Article

Pulmonary Hypertension in the Intensive Care Unit

Journal of Intensive Care Medicine 1-17 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0885066615583652 jic.sagepub.com

Jacob C. Jentzer, MD1,2 and Michael A. Mathier, MD1

Abstract Pulmonary hypertension occurs as the result of disease processes increasing pressure within the pulmonary circulation, eventually leading to right ventricular failure. Patients may become critically ill from complications of pulmonary hypertension and right ventricular failure or may develop pulmonary hypertension as the result of critical illness. Diagnostic testing should evaluate for common causes such as left heart failure, hypoxemic lung disease and pulmonary embolism. Relatively few patients with pulmonary hypertension encountered in clinical practice require specific pharmacologic treatment of pulmonary hypertension targeting the pulmonary vasculature. Management of right ventricular failure involves optimization of preload, maintenance of systemic blood pressure and augmentation of inotropy to restore systemic perfusion. Selected patients may require pharmacologic therapy to reduce right ventricular afterload by directly targeting the pulmonary vasculature, but only after excluding elevated left heart filling pressures and confirming increased pulmonary vascular resistance. Critically-ill patients with pulmonary hypertension remain at high risk of adverse outcomes, requiring a diligent and thoughtful approach to diagnosis and treatment. Keywords pulmonary hypertension, pulmonary arterial hypertension, right ventricular failure, right heart failure, pulmonary vasodilators

Introduction Pulmonary hypertension (PH) develops through a final common pathway of myriad cardiac and noncardiac disease processes that increase pulmonary artery (PA) pressures.1 Pulmonary hypertension contributes to critical illness primarily via right ventricular failure (RVF), ultimately leading to hemodynamic compromise and death.2-6 Disease processes directly impairing right ventricular (RV) contractility can produce RVF in the absence of PH.7-10 Most cases of PH encountered in clinical practice are produced by another disease process, being secondary to critical illness rather than causative of it.1 Identifying causes of PH requiring specific therapy can be challenging in critically ill patients, and direct treatment of PH is often less important than correcting the underlying disease process. Several reviews have discussed various aspects of PH and/or RVF in critical care settings.2-9 In this review, we will focus on the diagnosis and treatment of various etiologies of PH encountered in intensive care unit (ICU) patients, with an emphasis on management of critically ill patients with pulmonary arterial hypertension (PAH).

(TTE) in 28% of 449 unselected medical ICU patients at our institution. Forty-two percent of the 299 patients in whom PA pressures and left ventricular function could be evaluated had PH.11 Pulmonary hypertension was predicted by left ventricular ejection fraction (LVEF) below 50%, pulmonary embolism (PE), and lower serum bicarbonate.11 Potential etiologies of PH in these patients included reduced LVEF in 23%, PE in 12%, and respiratory failure in 23%.11 Right ventricular failure without PH can be produced by etiologies such as cardiomyopathy, RV ischemia/infarction, sepsis, and postoperative RVF.7-9 Common etiologies of PH encountered in the ICU are listed in Table 1. Most PH is caused by left heart disease (PH-LHD) or parenchymal/hypoxic lung disease (PHPLD), and true PAH is relatively infrequent.2,4,12,13 Acute PE is the most common cause of new-onset PH causing RV strain

1

University of Pittsburgh Medical Center Heart and Vascular Institute, Pittsburgh, PA, USA 2 Department of Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

Received March 25, 2014, and in revised form March 13, 2015. Accepted for publication March 16, 2015.

Incidence and Prognosis The epidemiology of PH in the ICU is not well characterized, but PH appears to be common in critically ill patients. An elevated tricuspid regurgitation (TR) velocity consistent with PH was identified on Doppler transthoracic echocardiography

Corresponding Author: Michael A. Mathier, University of Pittsburgh Medical Center Heart and Vascular Institute HVI at UPMC Presbyterian 200 Lothrop Street Pittsburgh, PA 15213, USA. Email: [email protected]

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Table 1. Causes of Pulmonary Hypertension in the ICU.a Left heart disease Left heart failure from systolic or diastolic dysfunction Restrictive cardiomyopathy Constrictive pericarditis Mitral valve regurgitation/stenosis Aortic valve regurgitation/stenosis Hypoxemic/parenchymal lung disease Acute respiratory distress syndrome Interstitial lung disease Chronic obstructive pulmonary disease Obstructive sleep apnea Obesity–hypoventilation syndrome Pneumonia Pneumothorax Sarcoidosis Thromboembolism Acute pulmonary embolism Chronic thromboembolic pulmonary hypertension Postoperative After cardiopulmonary bypass Cardiothoracic surgery complications Pulmonary arterial hypertension Idiopathic/familial/anorexigen associated Connective tissue disease (especially scleroderma) Eisenmenger syndrome/congenital heart disease HIV associated Portopulmonary hypertension Hemoglobinopathy associated Pulmonary veno-occlusive disease Abbreviations: HIV, human immunodeficiency virus; ICU, intensive care unit. a Adapted from Zamanian et al.2

↓ Venous oxygenaon Hypoxic vasoconstricon

↓ LV cardiac output ↓ Systemic perfusion ↓ Systemic BP ↑ Heart rate

↑ RV aerload ↓ Coronary perfusion ↑ RV ischemia

↓ RV systolic funcon ↓ RV cardiac output

↓ LV filling

↑ RV filling pressures ↑ RV dilaon ↑ Tricuspid regurgitaon

Figure 1. Pathophysiology of decompensated right ventricular failure. BP indicates blood pressure; RV, right ventricle; LV, left ventricle.2,3,5-7,9,10

and a frequent contributor to PH in acutely ill patients.4,7,14-18 Development of PH significantly increases mortality in heart failure, lung disease, or PE.13-15,19-23 Echocardiographic PH independently predicted mortality in our medical ICU patients

after controlling for other clinical factors (odds ratio 1.59, P ¼ .036).11 Echocardiographic RV dysfunction and RVF are major predictors of mortality in patients with PAH and predict increased mortality in other medical conditions.7,8,12-14,22-25

