of portal venous pressure and is measured by advancing a Swan-Ganz catheter into the hepatic vein with the balloon inflated, similar to the PAWP recording [28]. The free hepatic venous pressure (FHVP) is also recorded with the tip of the catheter into the hepatic vein (balloon deflated), 2–3 cm from the IVC. The difference between WHVP and FHVP is called “hepatic venous pressure gradient” (HVPG) and, when increased (>5 mmHg, but clinically significant when ≥10 mmHg) confirms the presence of portal hypertension (Fig. 5) [29].

Fig. 5.

Example of hepatic venous pressures measurement. Free and wedged hepatic venous pressures in a patient with liver cirrhosis. Note, the hepatic venous pressure gradient exceeding 10 mmHg.

Assuming that RAP is freely transmitted to the hepatic venous system, four scenarios are possible (Fig. 6):

• •Healthy individuals exhibit normal values of both WHVP and FHVP, resulting in a low hepatic wedge to RA (or FHVP) pressure gradient.
• •Patients with congestive heart failure exhibit elevation in both RAP and WHVP, maintaining a normal WHVP-RAP (or WHVP- FHVP) gradient.
• •Patients with portal hypertension without cardiac involvement have a pathological increase of the WHVP alone, with a resultant rise in HVPG.
• •Patients with congestive heart failure and liver involvement have an elevation of both WHVP and FHVP, with a predominance of the latter, leading to an increased HPVG.

Fig. 6.

Impact of congestive heart failure and liver disease on transhepatic gradient. Heart failure and/or liver cirrhosis affect free hepatic venous pressure and wedged hepatic venous pressure to a different extent, altering the hepatic venous pressure gradient.

In patients with advanced liver disease and increased intra-abdominal pressure, there is a discrepancy between RAP and FHVP. In this setting, the HVPG has shown superior clinical prognostic value than WHVP-RAP and is, therefore, preferred [29,30].

6. The prognostic implications of invasive haemodynamics

The latest International PH guidelines recommend the use of a three-strata model to predict mortality in patients with PAH. This model contains clinical, laboratory, functional, imaging, and invasive haemodynamic parameters, including RAP, CI, stroke volume index (SVI), MVO₂. Patients with RAP >14 mmHg, CI < 2.0 L/min/m2, SVI <31 mL/m2, or MVO₂<60 % are deemed at a high mortality risk (>20 % in one year). The guidelines also advise repeating the RHC at 3–6 months after changes in therapy, especially in patients with inadequate response to treatment or evidence of clinical deterioration [31].

Prognostic information can also be acquired during RHC by using provocation tests in specific subgroups of PAH. A reduction in PVR or mPAP during acute administration of inhaled NO has been shown to predict long-term outcome in patients with PAH [15]. Vasoreactivity testing is particularly important for the risk stratification of patients with idiopathic PAH, as previously described, with emphasis on repeating the RHC after establishing treatment with high-dose CCB, with responders exhibiting a far better prognosis that non-responders with similar baseline hemodynamics [32].

7. Special considerations in pulmonary hypertension associated with congenital heart disease

CC in CHD presents several challenges and requires expertise due to the heterogeneous underlying anatomical and physiological conditions, including:

• •Challenging access to the heart and pulmonary vasculature e.g. in patients with LA isomerism and interrupted IVC, in patients with a Mustard or Senning operation, and in patients with a Fontan circulation. In such cases, alternative access and catheters should be considered [33].
• •Sampling timing: serial oximetry is particularly important in patients with CHD and should ideally be collected rapidly to prevent errors due to changes in CO over prolonged periods [34].
• •Sedation or general anaesthesia can significantly affect haemodynamics, and in patients with shunts, can modify shunt fraction and the direction of the shunt by reducing SVR.
• •Sampling techniques: when obtaining an IVC sample, it is important to position the catheter below the diaphragm to avoid reflux from the RA (including saturated blood from an ASD with left-right shunting), but above the hepatic veins, pointing the catheter medially to prevent direct sampling from the hepatic veins or an anomalous pulmonary vein (e.g. scimitar syndrome). When sampling the SVC, high and low SVC samples should be obtained, always pointing the catheter laterally to avoid azygos vein flow, which is higher in oxygen content due to bronchial vein drainage [34]. In the case of anomalous drainage of the left upper pulmonary vein to the innominate vein, obtaining a reliable MVO₂ can be difficult as the high SVC is receiving partially saturated blood. Finally, direct LA access is recommended in patients with ASDs, to measure LA pressure, and pulmonary vein and LA saturations.
• •Pulmonary blood flow assessment: thermodilution should be avoided in patients with a left-right shunt. Fick calculations require a single value for PA saturations, yet in patients with patent ductus arteriosus (PDA) and left-right shunting there is a significant difference in saturations between the right pulmonary artery (RPA) and LPA. It is, therefore, advisable to sample in the distal LPA and RPA and average these values. Moreover, in the presence of a PDA, an accurate measurement of PVR may require temporary occlusion of the PDA for sampling of PA pressure. Alternatively, CMR can be used for non-invasive flow assessments (remembering a PDA-related left-right shunt will results in a Qp/Qs < 1 i.e. higher flow through the aortic than through the pulmonary valve).

