Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 7  |  Issue : 1  |  Page : 1-6

An update on the management of secondary pulmonary hypertension


Department of Anesthesiology, Faculty of Medicine, Cairo University, Cairo, Egypt

Date of Submission15-Apr-2013
Date of Acceptance02-May-2013
Date of Web Publication26-Jun-2014

Correspondence Address:
Mohamed A Bakry
MD,Department of Anesthesiology, Faculty of Medicine, Cairo University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJCA.0000430956.27576.15

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  Abstract 

Patients with long-standing mitral valve disease are at risk of developing pulmonary hypertension, which may present a formidable challenge for the cardiac anesthetist (perioperatively) during cardiac surgery. Pulmonary hypertension is an important risk factor for the development of acute right-sided heart failure during cardiac surgery. Even with early and adequate therapy, right ventricular (RV) failure is associated with increased morbidity and mortality. Adequate treatment of RV failure consists of different strategies. The main goal is to decrease RV afterload using vasodilating agents and reducing the pulmonary vascular tone. In this review, we will present an overview of the most recent management protocols used in the management of patients with secondary pulmonary hypertension.

Keywords: phosphodiesterase inhibitors type III, phosphodiesterase inhibitors type V, pulmonary hypertension, right ventricular failure, vasodilating agents


How to cite this article:
Bakry MA. An update on the management of secondary pulmonary hypertension. Egypt J Cardiothorac Anesth 2013;7:1-6

How to cite this URL:
Bakry MA. An update on the management of secondary pulmonary hypertension. Egypt J Cardiothorac Anesth [serial online] 2013 [cited 2021 Feb 27];7:1-6. Available from: http://www.ejca.eg.net/text.asp?2013/7/1/1/135455


  Introduction Top


Patients with long-standing mitral valve disease are at risk of developing pulmonary hypertension (PH), which may present a formidable challenge for the cardiac anesthetist (perioperatively) during cardiac surgery 1. PH is an important risk factor for the development of acute right-sided heart failure during cardiac surgery 2. Even with early and adequate therapy, right ventricular (RV) failure is associated with increased morbidity and mortality 3. Adequate treatment of RV failure consists of different strategies. The main goal is to decrease RV afterload by using vasodilating agents 4 and reducing the pulmonary vascular tone 5. In this review, we will present an overview of the most recent management protocols used in the management of patients with secondary PH.


  Functional anatomy of the right ventricle and the pulmonary artery Top


The right ventricle consists of a flattened tube wrapped around the left ventricle, with separate inlet and outlet orifices and a presumed contraction pattern simulating peristalsis. Such an arrangement is suited for pumping blood against a low resistance 4.

The large pulmonary arteries have prominent concentric elastic laminae in their walls, although the walls are strikingly thinner than those of systemic arteries of a similar diameter. Elastic arteries have a minimum diameter of 1 mm, after which the elastic laminae become limited to internal and external laminae with circular muscles in between. These small arteries are referred to as muscular arteries, although the amount of muscle is slight when compared with analogous systemic vessels. Vessels smaller than 100 μm lose their muscular layer and have only a single elastic lamina 6.


  The right ventricle as a pump Top


In physiological conditions, the systolic RV function is somewhat secondary, because simple negative pleural pressure produced by breathing promotes blood flow through the pulmonary circulation and ensures sufficient pulmonary venous return. This is possible because the pulmonary circulation offers very little resistance to flow. In contrast, in pathological conditions, in which there is some increase in pulmonary vascular resistance (PVR), the RV systolic function becomes essential to promote pulmonary blood flow.

Normal RV contraction is complex and includes the following: shortening of the ventricle along its long axis by action of the spiral muscles, which moves the tricuspid annulus toward the apex; an inward motion of the free RV wall toward the interventricular septum (systolic septal thickening), which further reduces the volume of the cavity (contraction of the left ventricle); and traction of the free RV wall, which contributes to a RV systole. Unlike the left ventricle, right ventricle systolic shortening is limited along its short axis and marked along its long axis 7.


  Physiology of pulmonary circulation Top


Pulmonary circulation is a high-flow and low-pressure circuit, which favors pulmonary gas exchange by preventing fluid movement out of the pulmonary vessels into the interstitial space and allows the right ventricle to operate at a low energy cost. However, because of the low pressures, pulmonary circulation is very sensitive to mechanical influences (flow generator), and the right ventricle is thin walled, making it poorly prepared for rapid changes in loading conditions 6.