Pathophysiology Acute RVF represents the inability of the RV to maintain normal cardiac output at a normal right atrial pressure (RAP), and the pathophysiology of PH-induced RVF is reviewed in detail elsewhere (Figure 1).2,3,5-7,9,10,15,26 Pulmonary hypertension is defined by elevated PA pressures, typically resulting from increased pulmonary vascular resistance (PVR) and/or increased pulmonary venous pressures, with elevated cardiac output contributing to some etiologies.12 Elevated PVR results from excessive pulmonary arteriolar vasoconstriction and/or pulmonary vascular obstruction.12 Patients with PH-induced RVF are prone to rapid deterioration through a vicious cycle of progressive shock, and even transient hypotension or hypoxemia can trigger an inexorably fatal downward spiral unless corrected promptly (Figure 1).2,4,5,10 Worsening hypotension in patients with RV dysfunction can result from inadequate RV preload, excessive RV afterload, deteriorating RV contractility, or inappropriate systemic vasodilation.8 The RV is very sensitive to changes in afterload and cannot maintain its stroke volume if PVR rises abruptly.2,7,8 Right ventricular dilation is characteristic of RVF, as the RV attempts to utilize preload reserve to compensate for acutely increased afterload from rising PVR.5,9,10,15 Right ventricular dilation increases RV wall tension and worsens TR, further reducing forward RV stroke volume. A distended RV can impinge on left ventricular (LV) diastolic filling and stroke volume through ventricular interdependence.2,5,8,10 Decreased RV output reduces LV filling and forward LV stroke volume, leading to systemic hypotension and RV myocardial hypoperfusion that can induce RV ischemia and further impair RV contractility.3,5-7,10 Tachycardia is often an adaptive mechanism to maintain cardiac output in the face of reduced stroke volume but can worsen RV ischemia and impair RV diastolic filling. Low cardiac output results in venous blood oxygen desaturation, which worsens arterial hypoxemia when pulmonary reserve is compromised. Hypoxia-induced pulmonary vasoconstriction constricts pulmonary arterioles in hypoxic lung segments to improve physiologic ventilation–perfusion (V/Q) matching and systemic oxygenation at the expense of increased PVR.23 Inflammatory cytokine release (ie, from sepsis or cardiopulmonary bypass) worsens RVF by producing pulmonary vasoconstriction, microvascular obstruction, myocardial depression, and systemic vasodilation.8,10,15

Clinical Presentation Acute RVF produces symptoms through systemic congestion and/or low cardiac output. Typical symptoms of isolated RVF include dyspnea and gastrointestinal symptoms, usually without orthopnea or paroxysmal nocturnal dyspnea.2,13 Signs and symptoms of low output include exertional light-headedness or

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Clinical findings suggesve of PH and/or RV failure TTE with Doppler • Esmated PA pressure • RV structure/funcon • LV structure/funcon • Exclude shunt

PH not likely • TR jet velocity =3m/s • Abnormal RV structure • Abnormal RV funcon

Evident underlying cause • Le heart disease • Hypoxic lung disease • Thromboembolism

Addional causes? • Elevated PAWP • Hypoxemia • Concomitant PE

Right heart catheterizaon • Assess PAP, PAWP, PVR

High PAWP, normal PVR • Le heart disease

Normal PAWP, high PVR • Chest CT + CTA • Nocturnal oximetry

High PAWP, high PVR • Le heart disease with “reacve PH”

Pulmonary congeson • PVOD

Evaluate causes of PAH • Serologic workup

• •

Idiopathic PAH Associated PAH

Figure 2. Diagnostic approach to newly recognized pulmonary hypertension in acutely ill patients. TTE indicates transthoracic echocardiogram; TR, tricuspid regurgitation; RV, right ventricle; LV, left ventricle; RHC, right heart catheterization; PAWP, pulmonary artery wedge pressure; PE, pulmonary embolism; PAP, pulmonary artery pressure; PVR, pulmonary vascular resistance; CT, computed tomography; CTA, CT angiography; PVOD, pulmonary veno-occlusive disease.12,41

syncope, altered mental status, hypotension with narrow pulse pressure, cool extremities, and renal insufficiency. Systemic congestion produces elevated jugular venous pressure, hepatomegaly, and volume overload with edema and ascites. Patients with PH-induced acute RVF of any etiology may present in extremis with hypotension/shock, tachycardia, hypoxemia, and tachypnea, mimicking massive acute PE. Inappropriate systemic vasodilation may occur as part of a systemic inflammatory response in end-stage RVF, even without infection. Most patients with PH-induced RVF have adequate cardiac output and elevated filling pressures.27 Patients with adequate perfusion and normal filling pressures often have compensated chronic RV dysfunction with a superimposed noncardiac illness. Patients with RVF admitted to the ICU often have hypotension and low cardiac output, despite elevated filling pressures including overt cardiogenic shock. Patients with low output and low filling pressures (‘‘cold and dry’’) from hypovolemia due to bleeding or excessive diuretic therapy are least common but have worse outcomes.27 In our experience, most patients with RVF having low output have elevated RV filling pressures, even without overt volume overload.

Cardiorenal Syndrome in RV Failure Acute renal dysfunction (cardiorenal syndrome) is a common and morbid problem in acute RVF.28 Impaired renal function

is common in patients with RVF, with approximately 40% to 50% having a glomerular filtration rate (GFR) below 60 mL/min and more than 20% having a GFR below 45 mL/min.29-31 Nearly 25% of patients with PAH admitted to the hospital develop acute kidney injury (AKI), and up to 20% to 40% of patients with PAH admitted to the ICU may require dialysis.31-33 Elevated creatinine, reduced eGFR, and AKI predict increased mortality in hospitalized patients with PAH having RVF, and in-hospital mortality reaches 70% in patients requiring dialysis.29-32,34 Chronic kidney disease, higher central venous pressure (CVP), and tachycardia predict AKI in patients with PAH having RVF.31 Adversely prognostic laboratory features characterizing cardiorenal syndrome in patients with PAH include anemia, hypoalbuminemia, and hyponatremia.28-30,34,35 The pathophysiologic mechanisms of renal dysfunction complicating PH-induced RVF likely overlap with those in cardiorenal syndrome complicating acute LV failure.28,35 Impaired renal blood flow may develop due to hypovolemia (overdiuresis or bleeding) or more often low cardiac output with marked neurohormonal activation complicated by ineffective circulating blood volume from anemia and hypoalbuminemia.28,35 Venous congestion (elevated renal venous pressure) plays a central role in acute cardiorenal syndrome, often to a greater extent than reduced cardiac output.10,28,31,36-39 Baseline GFR in patients with PH with or

