**6. Treatment of PH**

114 Perioperative Considerations in Cardiac Surgery

ventricle, resulting in increased right ventricular free wall tension and myocardial oxygen

Normally, the pulmonary circulation is a low pressure, high flow vascular bed accommodating the entire cardiac output with each heartbeat. Elevated pulmonary vascular resistance (PVR) may significantly contribute to right ventricular dysfunction, which may compromise the preload of the left ventricle inducing systemic hypotension. In patients with pathologically increased PVR, the right ventricle and left ventricle are interdependent and have similar vitally important functions. Right ventricular dilatation causes shifting of the intraventricular septum towards the left ventricle, leading to a smaller underfilled left ventricular cavity. The normal thin walls and crescent shape of the right ventricle result in a highly compliant right ventricular chamber, which is able to accommodate large increases in volume. However, the right ventricular adaptive mechanisms are not well suited to acute, large increases in pressure, (Fischer et al., 2003),

Furthermore systemic hypotension decreases right ventricular coronary perfusion pressure and oxygen delivery. Therefore, a vicious circle starts that can lead to exacerbation of right

The existence of sophisticated monitoring in this particular group of patients is deemed necessary because early diagnosis and prompt institution of therapy for acute PH is

Diagnosis is aided by awareness of existing preoperative risk factors, such as valvular pathology or intracardiac shunts that are associated with PH. The development of acute PH will result in clinical signs of relatively rapid onset relating to the development of tricuspid regurgitation: prominent central venous atrioventricular pulsatile pressure waveforms, right-sided heart failure and a holosystolic murmur at the lower border of the sternum that

Pulmonary artery pressure catheterization and transesophageal echocardiography (TOE)

Pulmonary artery pressure catheterization will demonstrate elevated right atrial pressure, right ventricular end-diastolic pressure and pulmonary artery pressure with normal or low pulmonary wedge pressures. In the case of right ventricular dysfunction without pulmonary vasoconstriction, the pulmonary artery pressure may also be normal. Hemodynamic parameters calculated and derived by thermodilution will reflect elevated PVR and a reduction in right ventricular stroke work index and right ventricular stroke work index / central venous pressure relationship and a reduction in cardiac output or right

TOE is an invaluable tool in the diagnosis of PH and right ventricular dysfunction, demonstrating both right ventricular volume and pressure overload. The two- dimension mode provides a subjective view of the increased ratio of right ventricle-to- left ventricle chamber size, paradoxical septal bulging, and deterioration in right ventricular function as

Color flow mapping will often reveal pulmonary and tricuspid regurgitation. The use of continuous wave Doppler across the regurgitant tricuspid valve allows quantification of the

consumption.

as this may happen after CPB.

required in order to prevent right ventricular failure.

constitute a valid monitoring tool for early detection of acute PH.

seen on five-chamber and 4-chamber long axis views (Figure 1).

increases in intensity during inspiration.

ventricular ejection fraction.

ventricular dysfunction.

**5. Diagnosis of PH** 

Therapeutic strategies should be aimed at the prevention of acute perioperative PH or at the prevention of further increases in the already existing PH. The cornerstone of treatment lies in prevention of right ventricular failure brought about by the abrupt increase of right ventricular afterload, since impaired RV function is associated with poor outcome in the surgical and non-surgical setting.

It is important to underline that the treatment of perioperative PH in cardiac surgery patients should start as promptly as possible. If clinicians do not react early, a vicious circle may start and the discontinuation from CPB may prove extremely difficult. Right ventricular failure and low cardiac output can occur several hours after weaning from CPB, so a high level of vigilance is required during the entire postoperative period.

The incidence of postoperative acute refractory right ventricular failure is only about 0.1% after cardiotomy, but this can rise to around 2-3% after heart transplantation and even to 20- 30% when a left ventricular assist device has been implanted (Kaul & Fields, 2000).

The appropriate treatment in order to prevent right ventricular failure is based on the following principles (Winterhalter et al., 2010):


Readministration of heparin and postoperative reinstitution of CPB may be necessary in refractory cases.

#### **6.1 Intravenous vasodilators**

The main goal of pulmonary vasodilatation is to lower right ventricular impedance, so as to decrease afterload and thus improve ventricular performance.

Traditional methods of treatment for perioperative PH included nitrates, prostaglandins, phospodiesterase -3 inhibitors and calcium channel blockers. The aforementioned therapeutic modalities represent three distinct pharmacological pathways.

**Nitrates** (sodium nitroprusside-SNP, nitroglycerin-NTG) are NO donors, releasing NO spontaneously, which is normally located in biological tissues. Both agents decrease PVR, but because of their nonselectivity, they often decrease systemic blood pressure to a degree that impairs right ventricular perfusion and can cause ischemia.

