Acute Pulmonary Hypertension

Jochen D. Muehlschlegel

Nicole Dobija

Emilio B. Lobato

CASE SUMMARY

A 67-year-old man with coronary artery disease is scheduled for myocardial resvascularization under cardiopulmonary bypass (CPB). He has a history of diabetes mellitus and requires daily subcutaneous NPH insulin. Intraoperative monitoring includes a pulmonary artery catheter and transesophageal echocardiography (TEE). Surgical revascularization is uneventful, and separation from CPB is accomplished without the use of inotropic agents. TEE findings shows good biventricular function, and his pulmonary artery pressure (PAP) is 25/16 mmHg. The initiation of intravenous protamine is associated with a sudden increase of PAP (65/40 mm Hg) and severe systemic hypotension (50/30 mmHg). TEE demonstrates a dilated and hypokinetic right ventricle (RV) with severe tricuspid regurgitation. The infusion of protamine is stopped, and CPB is reinstituted. A bolus of intravenous epinephrine, followed by an infusion, restores systemic blood pressure and improves right ventricular function. Milrinone and nitroglycerin are initiated and adjusted to avoid systemic hypotension. The patient experiences a gradual recovery over several minutes, with significant improvement in right ventricular function and decreased PAP within baseline values. Subsequently, he is weaned from CPB without any incident. After transfusion of multiple blood products and vigorous surgical hemostasis, he is transferred to the intensive care unit where he exhibits an uncomplicated recovery.

What Is the Normal Physiology of the Pulmonary Circulation?

The lungs are the only organs that receive the entire cardiac output (CO), and are able to accommodate this high flow by their low resistance.¹ Anatomically, pulmonary arterial vessels have larger diameters than their systemic counterparts, with a wall thickness only one third that of the aorta due to a thinner media and fewer smooth muscle cells (SMCs).²

The pulmonary circulation is a low pressure, low resistance circulation capable of handling large increases in flow. Normal PAP is approximately 25/8 mm Hg, with a mean pulmonary arterial pressure (MPAP) of 15 mm Hg, or approximately one sixth of the systemic circulation, and is maintained even with several-fold increase in flow. Although inherently imperfect, the following formula is frequently used in the clinical arena to derive pulmonary vascular resistance (PVR):

PVR = (MPAP — LAP)/CO

where PVR = pulmonary vascular resistance, MPAP = mean pulmonary artery pressure, LAP = left atrial pressure (or its surrogate, pulmonary artery occlusion pressure), and CO = cardiac output. The normal values are 1 to 1.5 Wood units or 80 to 120 dynes per cm³ (multiplying Wood units by 80). Other measurements include the transpulmonary gradient (TPG) (MPAP—LAP; nL ≈ 5 to 10 mm Hg) and the mean systemic arterial-to-pulmonary artery pressure ratio (normal ≥6 mmHg). PAP increases minimally with age, exercise, or high output states (e.g., pregnancy, anemia). However, the healthy lung has several compensatory mechanisms to attenuate an increase in intravascular pressure.

Of foremost importance is the presence of a large, recruitable vasculature, which is responsible for maintaining a constant PAP and PVR in response to increased pulmonary flow during exercise. Additionally, active pulmonary vasodilation occurs, which is regulated by endogenous nitric oxide (NO) and prostacyclin (PGI2).³ When pulmonary endothelial cells are exposed to chemical or mechanical stress, they synthesize NO and prostaglandin I2 (PGI2), which then diffuse toward SMCs. Nitric oxide mediates an increase in SMC cyclic guanosine monophosphate (cGMP), whereas PGI2 increases cyclic adenosine monophosphate (cAMP). Both intracellular mediators are known to facilitate smooth muscle relaxation.

How Does the Right Ventricle Differ from the Left Ventricle?

The RV provides low pressure perfusion to the pulmonary circulation, and is sensitive to changes in loading conditions and intrinsic contractility.⁴,⁵ The RV wraps around the left ventricle (LV) in a crescent shape, contracting in a peristaltic fashion. Contraction occurs in three phases and in different anatomic locations in the RV. The crista supraventricularis separates the sinus, or inflow, of the RV from the conus, or outflow. The sinus contracts first, most likely due to a higher Purkinje fiber density, thereby generating the initial RV pressure, whereas the conus sustains the pressure.⁴ First, there is contraction of the papillary muscles, followed by inward movement of the RV free wall toward the interventricular septum. Lastly, contraction of the LV causes wringing and further emptying of the RV. Unlike the LV, contraction of the RV is associated with sustained ejection during pressure increase and decline.⁴ Under normal loading conditions, the RV ejects blood against <25% of the resistance of the LV.⁶ This phenomenon explains the much thinner chamber walls of the RV, making it more compliant and susceptible to changes in preload.

