The Assessment of Acute Vasoreactivity During Right Heart Catheterizations for the Evaluation of Pulmonary Arterial Hypertension

Pulmonary hypertension (PH) is a progressive lung disease that affects the vasculature within the lungs and is characterized by a mean pulmonary artery pressure (mPAP) that is ≥25 mmHg at rest, as assessed by a right heart catheterization.¹ In 1998, the World Health Organization (WHO) proposed five separate categories for pulmonary hypertension that share similar characteristics in regards to pathogenesis, hemodynamics, and treatment strategies.² There have been three subsequent revisions based on the evidence and the current classification was published in 2013:²

• Group 1: Also referred to as pulmonary arterial hypertension (PAH). Etiologies including idiopathic, drug/toxin-induced, and heritable causes. This group also includes connective tissue disorders (e.g., scleroderma), portal hypertension, chronic hemolytic anemia (e.g., sickle cell disease), infective etiologies (e.g., HIV and schistosomiasis), and PH disease in adults due to congenital heart defects. PAH is characterized by a mean PAP of ≥25 mmHg, a pulmonary arterial wedge pressure (PAWP) of ≤15 mmHg, and a pulmonary vascular resistance (PVR) of >240 dynes-sec/cm⁵ (3 Wood units) compared to a normal PVR of 24-128 dynes-sec/cm⁵.^3,4
• Group 2: Secondary to left heart disease; includes patients with a mean PAWP (mPAWP) of >15 mmHg. 
• Group 3: Secondary to lung disease and/or hypoxemia.
• Group 4: Secondary to thromboembolic disease, also referred to as chronic thromboembolic pulmonary hypertension (CTEPH).
• Group 5: Secondary to various multifactorial causes such as sarcoidosis and chronic dialysis.

The prevalence rate of PH is estimated to be approximately 97 individuals per one million.¹ PAH is considerably rarer, with an estimated prevalence rate of 15-60 cases per million. PAH is two to four times more common in females than males.³

The pathophysiological features in PAH are complex and involve intricate interactions between genetic and environmental factors, as well as influences from several body systems including the lungs, heart, and immune system.⁵ Although excessive pulmonary arterial vasoconstriction is the primary problem in a minority of patients with PAH, the principal problem is pulmonary vascular remodeling, evidenced by the presence of hyperplasia and hypertrophy of the intimal, medial, and adventitial layers that eventually results in pulmonary vascular fibrosis and microthrombosis.⁶ Longstanding PAH results in hypertrophy and dysfunction of the right ventricle, severe tricuspid regurgitation, hypervolemia, and reduced cardiac output, resulting in cor pulmonale. Although survival rates for patients with PAH have improved significantly over the past 30 years with advances in treatment, the prognosis of patients with PAH is still grim; approximately 15% of patients who are diagnosed with PAH will die in the first year after diagnosis, even with appropriate treatment.⁷ Prior to the 1990s, the 5-year survival rate for patients with PAH was 34%.⁸ According to the 2015 REVEAL study, 5-year survival rates for patients with PAH are approximately 61.2-65.4%.⁹

Right Heart Catheterizations

A right heart catheterization (right heart cath) is considered to be the gold standard to definitively diagnose PH.¹⁰ During a right heart cath, a venous access device is inserted in the patient and a specially designed balloon-tip catheter (e.g., Swan-Ganz catheter) is advanced into the central venous system. A series of variables are measured during the procedure:¹

• Right atrial pressure;
• Right ventricular pressure;
• Pulmonary artery pressure (with mean);
• Pulmonary artery wedge pressure (PAWP);
• Venous oxygen saturations from high superior vena cava (SVC), inferior vena cava (IVC) and PA;
• Cardiac output by thermodilution method;
• Arterial O₂ saturation.

