**5. Hemodynamic consequences of acute pulmonary embolism**

#### **5.1. RV response to Acute PE**

**3.2. Electrocardiogram**

120 Pulmonary Hypertension

**4. Imaging studies**

**4.1. Echocardiography**

pattern may occur in 25-50% of patients.

The electrocardiographic manifestations of pulmonary embolism vary greatly from sinus tachycardia to conduction delays to patterns of RV strain (Panos 1988). Up to one quarter of patients with acute PE have normal electrocardiograms. Rhythm disturbances include tachycardia which is most common, atrial fibrillation, and atrial flutter. Conduction abnor‐ malities include first degree AV block, and left and right bundle branch block. The S1Q3T3

Multi-detector computed tomography pulmonary angiography (CTPA) is the current best imaging study for the diagnosis of acute PE (Mos 2012, Klok 2011). Image acquisition is timed to occur during opacification of the pulmonary arterial bed after an intravenous injection of contrast. This technique has both high sensitivity, 96-100%, and specificity, 97-98% (Remy-Jardin 2007). The use of intravenous contrast may be contraindicated in patients with allergies to iodinated contrast and those with renal insufficiency or who are at risk for contrast-induced nephropathy. A prospective study showed that 14 of 174 patients (8%) developed contrastinduced nephropathy after CTPA which significantly contributed to the adverse outcomes of patients suspected of having an acute PE (Mitchell 2012). The radiation exposure during a CTPA has been estimated to cause 150 excess cancer deaths per million scans (Remy-Jardin 2007). RV function can also be assessed during multi-detector CTPA and abnormal position of the interventricular septum, inferior vena cava contrast reflux, RV diameter to left ventricle (LV) diameter ratio > 1.0 and RV volume to LV volume ratio > 1.0 are predictive of poor outcomes and RV diameter to LV diameter ratio > 1.0 and RV volume to LV volume ratio > 1.0

In patients who are unable to undergo CTPA, ventilation perfusion scintigraphy (V/Q scan) is the next best imaging procedure for acute PE (Mos 2012). A normal V/Q scan effectively identifies patients who do not need anticoagulation treatment whereas a high probability V/Q scan has a positive predictive value >90% (PIOPED 1990). However, up to half of patients with suspected PE may have intermediate scans and require further testing to exclude or establish a diagnosis of PE (Anderson 2007). Intermediate scans occur less often in patients with a normal chest x-ray and no prior cardiopulmonary disease (Calvo-Romero 2005).

Transthoracic and transesophageal echocardiography (ECHO) can be used to image cardiac structure and function in patients with suspected PE. Rarely, intravascular thrombus can be visualized if the clot is large and located within the proximal pulmonary artery (Goldhaber 2002). Studies correlating perfusion lung scans with ECHO findings suggest that approxi‐ mately 92% of patients with PE and occlusion of greater than one third of the pulmonary vasculature demonstrate right ventricular hypokinesis (Wolfe 1994, McConnell 1996). Other echocardiographic findings in acute PE include right ventricular dilation, septal flattening and

are also predictive of 30 day mortality after acute PE (Kang 2011).

The response of the RV to acute PE depends upon its pre-existing level of function and hemodynamic relationship with the LV, the extent of pulmonary artery bed occlusion, and the degree of pulmonary arterial vasoconstriction caused by hypoxemia, release of vasoactive and bronchoactive mediators from platelets and vascular endothelial cells, and neural responses.

#### **5.2. Baseline cardiopulmonary status**

Approximately half of patients with acute PE have RV dysfunction at presentation and 14-17% have persistently reduced RV function six months later (Klok 2011, Stevinson 2007). Serial echocardiograms show that the PA pressure declines and RV dysfunction improves rapidly over the 30 days after presentation in approximately 90% of patients with acute PE and that age greater than 70 years and PAP greater than 50 mmHg are associated with persistent PH and RV dysfunction ( Ribeiro 1999).

