Pulmonary hypertension, defined as a mean pulmonary artery pressure (mPAP) greater than 25 mm Hg, is a common finding in critically ill patients. It can be related to the underlying critical illness (respiratory failure, pulmonary embolism, decompensated heart failure), pre-existing conditions (left-sided heart disease, chronic obstructive pulmonary disease (COPD), interstitial lung disease), or may be the primary cause of critical illness, as in the case of decompensated right heart failure due to pulmonary arterial hypertension (PAH). Initiation of appropriate therapy requires differentiating among these possible etiologies.

Pulmonary hypertension is classified into five groups based on similar pathology and response to treatment, according to the fourth World Symposium on Pulmonary Hypertension (Table 56.1) [1]. In this classification, groupings are based on whether the primary abnormality is in the precapillary arteries and arterioles (Group 1), postcapillary pulmonary veins and venules (Group 2), alveoli and capillary beds (Group 3), or due to chronic thromboemboli (Group 4). Group 5 comprises causes of pulmonary hypertension with multiple or unclear mechanisms.

PAH refers only to Group 1 and is distinct from other forms of pulmonary hypertension. PAH can be idiopathic (IPAH, formerly primary pulmonary hypertension or PPH), heritable (HPAH), or associated with underlying conditions such as collagen vascular disease, congenital heart disease, portal hypertension, HIV infection, and specific drugs (e.g., fenfluramine) or toxins (e.g., rapeseed oil). Pulmonary venous hypertension is the result of elevated pulmonary venous (e.g., sclerosing mediastinitis) or left-sided cardiac filling pressures that lead to passive elevation in pulmonary artery pressures (PAPs). This is typically caused by left ventricular (LV) systolic or diastolic heart failure, or valvular heart disease (mitral or aortic regurgitation or stenosis). Lung disease can cause pulmonary hypertension due to alveolar hypoxemia (hypoxic pulmonary vasoconstriction) and vascular destruction [2]. Chronic thromboembolic pulmonary hypertension (CTEPH) can be due to proximal and/or distal obstruction of the pulmonary vasculature by chronic thromboemboli.

Pulmonary hypertension related to critical illness can occur through multiple mechanisms, and therefore patients may fall into any of the above-described groups (Table 56.2). However, no matter the group, or the reason for admission to the intensive care unit (ICU), right heart failure in this setting is associated with a poor prognosis. Among patients with PAH or inoperable CTEPH admitted to the ICU with decompensated right heart failure, infection is the most commonly identified trigger (23% to 27%), with other causes including drug or dietary noncompliance, arrhythmia, pulmonary embolism, and pregnancy. In approximately 50% of cases of decompensated right heart failure, no precipitating etiology can be identified, suggesting it is due to underlying disease progression. Decompensated right heart failure requiring ICU admission is associated with a high mortality rate (32% to 41%) [3,4].

Decompensation of left heart disease can cause or worsen pulmonary venous hypertension. Exacerbations of chronic hypoxemic lung disease (chronic obstructive lung disease or interstitial lung disease) can be associated with pulmonary hypertension. Acute pulmonary embolism can cause pulmonary hypertension, depending on the degree of vascular obstruction. In a patient with normal pulmonary vasculature, greater than 50% obstruction of the pulmonary vasculature must occur before pulmonary hypertension occurs. Pulmonary hypertension may also occur following acute pulmonary embolism with lesser degree of pulmonary vascular obstruction in patients with underlying cardiopulmonary disease [5].

Pulmonary hypertension complicates most cases of acute respiratory distress syndrome (ARDS); for example, it has been reported in 93% to 100% of patients with severe ARDS [6,7]. When pulmonary hypertension occurs, it is almost always mild to moderate in severity; only 7% of patients have severe pulmonary hypertension [7]. The magnitude of pulmonary hypertension in ARDS correlates with severity of lung injury [8] and has adverse prognostic significance [9]. More recent data in the era of low tidal volume ventilation have demonstrated a significantly lower prevalence of echocardiographically detected acute cor pulmonale (25% vs. 61%) in patients with ARDS. The lack of direct hemodynamic data and differences in data acquisition in these studies (transesophageal vs. transthoracic echocardiograms) precludes definitive conclusion; however, these studies suggest that the incidence of pulmonary hypertension in ARDS may have decreased with changes in mechanical ventilation strategies [10,11]. Furthermore, a recent study has demonstrated a low rate of right ventricular (RV) failure among patients with ARDS [12].

The pulmonary circulation is the only vascular bed that accommodates the entire cardiac output while maintaining both low pressure and low vascular resistance. Normally, the pulmonary vasculature is able to accommodate increases in cardiac output without increases in pressure or resistance via dilation of pulmonary vessels and recruitment of previously closed vessels [13]. Pulmonary hypertension develops when abnormalities of the pulmonary vasculature lead to increases in pulmonary vascular resistance (PVR) and therefore increased RV afterload.

Because the RV normally ejects blood against a significantly lower afterload than the LV, it has a thinner wall and is therefore more compliant. This allows it to accommodate large increases in volume (preload). However, increases in afterload result in proportionate decreases in RV stroke volume [14]. Decreased RV stroke volume reduces blood return to the LV, thereby decreasing cardiac output. In addition, RV pressure overload causes “ventricular interdependence,” in which elevated right ventricular end-diastolic pressure (RVEDP) causes bowing of the interventricular septum toward the LV during diastole, preventing LV diastolic filling and further reducing cardiac output [15,16,17]. RV pressure overload can also open the foramen ovale, allowing the shunting of blood from right to left, with resultant hypoxemia [14].

Patients with PAH share common pathologic findings including intimal fibrosis, increased medial thickness, pulmonary arteriolar occlusion, and plexiform lesions [18]. Multiple molecular pathways involved in the pathogenesis of IPAH have been identified [19]. Patients with IPAH have an increase in mediators of vasoconstriction and vascular smooth muscle cell proliferation (thromboxane A2, Endothelin-1) [20,21,22] and a decrease in substances that promote pulmonary vasodilation and inhibition of vascular smooth muscle cell proliferation (prostacyclin, nitric oxide, vasoactive intestinal peptide) [23,24,25].

Pathologic findings of pulmonary hypertension associated with ARDS vary with the time course of illness. Micro- and macrothrombi have been demonstrated in most patients. Early in disease, there are findings of acute endothelial cell injury. In the intermediate phase, chronic capillary changes, fibrocellular obliteration of arteries, veins, and lymphatics can occur. Vascular remodeling with distorted, tortuous arteries and veins, arterial muscularization, and reduced capillary number are seen in late stages [26]. While hypoxia and hypoxic pulmonary vasoconstriction likely play a role in the pathogenesis of pulmonary hypertension seen in ARDS, both the pathologic findings and the persistence of pulmonary hypertension in ARDS even after correction of severe hypoxemia [27] suggest the presence of additional pathogenic mechanisms. Indeed, intravenous infusion of endotoxin increases PAP in sheep [28], suggesting that disease processes such as sepsis may contribute to the development of pulmonary hypertension associated with ARDS. Patients with ARDS have increased levels of the pulmonary vasoconstrictors thromboxane A2, LTC4, and LTD4 in bronchoalveolar lavage fluid [29,30]. Finally, circulating levels of endothelin-1 are elevated in patients with ARDS [31].