  Normal pulmonary vascular pressures and flows Top


The limits of normal resting pulmonary vascular pressures as derived from healthy resting supine young adults 8 are as follows:

  1. Pulmonary arterial pressure (PAP) systolic: mean, 19; limits of normal, 13–26 mmHg.
  2. PAP diastolic: mean, 10; limits of normal, 6–16 mmHg.
  3. PAP mean: mean, 13; limits of normal, 7–19 mmHg.
  4. PVR=mean PAP−mean left atrial pressure/Q, 67±30 dynes s/cm5 or 1±0.5 Wood units.


Mild to moderate levels of exercise normally do not increase mean pulmonary arterial pressure (mPAP) markedly, which reaches no more than the upper limit of normal of 20 mmHg; however, high levels of exercise may markedly increase pulmonary vascular pressure.

Therefore, as PH is defined as mPAP more than 20 mmHg at rest, it is also encountered if mPAP increases to more than 30 mmHg at exercise 9.


  Pathophysiology of pulmonary hypertension Top


PH is a general term for a disease process resulting in a progressive increase in the mPAP (mPAP≥25 mmHg at rest or ≥30 mmHg with exercise) 10.

According to the WHO revised clinical classification of Venice 2, pulmonary arterial hypertension (PAH) is a specific subtype of PH with a pulmonary capillary wedge pressure (PCWP) of 15 mmHg or less and a PVR of more than 3 Wood units. PAH can be idiopathic, familial, or secondary to a variety of conditions such as connective tissue disease, hemoglobinopathies, or HIV infection [Table 1] 2.
Table 1: Revised clinical classification of pulmonary hypertension

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Endothelial dysfunction resulting from an imbalance of endogenous vasoconstrictors (e.g. endothelin-1) and vasodilators (e.g. nitric oxide and prostacyclin) is thought to lead to vascular constriction, in-situ thrombosis, and progressive remodeling of the pulmonary arteries 11.

Vascular remodeling in PAH is characterized by distal pulmonary arterial smooth muscle cell hypertrophy and proliferation, with subsequent luminal narrowing and development of plexiform lesions. Regardless of the etiology, the pathological appearance is remarkably similar, suggesting an underlying, common disease pathway 12.

Patients with PH often present with signs and symptoms of right heart failure. The diagnostic evaluation includes a search for any underlying diseases, followed by right heart catheterization for the measurement of mPAP, PCWP, and PVR, and vasodilator testing. The 6 min walk test is performed at baseline and at follow-up to track exercise capacity and assess disease severity 13 [Figure 1].
Figure 1: Disease progression in pulmonary arterial hypertension 13. PAP, pulmonary arterial pressure.

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  Therapies for pulmonary hypertension Top


The treatment of secondary pulmonary artery hypertension (SPAH) is primarily directed at treatment of the underlying disease. Effective therapy should be instituted in the early stages, before irreversible changes in pulmonary vasculature occur. Once the cause of SPAH has been established, the management comprises specific interventional therapy, specific medical therapy, or general supportive therapy 14.

Specific interventional and medical therapies are instituted for conditions such as atrial septal defects, mitral stenosis, sleep apnea, and chronic pulmonary thromboembolic disease. General supportive therapy is administered to patients who have RV failure or to those in whom the cause cannot be addressed directly. The types of general supportive therapy are as follows.

Oxygen supplementation

Oxygen has a proven beneficial in reducing patient mortality in selected patients with PAH. Two large trials have demonstrated a definite mortality benefit for patients with chronic obstructive pulmonary disease, the most common cause of PAH. Survival rates are highest in patients who have less severe SPAH, in patients in whom the PAP decreases, or in patients in whom exercise capacity improves with oxygen therapy 15.

Vasodilators

Nitrates

The hemodynamic and antianginal actions of organic nitrates are mediated through vasodilatation of capacitance veins and conductive arteries. Dilatation of capacitance veins reduces ventricular volume and preload, thus lowering myocardial oxygen requirements and improving subendocardial blood flow 16.

Dilatation of systemic conductive arteries in combination with the reduction of left ventricular volume lowers the afterload, another determinant of myocardial oxygen consumption 16.