The four purposes of a right heart cath for the evaluation of PH are to confirm diagnosis, determine severity, potentially identify the cause (e.g., if the PAWP is >15 mmHg in Group 2 PH) and potentially assess vasoreactivity of the pulmonary vasculature.¹ If Group 2 PH is suspected (as evidenced by a PAWP of >15 mmHg), a direct measurement of the left ventricular end-diastolic pressure should also be performed in order to eliminate the possibility of misdiagnosis due to pulmonary artery dilation and the phenomenon of under-wedging.¹⁰ A right heart cath is required to confirm a diagnosis and guide treatment decisions when PAH and chronic thromboembolic pulmonary hypertension (CTEPH) is suspected (Class I, Level C evidence [Ic evidence]).¹ Performing a right heart cath is recommended in patients with suspected PH due to left heart disease or in patients with lung disease who are potential candidates for organ transplantation (Ic evidence).¹ 

Calculated measurements that are performed during a right heart cath include the pulmonary vascular resistance (PVR), PVR index, cardiac index, and cardiac output per the Fick equation.¹ If an intracardiac left-to-right shunt is suspected (as evidenced by a PA saturation of >75% or an excessively high cardiac output), additional venous saturations should be assessed to identify any abnormal “step-up” in the venous system that may help identify the location of the defect. In addition, the Fick equation should be used to assess cardiac output, rather than the thermodilution method, if a shunt is suspected.¹ A detailed description of the assessment of shunts associated with PH during a right heart cath is beyond the scope of this article.

Vasoreactivity Testing During a Right Heart Catheterization

If Group 1 PAH is confirmed as evidenced by a mean PAP of ≥25 mmHg, a PAWP of ≤15 mmHg, and a PVR >240 dynes-sec/cm⁵ (3 Wood units), it is generally recommended to evaluate the vasoreactive response to supplemental oxygen.¹¹ One hundred percent (100%) oxygen is administered to the patient for five minutes and PA pressures are subsequently reassessed.¹¹ If the PA pressures normalize with supplemental oxygen, the patient should be treated with oxygen therapy and further vasoreactivity testing does not need to be performed.¹¹ If the patient’s PA pressures remain significantly elevated with the oxygen challenge, acute vasodilator testing with medications should be performed if the patient has PAH due to heritable, idiopathic, or drug/toxin-induced causes (Ic evidence).¹ During acute vasodilator testing, a vasoactive medication is administered to the patient and the patient’s hemodynamic response is subsequently reassessed. If the patient demonstrates a favorable response to the vasoreactivity challenge, the patient is deemed as an “acute responder”, and should be treated with high-dose, oral, long-acting calcium channel blockers (CCBs) such as nifedipine, diltiazem, or amlodipine.^1,7 

Acute vasodilator testing was first performed by Dr. Paul Wood in 1958 on six patients with idiopathic PAH using acetylcholine.¹² Since then, multiple different vasoactive medications have been used to assess for pulmonary vascular vasoreactivity during right heart caths. Current European PH guidelines recognize the use of four different medications for this purpose: inhaled nitric oxide (iNO), intravenous epoprostenol, intravenous adenosine, or inhaled iloprost.¹ The U.S.-based Expert Consensus Document on Pulmonary Hypertension recognizes three medications: inhaled nitric oxide, intravenous adenosine, and intravenous epoprostenol.⁷ 

An Expert Center: Should It Be Done at Your Cath Lab?

It is important to consider whether right heart caths for the evaluation of PAH and vasoreactivity testing should performed in your cardiac cath lab. The risk of significant morbidity and mortality associated with right heart caths performed at expert centers is low, with a rate of 1.1% and 0.055%, respectively.¹ According to the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) Guidelines for Pulmonary Hypertension, “In patients with PH, it is recommended to perform right heart catheterizations in expert centres…as it is technically demanding and may be associated with serious complications (Class I, Level b evidence).”¹ The guidelines also state, “Vasoreactivity testing is indicated only in expert centres (Ic evidence).”¹ To qualify as an expert center, the European guidelines note that the healthcare institution should be managing at least 50 patients with Group 1 or Group 4 PH, and evaluate at least two new patients per month with documented Group 1 or Group 4 PH.¹

The Four Agents for Assessment of Pulmonary Vascular Vasoreactivity During Right Heart Cath

I.    Inhaled Nitric Oxide

Inhaled nitric oxide is recognized as the preferred agent of choice to assess for acute pulmonary vasoreactivity in patients with PAH by both the European PH Guidelines (Ic evidence) and the U.S.-based Expert Consensus Document.^1,7 Nitric oxide diffuses into the smooth muscle layers of the pulmonary vasculature, then activates guanylyl cyclase, which results in increased levels of cGMP, inactivation of smooth muscle Ca++ channels, and subsequent smooth muscle relaxation.¹³ Nitric oxide has the unique advantage of being rendered chemically inactive in the presence of hemoglobin, which isolates its effects to the pulmonary vasculature and virtually eliminates the risk of significant systemic side effects that are common with other agents.¹³ It is an odorless gas with a rapid onset of action, short half-life (approximately 3 minutes), and a short duration of action, which allows for an expeditious assessment of data and shorter procedural times.¹⁴ Compared to the other pharmacological options, nitric oxide demonstrates the best predictability in regards to identifying which patients might demonstrate a long-term favorable response to CCB therapy.¹⁵ 

