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1. Normal right heart hemodynamics

 

Systolic Pulmonary Artery Pressure (sPAP)	18 ¡V 25 mmHg
Diastolic Pulmonary Artery Pressure (dPAP)	6 ¡V 10 mmHg
Mean PAP	12 ¡V 16 mmHg
Pulmonary Capillary Wedge Pressure (PCWP)	6 ¡V 10 mmHg
Pulmonary Vascular Resistance (PVR)

2. Definition of pulmonary hypertension

 

- Sustained elevation of mean pulmonary artery pressure > 25 mmHg at rest

- Sustained elevation of mean pulmonary artery pressure > 30 mmHg with exercise

- or systolic right ventricle pressure of > 40 mmHg

 

 

3. Hemodynamic classification

 

Hemodynamic classification of the severity of pulmonary hypertension has been proposed by several groups. However, there are no generally accepted guidelines for hemodynamic classification of pulmonary hypertension. Nevertheless, such a classification is desired, because it may provide guidance for initiation and urgency of therapeutic measures. It may also be helpful for counceling of patients. Until a more definite classification by the WHO or another body is available, we propose to follow the Giessen Classification by Olschewski and colleagues.

Of note, the hemodynamic severity does not necessarily correlate with the functional severity. Therefore, functional and hemodynamic classification may not always go hand in hand.

Table: Randomized controlled clinical trials of prostacyclin analogues

Class	Symptoms	Echocardiography	RV Catheterization
Mild	NYHA I	Syst. PAP 35 - 55 mmHG	Mean PAP 21 - 40 mmHG
Moderate	NYHA II	Syst. PAP > 55 mmHG	Mean PAP > 40 mmHG
Severe	NYHA III	RV funktion impaired	SVO2 < 60%
Very severe	NYHA IV	RV function severely impaired	SVO2 < 50%

Syst. PAP = Systolic pulmonary artery pressure

Mean PAP = Mean pulmonary artery pressure

SVO₂ = mixed venous oxygen saturation

 

Adapted from Pulmonale Hypertonie: Pathophysiologie, allgemeine Massnahmen und Entwicklung einer pulmonal selektiven Therapie: Olschewski H. and Seeger W. editors, UNI-MED Verlag AG Bremen, 2000, page 51.

 

 

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 (mean PAP above 35 mmHg). 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. The vascular changes include intimal proliferation and fibrosis, medial and adventitial hypertrophy and hyperplesia encroaching on the lumen, and thrombosis in situ (1, 2).
 
These pathological changes are virtually irreversible (2) The vasoconstrictive component contributing the pulmonary hypertension is highly variable among the various causes of pulmonary hypertension and within one single etiology, e.g. primary PHTN (2). Vasodilator therapy aims to decrease vasoconstriction and thus to improve hemodynamics and symptoms. Unfortunately, only about 5-15 % of patients with pulmonary hypertension will response favorably to acute vasodilator therapies (3). In many patients vasodilator therapy exerts no response or an unfavorable response. Unfavorable responses include systemic hypotension, reflex tachycardia, increased load to the right ventricle and accelerated right heart failure (4). In patients with pulmonary hypertension secondary to intracardiac shunts vasodilator therapy might increase a right-left-shunting and impair the situation by increasing systemic hypoxia.

For all these reasons testing of the acute response to vasodilator therapy according to established protocols under continuous monitoring of pulmonary and systemic hemodynamics should be performed in all symptomatic patients with precapillary pulmonary hypertension. Positive response to acute challenge will identify patients who will benefit from long term therapy with calcium-channel blockers and who will have a better prognosis. This is true for patients with idiopathic pulmonary hypertension (5) and for patients with pulmonary hypertension associated with other conditions (6, 7).

Patients who do not respond to acute testing will not benefit from oral calcium-channel blocker therapy. Unfortunately, it is becoming practice for physicians to prescribe calcium-channel blockers to all patients with idiopathic pulmonary hypertension. This is unfortunate, may result in a quicker deterioration of these patients and should be strongly discouraged.
 
4b) Test drugs 
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. Prostacyclin is the most extensively tested drug and proved to yield the highest percentage of vasodilator responders (8). 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 (9). More limited data exist for the use of inhaled iloprost as an acute vasoreactivity testing agent. Recent data suggest that inhaled iloprost should be equivalent to iv prostacyclin and inhaled NO in terms of predicting response to CCBs (10).
 
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 - The vascular load to which a heart with pulmonary hypertension is exposed is composed of two components: a) the steady component which is measured by the vascular resistance and contributes about 75 % of the vascular load and b) the pulsatile component, which is regulated by the vessel compliance and contributes about 30 % to the vascular load in pulmonary hypertension (11).

3 - 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 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 (12).

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

 

Parameter measured	Desired acute changes	Comments
Mean pulmonary  artery pressure	> 10 mmHg fall to reach a mean PAP =< 40 mmHg	The mPAP decrease must be associated  with a normal or 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 increase 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 disease or right-to-left  shunting and prohibits chronic usage.
Pulmonary artery  (mixed venous)  oxygen  saturation	Increase	Should reflect the increase in cardiac  output and improved tissue oxygenation.

Adapted from Rubin LJ and Rich S. Medical Management. In Rubin LJ, Rich S (eds): Primary pulmonary hypertension. New York, Marcel Bekker, 1997, pp 271-286 and from Barst RJ et al JACC 2004; 43: 40S-47S
  
One can define two groups of patients according to the hemodynamic response to the acute pharmacologic testing:

Responders: patients with a mPAP decrease „d 10 mmHg to reach a mean PAP „T 40 mmHg with a normal or high cardiac output. Using these criteria, only 50 % 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:

1 - systemic symptomatic hypertension,
2 - increasing right atrial pressure by more than 20-50 %,
3 - reduction of cardiac index by more than 10 %,
4 - moderate to severe and intolerable side effects such as nausea, flushing, headache,
5 - 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.

References