Normally, the right ventricle is perfused during the entire cardiac cycle. In the presence of PH, the hypertrophic right ventricle generates elevated intracavital and intramural pressures, limiting the period of perfusion predominantly to diastole, thereby increasing the risk of right ventricular ischemia and failure in the presence of systemic hypotension. Therefore, nitrates can compromise right ventricular perfusion through their hypotensive action in the arterial part of the circulation. Furthermore, these drugs increase venous admixture by dilatation of pulmonary vessels supplying poorly ventilated alveoli and therefore abolishing the protective effect of hypoxic pulmonary vasoconstriction.

**Prostacyclins** (prostacyclin PGI2, prostaglandin-E1 PGE1) have been reported to have beneficial effects on pulmonary artery pressure and right ventricular function perioperatively. They act by stimulating adenylate cyclase to generate cAMP, but they also act non-selectively when administered intravenously and systemic hypotension limits their clinical effectiveness.

**Phosphodiesterase-3 inhibitors** (whose milrinone is the major representative) cause vasodilatation via inhibition of enzyme phosphodiesterase-3, increasing cAMP, which causes vasodilatation.

**Calcium channel blockers** also induce systemic vasodilatation but without sparing the systemic circulation.

Due the lack of selectivity to the pulmonary circulation of the aforementioned agents and the risk of a massive drop in the systemic blood pressure and right ventricular perfusion pressure, their administration should be avoided (Kieler-Jensen et al., 1993).

On the other hand, the importance of inhalable vasodilators has risen continuously over recent years. The advantage of these inhalable substances is their pulmonary selectivity and the subsequent reduction of systemic side effects, such as systemic hypotension. Also, the probability of ventilation-perfusion mismatch is low, as by inhalation primarily blood vessels close to the ventilated alveoli are dilated. The risks of shunt development and severe hypoxia are thus eliminated (Walmrath et al., 1997).

6.2 Inhalable vasodilators

The administration of inhalable pulmonary vasodilators, such as inhaled nitric oxide (NO), prostaglandins, NO donors (SNP-NTG) and milrinone is preferable over intravenous agents because of their pulmonary selectivity which is exerted without a concurrent increase in shunt fraction.

**Inhaled NO:** NO stimulates soluble guanylate cyclase (sGC) and increases cGMP. The latter activates cGMP- dependent protein kinases that are abundant in the cerebellum, smooth and cardiac myocytes, platelets, and leukocytes (Lucas et al., 2000). In turn, these kinases mediate a cGMP-induced decrease in intracellular calcium concentration in vascular smooth muscle and vasodilatation (Hanafy et al., 2001).

Inhaled NO is a selective pulmonary vasodilator without clinically significant effect on blood pressure and cardiac output. Its selective action results from the fixation of NO to the heme moiety of the hemoglobin molecule after passing through the pulmonary vessel wall. NO is then oxidized to nitrogen dioxide (NO2) and nitrogen trioxide (NO3). Hemoglobin is transformed to methemoglobin, which is secondarily reduced to hemoglobin by methemoglobin reductase. Although NO has no systemic hemodynamic effects, it does have extrapulmonary activity (Wang et al., 2003). That is, it interferes with platelet and leukocyte functions, fibrinolysis, and reperfusion injury by inhibiting expression of adhesion molecules at leukocyte surfaces and by activation of sCG, which lead to a rapid increase in platelet cGMP and inhibition of platelet aggregation. NOinduced favorable effect on cardiac function is based on reduction of right ventricular afterload. Even in patients with severe right ventricular dysfunction, NO improves cardiac output and right ventricular ejection fraction (Bhorade et al., 1999).Most of the studies used doses of 20 parts per million (ppm) (range 10-40 ppm). It is reasonable to start NO at the lowest possible dose and titrate upwards as required in patients with pulmonary hypertension.

Toxicity from NO results from the formation of methemoglobin, NO2 and peroxynitrite. Life-threatening increases in PVR have been noted with acute withdrawal of NO. To prevent rebound pulmonary hypertension, NO should be tapered off progressively without any attempt to discontinue it completely if FiO2 is higher than 50%. However, these disadvantages of NO therapy have called for research on inhaled alternatives to NO.