Inhaled nitric oxide is administered to the patient through a specially designed respiratory circuit via a face mask at a dose of 20-40 parts per million (ppm), although doses up to 80 ppm are mentioned in the literature.^7,14 It is typically co-administered with 100% oxygen.^11,16 Pulmonary arterial pressures and cardiac output are re-measured after 5-10 minutes of therapy and are compared to baseline measurements.^11,14,16

Side effects with nitric oxide are extremely rare and include rebound PH, pulmonary edema, and methemoglobinemia.¹⁷ Rebound PH and/or pulmonary edema may be encountered in patients with Group 2 PH, who should not undergo acute vasoreactivity testing, according to the current guidelines.^1,7 Methemoglobin can be formed when nitric oxide is chemically inactivated by hemoglobin; methemoglobin has a much stronger affinity for hemoglobin than oxygen.¹⁷ Signs and symptoms of methemoglobinemia can include chocolate-brown color of the blood, cyanosis, headache, dyspnea, seizures, coma, metabolic acidosis, and hemodynamic instability.¹⁸

The disadvantages of nitric oxide include limited availability and cumbersome administration, which may necessitate the use of a respiratory therapist in the cardiac cath lab setting. Nitric oxide is also relatively expensive, costing significantly more as compared to intravenous epoprostenol, but much less than the current cost of intravenous adenosine. There is only a single supplier for inhaled nitric oxide in the U.S. (Mallinckrodt) and it requires the specially designed Inomax delivery system/respiratory circuit for administration.¹⁷ The delivery system is provided at no cost by Mallinckrodt if the gas is purchased from them. Although vasoreactivity testing with nitric oxide only requires approximately 5-10 minutes to perform a full study, there is a one-hour minimum flat fee every time the gas is administered.

II.    Intravenous Epoprostenol

Epoprostenol is a prostacyclin analogue with robust pulmonary vasodilatory effects and was the first medication to be approved for the chronic treatment of PAH.⁸ It is recognized as the primary alternative agent to inhaled nitric oxide in European guidelines (Ic evidence) and is recognized as alternative agent in the 2009 U.S. Expert Consensus Report.^1,7 Epoprostenol is a prostaglandin (PGI2) receptor agonist that increases intracellular cAMP levels and results in smooth relaxation.¹⁶ Epoprostenol has direct and indirect vasodilatory effects on vascular smooth muscle, as well as having anti-proliferative, anti-inflammatory, and platelet-suppressing effects, which makes it an attractive option for the chronic management of PAH.⁸ It also has direct inotropic effects that can confound data interpretation.¹⁹ Intravenous epoprostenol has a short half-life of approximately 3-6 minutes.^8,20 In the U.S., two brands of epoprostenol are available: Flolan (GlaxoSmithKline) and Veletri (Actelion Pharmaceuticals). It is important to note that Flolan is unstable at room temperature and therefore, the undiluted vials must be kept in a refrigerated environment.²¹ Veletri is stable at room temperature; refrigeration is not required.²¹

Epoprostenol can be infused through a peripheral or centrally inserted venous catheter, and is typically initiated at a dosage of 2 ng/kg/min.¹⁴ Dosages are increased at 2 ng/kg/min increments every 10-15 minutes until a maximum dose of 12 ng/kg/min is reached.¹⁴ Pulmonary arterial pressures and cardiac output are then re-measured and compared to baseline measurements.

