Right heart failure medical therapy: Difference between revisions
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__NOTOC__ | __NOTOC__ | ||
{{Right heart failure}} | {{Right heart failure}} | ||
{{CMG}}; | {{CMG}};{{AE}} [[User:Jad Z Al Danaf|Jad Z Al Danaf]]; [[User:Rim Halaby|Rim Halaby]] | ||
==Overview== | ==Overview== | ||
Currently, the basis of therapy for | Currently, the basis of therapy for right heart failure is most importantly cautious [[diuresis]], [[sinus rhythm]] maintenance and management of the underlying cause whenever feasible. Management of right heart failure, although largely empiric, can be tailored for etiology specific therapy such as [[anticoagulation]] in case of a [[pulmonary embolism]] or [[antibiotic]]s in the case of [[endocarditis]]. Management also comprises optimizing right ventricular [[preload]], [[afterload]] and [[contractility]]. Since [[atrial fibrillation]] and high grade [[AV block]] cause detrimental hemodynamic instability, in the setting of a right heart failure in particular, maintaining [[sinus rhythm]] and [[AV node|AV]] synchrony is important <ref name="Haddad"> Haddad F. et al. Right Ventricular function in Cardiovascular Disease, Part II: Pathophysiology, Clinical Importance and Management of Right Ventricular failure. Circulation. 2008;117:1717-1731</ref><ref>Skhiri M. et al. Evidence-Based Management of Right Heart Failure: a Systematic Review of an Empiric Fiel. Rev Esp Cardiol. 2010;63(4):451-71</ref>. | ||
==Medical Therapy== | ==Medical Therapy== | ||
===General Measures=== | ===General Measures=== | ||
*[[Diuretics]] | *[[Diuretics]] | ||
| Line 13: | Line 12: | ||
*[[Oxygen]] in some conditions | *[[Oxygen]] in some conditions | ||
==Management of Acute Right Heart Failure== | ===Management of Acute Right Heart Failure=== | ||
===1- Preload Optimization | ====1- Preload Optimization==== | ||
*In case of | *In case of [[hypovolemia]], 300-600cc [[normal saline]] boluses can be given but to be stopped if the patient is not responsive | ||
*In case of | *In case of [[hypervolemia]], progressive [[diuresis]] can be started with a goal of 500cc daily negative balance. | ||
*If the patient is still | *If the patient is still hemodynamically unstable following [[preload]] optimization, [[dobutamine]] is commonly used as a [[vasopressors]], however if the patient remains refractory to that, then surgical interventions including [[transplantation]] and assist devices should be considered. | ||
===2- Afterload Optimization:=== | ====2- Afterload Optimization:==== | ||
* | *i[[NO]], intravenous or inhaled [[epoprostenol]] with [[ionotropic effect|inotropic]] support are commonly used in a setting of [[PAH]]. | ||
===3- Maintaining Sinus Rhythm:=== | ====3- Maintaining Sinus Rhythm:==== | ||
*Cardioversion and pacemaker insertion are the first line therapies for | *[[Cardioversion]] and [[pacemaker]] insertion are the first line therapies for [[tachyarrhythmia]]s and high grade [[AV block]] in the setting of an acute right heart failure <ref name="Haddad"> Haddad F. et al. Right Ventricular function in Cardiovascular Disease, Part II: Pathophysiology, Clinical Importance and Management of Right Ventricular failure. Circulation. 2008;117:1717-1731</ref><ref name="Vizza">Vizza CD, Rocca GD, Roma AD, Iacoboni C, Pierconti F, Venuta F, Rendina E, Schmid G, Pietropaoli P, Fedele F. Acute hemodynamic effects of inhaled nitric oxide, dobutamine and a combination of the two in patients with mild to moderate secondary pulmonary hypertension. Crit Care. 2001;5:355–361</ref><ref name="Dell">O’Rourke RA, Dell’Italia LJ. Diagnosis and management of right ventricular myocardial infarction. Curr Probl Cardiol. 2004;29:6–47.</ref>. | ||
===4- Treatment of Specific Underlying Conditions | ====4- Treatment of Specific Underlying Conditions==== | ||
====Right Ventricular Myocardial Infarction==== | =====Right Ventricular Myocardial Infarction===== | ||