Nitrates dilate epicardial coronary arteries, including stenotic segments, which can have beneficial effects. Nitrates also dilate collateral vessels, which can improve blood flow to areas with ischemia 16.

(a) Sodium nitroprusside

Mechanism of action of organic nitrates: Organic nitrates are prodrugs and must be biodegraded to generate therapeutic effects. This biotransformation involves denitration of the nitrate with the subsequent liberation of nitric oxide. Nitric oxide stimulates guanylylcyclase, which leads to the conversion of guanosine triphosphate into cyclic guanosine monophosphate (cGMP), which in turn causes vasodilation 16.

(b) Nitric oxide

Nitric oxide is also known as endothelium-derived relaxing factor. In addition to exerting vasodilating effects, it reduces platelet adhesion and aggregation. Administration of nitrates has similar effects. Nitric oxide is also involved in the control of endothelial function and vascular growth as well as in myocardial contractility 17.

(c) Nitroglycerin

Mechanism of action: Nitroglycerin relaxes vascular smooth muscles, with venous dilatation predominating over arterial dilatation. Its mechanism of action is presumably similar to that of sodium nitroprusside.

Although vasodilator therapy can decrease PVR, very few studies show long-term clinical improvement in patients with secondary PH.

Vasodilators increase the cardiac output, and reduced peripheral vascular resistance results in only modest changes in PAP. Furthermore, vasodilators have short-term deleterious effects in a significant number of patients with secondary PH; these adverse effects include deterioration of the RV function, severe hypotension, worsening of ventilation due to ventilation–perfusion mismatch, and hypoxemia 18.

Calcium channel blockers

As pulmonary artery vasoconstriction may contribute to the pathogenesis of PAH, patients who may benefit from long-term therapy with calcium channel blockers can be identified by performing an acute vasodilator challenge 19.

A reduction of both mPAP and PVR by at least 20% is a usual indication for the initiation of oral therapy with calcium channel blockers. Long-term therapy with a calcium channel blocker is not recommended unless this criterion is met 19.

Prostacyclin therapy

Intravenous prostacyclin

Prostaglandin I2 (prostacyclin)

Prostaglandin I2 induces relaxation of vascular smooth muscles and inhibits their growth and platelet aggregation 20.

Epoprostenol

A prospective, randomized, open trial was carried out on 81 patients with primary pulmonary hypertension (PPH). After 12 weeks, epoprostenol therapy led to functional improvement, as shown by an improved 6-min walk test, and a decrease of 8% in mPAP. Epoprostenol is administered only by continuous intravenous infusion with the use of a portable infusion pump connected to a permanent catheter.

Common side effects of epoprostenol include jaw pain, headache, diarrhea, flushing, leg pain, and nausea, although they are generally mild and dose related. Other complications include catheter-related sepsis, pump failure, or dislocation of the central venous catheter. Sudden drug interruption may be life-threatening 21.

Subcutaneous treprostinil

Treprostinil is a stable prostacyclin analogue administered as a continuous subcutaneous infusion. A recent study showed that patients with PPH had an improvement in the 6-min walk distance, dyspnea, signs and symptoms of PH, and hemodynamic measurements. Local pain at the infusion site is a potential issue with this therapy 21.

Oral beraprost

Beraprost sodium is absorbed rapidly after oral administration and reaches a peak concentration after 30 min. It has an elimination half-life of 35–40 min.

Inhaled iloprost

Iloprost is a chemically stable prostacyclin analogue that can be delivered by an inhaler by producing aerosol particles that deposit in the alveoli. The disadvantage of iloprost is its short duration of action; therefore, it must be inhaled as many as six times a day 20.

Side effects of iloprost include cough, hypotension, and syncope. The long-term efficacy of inhaled iloprost remains to be established. Iloprost has been approved for treating PPH in Europe and the USA.

Endothelin receptor antagonists

Bosentan

Endothelin-1 exerts a direct vasoconstrictor effect and leads to the proliferation of vascular smooth muscle cells. It is a proinflammatory mediator 22. The effects of endothelin-1 are mediated through the EtA and EtB endothelin receptors. EtA receptors mediate sustained vasoconstriction and proliferation of vascular smooth muscle cells. EtB receptors result in clearance of endothelin and induce the production of nitric oxide and prostacyclin by endothelial cells. Bosentan is an orally active dual (EtA and EtB) endothelin receptor antagonist.