The RV also has a more favorable myocardial oxygen supply/demand profile than the LV. Coronary blood flow occurs during both systole and diastole because of factors such as lower intramyocardial resistance, less subendocardial compression, and favorable left-to-right transcoronary collateral gradient. Right ventricular oxygen demand is reduced compared to the LV due to its smaller muscle mass and lower systolic and diastolic pressures. The RV has a dual blood supply: the right coronary artery supplies the ventricular free wall and inferior third of the interventricular septum, whereas the perfusion of the anterior RV and the anterior two thirds of the septum is derived from branches of the left anterior descending artery.

In the past, abnormalities of the RV have been attributed solely to a failing right ventricular myocardium, outflow obstruction, or an excessive volume load that cannot be handled by the thinner musculature of the RV. Recently, however, it has been demonstrated that interventricular dependence is essential for normal biventricular function, especially for optimal right ventricular physiology.⁷ The close anatomic relation between the right and left ventricle, along with circular muscle fibers spanning both ventricles, explain their interdependence. Experimental studies have shown that adequate LV contraction is responsible for 20% to 40% of right ventricular systolic pressure and ejection.⁸

TABLE 17.1 Relation between Pulmonary Flow, Pressure, and Resistance

Condition	MPAP [mm Hg] (Upstream Pressure)	LAP [mm Hg] (Downstream Pressure)	<TPG [mm Hg]	Pulmonary Flow	PVR^a
Normal	15	10	5	5.0	1.0
↑ flow	25	10	15	10.0	1.5
↑ downstream pressure	30	25	5	5.0	1.0
↑ PVR	30	10	20	5.0	4.0
↑↑↑ PVR	25	5	20	2.5	8.0
^aPVR, pulmonary vascular resistance (Wood Units-[TPG/pulmonary flow]).
MPAP, mean pulmonary arterial pressure; LAP, left atrial pressure; TPG, transpulmonary gradient.

What Constitutes Pulmonary Hypertension?

Owing to the dynamic state of the pulmonary circulation, PAP often fluctuates. However, because of the various compensatory mechanisms normally present, such values are kept within a relatively narrow range. Pulmonary hypertension is said to be present if the MPAP is >25 mmHg (normal 15 mmHg) at rest or >30 mmHg during exercise.⁹

It is important to recognize that increased PAP is not necessarily ominous; conversely, the presence of a normal PAP may not be reassuring. This is best explained by analyzing the components of the formula utilized to calculate PVR, as previously shown. Table 17.1 shows the relation between the pulmonary artery and LAP, flow, and resistance in various pathophysiologic states. In the perioperative period, most episodes of pulmonary hypertension are associated with a significant component of pulmonary vasoconstriction, either in response to acute elevation of LAPs or as a primary pulmonary pathology (e.g., embolism, hypoxia, reperfusion).

What Is the Etiology of Chronic Pulmonary Hypertension?

In 1998, during the Second World Symposium on Pulmonary Hypertension, a clinical classification of pulmonary hypertension was proposed and then modified in 2003 (see Table 17.2).

Regardless of the etiology, chronic pulmonary hypertension is characterized by SMC, fibroblast proliferation, and pulmonary vascular remodeling; this results in
endothelial thickening and hyperplasia, causing an increase in PVR. Vascular endothelial cell dysfunction or injury leads to an imbalance between vasodilators and vasoconstrictors, prothrombotic and antithrombotic elements, growth inhibitor, and mitogenic factors.¹⁰

TABLE 17.2 WHO Classification of Chronic Pulmonary Hypertension

Pulmonary Arterial Hypertension (PAH)
Idiopathic (IPAH)
Familial (FPAH)
Associated (APAH):
	Collagen vascular disease
	Congenital systemic-to-pulmonary shunts
	Portal hypertension
	HIV infection
	Drugs and toxins
	Other
Associated with significant venous or capillary involvement:
	Pulmonary veno-occlusive disease (PVOD)
	Pulmonary capillary hemangiomatosis (PCH)
Persistent pulmonary hypertension of the newborn
Pulmonary Hypertension with Left Heart Disease
Left-sided atrial or ventricular heart disease
Left-sided valvular heart disease
Pulmonary Hypertension Associated with Lung Diseases and/or Hypoxemia
Chronic obstructive pulmonary disease
Interstitial lung disease
Sleep-disordered breathing
Alveolar hypoventilation disorders
Chronic exposure to high altitude
Development abnormalities
Pulmonary Hypertension Due to Chronic Thrombotic and/or Embolic Disease
Thromboembolic obstruction or proximal pulmonary arteries
Thromboembolic obstruction of distal pulmonary arteries
Nonthrombotic pulmonary embolism (tumor, parasites, foreign material)
Miscellaneous
Sarcoidosis
Pulmonary Langerhans cell histiocytosis
Lymphamgiomatosis
Compression of pulmonary vessels by adenopathy
Tumor
Fibrosing mediastinitis
Other process
WHO World Health Organization; HIV, human immunodeficiency virus.
From: Simmonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43:10S. Copyright 2004 American College of Cardiology Foundation.