*In patients presenting with right ventricle myocardial infarction, recent studies have shown that reperfusion therapy via percutaneous | *In patients presenting with right ventricle myocardial infarction, recent studies have shown that [[reperfusion therapy]] via [[percutaneous coronary intervention]] ([[PCI]]) reduces the incidence of developing a [[complete heart block]] and improves right ventricular [[ejection fraction]]. In addition, recovery occurred in a considerable amount of survivors of right ventricular myocardial infarction without acute reperfusion intervention, reiterating the significance of myocardial stunning in right ventricular function <ref name="Dell">O’Rourke RA, Dell’Italia LJ. Diagnosis and management of right ventricular myocardial infarction. Curr Probl Cardiol. 2004;29:6–47.</ref>. | ||
====Pulmonary Embolism==== | ====Pulmonary Embolism==== | ||
| Line 33: | Line 32: | ||
====Chronic Obstructive Pulmonary Disease==== | ====Chronic Obstructive Pulmonary Disease==== | ||
In | In [[chronic obstructive pulmonary disease]] ([[COPD]]), long-term [[oxygen therapy]] may improve [[cor pulmonale]]. | ||
====Pulmonary Arterial Hypertension==== | ====Pulmonary Arterial Hypertension==== | ||
*Treatment is determined by whether the PH is arterial, venous, hypoxic, thromboembolic, or miscellaneous. Since pulmonary | *Treatment is determined by whether the PH is arterial, venous, hypoxic, thromboembolic, or miscellaneous. Since pulmonary venous hypertension is synonymous with [[congestive heart failure]], the treatment is to optimize left ventricular function by the use of [[diuretic]]s, [[beta blocker]]s, [[ACE inhibitor]]s, etc., or to repair/replace the [[mitral valve]] or [[aortic valve]]. | ||
*In [[PAH]], lifestyle changes, [[digoxin]], [[diuretic]]s, oral [[anticoagulant]]s, and oxygen therapy are considered | *In [[PAH]], lifestyle changes, [[digoxin]], [[diuretic]]s, oral [[anticoagulant]]s, and [[oxygen]] therapy are considered conventional therapy, but have never been proven to be beneficial in a randomized, prospective manner. | ||
*The combination of | *The combination of [[dobutamine]] (2 to 5 μg/kg.min ) and [[NO]] in the setting of right heart failure secondarily to [[pulmonary hypertension]] have been shown to be beneficial in increasing the [[cardiac output]] and decreasing the pulmonary vascular resistance. As for [[digoxin]] therapy, it has been studied in patients with [[pulmonary hypertension]] and chronic pulmonary disease, where it was shown to improve [[CO]] by about 10% in an acute setting of right heart failure, but no studies have supported its use for a long term <ref>Skhiri M. et al. Evidence-Based Management of Right Heart Failure: a Systematic Review of an Empiric Fiel. Rev Esp Cardiol. 2010;63(4):451-71</ref><ref name="Vizza">Vizza CD, Rocca GD, Roma AD, Iacoboni C, Pierconti F, Venuta F, Rendina E, Schmid G, Pietropaoli P, Fedele F. Acute hemodynamic effects of inhaled nitric oxide, dobutamine and a combination of the two in patients with mild to moderate secondary pulmonary hypertension. Crit Care. 2001;5:355–361</ref>. | ||
*High dose [[calcium channel blocker]]s are useful in only 5% of | *High dose [[calcium channel blocker]]s are useful in only 5% of idiopathic [[PAH]] patients who are vasoreactive by [[Swan-Ganz catheter]]. Unfortunately, calcium channel blockers have been largely misused, being prescribed to many patients with non-vasoreactive PAH, leading to excess morbidity and mortality. | ||
====Vasoactive substances==== | ====Vasoactive substances==== | ||
Three major pathways are involved in the abnormal proliferation and contraction of the smooth-muscle cells of the pulmonary artery in patients with pulmonary arterial hypertension. These pathways correspond to important therapeutic targets in this condition and play a role in determining which of three classes of drugs — [[endothelin receptor antagonist]]s, [[phosphodiesterase]] type 5 inhibitors, and prostacyclin derivatives — will be used. | Three major pathways are involved in the abnormal proliferation and contraction of the smooth-muscle cells of the pulmonary artery in patients with [[pulmonary arterial hypertension]]. These pathways correspond to important therapeutic targets in this condition and play a role in determining which of three classes of drugs — [[endothelin receptor antagonist]]s, [[phosphodiesterase]] type 5 inhibitors, and [[prostacyclin]] derivatives — will be used. | ||