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Table 2. Causes of Acute Decompensation in Patients With Pulmonary Arterial Hypertension.2,3,5,27,29,34 Acute deterioration of chronic PAH  Worsening of underlying disease  Deterioration in right ventricular function  Fluid overload or diuretic noncompliance  Acute kidney injury + metabolic acidosis  Hypovolemia (esp gastrointestinal bleeding)  Arrhythmia (esp atrial arrhythmias > heart block)  Medication noncompliance/withdrawal  Infection/sepsis (esp pneumonia or line infection)  Increased demand, ex pregnancy, anemia, surgery  Right ventricular ischemia/injury Worsening hypoxemia in PH  Right ventricular failure with low mixed venous saturation  Pump/catheter malfunction with IV prostanoids  Pulmonary embolism or in situ pulmonary thrombosis  Pneumonia/atelectasis (V/Q mismatch)  Pneumothorax or large pleural effusion  Sepsis (increased cardiac output / demand)  Right-to-left shunt, ex via patent foramen ovale  Pulmonary edema, esp PVOD Worsening hypotension or cardiac output in PH  Worsening right ventricular systolic function  Increase in pulmonary vascular resistance  Worsening tricuspid regurgitation  Hypovolemia, esp bleeding  Medication side effects  Sepsis or vasodilatory state  Arrhythmia  Pericardial effusion with tamponade  Initiation of mechanical ventilation Abbreviations: IV, intravenous; V/Q, ventilation-perfusion; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; esp, especially; PVOD, pulmonary veno-occlusive disease.

without RVF is predicted by higher RAP, reduced renal blood flow, and reduced cardiac output.36,39 Right ventricular dysfunction and TR can exacerbate venous congestion and are associated with lower eGFR and/or lower cardiac output in patients with chronic LV failure.38,40 Diuresis may transiently worsen renal function in patients with acute cardiorenal syndrome, but relief of venous congestion is central to clinical improvement.10,28

Diagnostic Evaluation In the ICU, patients may present with RVF from de novo acute PH (newly diagnosed PH) or acute-on-chronic PH (deterioration of prior chronic PH), along with patients having incidentally discovered PH without overt RVF. The diagnostic assessment in de novo PH seeks to identify treatable secondary causes and recognize patients who are likely to benefit or be harmed by PAH-specific therapy (Figure 2), while the diagnostic assessment in patients with established PH aims to identify factors triggering decompensation (Table 2). Distinguishing patients who are critically ill because of PH (and will require PH treatment) from patients whose PH is

secondary to critical illness (who are more common in our experience) remains challenging. In critically ill patients, multiple underlying disease processes often contribute to worsening PH and/or RVF rather than a single correctible factor. Transthoracic echocardiography remains the first-line test for patients with suspected PH and/or RVF to estimate PA systolic pressure (PASP) and assess RV structure and function.41-43 Echocardiographic assessment of PASP depends on the peak TR jet Doppler velocity plus an estimate of the RAP, although this method lacks both sensitivity and specificity for PH.12,42,43 Patients with an estimated PASP >40 mm Hg or peak TR jet velocity 3 m/s on echocardiogram are likely to have PH at right heart catheterization (RHC), with higher specificity at higher PASP values.41-43 In our medical ICU patients, a TR jet velocity 3 m/s on TTE had up to 90% positive predictive value for PH in patients undergoing RHC, despite a poor negative predictive value.11 Because of the limited ability of the RV to tolerate acute increases in afterload, severe elevations in PA pressures generally represent a more chronic disease process, allowing time for the RV to adapt (especially in the presence of RV hypertrophy). Echocardiographic RV dysfunction is characterized by a dilated, hypocontractile RV with flattening or paradoxical motion of the interventricular septum, and these findings are characteristic of decompensated RVF.4,5,25 Echocardiographic evidence of PH-LHD includes LV systolic or diastolic dysfunction, mitral valve disease, left atrial enlargement, and/or Doppler evidence of elevated LV filling pressures.13,43,44 Mild LV diastolic dysfunction (abnormal relaxation) can be induced by ventricular interdependence from RV dilation, but higher degrees of LV diastolic dysfunction suggest PH-LHD.13,44 Echocardiography often identifies pericardial effusions in patients with PH, which rarely cause tamponade but are associated with adverse prognosis and a high mortality rate after drainage.25,45 In critically ill patients with PH and/or RVF, we favor early RHC to establish the diagnosis, determine the etiology, and assess the filling pressures (Figure 2). This includes patients in whom clinical suspicion for PH remains high, despite normal TR jet velocity (ie, an abnormal RV on echocardiogram). Pulmonary hypertension is defined hemodynamically by an elevated mean PA pressure (mPAP) 25 mm Hg by RHC, and RHC helps to differentiate common types of PH.41 We typically use a PA catheter (PAC) to guide therapy in unstable patients with PH and/or RVF, especially if PAH-specific therapy is considered.5,8 Early use of a PAC to guide therapy was associated with reduced mortality in 1 study of patients with PH having RVF, despite failure of PAC-guided therapy to reduce mortality in general critically ill patients.32,46 Caution is required during RHC in patients with PH due to the risk of potentially fatal PA rupture.47 The RHC allows measurement of PA wedge pressure (PAWP) and calculation of PVR, which corrects for elevated PAWP and cardiac output to identify pulmonary vascular disease.12 Pulmonary hypertension caused by left heart disease (postcapillary PH) is defined by an elevated PAWP >15 mm Hg with normal or reduced cardiac output. Most patients have normal PVR, although

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First-line therapies

Treatment goals

Second-line therapies

Normalize oxygenaon

Supplemental oxygen Noninvasive venlaon

Mechanical venlaon • Low airway pressures

Opmize preload (CVP)

Low CVP → fluids High CVP → diurecs

Transfusion if anemic Ultrafiltraon

Maintain cardiac output

Stable BP → inodilator Low BP → dopamine

Epinephrine

Restore systemic BP • SVR > PVR

Norepinephrine Vasopressin

Epinephrine/dopamine Phenylephrine

PAH +/- CTEPH Intravenous epoprostenol

Inhaled prostanoids/NO Add-on sildenafil?