Sitaxsentan

Selective blockers of the endothelin receptor EtA, such as sitaxsentan 23, are being evaluated for the treatment of PAH. While blocking the vasoconstrictor effects of EtA receptors, the vasodilator and clearance effects of EtB receptors can be maintained simultaneously. Continuous monitoring of liver function is recommended.

Phosphodiesterase inhibitors type III

Milrinone, enoximone, amrinone

The efficacy of milrinone was shown in the European Milrinone Multicentre Trial and subsequently in the weaning of high-risk patients from cardio pulmonary hypertension (CPB) 24. Significant increases in stroke volume and the cardiac index and reductions in PCWP, right atrial pressure, mPAP, mean arterial pressure, and systemic vascular resistance were seen 24. Pharmacokinetic and pharmacodynamic studies have shown that a loading dose of 50 μg/kg of milrinone, followed by a continuous infusion of 0.50 μg/kg/min, results in a significant increases in the cardiac output and oxygen delivery after CPB 25.

Phosphodiesterase inhibitors type V

Sildenafil citrate, revatio, cialis

Mechanism of action: Sildenafil is a selective and potent inhibitor of phosphodiesterase type V. Phosphodiesterase type V specifically degrades cGMP and is found in high concentrations in pulmonary arteries and the corpora cavernosum 26.

Phosphodiesterase inhibitors type V increases the activity of endogenous nitric oxide and enhances cGMP-mediated pulmonary vasodilatation through inhibition of the breakdown of cGMP by phosphodiesterase type V. They have acute and prolonged vasodilatory effects in PH. A short-term study on intravenous sildenafil during right heart catheterization showed that sildenafil reduced PVR in a dose-dependent manner 26.

Sildenafil is a drug that has shown promise in PH. A recent randomized placebo-controlled study evaluated the efficacy of oral sildenafil in idiopathic PAH and PAH caused by Eisenmenger syndrome 26.

The primary endpoint of efficacy was an improvement in the distance covered in the 6-min walk test, which improved from 262 to 358.9 after treatment with sildenafil. The PAP decreased from 98 to 78 mmHg, and the New York heart association class improved 26.

No significant fall in blood pressure was observed with placebo and sildenafil, and no serious side effects of the drug were observed in the study. Although all the patients in this study had PPH, the drug could be effective in SPAH as well.

Combination therapy

To maximize the clinical benefit, the combined use of drugs with different mechanisms of action is a promising option for the treatment of PAH. Long-term combination therapies have recently been evaluated in patients with severe disease 18. Combined therapy with sildenafil or bosentan has produced favorable outcomes in some patients already receiving oral, inhaled, or intravenous prostacyclin analogues 18. Additional studies are needed to guide optimal use of combined therapy in patients with PAH.

Other therapies

Anticoagulants 18

Are used regularly in patients with primary PAH because they help reduce symptoms and may provide a survival benefit. The role of anticoagulants has not been established in patients with SPAH.

Nonetheless, anticoagulation with warfarin is indicated in patients with chronic pulmonary emboli, pulmonary veno-occlusive disease, and atrial fibrillation induced by left or right heart failure.

Fluid removal with diuretics 18

This procedure reduces hepatic congestion and pulmonary edema. However, diuresis should be instituted with caution to avoid hypokalemia, metabolic alkalosis, and a decrease in cardiac output. Phlebotomy should be considered if the patient’s hematocrit value is greater than 60%.

Digoxin 27

It has been shown to be beneficial for patients with supraventricular tachycardia or associated left ventricular dysfunction multifocal atrial tachycardia; however, verapamil has proven to be better than digoxin in controlling the heart rate.

Magnesium

It has a key role in cellular energy transfer and use (involving ATP) as well as in cell membrane function. It is widely used as an adjunct for the treatment of arrhythmias after myocardial infarction and CPB. Magnesium may influence hemodynamic performance through modulation of the vascular tone, intracellular calcium, catecholamine activity, and ATP metabolism 28.

Surgical therapy

Atrial septostomy

This procedure relieves pressure on the right side of the heart but at the cost of lower oxygen levels in blood (hypoxia) 18.