=====Prostaglandins===== | =====Prostaglandins===== | ||
[[Prostacyclin]] ([[prostaglandin]] I<sub>2</sub>) is commonly considered the most effective treatment for PAH. [[Epoprostenol]] (synthetic [[prostacyclin]], marketed as Flolan®) is given via continuous infusion that requires a semi-permanent [[central venous catheter]]. This delivery system can cause [[sepsis]] and [[thrombosis]]. Flolan® is unstable, and therefore has to be kept on ice during administration. Since it has a half-life of 3 to 5 minutes, the infusion has to be continuous (24/7), and interruption can be fatal. Other [[prostanoid]]s have therefore been developed. [[Treprostinil]] (Remodulin®) can be given intravenously or subcutaneously, but the subcutaneous form can be very painful. | [[Prostacyclin]] ([[prostaglandin]] I<sub>2</sub>) is commonly considered the most effective treatment for PAH. [[Epoprostenol]] (synthetic [[prostacyclin]], marketed as Flolan®) is given via continuous infusion that requires a semi-permanent [[central venous catheter]]. This delivery system can cause [[sepsis]] and [[thrombosis]]. Flolan® is unstable, and therefore has to be kept on ice during administration. Since it has a half-life of 3 to 5 minutes, the infusion has to be continuous (24/7), and interruption can be fatal. Other [[prostanoid]]s have therefore been developed. [[Treprostinil]] (Remodulin®) can be given intravenously or subcutaneously, but the subcutaneous form can be very painful. [[Iloprost]] (Ilomedin®) is also used in Europe intravenously and has a longer half life. [[Iloprost]] (marketed as Ventavis®) is the only inhaled form of [[prostacyclin]] approved for use in the US and Europe. This form of administration has the advantage of selective deposition in the lungs with less systemic side effects. | ||
=====Endothelin receptor antagonists===== | =====Endothelin receptor antagonists===== | ||
The dual | The dual [[endothelin]] receptor antagonist [[bosentan]] (marketed as Tracleer®) was approved in 2001. Approved in June 2007, [[ambrisentan]] is marketed as Letairis® in U.S. by [[Gilead Sciences]].<ref>cite press release [[Sitaxsentan]]</ref>, a selective endothelin receptor antagonist that blocks only the action of ET, has been approved for use in Canada and the European Union, to be marketed under the name Thelin®. Sitaxsentan has not been approved for marketing by the US FDA. A new trial is being planned to address FDA's concerns. | ||
=====Phosphodiesterase type 5 inhibitors===== | =====Phosphodiesterase type 5 inhibitors===== | ||
| Line 54: | Line 53: | ||
=====Other agents===== | =====Other agents===== | ||
[[Vasoactive intestinal peptide]] by inhalation should enter clinical trials for PAH in 2007. PRX-08066 is a serotonin antagonist currently being developed for hypoxic pulmonary hypertension. | [[Vasoactive intestinal peptide]] by inhalation should enter clinical trials for PAH in 2007. PRX-08066 is a [[serotonin antagonist]] currently being developed for hypoxic pulmonary hypertension. | ||
==Management of Chronic Heart Failure== | ==Management of Chronic Heart Failure== | ||
===Management of Chronic Right Heart Failure Based on the Stage of Right Heart Failure=== | ===Management of Chronic Right Heart Failure Based on the Stage of Right Heart Failure<ref name="Haddad"> Haddad F. et al. Right Ventricular function in Cardiovascular Disease, Part II: Pathophysiology, Clinical Importance and Management of Right Ventricular failure. Circulation. 2008;117:1717-1731</ref>=== | ||
{|class="wikitable" border="1" | {|class="wikitable" border="1" | ||
|- | |- align="center" | ||
|'''Stage A''' | |'''Stage A''' | ||
|'''Stage B''' | |'''Stage B''' | ||
|'''Stage C''' | |'''Stage C''' | ||
|'''Stage D''' | |'''Stage D''' | ||
|- | |- align="center" | ||
|'''At risk for RVF but no structural disease or any symptoms''' | |'''At risk for RVF but no structural disease or any symptoms''' | ||
