1. Normal pulmonary hemodynamics
|Systolic Pulmonary Artery Pressure (sPAP)||18 - 25 mmHg|
|Diastolic Pulmonary Artery Pressure (dPAP)||6 - 10 mmHg|
|Mean PAP||12 - 16 mmHg|
|Pulmonary artery occluded pressure (Paop) or wedge pressure||6 - 10 mmHg|
|Pulmonary Vascular Resistance (PVR)||50 – 150 dyn sec cm-5|
2. Definition of pulmonary hypertension
Pulmonary hypertension (PH) is a hemodynamic condition defined as an increase in mean pulmonary artery pressure (PAP) ≥ 25 mmHg at rest as assessed by right heart catheterization (RHC). PH can be found in several conditions as shown in the table below.
Among the several conditions pulmonary arterial hypertension (PAH), group 1 of the Danapoint classification, is a clinical condition characterized by the presence of pre capillary PH in absence of other causes of pre-capillary PH such as PH due to lung diseases, chronic thromboembolic PH, or other rare diseases. PAH includes different forms that share a similar clinical picture and virtually identical pathological changes of the lung microcirculation
It is of note that at the recent Danapoint conference of PH, the definition of PH on exercise as a mean PAP ≥ 30 mmHg as assessed by RHC has been omitted because not supported by published data. However, there are several conditions in which PAP at rest is between < 25 mmHg but a disproportionate increase in PAP occurs during exercise, explaining exertional dyspnea in patients without other causes of exertional dyspnea. This may be particularly observed in patients with scleroderma and may be of prognostic value.
3. Hemodynamic evaluation of PH severity
Evaluation of severity of patients with PAH is of relevance for the diagnostic process and therapeutic decision making. The clinical assessment of the patient has a pivotal role in the choice of the initial treatment, the evaluation of the response to therapy and the possible escalation of therapy is needed. Importantly the clinical assessment does not base only upon hemodynamic parameters but includes also clinical examination and biochemical as well as echocardiographic parameters. From the hemodynamic point of view a patient is considered stable if its peak VO₂ is > 15 ml/min/kg, right atrial pressure (Pra) is < 8 mmHg and cardiac index (CI) is > 2.5 l/min/m². On the other hand a patient is considered unstable or deteriorating if its peak VO₂ is < 12 ml/min/kg, Pra > 15 mmHg and CI < 2.0 l/min/m². Dose the patient has signs of organ hypoperfusion as indicated by a deterioration of renal function, elevated liver enzymes and an increase blood lactate level urgent intervention an admission in the intensive care unit is recommended. It is of note that the magnitude of PAP dose correlate poorly with symptoms and outcome because it is determinate not only by pulmonary vascular resistance but also by the performance of the right heart. Thus PAP alone should not be used for therapeutic decision making. In an unstable and decompensated stated the PAP be lower the in a stable condition because of low cardiac output.
The following table may help to assess PAH patient hemodynamic stability and prognosis:
|Better prognosis||Determinants of prognosis||Worse prognosis|
|Peak VO2 > 15 ml/min/kg||O2 consumption during exercise testing||Peak VO2 < 12 ml/min/kg|
|Normal or near-normal||BNP/NT-proBNP||Very elevated, rising|
No pericardial effusion
TAPSE > 2.0 cm
TAPSE < 1.5 cm
|CI > 2.5 l/min/m2||Cardiac Indes (CI)||CI < 2.0/l/min/m2|
|Pra < 8 mmHg||Right atrial pressure (Pra)||Pra > 15 mmHg|
4. Hemodynamic assessment of vasodilator therapy
Diagnostic catheterization is needed to confirm the diagnosis of pulmonary hypertension and to establish its causes. This diagnostic catheterization should be immediately followed by pharmacological testing of vasodilator therapy response in patients in whom symptoms and/or disease severity warrant treatment A complete right heart catheterization and an invasive monitoring of the systemic pressures are mandatory. In addition, a venous line for drug infusion should be positioned.
4a) Rationale for pharmacological tests
The increased pulmonary vascular resistance in pulmonary hypertension results from extensive vascular changes and vasoconstriction. Several drugs are suitable for assessment of acute vasodilator challenge. The most common used and documented are: iv prostacyclin, iv adenosine, inhaled nitric oxide and inhaled iloprost.