Lung transplantation

This procedure cures PAH, but leaves the patient with the complications of transplantation, and has a postsurgical median survival of just over 5 years 18.

Pulmonary thromboendarterectomy

This is a surgical procedure that is used for the treatment of chronic thromboembolic PH. It is a very difficult major procedure that is at present performed in a few select centers. Case series show remarkable success in most patients 29.


  Conclusion Top


PH and RV failure continue to be an intraoperative challenge to anesthetists; the main goal is proper understanding of the pathophysiology and implementation of proper management along with proper timing. The new phosphodiesterase inhibitors type V drugs provide a new promising hope in such cases and should be considered alone or as part of combined therapy.[29]

 
  References Top

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6.Ghofrani HA, Wiedemann R, Rose F, Olschewski H, Schermuly RT, Weissmann N, et al..Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension.Ann Intern Med2002;136:515–522.  Back to cited text no. 6
    
7.Lambertz H, Schuhmacher U, Tries HP, Stein T.Improvement of pulmonary venous flow Doppler signal after intravenous injection of Levovist.J Am Soc Echocardiogr1997;10:891–898.  Back to cited text no. 7
    
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14.Alexopoulos D, Lazzam C, Borrico S, Fiedler L, Ambrose JA.Isolated chronic mitral regurgitation with preserved systolic left ventricular function and severe pulmonary hypertension.J Am Coll Cardiol1989;14:319–322.  Back to cited text no. 14
    
15.Ashutosh K, Dunsky M.Noninvasive tests for responsiveness of pulmonary hypertension to oxygen. Prediction of survival in patients with chronic obstructive lung disease and cor pulmonale.Chest1987;92:393–399.  Back to cited text no. 15
    
16.Harrison DG, Bates JN.The nitrovasodilators: new ideas about old drugs.Circulation1993;87:1461–1467.  Back to cited text no. 16
    
17.Kelly RA, Balligand JL, Smith TW.Nitric oxide and cardiac function.Circ Res1996;79:363–380.  Back to cited text no. 17
    
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20.Christman BW, McPherson CD, Newman JH, King GA, Bernard GR, Groves BM, et al..An imbalance between the excretion of thromboxane and prostacyclin metabolites in pulmonary hypertension.N Engl J Med1992;327:70–75.  Back to cited text no. 20
    
21.Rosenzweig EB, Kerstein D, Barst RJ.Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects.Circulation1999;99:1858–1865.  Back to cited text no. 21
    
22.Rubin LJ, Badesch DB, Barst RJ, Galiè N, Black CM, Keogh A, et al..Bosentan therapy for pulmonary arterial hypertension.N Engl J Med2002;346:896–903.  Back to cited text no. 22
    
23.Langleben D, Hirsch AM, Shalit E, Lesenko L, Barst RJ.Sustained symptomatic, functional and hemodynamic benefit with the endothelin-A receptor antagonist, sitaxsentan, in patients with pulmonary arterial hypertension: a 1-year follow-up study.Chest2004;126:1377–1381.  Back to cited text no. 23
    
24.Doolan LA, Jones EF, Kalman J, Buxton BF, Tonkin AM.A placebo-controlled trial verifying the efficacy of milrinone in weaning high-risk patients from cardiopulmonary bypass.J Cardiothorac Vasc Anesth1997;11:37–41.  Back to cited text no. 24
    
25.Butterworth JF IV, Hines RL, Royster RL, James RL.A pharmacokinetic and pharmacodynamic evaluation milrinone in adults undergoing cardiac surgery.Anesth Analg1995;81:783–792.  Back to cited text no. 25
    
26.Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R.A randomized, placebo-controlled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension.Am Heart J2006;151:851.e1–851.e5.  Back to cited text no. 26
    
27.Palevsky HI, Fishman AP.Chronic cor pulmonale. Etiology and management.JAMA1990;263:2347–2353.  Back to cited text no. 27
    
28.Satur CMR.Magnesium and its role in cardiac surgical practice: a review.J Clin Basic Cardiol2002;5:67–73.  Back to cited text no. 28
    
29.Mellemkjær S, Ilkjær LB, Klaaborg KE, Christiansen CL, Severinsen IK, Nielsen Kudsk JE, et al..Pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension. Ten years experience in Denmark.Scand Cardiovasc J2006;40:49–53.  Back to cited text no. 29
    


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