**Cardiopulmonary bypass**

Pulmonary damage during cardiopulmonary bypass (CPB) is one of the important etiologies of PH in cardiac surgery. This is mainly due to the fact that the lungs are ischemic during CPB. The underlying mechanisms include 1) release of cytokines through endotoxin production (Downing & Edmunds, Jr., 1992), 2) complement activation and 3) ischemia reperfusion injury (Wan et al., 1997; Asimakopoulos et al., 1999) which leads to the production of free radicals, endothelin and prostacyclin derivatives with nitric oxide inhibition (Wan et al., 1997). The resulting systemic inflammatory response, pulmonary reperfusion syndrome as well as the transfusion of blood products may all exacerbate PH (Fig. **7**) (Lesage et al., 1966; Kaul & Fields, 2000).

The most important causes of PH in cardiac surgery, illustrated in Fig. **5**, are classified according to their originating anatomical site: pre-capillary, capillary and post-capillary.

Pulmonary embolism is an example of a pre-capillary PH. It may occur before, during or after CPB leading to the development or the exacerbation of PH. Thrombus, air and even carbon dioxide (Martineau et al., 2003) can cause pulmonary embolism. Pulmonary embolisms are rare in the immediate cardiac postoperative period. However, patients at risk include patients with predisposing factors to PH and patients with chronic thromboembolic pulmonary hypertension (CTEPH) (Fig. **6**). The incidence of CTEPH is uncertain, but it represents a frequent cause of PH occurring in up to 4% of patients after an acute

Fig. 6. Chronic pulmonary embolism. (**A, B**) Mid-esophageal ascending aorta (Ao) long-axis view in a 65-year-old woman with chronic pulmonary embolism shows the mobile clot adherent to the right pulmonary artery (RPA) wall. *(*LA: left atrium; LV: left ventricle). With

Pulmonary damage during cardiopulmonary bypass (CPB) is one of the important etiologies of PH in cardiac surgery. This is mainly due to the fact that the lungs are ischemic during CPB. The underlying mechanisms include 1) release of cytokines through endotoxin production (Downing & Edmunds, Jr., 1992), 2) complement activation and 3) ischemia reperfusion injury (Wan et al., 1997; Asimakopoulos et al., 1999) which leads to the production of free radicals, endothelin and prostacyclin derivatives with nitric oxide inhibition (Wan et al., 1997). The resulting systemic inflammatory response, pulmonary reperfusion syndrome as well as the transfusion of blood products may all exacerbate PH

pulmonary embolism (Pengo et al., 2004; Tapson & Humbert, 2006).

permission from Denault *et al*. (Denault et al., 2010a).

(Fig. **7**) (Lesage et al., 1966; Kaul & Fields, 2000).

**3.1 Review of the factors involved** 

**3.1.1 Pre-capillary Pulmonary embolism** 

**3.1.2 Capillary** 

**Cardiopulmonary bypass** 

Fig. 7. Unexpected pulmonary hypertension upon weaning from cardiopulmonary bypass (CPB) in a 76-year-old woman after aortic valve replacement (AVR). The CPB duration was 71 minutes. A significant increase in pulmonary arterial pressure in relation to the systemic arterial pressure was observed as the patient was weaned from CPB. No mechanical causes were found.

During CPB, blood is exposed to an artificial surface for oxygenation before it is sent back into the systemic circulation. This is associated with an inflammatory reaction secondary to endothelial activation, activation of the complement cascade, neutrophils, thrombin and platelets. Since the heart and lungs do not receive blood during CPB, cardioplegia solutions are used to preserve heart function, however, no specific protection is undertaken for the pulmonary circulation. In some patients, this may result in pulmonary reperfusion syndrome associated with postoperative endothelial dysfunction and PH or in post-CPB respiratory distress syndrome. The latter phenomenon, similar to the respiratory distress syndrome in adults, is characterized by an increased capillary permeability leading to a reduction in oxygenation, increased alveolar-arterial gradient, decreased lung compliance, increased pulmonary vascular resistance (PVR), and exacerbation of preoperative PH. Activation of the endothelin system during CPB increases endothelin ET-1 concentrations and correlates with CPB duration, severity of PH and post-CPB myocardial dysfunction. For this reason, CPB duration plays a major role in the incidence of mortality in cardiac surgery. Post-CPB PH can lead to RV dysfunction which, when severe, is fraught with a 44 to 86% mortality rate.

#### **Protamine**

The administration of protamine can induce catastrophic pulmonary vasoconstriction in up to 1.8% of patients (Ocal et al., 2005). Protamine is administered in CPB to neutralize the anti-clotting effects of heparin and has the capacity to activate the complement cascade. Thus, when given at the end of CPB, it can induce PH associated with adverse hemodynamic responses that range from minor perturbations to cardiovascular collapse, and may occur in three forms: systemic hypotension, anaphylactoid reaction and catastrophic PH (Viaro et al., 2002). The mechanism of protamine-induced PH is thought to be caused by an imbalance of vasoconstrictors and vasodilators leading to a reduction in nitric oxide release from the pulmonary vasculature (Viaro et al., 2002).

#### **Lung diseases and/or hypoxia**

In this category, the predominant cause of PH is alveolar hypoxia as a result of impaired control of breathing or lung disease.