4b) Test drugs
Prostacyclin is the most extensively tested drug and proved to yield the highest percentage of vasodilator responders . Inhaled nitric oxide is a selective pulmonary vasodilator. Apart from its almost total absence of systemic effects, it can also reduce intrapulmonary shunting and increase arterial oxygenation . More limited data exist for the use of inhaled iloprost as an acute vasoreactivity testing agent.
4c) Definition of response
In order to correctly interpret the data of acute vasodilator challenge one has to take the following points into consideration.
1 - One difficulty for assessing changes in pulmonary vascular resistance is the physiologic variation of pulmonary artery pressures and resistances. The reasons for this variability are not understood. To overcome this variation, a long enough baseline period for adaptation of the pressures is needed after the insertion of the catheter.
2 - A decrease in pulmonary vascular resistance can not be equaled with a pulmonary vascular vasodilation. In pulmonary hypertension it is no linear correlation between transpulmonary gradient and cardiac output. This correlation becomes only linear after a certain critical pressure. This critical pressure is needed to open vessels in order for blood to flow. Therefore, in pulmonary and cardiac output. This correlation becomes only linear after a certain critical pressure. This critical pressure is needed to open vessels in order for blood to flow. Therefore, in pulmonary hypertension a real pulmonary vasodilation is only present if in addition to a decreased pulmonary vascular resistance a reduction in the transpulmonary gradient and of the mean pulmonary artery pressure is achieved .
According to the above methodological and pathophysiological considerations several points have to be taken into account during testing. See table below:
Hemodynamic assessment of vasodilators in pulmonary hypertension
|Prameter measures||Desired acute chagnes||Comments|
|Mean pulmonary artery pressure||> 10 mmHg fall to reach a mean PAP ≤ 40 mmHg||The mPAP decrease must be associated with a normalor high cardiac output|
|Right atrial pressure||No change or fall||An increase in RA pressure signals impending RV failure|
|Pulmonary artery occluded pressure (wedge pressure)||No change||An increas in wedge pressure suggests pulmonary veno-occlusive disease or coexisting LV dysfunction|
|Systemic blood pressure||Minimal fall, mean arterial pressure should remain above 90 mmHg||A significant hypotensive response makes chronic vasodilator therapy contraindicated|
|Cardiac output||Normal or increased||The increase should be related to increased stroke volume and not solely due to increased heart rate|
|Heart rate||No significant change||A chronic increased heart rate will result in RV failure|
|Systemic arterial oxygen saturation||Increase if reduced on room air, little change if normal||A fall in systemic arterial oxygen saturation suggests lung diesease or right-to-lef shunting and prohibits chronic usage|
|Pulmonary artery (mixed venous) oxygen saturation||Increase||Should reflect the increse in cardiac output and improved tissue oxygenation|
One can define two groups of patients according to the hemodynamic response to the acute pharmacologic testing:
- Responders: patients with a mPAP decrease > 10 mmHg to reach a mean PAP < 40 mmHg with a normal or high cardiac output. Using these criteria, only 10 % of the acute responders will have a sustained benefit from therapy with a calcium-channel blocker.
- Nonresponders: no significant change of the mean pulmonary vascular pressure or symptomatic systemic hypotension and no change or a reduction of cardiac index, possibly accompanied by an increase in right atrial pressure.
4d) Interruption criteria and side effects
The goal of pharmacologic testing is to identify patients who may benefit from long-term therapy with CCBs. Criteria for interruption are as follows:
- systemic symptomatic hypertension,
- increasing right atrial pressure by more than 20-50 %,
- reduction of cardiac index by more than 10 %,
- moderate to severe and intolerable side effects such as nausea, flushing, headache,
- achievement of the maximal scheduled dose
Acute administration of vasodilator therapy in patients with pulmonary hypertension can have serious adverse consequences. The most common scenario is a systemic vasodilation that can not be counterbalanced by an increase in cardiac output, because the right heart is unable to increase its output against the high pulmonary resistance. This can be aggravated by elevated right atrial pressure that together with a decreased coronary perfusion will produce right ventricular ischemia and does hasten right heart failure. An incidence of serious adverse effect has been reported to be around 6 to 10 %. An appropriate treatment is usually difficult.