Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review

The normal pulmonary circulation is a high-flow, low-pressure system. Unlike the left ventricle (LV), the thin-walled right ventricle tolerates poorly acute increases in afterload. This may lead to acute distention (Figure 1) [4, 43], with a resulting increase in oxygen consumption and reduction in contractility [44]. The dilated RV, together with paradoxic intraventricular septal movement [45], lead to reduced LV filling [46], cardiac output (CO), and oxygen delivery [47]. The principle of ventricular interdependence is important in most settings: superficial myocardial fibers encircle both ventricles; thus they are contained within the same pericardial cavity (except maybe after cardiac surgery), as well as sharing a septum, effectively existing "in series" [48, 49]. This explains the decrease in LV output seen during positive-pressure ventilation [48, 50, 51] and why RV pressure and volume overload cause diastolic dysfunction of the LV [52]. Furthermore, because of the RV/LV interactions, the LV may markedly depend on atrial contraction for filling and may tolerate atrial fibrillation and vasodilating therapy particularly poorly [49, 53, 54].

In addition, perfusion of the right coronary artery is usually dependent on a pressure gradient between the aorta and the right ventricle, which, in the setting of increased RV afterload and decreased coronary blood flow, may lead to RV ischemia [55], with further severe hemodynamic decompensation [56] (Figure 2). In acute-on-chronic RV-pressure overload, the already-hypertrophied RV tolerates much higher pressures before decompensation [57, 58], although the ability of the RV to augment CO in chronic PH may be restricted by its relatively "fixed" afterload. In any setting, the most common cause of increased RV afterload is an increase in PVR (Table 2).

The gold standard for the diagnosis and management of PH and RV dysfunction in the ICU setting is considered by some to be through pulmonary artery catheterization (PAC), even though most of the information can be obtained noninvasively by echocardiography: the requirement for PAC in this population remains controversial. It must, however, be acknowledged that it provides the only direct continuous measurement of right-sided pressures and direct measurement of RV afterload, whereby, through measurement of cardiac output, pulmonary pressures and the pulmonary artery occlusion pressure (PAOP, the "wedge"), the PVR can be calculated (Figure 3). Overall outcomes are not improved when the PAC is used in general in critically ill patients; and complications do occur [59]: the use in general is therefore declining. However, no studies have been done in the "pulmonary vascular" subpopulation. Alternative invasive hemodynamic measurements, such as CVP, may be useful surrogates for volume status in RV failure, by using the diastolic component of the CVP. Importantly, when monitoring CVP in patients with significant tricuspid regurgitation (TR), the variable V wave may be misleading, as it is included in the mean CVP calculation on most automated machines, and if rising, indicates RV overdistention. In the setting of cardiac surgery, one study shows that PAC use has reduced from 100% to 9% from 1997 to 2001, thought to reflect increased use of transesophageal echocardiography (TEE) [60]. In the setting of cardiac surgery, PAC may remain indicated for patients with PH and low CO and those predicted to have a difficult postoperative course [60], when a Swan introducer sheath may be inserted preemptively, or inserted for continuous monitoring after a diagnosis of RV dysfunction made with echocardiography [61]. PAC is also a useful cardiac monitor with intraaortic balloon counterpulsation. Few data exist on PAC in other settings of pulmonary vascular dysfunction in the ICU, but one study suggests that PVR may be a poor indicator of pulmonary-circulation status in ventilated patients with ALI/ARDS [62]. The role of echocardiography, both transthoracic (TTE) and TEE, is increasingly recognized in assessing RV function in many ICU settings [63‐65] and provides essential information about RV geometry and function. PA pressures may be assessed by estimating the systolic-pressure gradient across the tricuspid valve by using the modified Bernoulli equation [9, 66, 67], and although the correlation between invasive and sonographic measurement has been shown to be excellent in these studies, no studies have correlated PAC with echocardiographic measurements in the ICU population. In reality, a combination of invasive and noninvasive techniques is used. Biomarkers such as brain natriuretic peptide (BNP) are useful in monitoring chronic PAH [68], in risk-stratifying acute pulmonary embolism (see later) [69‐71], and in identifying ARDS-related pulmonary vascular dysfunction [72], although their role is less clear in other ICU settings.

The diagnosis and management of acute pulmonary embolism (PE) warrants a specific mention, as it is a relatively common cause of acute RV failure in the ICU [73]. Available therapies include thrombolysis and embolectomy, reducing the clot burden and acute mortality [74, 75], as well as reducing the longer-term risk of chronic thromboembolic PH [76]. Given that more than half of related deaths occur within an hour of the onset of symptoms [77], effective supportive treatment of shock is paramount. Patients presenting with acute PE are risk stratified according to the effects of elevated RV afterload: hypotensive patients and those with elevated cardiac biomarkers or echocardiographic indices of RV strain, or both, are deemed at increased risk, and thrombolysis is indicated [78].

The management of PH and RV dysfunction in the ICU is challenging. No agreed algorithms exist, although treatment should aim to prevent pulmonary hypertensive crises and acute cor pulmonale [79]. These comprise the spectrum of acute pulmonary vascular dysfunction and may result in cardiovascular collapse due to resulting biventricular failure. Management principles include the following: 1) optimization of RV preload, 2) optimization of RV systolic function, 3) reduction of afterload by reduction of increased PVR, and 4) maintenance of aortic root pressure to ensure sufficient right coronary artery filling pressure (Table 3).