Lung volumes exert a differential effect on the resistance of intra- and extra-alveolar vessels, which accounts for the unique U-shaped relationship between lung volume and pulmonary vascular resistance (PVR) (Fig. **8**). At functional residual capacity (FRC), PVR is minimal but increases at large or total lung capacity (TLC) and small lung volumes. Clinically, this may be observed when hyperinflation of the lungs greatly increases PVR (Fischer et al., 2003).

Fig. 8. Relationship between lung volume and pulmonary vascular resistance (PVR). At functional residual capacity (FRC) PVR is minimal and increases at large or total lung capacity (TLC) and residual volume decreases at small lung volumes. The differential effect on intra- and extra-alveolar vessels accounts for the U-shaped relationship of PVR and lung volume. Adapted from Fischer *et al*. (Fischer et al., 2003).

Changes in cardiac output (CO), airway pressure, and gravity may affect the pulmonary circulation. Therefore, patients with PH already have a restricted pulmonary circulation and increases in oxygen demand may further worsen PH and lead to right heart failure.

Application of high levels of positive end-expiratory pressure (PEEP) may narrow capillaries in well-ventilated lung areas (intra-alveolar) and divert blood flow to less wellventilated or non-ventilated areas (extra-alveolar). Thus, intrapulmonary shunts may result in desaturation of mixed venous blood, potentially leading to hypoxia.

anti-clotting effects of heparin and has the capacity to activate the complement cascade. Thus, when given at the end of CPB, it can induce PH associated with adverse hemodynamic responses that range from minor perturbations to cardiovascular collapse, and may occur in three forms: systemic hypotension, anaphylactoid reaction and catastrophic PH (Viaro et al., 2002). The mechanism of protamine-induced PH is thought to be caused by an imbalance of vasoconstrictors and vasodilators leading to a reduction in

In this category, the predominant cause of PH is alveolar hypoxia as a result of impaired

Lung volumes exert a differential effect on the resistance of intra- and extra-alveolar vessels, which accounts for the unique U-shaped relationship between lung volume and pulmonary vascular resistance (PVR) (Fig. **8**). At functional residual capacity (FRC), PVR is minimal but increases at large or total lung capacity (TLC) and small lung volumes. Clinically, this may be observed when hyperinflation of the lungs greatly increases PVR (Fischer et al., 2003).

Fig. 8. Relationship between lung volume and pulmonary vascular resistance (PVR). At functional residual capacity (FRC) PVR is minimal and increases at large or total lung capacity (TLC) and residual volume decreases at small lung volumes. The differential effect on intra- and extra-alveolar vessels accounts for the U-shaped relationship of PVR and lung

Changes in cardiac output (CO), airway pressure, and gravity may affect the pulmonary circulation. Therefore, patients with PH already have a restricted pulmonary circulation and

Application of high levels of positive end-expiratory pressure (PEEP) may narrow capillaries in well-ventilated lung areas (intra-alveolar) and divert blood flow to less wellventilated or non-ventilated areas (extra-alveolar). Thus, intrapulmonary shunts may result

increases in oxygen demand may further worsen PH and lead to right heart failure.

in desaturation of mixed venous blood, potentially leading to hypoxia.

volume. Adapted from Fischer *et al*. (Fischer et al., 2003).

nitric oxide release from the pulmonary vasculature (Viaro et al., 2002).

**Lung diseases and/or hypoxia** 

control of breathing or lung disease.

Hypoxia may also be caused by right-to-left intracardiac shunting through a patent foramen ovale (PFO) or a congenital heart defect. Pulmonary hypertension can lead to RV dysfunction causing increased pressure in the right atrium. In turn, the increase in Pra may result in opening of a PFO, present in 20-30% of the general population (Sukernik et al., 2001), increasing the severity of hypoxia. In contrast to systemic arteries, pulmonary vessels constrict with hypoxia (Euler-Liljestrand reflex) and dilate in the presence of hyperoxia (Fischer et al., 2003), which explains the exacerbation of PH with hypoxia.

Hypercapnia can occur especially in the case of acute lung injury during or after the procedure. The increase in partial pressure of carbon dioxide (PCO2) will cause vasoconstriction and therefore worsen PH.

Increases in CO distend open vessels and recruit previously closed vessels so that when the cross-sectional area of pulmonary circulation increases, PVR decreases.

Mechanical compression of pulmonary vessels is transmitted to the surrounding cardiac pressure and contributes to increase PAP. Hemothorax or tension pneumothorax may be responsible for an elevation in intrathoracic pressure.

In addition, gravity influences blood flow in the pulmonary circulation. Both regional blood flow and ventilation are greater in the dependent areas of the lung (intra-alveolar). Hence, the relationship between alveolar and hydrostatic pressure bears important clinical consequences.

Multiple molecular pathways are involved in the regulation of PVR, namely nitric oxide, prostacyclin, endothelin-1 and serotonin pathways (Humbert et al., 2004). Nitric oxide and prostacyclin are endogenous vasodilators produced in the pulmonary vascular endothelium. Endothelin-1 is an endogenous vasoconstrictor peptide secreted by the vascular endothelium and plays a role in pulmonary vasoconstriction and vascular smooth muscle proliferation (McLaughlin & McGoon, 2006). The neurotransmitter serotonin and the serotonin receptor transporter are also involved in the regulation of pulmonary vascular tone. Therefore, an imbalance in these pathways may result in vasoconstriction and vascular remodelling, potentially leading to progressive pulmonary vascular disease.