Idiopathic pulmonary hypertension (IPH), formerly known as primary pulmonary hypertension, is extremely rare, associated with very high PAPs (>60 mmHg), and carries a poor prognosis.⁹

Secondary pulmonary hypertension is more common and, in general, is less severe than IPH. It is more likely to be encountered in the perioperative setting.¹¹ Symptoms and signs usually do not reflect the underlying disease but rather the impact of the abnormal pulmonary vasculature on the RV, pulmonary pressures, and oxygen saturation.¹² Secondary pulmonary hypertension can be divided into the following three categories:

Pulmonary venous hypertension
Pulmonary vascular obstruction
Hypoxemia

Pulmonary venous pressure elevation usually results from left ventricular pathology (e.g., mitral valve disease, diastolic dysfunction) or pulmonary veno-occlusive disease (e.g., drug related, invasive tumors). With pulmonary vascular obstruction, one has to differentiate between those disease processes from parenchymal disease (e.g., interstitial lung disease, cystic fibrosis) and those without (e.g., pulmonary embolus, vasculopathy). Lastly, hypoxemia can be a result of living at high altitude, having an underlying central neurologic ventilatory problem, or having airway disease (e.g., asthma, obstructive sleep apnea). Often, secondary pulmonary hypertension is multifactorial rather than the result of one isolated disease process.

What Is the Role of the Right Ventricle in Chronic Pulmonary Hypertension?

Unlike acute pulmonary hypertension (APH) that frequently precipitates right ventricular failure in a previously normal individual, the presence of a gradual increase in PAP (e.g., lung disease, chronic obstructive pulmonary disease [COPD], chronic thromboembolic diagnosis) is relatively well tolerated initially. Alteration of the RV structure or function due to pulmonary hypertension caused by disease to the lung or the pulmonary vasculature lead to hypertrophy and later to dilatation. The term cor pulmonale is utilized to describe such condition.

With slow progression of the underlying lung disease, the RV adapts by assembling new sarcomeres in parallel to increase wall thickness;⁴ therefore, the RV will take on a more spherical shape and resemble the LV.¹³ Once myocyte and chamber contractile dysfunction develop, the RV will begin to dilate and transit from concentric to
eccentric hypertrophy. Further progression of the disease, or the presence of a stimulus triggering acute pulmonary vasoconstriction, may result in decompensated RV failure.

What Is the Etiology of Acute Pulmonary Hypertension?

The pulmonary vasculature is composed 40% of capillaries, 50% of arteries, and 10% of veins, whereby only arteries and veins are able to actively dilate and constrict SMCs. Physiologically, the release of endothelial cell-mediated vasodilators (NO, PGI2) maintains a low PVR. According to Poiseuilles law, PVR is inversely related to the fourth power of the radius of the pulmonary artery or arterioles. Therefore, even mild structural or functional narrowing of the pulmonary vasculature can increase PAP. Mediator-induced vasoconstriction or a loss of physiologic vasodilation will increase PVR and subsequently PAP. Important etiologic factors responsible for perioperative APH are shown in Table 17.3

Thrombi can be microscopic or macroscopic in size. Microscopic thrombi are a result of an imbalance between procoagulatory and anticoagulatory factors, often a consequence of endothelial damage or systemic coagulation. Sepsis and the acute respiratory distress syndrome (ARDS) are classic examples of microscopic thrombi, in which the increase in PAP is more gradual. This is in sharp contrast to macroscopic thrombi or emboli that can cause acute catastrophic obstruction and vasoconstriction, leading to acute right ventricular failure and cardiovascular collapse. The topic of pulmonary embolism is discussed in detail in Chapter 13.

TABLE 17.3 Etiology of Perioperative Pulmonary Hypertension

Embolism
	Clots
		Deep vein thrombosis
		Opening tourniquet
		Labor and pregnancy
	Fat (bone cement)
	Air embolism
		Iatrogenic
	Negative venous pressure (e.g., sitting craniotomy)
	CO₂ embolism
		Laparoscopy
	Amniotic fluid
Drug-induced pulmonary vasoconstriction
	Protamine
Ischemia-reperfusion
	Congenital heart disease surgery
	Aortic declamping
	Post cardiopulmonary bypass
Diffuse lung injury
Loss of pulmonary parenchyma

Those undergoing CPB represent a unique subset of patients, in whom the development of pulmonary hypertension is actually a predictor of long-term mortality and myocardial infarction.¹¹ Organ damage after CPB is produced by two closely related mechanisms: Systemic inflammatory response syndrome (SIRS) and ischemia/reperfusion injury. The SIRS is triggered by the exposure of blood to the large synthetic contact surfaces of the extracorporeal circulation, whereas ischemia/reperfusion injury triggers effects mainly in the heart and lungs.¹⁴,¹⁵,¹⁶ The pulmonary endothelium has a central role in the pathophysiology of APH.¹⁷ The endothelial cells modulate pulmonary vascular tone through the release of endothelium-derived, constricting factor (EDCF) and endothelium-derived relaxing factors (EDRFs), including endothelin-1, NO, and prostacyclin.¹⁸ Injury will cause an imbalance between these factors and an increased production of the very potent vasoconstrictor, endothelin-1.

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