Reduce RV aerload • Selected paents

PH-LHD Nitroglycerin Nitroprusside

Milrinone > dobutamine Chronic LVAD unloading

Advanced therapies

PH-PLD Inhaled NO/prostanoids

ECMO if refractory

Figure 3. Clinical management of pulmonary hypertension-induced right ventricular failure. CVP indicates central venous pressure; BP, blood pressure; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance; CTEPH, chronic thromboembolic pulmonary hypertension; PH-LHD, pulmonary hypertension due to left heart disease; PH-PLD, pulmonary hypertension due to parenchymal lung disease; ECMO, extracorporeal membrane oxygenator support; NO, inhaled nitric oxide; LVAD, left ventricular assist device.2-10,12,13,22,48 Table 3. Simplified Approach to Right Ventricular Failure Etiology and Treatment.8,20 Blood pressure

Cardiac output

CVP

DPVR

Cause

Primary Treatment

# # # # $ $

# # # $" $" $

# " " $" " #

$" " $ $" $" $

Hypovolemia Worsening PH RV dysfunction Vasodilation Volume overload Compensated

Volume PAH-specific therapy Inotropes Vasopressors Diuretics None

Abbreviations: CVP, central venous pressure; DPVR, change in pulmonary vascular resistance; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension; RV, right ventricular. Note. Arrows reflect direction and magnitude of effect (# = reduction, $ = no change, $" = no change or increase, " = increase, ## = strong decrease, "" = strong increase).

patients with elevated PVR and ‘‘out-of-proportion’’ PH have a worse prognosis.12,13,44,48 Patients with mPAP 25 mm Hg, PAWP 15 mm Hg, and PVR >3 Wood units (WU) have precapillary PH including PAH, acute PE, hypoxic/parenchymal lung disease, chronic thromboembolic PH (CTEPH), and other miscellaneous causes (see Table 1).41 Exclusion of PE is warranted, given the frequent occurrence of occult PE in patients with other apparent causes of PH such as lung disease or LV failure.16-18 Computed tomography (CT) or invasive pulmonary angiography may be appropriate for acutely ill patients, while radionuclide V/Q scanning is more sensitive for excluding CTEPH in stable patients.12,14,16,17,41 Chest radiography and chest CT can identify parenchymal lung disease or features suggestive of pulmonary

veno-occlusive disease (PVOD) such as pulmonary congestion, interstitial edema, pleural effusions, ground-glass opacities, and thickened septal lines.2,49,50 Patients with precapillary PH and negative imaging are likely to have PAH but require further workup to identify specific diseases associated with PAH.41

Treatment of RVF The treatment of acute RVF involves correcting reversible causes of decompensation (Table 2), optimizing RV preload, supporting RV contractility, and reducing PVR while maintaining systemic vascular resistance (SVR) and mean arterial pressure (MAP; Figure 3).2-10,14,20,24,25,51 A simplified approach to RVF (Table 3) emphasizes the diagnosis and

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initial treatment of the dominant pathophysiologic process, although combination therapy is often required to stabilize patients with RVF.8,20

Preload Optimization Volume loading. The dysfunctional RV may require an abnormally elevated RAP (up to 12-15 mm Hg) to maintain cardiac output due to diastolic dysfunction, so patients with RVF having hypotension and/or hypoperfusion may require volume loading to optimize cardiac output.3,7,8 This practice is primarily based on expert opinion, with few primary data to guide the quantity, rate, or targets of fluid therapy in patients with PH. Patients with acute PH (particularly acute PE) may be more likely to respond favorably to volume administration compared to patients with chronic PH who usually have elevated RV filling pressures even in the absence of gross volume overload.3,7,14,15,24,52 Despite favorable effects in animal models, patients with acute RV dysfunction caused by RV infarction may not consistently respond to volume loading and responded more reliably to inotropic support in some studies.53-55 Volume loading is considered more appropriate when CVP is low but should be discontinued if CVP rises without improved systemic hemodynamics. Cautious fluid administration can be continued if the CVP remains low without pulmonary congestion.7,14,24,52 Based on expert opinion, a reasonable fluid challenge for a patient with acute RV dysfunction or acute PH is up to 500 mL over 15 to 20 minutes, while the fluid challenge in a patient with chronic PH should be smaller (up to 250 mL).5,9,7,14,24,52 A CVP >15 mm Hg is rarely needed to optimize RV stroke volume, and markedly elevated CVP (especially >20 mmHg) can impair RV function via increased RV wall stress and functional TR, leading to worsening systemic hemodynamics.3,4,7 Empiric fluid administration can worsen decompensated RVF and is not recommended without assessment of CVP.5-9 Volume removal. Patients with systemic congestion in the absence of hypotension or hypoperfusion typically improve with volume removal alone and may not need vasoactive drugs. Relief of RV volume overload can improve RV function by reversing RV overdistention and septal shift, so volume removal may be warranted even in patients with hypotension having low output and high CVP.3,4 Most acutely ill patients with PH-induced RVF warrant empiric diuresis, particularly with worsening hypoxemia, gross fluid overload, or elevated CVP.3 Intravenous loop diuretics are first line for volume overload and titrated to the lowest filling pressures that relieve congestion while maintaining adequate systemic hemodynamics.51 We prefer a continuous furosemide infusion to allow gradual diuresis and avoid abrupt swings in filling pressures. Furosemide infusion rates 30 mg/h have been reported in the literature.33,56 Resistance to an adequate loop diuretic dose (10-20 mg/h furosemide infusion) can often be overcome by adding a thiazide-type diuretic.33,51,56 In our experience, diuretic resistance in RVF is usually due to low cardiac output, especially in the presence of hypotension, hyponatremia, and/or

worsening renal function. Extracorporeal fluid removal via ultrafiltration can be used for persistent volume overload, despite combination diuretic therapy, although the need for dialysis or ultrafiltration to manage refractory cardiorenal syndrome portends a grim prognosis.4,32,51,57