We performed a systematic review of the literature over the period from 1980 to 2010, by using set search terms, and the electronic database of the US National Library of Medicine and National Institute of Health (PubMed). After initial identification, abstracts were reviewed for relevance, and appropriate studies were included in the review. Reference lists of relevant articles were hand-searched for further studies and reports. The search was limited to publications in English. Studies were deemed suitable for inclusion according to the criteria listed and where the patient population and study design was defined; and the outcomes were limited to those depending on the specific GRADE question (see Additional file 1). The breakdown of articles obtained by the systematic search is shown (Table 4). After identification, relevant studies were included and subjected to a GRADE analysis [80, 81] to see whether we could make specific management recommendations.

Management of PH with associated RV dysfunction in the ICU setting can be broken down into several treatment goals (Table 3). The first is to ensure adequate but not excessive RV filling or preload in the context of sufficient systemic blood pressure. The second goal is to maximize RV myocardial function, whether with inotropic support, rate or rhythm management, atrioventricular synchronization [82, 83], or by using mechanical devices. The third is to offload the right ventricle by reducing the PVR with pulmonary vasodilators as well as by ensuring adequate oxygenation, avoiding hypercapnia and acidosis, and by minimizing mechanical compression of pulmonary vessels (for example, due to excessive airway plateau pressure). The fourth is to maintain adequate aortic root pressure to allow sufficient right coronary arterial perfusion.

Systemic hypotension may relate to sepsis, overdiuresis, or progression of RV failure itself. Principles of volume management and vasopressor use are summarized.

Based on overall very-low-quality evidence (see Additional file 1), the following WEAK recommendation is made: Close monitoring of fluid status according to effects on RV function is recommended. Initial carefully monitored limited volume loading may be useful after acute PE, but may also worsen RV performance in some patients with pulmonary vascular dysfunction, and vasoactive agents may be required.

Based on mostly low-quality evidence (see Additional file 1), the following WEAK recommendation is made: NE may be an effective systemic pressor in patients with acute RV dysfunction and RV failure, as it improves RV function both by improving SVR and by increasing CO, despite potential increases in PVR at higher doses.

Based on mostly low-quality evidence (see Additional file 1), the following WEAK recommendation is made: In patients with vasodilatory shock and pulmonary vascular dysfunction, low-dose AVP may be useful in difficult cases that are resistant to usual treatments, including norepinephrine.

The next major goal is to improve RV myocardial function by using inotropes. The use of mechanical support is discussed later. For sympathomimetic agents, desirable cardiac β₁ effects at lower doses maybe offset by chronotropic effects precipitating tachyarrhythmias [140], as well as worsening pulmonary vasoconstriction at higher doses [102] through α-agonism. Systemic hypotension may result from these agents and with phosphodiesterase inhibitors, which may necessitate co-administration of vasopressors.

Based on low-moderate-quality evidence (see Additional file 1), a WEAK recommendation can be made that low-dose dobutamine (up to 10 μg/kg/min) improves RV function and may be useful in patients with pulmonary vascular dysfunction, although it may reduce SVR. Dopamine may increase tachyarrhythmias and is not recommended in the setting of cardiogenic shock (STRONG recommendation based on high-quality evidence level).

Based on mostly moderate-quality evidence (see Additional file 1), a STRONG recommendation can be made that PDE III inhibitors improve RV performance and reduce PVR in patients with acute pulmonary vascular dysfunction, although systemic hypotension is common, usually requiring coadmininstration of pressors. Based on low-quality evidence (see Additional file 1), a WEAK recommendation can be made that inhaled milrinone may be useful to minimize systemic hypotension and V/Q mismatch in pulmonary vascular dysfunction.

Based on mostly low-quality evidence (see Additional file 1), a WEAK recommendation can be made that levosimendan may be considered for short-term improvements in RV performance in patients with biventricular heart failure.

Physiologic coupling between the RV and the pulmonary circulation is a vital form of autoregulation of pulmonary circulatory flow (Figure 2). The RV is even less tolerant of acute changes in afterload than the LV, presumably because of the lower myocardial muscle mass [199]. In sepsis, a reduction in PVR will increase the RV ejection fraction at no additional cost to cardiac output [47], but at levels beyond moderate PH, LV filling may be reduced, and ultimately cardiac output will decrease [199]. Measures to reduce RV afterload may be nonpharmacologic (Table 3) or pharmacologic (Table 6).

Based on mostly moderate-quality evidence (see Additional file 1), the following STRONG recommendation is made: pulmonary vasodilators reduce PVR, improve CO and oxygenation, and may be useful when PH and RV dysfunction are present, notably after cardiac surgery.

Based on mostly moderate-quality evidence (see Additional file 1), the ICU side-effect profile of intravenous pulmonary vasodilators may be less favorable than that of inhaled agents. The following STRONG recommendation is therefore made: Consideration should be given to the use of inhaled rather than systemic agents when systemic hypotension is likely, and concomitant vasopressor use should be anticipated.

Based on mostly high-quality evidence (see Additional file 1), the following STRONG recommendation is made: give consideration for the use of NO as a short-term therapy to improve oxygenation indices but not outcome in patients with ARDS. Based on low-quality evidence (see Additional file 1), a WEAK recommendation is made that pulmonary vasodilators may also be useful treat PH associated with RV dysfunction in ARDS.

Based on mostly low-quality evidence (see Additional file 1), the following WEAK recommendation is made: Oral sildenafil may reduce PVR and facilitate weaning from NO after cardiac surgery in selected patients with PH, without adverse effects on systemic blood pressure in well-selected patients.

This encompasses RV "protective" strategies to avoid factors (Table 3) that may further increase PVR. Mechanical devices are also increasingly used to give a failing RV a bridge to recovery or transplantation.

Based on mostly very-low-quality evidence, the following WEAK recommendation is made: Mechanical therapies including ECMO and IABP may have a role as rescue therapies in reversible pulmonary vascular dysfunction or while awaiting definitive treatment.