#### **5.3. Extent of pulmonary vascular occlusion**

In a series of 690 patients diagnosed with PE, the number of occluded pulmonary artery segments ranged from 1 to 17 and was normally distributed with a mean of 9.2 segments representing 51.2% of the pulmonary arterial bed (Guintini 1995). Because the pulmonary vasculature is a high capacitance system, earlier studies suggested that occlusion of 70% or more of the pulmonary vasculature is required for the elevation of pulmonary pressures (Sabiston 1965, Wagenvort 1995). Subsequent studies using measures of pulmonary vascular bed occlusion such as the Miller index, the Walsh score, or the Qanadli index suggested that obstruction of at least 30-40% identifies greater than 90% of patients with RV dilation (Qanadli 2001). However, further studies have shown that the RV ejection fraction determined with or without electrocardiographic synchronization and the RV/LV ratio are better predictors of clinical outcome than the pulmonary artery obstruction index (van der Bijl 2011)

### **5.4. Effects of vasoactive and broncho-active mediators**

#### *5.4.1. Vasoactive mediators*

In experimental animal models of occlusive pulmonary embolism, blockage of vasoconstrict‐ ing mediators such as thromboxane A2 (TxA2), serotonin, endothelin-1, and prostaglandin F2alpha decreases pulmonary vascular resistance (Smulders 2000, Jones 2003, Reeves 1976 Reeves 1983, Todd 1981, Todd 1983, Breuer 1985, Battistini 2003, Kapsch 1981) suggesting that these factors play a significant role in increased pulmonary vascular resistance and elevated pulmonary pressures after acute PE.

pulmonary bed. The effect of acetylcholine and sympathomimetics on pulmonary artery pressure is dependent upon the resting pressure and the same mediator may have constricting or dilating effects depending upon whether the baseline pressure is normal or increased (Stratmann 2003). Acute PE may also trigger the short lived von Bezold-Jarisch reflex which is manifest by apnea, bradycardia, and hypotension and may contribute to sudden death associated with PE (Stratmann 2003). This reflex may be mediated by J receptors, pulmonary

Acute Thromboembolic Pulmonary Hypertension

http://dx.doi.org/10.5772/56719

123

The obstructive and vasoconstricting effects of acute PE on the pulmonary vasculature cause a sudden increase in the RV afterload that elevates RV wall tension dilating the RV, reducing its contractility, and impairing systolic and diastolic function. Right ventricular dilation distorts the anatomic configuration of the heart. Acute tricuspid valve insufficiency may be precipitated by elevated pulmonary arterial pressures coupled with physical dilation of the valvular annulus that causes misalignment of the leaflets. In addition, as the RV dilates, the interventricular septum flattens or bows toward the LV impairing its filling. LV preload is thus reduced by decreased RV output, tricuspid insufficiency, and diminished left ventricular filling. As preload falls, left ventricular output decreases and systemic hypotension ensues. Right ventricular ischemia or infarction may be caused by reduced myocardial perfusion, increased right ventricular wall tension, and compression of the right coronary artery reducing

After acute PE, neutrophilic infiltration of the right ventricular outflow tract occurs within 6 hours and subsequently resolves over the ensuing week (Watts 2008). Histopathologically, there is evidence of myocyte lysis and necrosis (Begieneman 2008) Monocytes are also present during the acute period and persist for at least 6 weeks; however, their phenotype transforms

The diagnostic evaluation of PE often is a multistep process which includes clinical evaluation, examination, laboratory assessment, and both noninvasive as well as invasive testing. Pulmonary angiography remains the gold standard to prove the presence of PE. However, this invasive test is not always readily available and does carry procedural risk. Other diagnostic modalities such as CTPA and V/Q scanning are used routinely in the assessment of possible

PE is suspected in many patients presenting with acute worsening of dyspnea or chest pain. When evaluating patients for the possibility of PE, the use of a validated tool to predict pretest

irritant receptors, and pulmonary C-fibers.

blood flow. (Piazza 2005, 2013) Figure 1.

from inflammatory to healing over this period (Watts 2008).