#### **Prostaglandins**

116 Perioperative Considerations in Cardiac Surgery

Readministration of heparin and postoperative reinstitution of CPB may be necessary in

The main goal of pulmonary vasodilatation is to lower right ventricular impedance, so as to

Traditional methods of treatment for perioperative PH included nitrates, prostaglandins, phospodiesterase -3 inhibitors and calcium channel blockers. The aforementioned

**Nitrates** (sodium nitroprusside-SNP, nitroglycerin-NTG) are NO donors, releasing NO spontaneously, which is normally located in biological tissues. Both agents decrease PVR, but because of their nonselectivity, they often decrease systemic blood pressure to a degree

Normally, the right ventricle is perfused during the entire cardiac cycle. In the presence of PH, the hypertrophic right ventricle generates elevated intracavital and intramural pressures, limiting the period of perfusion predominantly to diastole, thereby increasing the risk of right ventricular ischemia and failure in the presence of systemic hypotension. Therefore, nitrates can compromise right ventricular perfusion through their hypotensive action in the arterial part of the circulation. Furthermore, these drugs increase venous admixture by dilatation of pulmonary vessels supplying poorly ventilated alveoli and

**Prostacyclins** (prostacyclin PGI2, prostaglandin-E1 PGE1) have been reported to have beneficial effects on pulmonary artery pressure and right ventricular function perioperatively. They act by stimulating adenylate cyclase to generate cAMP, but they also act non-selectively when administered intravenously and systemic hypotension limits their

**Phosphodiesterase-3 inhibitors** (whose milrinone is the major representative) cause vasodilatation via inhibition of enzyme phosphodiesterase-3, increasing cAMP, which

**Calcium channel blockers** also induce systemic vasodilatation but without sparing the

Due the lack of selectivity to the pulmonary circulation of the aforementioned agents and the risk of a massive drop in the systemic blood pressure and right ventricular perfusion

On the other hand, the importance of inhalable vasodilators has risen continuously over recent years. The advantage of these inhalable substances is their pulmonary selectivity and the subsequent reduction of systemic side effects, such as systemic hypotension. Also, the probability of ventilation-perfusion mismatch is low, as by inhalation primarily blood vessels close to the ventilated alveoli are dilated. The risks of shunt development and severe

The administration of inhalable pulmonary vasodilators, such as inhaled nitric oxide (NO), prostaglandins, NO donors (SNP-NTG) and milrinone is preferable over intravenous agents because of their pulmonary selectivity which is exerted without a concurrent increase in

**Inhaled NO:** NO stimulates soluble guanylate cyclase (sGC) and increases cGMP. The latter activates cGMP- dependent protein kinases that are abundant in the cerebellum, smooth and

pressure, their administration should be avoided (Kieler-Jensen et al., 1993).

hypoxia are thus eliminated (Walmrath et al., 1997).

therefore abolishing the protective effect of hypoxic pulmonary vasoconstriction.

decrease afterload and thus improve ventricular performance.

that impairs right ventricular perfusion and can cause ischemia.

therapeutic modalities represent three distinct pharmacological pathways.

refractory cases.

clinical effectiveness.

causes vasodilatation.

systemic circulation.

6.2 Inhalable vasodilators

shunt fraction.

**6.1 Intravenous vasodilators** 

#### Inhaled **prostacyclin** (PGI2)

Prostacyclin is a member of the prostaglandin family derived from arachidonic acid.

Inhaled **prostacyclin** seems to be the more favorable agent because of its lack of toxicity, ease of application, and reduced cost. Similar to NO, it is produced by the vascular endothelium and is involved in the regulation of vascular tone and in localized thrombotic and inflammatory processes. PGI2 stimulates the endothelial release of NO, while NO, in turn, increases the synthesis of endogenous PGI2. In vivo, PGI2 is spontaneously hydrolyzed to its inactive metabolite 6-keto-prostaglandin-F1a with a half life of 3-6 min.

Inhaled PGI2 produces comparable effects to NO. The two agents have been compared in both animal and clinical studies, which have showed that inhaled PGI2 produces greater decreases in PVR while NO induces greater improvements in oxygenation (Lowson, 2002). Moreover, Fattouch et al (Fattouch et al., 2005) have shown similar effectiveness for NO and inhaled prostacyclin in the treatment of pulmonary hypertension after mitral valve replacement in a randomized, double-blinded clinical trial. PGI2 and its metabolites are remarkably non-toxic compared with NO. A prominent side-effect of inhaled PGI2 is inhibition of platelet aggregation. Impaired in vitro platelet aggregation was noted after 2h of inhaled PGI2 in patients undergoing cardiac surgery, but was not associated with an increase in chest tubes drainage or transfusion requirements even when therapy was continued for 6 h (Lowson, 2002). Systemic hypotension is another potential side effect of inhaled PGI2, suggesting that there is a minimal absorption of inhaled PGI2 from the lungs into the systemic circulation. Moreover, abrupt withdrawal of inhaled PGI2 may cause rebound increases in PH. (Lowson, 2002)

Variable dose delivery, alteration of ventilation volumes, pressures, FiO2, and solvent evaporation with drug-concentrating effect are other obvious disadvantages. Plasma halflife of prostacyclin is 3 to 6 minutes.