Vasoactive Therapies Support with vasoactive drugs including vasodilators, inotropes, and/or vasopressors may be required to reverse severe RVF with low output and/or systemic hypotension when preload optimization is inadequate to restore hemodynamics. The goals of vasoactive drug therapy are to reduce PVR, maintain SVR, and increase cardiac output to improve MAP and organ perfusion.2 Most patients with hypotension having RVF have low cardiac output, but hypotension with preserved cardiac output and low SVR suggests inappropriate vasodilation requiring vasopressor therapy (Table 3).20 Hypotension with reduced cardiac output and adequate/increased CVP suggests worsening RVF from excessive RV afterload (increased PVR) and/or reduced RV contractility (stable PVR; Table 3).20 Pulmonary arterial hypertension–specific therapies can be effective monotherapy for worsening RVF when elevated PVR is the dominant etiology. Inotropic support is often required for low-output RVF, especially if RV contractility is impaired. Certain vasoactive drugs including PAH-specific therapies can simultaneously increase RV inotropy and reduce PVR to reverse RVF.8,10,13,58-60 Vasopressors may be required to support MAP in patients with severe hypotension, especially with inadequate vascular tone. In-hospital mortality approaches 50% in patients with severe PAH-induced RVF who require support with vasopressors and/or inotropes, especially at higher doses.27,29,30,32,34,61 Pulmonary arterial hypertension–specific therapies. The underlying etiology of PH determines the need for therapy targeting the pulmonary vasculature and the most appropriate type of drug (if indicated; Figure 3). Treatment with PAH-specific drugs has only been associated with improved outcomes in outpatients with chronic PAH, representing a minority of all patients with PH.12 Relatively few critically ill patients with PH and/or RVF will have an underlying etiology that warrants PAH-specific therapy, so PH is not always a plausible target for therapy and PAH-specific therapies are unlikely to improve outcomes in unselected patients.2 Appropriate use of PAH-specific therapy can be lifesaving in severe RVF due to PAH and may obviate the need for inotropic therapy, but off-label use of systemic PAH-specific drugs in patients with other forms of PH may lead to life-threatening complications when used injudiciously.12 In his article, we discuss off-label uses of these drugs in selected non-PAH patient subsets based on evidence from clinical studies and personal experience supporting a limited role in certain situations, but PAH-specific drugs should not be used routinely in non-PAH patients. Importantly, there is no evidence supporting any outcomes benefit for off-label use

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Table 4. Vasoactive Drugs Used for Support in Right Ventricular Failure.5,6,9,58-60,65,81-86,92 Inotropes

Effect on PVR Effect on SVR PVR/SVR Ratio

Dobutamine58-60,81-83 Milrinone59,60,84,85 Norepinephrine65,92 Dopamine Epinephrine Vasopressin85,86 Phenylephrine65,92

#$a ## " " " # ""

#$a # " " " " "

$ # $ $ $ # "

Abbreviations: PVR, pulmonary vascular resistance; SVR, systemic vascular resistance. a The effects of dobutamine on PVR and SVR are variable based on pathophysiology and dosing.

of PAH-specific therapies, and such use is investigational and potentially harmful when used inappropriately. Patients with precapillary PH (elevated PVR and normal PAWP) without parenchymal/hypoxemic lung disease or acute PE (especially PAH or CTEPH) are more likely to have low-output RVF with severely elevated PVR requiring PAH-specific therapies for stabilization, including intravenous prostanoids.3 Correction of the underlying disease process causing PH is often more important than treating elevated PA pressures, especially in patients with PH-LHD or PH-PLD. Selected patients with persistent RVF after correction of underlying conditions may be candidates for offlabel PAH-specific therapy if PVR is significantly elevated.12 Inhaled pulmonary vasodilators may have broader applicability, including selected patients with PH-PLD, postoperative PH, and RVF without PH.6-8,21-23,25 Pulmonary vascular resistance is a more relevant therapeutic target in RVF than PA pressures because deteriorating RV function and declining cardiac output can reduce PA pressures.7,8,12 While the acute effects of PAH-specific drugs on PVR may involve pulmonary arteriolar vasodilation, their chronic disease-modifying effects involve favorable pulmonary vascular remodeling.12,62,63 Most systemic vasoactive drugs produce parallel effects on the pulmonary and systemic vessels, contrary to the goal of reducing PVR while increasing SVR (Table 4).5,9,13,64,65 Pulmonary arterial hypertensionspecific drugs produce relatively greater pulmonary vasodilation than systemic vasodilation, but systemic vasodilation often produces hypotension.5,8,9 Only inhaled pulmonary vasodilators, such as nitric oxide (NO) or inhaled prostanoids, can reduce PVR without significant effects on MAP.58,64,66-77 The use of PAH-specific therapies and inhaled pulmonary vasodilators is discussed subsequently in the section on PAH. Inotropes. Inotropic drugs may reverse low cardiac output due to RVF at the expense of tachycardia, increased myocardial oxygen demand, arrhythmias, and potentially systemic vasodilation (Table 4).6 Dobutamine and dopamine are the most commonly used inotropes for patients with