**5.5. Diagnosis of acute pulmonary embolism**

*5.4.4. Myocardial inflammation*

PE (Tapson 2012).

**6. Clinical prediction rules**

*5.4.3. RV response to changes in the pulmonary vasculature*

Platelets produce TxA2 after activation; other less significant sources of TxA2 are endothelial cells and monocytes (Smulders 2000). TxA2 production occurs quickly after PE and the level of production correlates with mortality in animal models (Reeves 1983). Reduction of TxA2 production by COX inhibitors diminishes the increase in pulmonary artery pressure by 40-60% in various models of PE (Weidner 1979Konstam 1987).

Within the lung, serotonin is produced by activated platelets and is a potent vasoconstrictor. Serotonin levels increase in the pulmonary circulation after PE and infusion of serotonin can produce hemodynamic changes similar to PE (Thompson 1986, Breuer 1985). Inhibition of monoamine oxidase which degrades serotonin accentuates the vascular response to PE and reduction of platelet serotonin by reserpine diminishes the hemodynamic effect of PE (Rosoff 1971, Miczoch 1978, Gurewich 1968). Serotonin inhibitors markedly reduce pulmonary vascular resistance in various animal models of PE and a combination of TxA2 and serotonin inhibitors completely prevents mortality due to massive PE in rabbits (Todd 1981, Todd 1983).

Prostacyclin (PGI2) is a vasodilator produced by endothelial cells that antagonizes many of the effects of TxA2 and serotonin. Blocking PGI2 production or its effects augments the deleterious hemodynamic effects of PE (Smulders 2000).

Endothelins are potent vasoconstrictors produced by various pulmonary cells including endothelial cells, epithelial cells, monocytes, and macrophages. These mediators are potent vascular and bronchial constrictors and induce increases in pulmonary vascular resistance, decreases in pulmonary compliance and hypoxemia due to deranged ventilation-perfusion relationships. The effect of endothelin receptor antagonists on the hemodynamic consequences of PE are complex and vary depending upon the PE model and animal species (Battistini 2003).

Intravascular hemolysis may also occur during acute PE releasing free hemoglobin that may decrease pulmonary nitric oxide which may promote pulmonary vasoconstriction (Kline 2009).

#### *5.4.2. Neural factors*

In the resting state, the pulmonary arterial tree is nearly maximally dilated with little or no resting tone (Stratmann 2003). Vasodilating innervation is variable throughout most of the pulmonary arterial system but is consistently present in arteries >700 micrometers in diameter. In contrast, noradrenergic vasoconstrictive innervation is present throughout the entire pulmonary bed. The effect of acetylcholine and sympathomimetics on pulmonary artery pressure is dependent upon the resting pressure and the same mediator may have constricting or dilating effects depending upon whether the baseline pressure is normal or increased (Stratmann 2003). Acute PE may also trigger the short lived von Bezold-Jarisch reflex which is manifest by apnea, bradycardia, and hypotension and may contribute to sudden death associated with PE (Stratmann 2003). This reflex may be mediated by J receptors, pulmonary irritant receptors, and pulmonary C-fibers.

#### *5.4.3. RV response to changes in the pulmonary vasculature*

The obstructive and vasoconstricting effects of acute PE on the pulmonary vasculature cause a sudden increase in the RV afterload that elevates RV wall tension dilating the RV, reducing its contractility, and impairing systolic and diastolic function. Right ventricular dilation distorts the anatomic configuration of the heart. Acute tricuspid valve insufficiency may be precipitated by elevated pulmonary arterial pressures coupled with physical dilation of the valvular annulus that causes misalignment of the leaflets. In addition, as the RV dilates, the interventricular septum flattens or bows toward the LV impairing its filling. LV preload is thus reduced by decreased RV output, tricuspid insufficiency, and diminished left ventricular filling. As preload falls, left ventricular output decreases and systemic hypotension ensues. Right ventricular ischemia or infarction may be caused by reduced myocardial perfusion, increased right ventricular wall tension, and compression of the right coronary artery reducing blood flow. (Piazza 2005, 2013) Figure 1.