Side effects with epoprostenol are more commonly encountered compared to inhaled nitric oxide, and include flushing (58%), headache (49%), nausea/vomiting (32%), and hypotension (16%).²⁰ Less common side effects include chest pain, anxiety, dizziness, bradycardia, dyspnea, abdominal pain, musculoskeletal pain, and tachycardia.²⁰ Importantly, these side effects were reported in Phase III trials in patients who were receiving the medication as a long-term infusion and therefore, may not accurately represent the frequency of side effects during vasoreactivity testing.²⁰

Advantages of intravenous epoprostenol are the profound vasodilatory effects on the pulmonary vasculature, ease of administration, and its relative affordability (it is approximately 39% less expensive than inhaled nitric oxide). Disadvantages are the peripheral vasodilatory effects, indirect positive effects on cardiac output and heart rate, frequency of side effects, and lengthy procedural times (approximately 60 minutes) if the maximum titration rate is achieved.^8,14,16 In addition, Flolan (but not Veletri) must be stored in a refrigerated environment.²¹

III. Intravenous Adenosine

Adenosine is an endogenous substance that activates adenosine-2 receptors, resulting in increased cAMP levels and resultant smooth muscle relaxation.¹⁶ The European PH Guidelines considered it an acceptable alternative for vasoreactivity testing if access to inhaled nitric oxide is not available (Class II, Level a evidence).¹ The U.S. Expert Consensus Document on PH also recognizes its use if inhaled nitric oxide is not available.⁷ Unlike epoprostenol, it is stable at room temperature and has an extremely short half-life of 5-10 seconds.¹⁶ Adenosine has both pulmonary vascular and systemic vascular effects that result in decreases in PVR, as well as systemic vascular resistance (SVR). Increases in cardiac output are typically observed as an indirect result of peripheral vasodilation and compensatory tachycardia.¹⁹ 

Acute vasodilator testing with adenosine is typically accomplished by initiating an infusion at 50 mcg/kg/min and increasing by 50 mcg/kg/min increments every 2-5 minutes, until a maximum dose of 250-350 mcg/kg is obtained.^7,14,16,19 Some studies have utilized a maximum dosage of 500 mcg/kg/min.¹⁹ Pulmonary arterial pressures and cardiac output are then re-measured and compared to baseline measurements.

Side effects with adenosine are frequently encountered; however, most side effects are of short duration due to the short half-life of the medication.¹⁹ Commonly encountered side effects include palpations, dyspnea, flushing, hypotension, headaches, bronchospasm, bradycardia, heart blocks, and chest pain. Although these side effects tend to resolve quickly after the discontinuation of the infusion, they can be severe enough to limit the maximum infusion dosage, confounding the collection of accurate data.¹⁹ In a 2009 study of 39 subjects by Oliveira et al comparing the efficacy of intravenous adenosine to inhaled nitric oxide,²³ subjects (59%) experienced side effects severe enough that the maximum infusion dosage of 500 mcg/kg/min was not obtained.¹⁹ 

Advantages of intravenous adenosine include its universal availability and ease of administration. Disadvantages include frequently encountered side effects, influences on cardiac output, and questionable efficacy regarding the ability of identifying which patients might respond to CCB therapy.¹⁹ In the past, adenosine was an inexpensive option for vasodilator testing, but the price (direct patient cost) of adenosine has increased dramatically in the past few years, making it a much more expensive option compared to the other pharmacological agents.

IV. Inhaled Iloprost

Iloprost, like epoprostenol, is a prostaglandin (PGI2) analogue which increases intracellular cAMP levels and results in smooth muscle relaxation.¹⁶ Iloprost can be administered either intravenously or by the inhalation route, although the inhalation route is typically used for vasoreactivity testing.¹⁶ When the inhalation route is utilized, it demonstrates significant pulmonary specificity with potent vasodilatory effects and decreased systemic side effects.¹⁶ The 2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension recognize inhaled iloprost as an alternative to inhaled nitric oxide, intravenous epoprostenol, and intravenous adenosine for assessment of vasoreactivity (Class IIb); however, its use is not recognized by the 2009 U.S. Expert Consensus Document on PH.^1,7 It has limited availability in the U.S., so most studies using iloprost have been performed in Europe and China.¹⁶

For inhaled administration, 50 mcg of iloprost is diluted in 5 mL of 0.9% normal saline and administered via a “rain drop” nebulizer circuit.²² Typically, it is initially administered at a dose of 2.5 mcg and is increased to a maximum dose of 5 mcg, although some studies have utilized a maximum dose of 17 mcg.^14,22 Since iloprost has a significantly longer half-life compared to epoprostenol (20-30 minutes vs 3-6 minutes, respectively), repeat hemodynamic measurements are typically performed 30 minutes after the drug is initiated.^14,16 Due to the prolonged half-life, subjects can demonstrate pulmonary vasodilatory effects for 1-2 hours after administration.²²