PH-induced RVF, with no direct comparisons supporting either drug.27,29,30,32,34 Dopamine and dobutamine produce relatively similar hemodynamic effects at usual doses of 2 to 10 mg/kg/min, with higher doses producing worsening tachycardia without improving cardiac output, and dobutamine produces greater augmentation of cardiac output, while dopamine increases MAP and SVR to a greater extent.2,5-7,9,58,78-80 In our clinical experience, dopamine tends to cause excessive tachycardia limiting dose titration, while the modest systemic vasodilating effects of dobutamine can produce hypotension. We prefer dobutamine over dopamine for acute inotropic support in unstable patients, although dopamine is a reasonable choice in patients who are hypotensive and not excessively tachycardic.2,3,6-9,30,34 The effects of dobutamine on PVR in humans with PH remain uncertain, with conflicting effects reported by various studies in heterogeneous patient populations. The primary effect of dobutamine in PH appears to be an increase in cardiac output that reduces the measured PVR with minimal if any direct effects on the pulmonary vasculature.2,5-7,9,58,81-83 Milrinone produces a greater reduction in PVR and SVR and less tachycardia than dobutamine for a given increase in cardiac output and/or RV systolic function, leading to greater reductions in MAP, PA pressures, and PAWP, despite a lesser inotropic effect.6,8,10,13,59,60 Dobutamine and milrinone primarily lower PVR by increasing cardiac output, with lesser direct effects on pulmonary vascular tone that are more significant with milrinone.58,81,84 Milrinone is our preferred inotrope for RVF, especially in normotensive patients and those with PHLHD, postoperative PH, or undifferentiated PH.3,5,6,8-10,25 Vasopressors may be required to counteract the prominent systemic vasodilating effects of milrinone, and combining milrinone and vasopressin may support cardiac output and reduce PVR while maintaining MAP, especially after cardiac surgery.6,9,21,25,68,85-87 At low doses, epinephrine effectively augments RV contractility and may be synergistic with milrinone when used for postoperative RVF.2,6,9,88-91 In PAHinduced RVF, reduction in RV afterload using PAH-specific therapies is more important than RV inotropic support, but epoprostenol and sildenafil can have positive inotropic effects on the RV.8,10,13 Vasopressors. Patients with severe hypotension having PH and RVF require vasopressors to support organ perfusion pressure and prevent death from progressive hemodynamic deterioration, particularly in the setting of inappropriate systemic vasodilation (Table 4). Vasopressor therapy should generally maintain the MAP higher than mPAP (ie, SVR greater than PVR) to reduce septal bowing and ensure an adequate pressure gradient for RV perfusion.5,6 Alpha 1 agonist vasopressors (including high doses of dopamine and epinephrine) constrict both pulmonary and systemic vessels, potentially worsening RV afterload while supporting MAP.5,6,9,65,92 Norepinephrine appears to have more favorable effects on cardiac output and calculated PVR than phenylephrine due

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to modest inotropic effects.2,6,9,65,92 Vasopressin may produce endothelium-dependent pulmonary vasodilation to slightly reduce PVR while increasing SVR, making this drug useful when SVR is low in patients with RVF.2,6,9,85-87,93,94 Norepinephrine is our first-line vasopressor for patients with severe hypotension, and we often add vasopressin based on its slight PVR lowering and lack of tachycardic effects.2,3,5,6,8,9,34,94 Dopamine can be useful for vasopressor support due to its positive inotropic effects, despite an increased risk of tachyarrhythmias and less effective MAP augmentation than norepinephrine.6,27,29,32,78 Epinephrine can effectively raise MAP and support RV inotropy but often produces tachycardia, arrhythmias, and lactic acidosis.88,89

Supportive Care Oxygenation. Oxygen is the most important physiologic pulmonary vasodilator, and increased fraction of inspired oxygen (FIo2) can counter hypoxic pulmonary vasoconstriction and reduce PVR, making supplemental oxygen the first-line therapy for patients with hypoxemia having PH.95 Worsening hypoxemia is common in decompensated PAH (see Table 2), and patients should receive supplemental oxygen to raise SaO2 >92%.3,5,8 For selected patients with PAH having low systemic oxygen delivery, using higher FIo2 to increase SaO2 may maximize reduction in PVR.95 For some patients with PH-PLD, restoration of normoxia may be sufficient to reverse PH.22 Hypoxemia in patients with PH usually responds to supplemental oxygen, although intracardiac shunting through a patent foramen ovale can produce hypoxemia that may resolve with lowering RAP and increasing SVR.2,7 Maintenance of normocapnia (PaCO2 35-40 mm Hg) is recommended because hypercarbia and acidosis can further increase PVR by augmenting hypoxic pulmonary vasoconstriction, while hyperventilation can improve PVR transiently.2,6-8,20 Ventilator management of patients with PH is discussed subsequently in the section on PH due to lung disease. Arrhythmia management. Atrial fibrillation and atrial flutter are the most frequent sustained arrhythmias in patients with PAH-induced RVF and may be associated with increased mortality.29,30,61 The dysfunctional RV is highly dependent on atrial contraction to maintain adequate filling, particularly at rapid heart rates.3,5 Cardiac arrhythmias that impair atrioventricular (AV) synchrony, such as atrial fibrillation/flutter or complete heart block, often produce hemodynamic compromise in patients with RVF.2,7,9 Electrical therapy is the first line for unstable patients, including cardioversion for tachyarrhythmias, and bradyarrhythmias (i.e. after cardioversion) are poorly tolerated and respond best to AV sequential pacing.3,7,9 Amiodarone is the first line for most tachyarrhythmias due to its lower risk of hypotension and lesser negative inotropic effects.3 Digoxin can provide rate control of atrial arrhythmias in selected patients with preserved renal function, but its positive inotropic effects are not clinically relevant in severe RVF.3,96

Table 5. Mortality Predictors of Hospitalized Patients With Pulmonary Artery Hypertension.27,29,30,32,34,61,97 Baseline patient characteristics Connective tissue disease–associated PAH27,29 PH due to hypoxemic lung disease32 WHO functional class29 Chronic use of prostanoids32 Comorbidity index29 Clinical presentation ‘‘Cold–dry’’ hemodynamic profile27 Higher respiratory rate30 Lower systolic/mean blood pressure29,34 Sepsis/infection during hospitalization32,34,61 Respiratory failure32 Atrial fibrillation61 Higher mean airway pressure61 Testing abnormalities Lower sodium29,30,34 Higher creatinine/lower GFR29,30,34 Higher BNP/NT-proBNP30,32,34 Higher CRP34 Greater degree of tricuspid regurgitation30 Lower albumin30 Severity of illness scores APACHE-II32 SAPS-II34 Treatments provided Inotropes/vasopressors, esp. higher dose27,34,61 Dialysis32 Mechanical ventilation32 Cardiopulmonary resuscitation32,97 Lack of early PA catheter-guided therapy32 Abbreviations: WHO, World Health Organization; GFR, glomerular filtration rate; BNP, B-type natriuretic peptide; NT-proBNP, N-terminal pro-BNP; CRP, C-reactive protein; APACHE, Acute Physiology and Chronic Health Evaluation Score; SAPS, Severe Acute Physiology Score; PA, pulmonary artery; PAH, pulmonary arterial hypertension; PH, pulmonary hypertension.