|'''RV dysfunction or structural disease with no symptoms''' | |'''RV dysfunction or structural disease with no symptoms''' | ||
| Line 74: | Line 73: | ||
• Close monitoring of RV function | • Close monitoring of RV function | ||
• Lifestyle modification (healthy diet, smoking and alcohol cessation, exercise) | • Lifestyle modification (healthy diet, [[smoking]] and [[alcohol]] cessation, [[exercise]]) | ||
• Family or genetic screening | • Family or genetic screening | ||
| Line 82: | Line 81: | ||
+ | + | ||
[[ACEI]] or [[ARB]] or [[beta blocker]] in case of systemic RVF | |||
+ | + | ||
Anticoagulation in case of RH thrombus, atrial flutter/fibrillation, PAH and CTEPH | [[Anticoagulation]] in case of RH thrombus, [[atrial flutter]]/[[atrial fibrillation|fibrillation]], [[PAH]] and CTEPH | ||
+ | + | ||
| Line 100: | Line 99: | ||
+ | + | ||
Diuretics + Digoxin | [[Diuretics]] + | ||
[[Digoxin]] | |||
+ | + | ||
CRT, | CRT, [[ablation]], and [[cardioversion]] in selected cases | ||
|Measures in stages A, B and C | |Measures in stages A, B and C | ||
| Line 110: | Line 109: | ||
+ | + | ||
• Atrial septostomy in some patients with Pulmonary hypertension | • Atrial septostomy in some patients with [[Pulmonary hypertension]] | ||
• Heart transplantation | • [[Heart transplantation]] | ||
• ECMO | • [[ECMO]] | ||
• RV / LV assist devices | • RV / LV assist devices | ||
| Line 120: | Line 119: | ||
• Chronic inotropes | • Chronic inotropes | ||
+ | + Compassionate end of life care whenever applicable | ||
|} | |} | ||
RH: [[Right heart]]; PAH: [[pulmonary arterial hypertension]]; CTEPH: [[Chronic Thromboembolic Pulmonary Hypertension]]; ECMO: [[extracorporeal membrane oxygenation]]; CRT: cardiac resynchronization therapy. | |||
===Management of Chronic Right Heart Failure Based on the Underlying Etiology<ref name="pmid20334811">{{cite journal| author=Skhiri M, Hunt SA, Denault AY, Haddad F| title=[Evidence-based management of right heart failure: a systematic review of an empiric field]. | journal=Rev Esp Cardiol | year= 2010 | volume= 63 | issue= 4 | pages= 451-71 | pmid=20334811 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20334811 }} </ref>=== | |||
====Pulmonary Arterial Hypertension==== | |||
*[[Diuretics]] | |||
*[[Anticoagulation]] | |||
*[[phosphodiesterase inhibitors|PDE5 inhibitors]], Prostanoids ([[prostacyclin]]-PG I2), [[endothelin receptor blockers]] | |||
*[[Oxygen]] | |||
====Pulmonary Thromboembolism==== | |||
*[[Anticoagulation]] | |||
*[[phosphodiesterase inhibitors|PDE5 inhibitor]] ([[sildenafil]]) | |||
*[[Endarterectomy]] ([[Chronic Thromboembolic Pulmonary Hypertension|CTEPH]]) | |||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
{{WH}} | |||
{{WS}} | |||
[[Category:Disease]] | |||
[[Category:Cardiology]] | [[Category:Cardiology]] | ||
[[Category:Pulmonology]] | [[Category:Pulmonology]] | ||
[[Category: | [[Category:Up-To-Date]] | ||
[[Category: | [[Category:Up-To-Date cardiology]] | ||
Latest revision as of 00:02, 30 July 2020
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Right heart failure Microchapters |
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Treatment |
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Right heart failure medical therapy On the Web |
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Risk calculators and risk factors for Right heart failure medical therapy |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Jad Z Al Danaf; Rim Halaby
Overview
Currently, the basis of therapy for right heart failure is most importantly cautious diuresis, sinus rhythm maintenance and management of the underlying cause whenever feasible. Management of right heart failure, although largely empiric, can be tailored for etiology specific therapy such as anticoagulation in case of a pulmonary embolism or antibiotics in the case of endocarditis. Management also comprises optimizing right ventricular preload, afterload and contractility. Since atrial fibrillation and high grade AV block cause detrimental hemodynamic instability, in the setting of a right heart failure in particular, maintaining sinus rhythm and AV synchrony is important [1][2].