Catheterization in complex CHD, such as patients with univentricular heart and a Fontan-type circulation, presents several challenges:

• •Fontan failure can result from flow restriction within the Fontan circulation, such as stenosis of the Fontan pathway, hypoplasia of the PAs, distortion, vasoconstriction, flow mismatch, extrinsic obstruction of the pulmonary vessels, or left-sided issues [35]. CC in these patients should complement non-invasive assessment and be targeted to the information that cannot be otherwise obtained, e.g. measurement of Fontan pressures and calculation of PVR.
• •Assessing pulmonary blood flow: in this setting, multiple sources of pulmonary blood flow may be present, e.g. classic Glenn, bidirectional Glenn anastomosis as part of a TCPC connection, or bilateral bidirectional Glenn anastomosis in the setting of interrupted IVC with azygos continuation (Kawashima procedure). Obtaining a single value of PA saturation that can be used to estimate oxygen content in the PA can be tricky.
• •Evaluating collaterals: patients with Glenn and Fontan circulation often develop collateral vessels. Systemic veno-venous collaterals allow SVC return to bypass the pulmonary circulation and bring deoxygenated blood to the systemic circulation. Arterio-venous malformations within the lung allow blood to bypass the pulmonary capillaries and can also contribute to systemic desaturation. Residual aortopulmonary collaterals can compete with systemic venous return to the lungs and also cause ventricular overload [36]. Targeted angiography during CC is, thus, often required.
• •Fontan fenestration: a fenestration is often created during the Fontan operation and may be left open long-term. Its purpose is to allow pressure relief of the Fontan circulation at the expense of systemic desaturation and the risk of paradoxical emboli. The fenestration is often closed soon after the Fontan operation, providing that Fontan haemodynamics are adequate; on the other hand, it can be enlarged/stented if pressures in the circuit are high [37].
• •Assessment of liver involvement: Fontan-associated liver disease is well-described and common in this population due to the chronic hepatic congestion. Liver involvement can and should be assessed during CC by measuring WHVP and HVPG, as described above [29].

8. Conclusions

Despite its invasive nature and major improvements in imaging, CC remains fundamental to cardiology and PH practice. It is the gold standard for the assessment of intracardiac and pulmonary pressures, detection and quantification of shunts and other hemodynamic lesions, and is integral in the diagnosis and classification of PH. It also provides valuable prognostic information. Expertise and careful quality control are required to minimize complications and obtain reliable data, especially in special cohorts, such as those with CHD.

Funding

None.

CRediT authorship contribution statement

Giulia Guglielmi: Writing – review & editing, Writing – original draft. Kaushiga Krishnathasan: Writing – review & editing, Writing – original draft. Andrew Constantine: Writing – review & editing, Supervision. Konstantinos Dimopoulos: Writing – review & editing, Writing – original draft, Validation, Supervision, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Konstantinos Dimopoulos reports a relationship with Janssen-Cilag Ltd that includes: speaking and lecture fees. Kaushiga Krishnathasan reports a relationship with Janssen-Cilag Ltd that includes: speaking and lecture fees. Andrew Constantine reports a relationship with Janssen-Cilag Ltd that includes: speaking and lecture fees. IJCCHD Editorial Board membership, Konstantinos Dimopoulos If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.