Disease-Specific PH Therapy Pulmonary Arterial Hypertension Hospital admission in patients with PAH is a morbid occurrence, with in-hospital mortality of 9% overall that increases to 14% to 17% for patients with RVF.29,30 Critically ill patients with PAH admitted to the ICU have in-hospital mortality rates exceeding 30% to 40% plus an additional 10% to 20% mortality during the next 3 to 6 months for hospital survivors.27,29,30,32,34,61 Mortality predictors of hospitalized patients with PAH are shown in Table 5.27,29,30,32,34,61,97 Death in hospitalized patients with PAH is most often due to hemodynamic compromise from progressive RVF ultimately resulting in cardiac arrest, often with a bradycardic arrest rhythm.29,30,97 Patients with PAH having cardiac arrest have dismal outcomes—only 21% of resuscitative attempts are initially successful, with 90-day survival of 6%.32,97 The most common reason for hospital admission in patients with PAH is RVF, followed by infection/sepsis (especially line sepsis and pneumonia), medication noncompliance, respiratory failure, bleeding (especially gastrointestinal), syncope,

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arrhythmias (especially atrial fibrillation/flutter), and PE.27,29,34 Infection and sepsis are important causes of death in patients with PAH, and severe septic shock in patients with PAH may be associated with a 1-year survival of below 30%.27,29,30,32,34,61 Potential triggers for decompensation of chronic PAH are listed in Table 2, although a cause for decompensation can only be identified in about half of the patients.2,3,5,7,27,29,34 Interruption of chronic prostanoid infusion can lead to rapid deterioration including rebound PH and death.12,62,98 For patients with PAH admitted with decompensated RVF, initiation or intensification of PAH-specific therapies is generally required for stabilization. Intravenous prostanoid therapy. Intravenous prostanoids (prostacyclin derivatives) are the most potent PAH-specific drugs and are indicated for severely ill patients with PAH.2,3,12,62,63,98 Critically ill patients with PAH warrant parenteral prostanoid therapy rather than oral therapy, and inhaled pulmonary vasodilators can be useful for acute stabilization.2,3,12,69 Intravenous epoprostenol (Flolan (GlaxoSmithKline, London, UK) and Veletri (Actelion Pharmaceuticals, Basel, Switzerland)) is preferred for unstable patients due to its short half-life (less than 6 minutes), allowing rapid titration (Figure 3).8,9,62,98 The longer acting analogue treprostinil (Remodulin) has a half-life of up to 4 hours, making it more suitable for chronic therapy.62,98 Early initiation of intravenous epoprostenol is recommended for critically ill patients with RVF due to PAH, who are not on systemic prostanoid therapy, titrated to the maximum-tolerated dose while avoiding systemic hypotension.3 The de novo starting epoprostenol dose is 1 to 2 ng/kg/min that can be increased by 0.5 to 1 ng/kg/min (up to 2 ng/kg/min) as often as every 15 to 30 minutes in the ICU up to an initial target dose of 6 to 10 ng/kg/min, then increased more gradually to the usual chronic dose of 25 to 40 ng/kg/min or more.2,8,12,62,98 Epoprostenol dose titration is limited by systemic hypotension or side effects such as headache, flushing, nausea/ vomiting/diarrhea, jaw or musculoskeletal pain; and mild to moderate thrombocytopenia often occurs and may promote gastrointestinal bleeding.62,98 When side effects warrant dose reduction of epoprostenol, the dose is decreased by 1 to 2 ng/kg/min every 15 minutes to the highest tolerated dose.62 Patients who develop worsening RVF despite chronic systemic prostanoids may require an increased dose, and we often switch subcutaneous to intravenous prostanoid therapy to ensure reliable drug delivery. Complications of parenteral prostanoids. Clinical deterioration after initiation of systemic PAH therapy in a patient with PH should prompt drug discontinuation and confirmation of the underlying PH etiology. Worsening hypoxemia after initiation of intravenous prostanoid therapy occurs due to V/Q mismatch or development of pulmonary edema, suggesting an etiology other than pure PAH. Systemic PAH-specific therapy can produce V/Q mismatch in the presence of parenchymal lung disease or PE by antagonizing hypoxic pulmonary vasoconstriction and increasing perfusion of poorly ventilated lung units.4,5,8,23 Worsening hypoxemia unresponsive to supplemental oxygen after starting a systemic PAH-specific drug may warrant switching