Medical Therapy
General Measures
Management of Acute Right Heart Failure
1- Preload Optimization
- In case of hypovolemia, 300-600cc normal saline boluses can be given but to be stopped if the patient is not responsive
- In case of hypervolemia, progressive diuresis can be started with a goal of 500cc daily negative balance.
- If the patient is still hemodynamically unstable following preload optimization, dobutamine is commonly used as a vasopressors, however if the patient remains refractory to that, then surgical interventions including transplantation and assist devices should be considered.
2- Afterload Optimization:
- iNO, intravenous or inhaled epoprostenol with inotropic support are commonly used in a setting of PAH.
3- Maintaining Sinus Rhythm:
- Cardioversion and pacemaker insertion are the first line therapies for tachyarrhythmias and high grade AV block in the setting of an acute right heart failure [1][3][4].
4- Treatment of Specific Underlying Conditions
Right Ventricular Myocardial Infarction
- In patients presenting with right ventricle myocardial infarction, recent studies have shown that reperfusion therapy via percutaneous coronary intervention (PCI) reduces the incidence of developing a complete heart block and improves right ventricular ejection fraction. In addition, recovery occurred in a considerable amount of survivors of right ventricular myocardial infarction without acute reperfusion intervention, reiterating the significance of myocardial stunning in right ventricular function [4].
Pulmonary Embolism
In pulmonary embolism, thrombolysis (enzymatic dissolution of the blood clot) is advocated if there is dysfunction of the right ventricle.
Chronic Obstructive Pulmonary Disease
In chronic obstructive pulmonary disease (COPD), long-term oxygen therapy may improve cor pulmonale.
Pulmonary Arterial Hypertension
- Treatment is determined by whether the PH is arterial, venous, hypoxic, thromboembolic, or miscellaneous. Since pulmonary venous hypertension is synonymous with congestive heart failure, the treatment is to optimize left ventricular function by the use of diuretics, beta blockers, ACE inhibitors, etc., or to repair/replace the mitral valve or aortic valve.
- In PAH, lifestyle changes, digoxin, diuretics, oral anticoagulants, and oxygen therapy are considered conventional therapy, but have never been proven to be beneficial in a randomized, prospective manner.
- The combination of dobutamine (2 to 5 μg/kg.min ) and NO in the setting of right heart failure secondarily to pulmonary hypertension have been shown to be beneficial in increasing the cardiac output and decreasing the pulmonary vascular resistance. As for digoxin therapy, it has been studied in patients with pulmonary hypertension and chronic pulmonary disease, where it was shown to improve CO by about 10% in an acute setting of right heart failure, but no studies have supported its use for a long term [5][3].
- High dose calcium channel blockers are useful in only 5% of idiopathic PAH patients who are vasoreactive by Swan-Ganz catheter. Unfortunately, calcium channel blockers have been largely misused, being prescribed to many patients with non-vasoreactive PAH, leading to excess morbidity and mortality.
Vasoactive substances
Three major pathways are involved in the abnormal proliferation and contraction of the smooth-muscle cells of the pulmonary artery in patients with pulmonary arterial hypertension. These pathways correspond to important therapeutic targets in this condition and play a role in determining which of three classes of drugs — endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclin derivatives — will be used.
Prostaglandins
Prostacyclin (prostaglandin I2) is commonly considered the most effective treatment for PAH. Epoprostenol (synthetic prostacyclin, marketed as Flolan®) is given via continuous infusion that requires a semi-permanent central venous catheter. This delivery system can cause sepsis and thrombosis. Flolan® is unstable, and therefore has to be kept on ice during administration. Since it has a half-life of 3 to 5 minutes, the infusion has to be continuous (24/7), and interruption can be fatal. Other prostanoids have therefore been developed. Treprostinil (Remodulin®) can be given intravenously or subcutaneously, but the subcutaneous form can be very painful. Iloprost (Ilomedin®) is also used in Europe intravenously and has a longer half life. Iloprost (marketed as Ventavis®) is the only inhaled form of prostacyclin approved for use in the US and Europe. This form of administration has the advantage of selective deposition in the lungs with less systemic side effects.