#### *5.4.4. Myocardial inflammation*

**5.4. Effects of vasoactive and broncho-active mediators**

in various models of PE (Weidner 1979Konstam 1987).

hemodynamic effects of PE (Smulders 2000).

2009).

*5.4.2. Neural factors*

In experimental animal models of occlusive pulmonary embolism, blockage of vasoconstrict‐ ing mediators such as thromboxane A2 (TxA2), serotonin, endothelin-1, and prostaglandin F2alpha decreases pulmonary vascular resistance (Smulders 2000, Jones 2003, Reeves 1976 Reeves 1983, Todd 1981, Todd 1983, Breuer 1985, Battistini 2003, Kapsch 1981) suggesting that these factors play a significant role in increased pulmonary vascular resistance and elevated

Platelets produce TxA2 after activation; other less significant sources of TxA2 are endothelial cells and monocytes (Smulders 2000). TxA2 production occurs quickly after PE and the level of production correlates with mortality in animal models (Reeves 1983). Reduction of TxA2 production by COX inhibitors diminishes the increase in pulmonary artery pressure by 40-60%

Within the lung, serotonin is produced by activated platelets and is a potent vasoconstrictor. Serotonin levels increase in the pulmonary circulation after PE and infusion of serotonin can produce hemodynamic changes similar to PE (Thompson 1986, Breuer 1985). Inhibition of monoamine oxidase which degrades serotonin accentuates the vascular response to PE and reduction of platelet serotonin by reserpine diminishes the hemodynamic effect of PE (Rosoff 1971, Miczoch 1978, Gurewich 1968). Serotonin inhibitors markedly reduce pulmonary vascular resistance in various animal models of PE and a combination of TxA2 and serotonin inhibitors completely prevents mortality due to massive PE in rabbits (Todd 1981, Todd 1983).

Prostacyclin (PGI2) is a vasodilator produced by endothelial cells that antagonizes many of the effects of TxA2 and serotonin. Blocking PGI2 production or its effects augments the deleterious

Endothelins are potent vasoconstrictors produced by various pulmonary cells including endothelial cells, epithelial cells, monocytes, and macrophages. These mediators are potent vascular and bronchial constrictors and induce increases in pulmonary vascular resistance, decreases in pulmonary compliance and hypoxemia due to deranged ventilation-perfusion relationships. The effect of endothelin receptor antagonists on the hemodynamic consequences of PE are complex and vary depending upon the PE model and animal species (Battistini 2003).

Intravascular hemolysis may also occur during acute PE releasing free hemoglobin that may decrease pulmonary nitric oxide which may promote pulmonary vasoconstriction (Kline

In the resting state, the pulmonary arterial tree is nearly maximally dilated with little or no resting tone (Stratmann 2003). Vasodilating innervation is variable throughout most of the pulmonary arterial system but is consistently present in arteries >700 micrometers in diameter. In contrast, noradrenergic vasoconstrictive innervation is present throughout the entire

*5.4.1. Vasoactive mediators*

122 Pulmonary Hypertension

pulmonary pressures after acute PE.

After acute PE, neutrophilic infiltration of the right ventricular outflow tract occurs within 6 hours and subsequently resolves over the ensuing week (Watts 2008). Histopathologically, there is evidence of myocyte lysis and necrosis (Begieneman 2008) Monocytes are also present during the acute period and persist for at least 6 weeks; however, their phenotype transforms from inflammatory to healing over this period (Watts 2008).

#### **5.5. Diagnosis of acute pulmonary embolism**

The diagnostic evaluation of PE often is a multistep process which includes clinical evaluation, examination, laboratory assessment, and both noninvasive as well as invasive testing. Pulmonary angiography remains the gold standard to prove the presence of PE. However, this invasive test is not always readily available and does carry procedural risk. Other diagnostic modalities such as CTPA and V/Q scanning are used routinely in the assessment of possible PE (Tapson 2012).