Common side effects with iloprost per the Phase III clinical trials include increased cough (39%), headache (30%), and flushing (27%).²³ Less common side effects include flu-like syndrome, trismus, nausea, hypotension, and vomiting.²³ Importantly, these side effects were reported in patients who were receiving the medication for a median timeframe of 15 weeks and therefore, may not accurately represent the frequency of side effects during vasoreactivity testing.²³ In one study by Jing et al of 74 patients undergoing vasoreactivity testing with iloprost, only 2.7% of patients experienced significant side effects, primarily increased cough and hypotension.²⁴

Advantages of iloprost are its relative pulmonary specificity of actions and profound pulmonary vasodilatory effects. Disadvantages are its limited availability, relatively long half-life, side effect profile, requirement of specialized equipment for administration, and relatively low level of evidence supporting its use. The cost of iloprost was not available for the purposes of this review, as it is not widely available for use in the United States.

Criteria for “Acute Responders”

In 2009, the ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension were updated and a more conservative definition of acute vasoresponsiveness was adopted. According to the guidelines, “A positive acute response is defined as a reduction of the mPAP ≥10 mmHg to reach an absolute value of mPAP ≤40 mmHg with an increased or unchanged cardiac output.”¹ According to McLaughlin et al, “Although this stringent definition may misclassify a few patients who could be treated effectively with long-term oral calcium channel blockers, it will reliably identify those who are least likely to benefit from oral calcium channel blocker therapy and, therefore, provides the greatest degree of safety.”⁷ Some institutions consider a decrease of cardiac output within 10% of baseline to be within the range of error, so a patient can still be considered an acute responder if their cardiac output decreases <10% from baseline measurement.¹¹ 

The ESC/ERS guidelines do not provide any guidance if the patient has a mean PAP between 25 and 39 mmHg. If the patient meets these criteria, the cardiac cath labs at the University of Colorado will still perform vasoreactivity testing, and an acute response is defined as a reduction of mPAP of ≥10 mmHg with an increased or unchanged cardiac output, as per above.¹¹ 

Approximately 10% of patients who undergo vasoreactivity testing will meet the criteria as an “acute responder.”^1,14 Our review of 5 separate studies utilizing different pharmacological methods indicated that the range of acute response was 0-26%, depending upon the pharmacological method utilized.^15,19,25-27 Acute responders with idiopathic, heritable, or drug/toxin-induced PAH should be treated with high-dose, long-acting CCBs such as nifedipine, diltiazem, or amlodipine.^1,7 Once the patient is placed on CCBs, approximately 50% of acute responders will demonstrate a positive long-term (>1 year) benefit from CCB monotherapy.^1,14

Conclusion

Performance of a right heart catheterization on a patient who has pulmonary hypertension is critical to provide a definitive diagnosis, to determine the severity of their disease, possibly identify a cause of their disease, and possibly determine an appropriate course of treatment through the performance of vasoreactivity testing. According to the guidelines, there are several pharmaceutical options that can be used for vasoreactivity testing. The astute clinician must consider efficacy, predictability, feasibility, safety, and cost when determining which protocol should be employed in their cardiac cath lab. It is also important for the clinician to keep up to date, as clinical guidelines are updated periodically, based on current evidence. Finally, the management of the cardiac catheterization laboratory should evaluate whether right heart catheterizations and pulmonary vasoreactivity testing should be performed at all in their facility, as suggested by the 2015 ESC/ERS guidelines.

Acknowledgements: A sincere thanks to the following individuals who were very supportive and helpful in the creation of this project/article: Dr. Wendy Austin, Cindy Baclasky, Dr. Todd Bull, Dr. Phillip Dattilo, Diane Gutierrez, Dr. Emily Hass, Carol Mackes, Dr. Richard Milchak, Dr. Marcia Patterson, Dr. Brad Oldemeyer, Dr. Lance Richards, & Dr. Audrey Snyder. This article is dedicated to my good friend Star Grimm who was the inspiration for this project.       

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Disclosure: Keith Volk, RN, MSN, CCRN, reports no conflicts of interest regarding the content herein.​

Keith Volk, RN, can be contacted at keith.volk@uchealth.org.