Endothelin receptor antagonists
The dual endothelin receptor antagonist bosentan (marketed as Tracleer®) was approved in 2001. Approved in June 2007, ambrisentan is marketed as Letairis® in U.S. by Gilead Sciences.[6], a selective endothelin receptor antagonist that blocks only the action of ET, has been approved for use in Canada and the European Union, to be marketed under the name Thelin®. Sitaxsentan has not been approved for marketing by the US FDA. A new trial is being planned to address FDA's concerns.
Phosphodiesterase type 5 inhibitors
Sildenafil, a selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5), was approved for the treatment of PAH in 2005. It is marketed for PAH as Revatio®. Tadalafil (currently marketed as Cialis® for erectile dysfunction) is currently is Phase III clinical trials.
Other agents
Vasoactive intestinal peptide by inhalation should enter clinical trials for PAH in 2007. PRX-08066 is a serotonin antagonist currently being developed for hypoxic pulmonary hypertension.
Management of Chronic Heart Failure
Management of Chronic Right Heart Failure Based on the Stage of Right Heart Failure[1]
| Stage A | Stage B | Stage C | Stage D |
| At risk for RVF but no structural disease or any symptoms | RV dysfunction or structural disease with no symptoms | RVF with previous or current HF symptoms | Refractory RVF that requires specialized interventions for RV support |
| • Manage underlying etiology
• Close monitoring of RV function • Lifestyle modification (healthy diet, smoking and alcohol cessation, exercise) • Family or genetic screening |
Measures in stage A
+ ACEI or ARB or beta blocker in case of systemic RVF + Anticoagulation in case of RH thrombus, atrial flutter/fibrillation, PAH and CTEPH + ICD in selected cases + Surgical procedure in selected cases such as valvular or congenital heart diseases |
Measures in stages A and B
+ CRT, ablation, and cardioversion in selected cases |
Measures in stages A, B and C
+ • Atrial septostomy in some patients with Pulmonary hypertension • ECMO • RV / LV assist devices • Chronic inotropes + Compassionate end of life care whenever applicable |
RH: Right heart; PAH: pulmonary arterial hypertension; CTEPH: Chronic Thromboembolic Pulmonary Hypertension; ECMO: extracorporeal membrane oxygenation; CRT: cardiac resynchronization therapy.
Management of Chronic Right Heart Failure Based on the Underlying Etiology[7]
Pulmonary Arterial Hypertension
- Diuretics
- Anticoagulation
- PDE5 inhibitors, Prostanoids (prostacyclin-PG I2), endothelin receptor blockers
- Oxygen
Pulmonary Thromboembolism
References
- ↑ 1.0 1.1 1.2 Haddad F. et al. Right Ventricular function in Cardiovascular Disease, Part II: Pathophysiology, Clinical Importance and Management of Right Ventricular failure. Circulation. 2008;117:1717-1731
- ↑ Skhiri M. et al. Evidence-Based Management of Right Heart Failure: a Systematic Review of an Empiric Fiel. Rev Esp Cardiol. 2010;63(4):451-71
- ↑ 3.0 3.1 Vizza CD, Rocca GD, Roma AD, Iacoboni C, Pierconti F, Venuta F, Rendina E, Schmid G, Pietropaoli P, Fedele F. Acute hemodynamic effects of inhaled nitric oxide, dobutamine and a combination of the two in patients with mild to moderate secondary pulmonary hypertension. Crit Care. 2001;5:355–361
- ↑ 4.0 4.1 O’Rourke RA, Dell’Italia LJ. Diagnosis and management of right ventricular myocardial infarction. Curr Probl Cardiol. 2004;29:6–47.
- ↑ Skhiri M. et al. Evidence-Based Management of Right Heart Failure: a Systematic Review of an Empiric Fiel. Rev Esp Cardiol. 2010;63(4):451-71
- ↑ cite press release Sitaxsentan
- ↑ Skhiri M, Hunt SA, Denault AY, Haddad F (2010). "[Evidence-based management of right heart failure: a systematic review of an empiric field]". Rev Esp Cardiol. 63 (4): 451–71. PMID 20334811.