to an inhaled pulmonary vasodilator.4,22 New-onset pulmonary edema after initiation of intravenous prostanoid therapy suggests either elevated PAWP (PH-LHD) or PVOD, requiring empiric diuresis and often discontinuation of prostanoid therapy.13,49 Catheter infection and malfunction are common complications of chronic intravenous prostanoid use, requiring peripheral intravenous prostanoid infusion to prevent lifethreatening drug interruption when the catheter is removed.12,62,98 Chronic prostanoid overdosing can produce high-output HF requiring dose reduction.98 Inhaled therapies. Inhaled pulmonary vasodilators locally dilate pulmonary arterioles in ventilated lung units, improving oxygenation via V/Q matching and reducing PVR.6,22,23,58,64,66-77,99 Inhaled pulmonary vasodilators can be useful to stabilize patients with PAH, while intravenous prostanoids are titrated and may be first line for postoperative RVF with or without PH.5,8,21,25,69,70 When initiating any PAH-specific drug, PAWP should be controlled prior to starting inhaled pulmonary vasodilator therapy to prevent pulmonary edema.69 The best studied inhaled pulmonary vasodilator is NO, but recent reports describe the use of inhaled epoprostenol, inhaled iloprost, and inhaled milrinone.58,64,66-77,99,100 Inhaled NO has several limitations including high cost, flat dose response, and risk of dangerous rebound PH after withdrawal.69 At usual starting doses of 10 parts per million (ppm), inhaled NO can improve V/Q matching and hypoxemia, while doses of 20 ppm may reduce PVR more effectively and doses of 40 to 80 ppm appear to add little in clinical efficacy.13,69 Addition of sildenafil can increase the response to inhaled NO and may reduce the risk of rebound PH after inhaled NO withdrawal.6,101-105 Inhaled epoprostenol is administered at a usual dose of *50 ng/kg/min (range 10-85 ng/kg/min) or a fixed concentration of 10 to 20 mg/mL nebulized at 0.2 to 0.3 mL/min. The drug is often started at maximum dose then downtitrated based on the response.6,70 Nebulization of epoprostenol at up to 50 to 85 ng/kg/min provides similar hemodynamic effects as inhaled NO at 20 ppm but costs significantly less.70,72-76 Inhaled iloprost (Ventavis, Actelion Pharmaceuticals, Basel, Switzerland) has a moderate half-life (20-30 minutes) that allows intermittent administration in patients who are not mechanically ventilated, unlike inhaled NO or inhaled epoprostenol that must be continuously administered through the ventilator.62,98 Usual inhaled iloprost doses for chronic therapy are 2.5 to 5 mg every 3 to 4 hours (6-9 per day), but single doses up to 10 to 20 mg have been reported during weaning from cardiopulmonary bypass.21,62,71,98 Inhaled milrinone (1 mg/mL nebulized at 0.20.3 mL/min) reduces PVR and improves V/Q matching with less hypotension compared to intravenous milrinone.6,66,68 To date, no studies have shown a mortality benefit of inhaled pulmonary vasodilators in any patient population. Oral agents. Oral PAH-specific therapies are used primarily for chronic PAH in stable outpatients and are rarely started acutely in the ICU except in selected treatment-naive patients with PAH after stabilization with intravenous prostanoids.12,25 When

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patients with PAH on chronic oral PAH-specific therapy decompensate and develop RVF, initiation of prostanoid therapy is indicated, but preexisting oral PAH-specific drugs can be continued in the absence of adverse effects.12,98 Hypotension from oral PAH-specific therapy is typically mild and may not warrant drug discontinuation, but holding oral PAH-specific drugs when the patient is hypotensive (ie, from sepsis) is reasonable and rarely associated with rebound worsening of PH, especially if the patient is receiving an alternative PAH-specific drug. The phosphodiesterase (PDE)-5 inhibitor sildenafil is the only oral PAH-specific drug we consider using in the acute setting due to its rapid onset (15-30 minutes) and short duration of action (up to 4-6 hours).2,8,62,98 Sildenafil at usual doses of 20 to 40 mg every 8 hours can improve hemodynamics in selected patients with PAH, PH-LHD, or postoperative PH and can facilitate weaning of inhaled pulmonary vasodilators at a modest risk of systemic hypotension.6,8,13,101-103,105,106 Both milrinone and PDE-5 inhibitors may synergistically augment the effects of prostanoids and inhaled NO, suggesting a role for combination therapy.66,101-105 We avoid endothelin receptor antagonists (ERAs) in acutely ill patients due to their prolonged duration of action, delayed onset of effect, and risk of fluid retention and hepatoxicity.8,12,13 The new guanlyate cyclase activator riociguat mimics the effect of a PDE-5 inhibitor by directly stimulating guanlyate cyclase.107,108 Studies of oral PAH-specific drugs in critically ill patients are lacking, except for studies examining off-label use in selected patient populations that have not shown an outcome benefit. Disease-specific considerations in PAH. Hemoptysis is an uncommon but potentially fatal complication of PAH, related to bronchial artery hypertrophy and/or hemodynamic progression complicated by coagulopathy from chronic anticoagulation and antiplatelet effects of prostanoid therapy.109,110 Bronchial artery embolization may be effective for terminating acute episodes of hemoptysis but recurrent hemoptysis is frequent.110,111 Pulmonary arterial hypertension associated with connective tissue disease (particularly systemic lupus erythematosus) may worsen during disease flares, requiring augmented immunosuppression.3 Pulmonary veno-occlusive disease is a dangerous subtype of PAH producing postcapillary pulmonary vascular obstruction resulting in hydrostatic pulmonary edema in response to dilation of pulmonary arterioles by PAH-specific therapy.2,12,49 With aggressive diuretic therapy, some patients with PVOD may tolerate low-dose intravenous prostanoid therapy but prognosis remains poor.3,12,49 The following 3 PAH scenarios require especially careful management in conjunction with a PAH specialist and will not be discussed in detail here: portopulmonary hypertension, PAH from congenital heart disease complicated by right-to-left shunting (Eisenmenger syndrome), and management of patients with PAH in the peripartum period.

Pulmonary hypertension Associated With LV Disease Pulmonary hypertension caused by left heart disease is the most common cause of PH overall but rarely warrants therapy

targeting the pulmonary vasculature.4,12,13 For most patients with PH-LHD, elevated PA pressures reflect elevated LV filling pressures from diastolic dysfunction.13,44 Volume removal is central to treatment of PH-LHD, and PA pressures often normalize after diuresis and reduction in PAWP.13 Nonselective vasodilators are the preferred vasoactive drugs for treatment of PH-LHD, with inotropes reserved for patients with inadequate systemic hemodynamics (Figure 3).5,13 Nonselective vasodilators such as nitroglycerin and nitroprusside reduce SVR and decrease PA pressures by lowering PAWP with lesser effects on PVR and are first line when MAP is normal or elevated.13,51,64,112 Nesiritide was associated with renal dysfunction in patients with PH and RVF and may not lower PVR.113-115 Both milrinone and dobutamine provide inotropic support when vasodilators are inadequate in RVF due to PH-LHD. We prefer milrinone due to its more effective lowering of PAWP and PVR, but inotropes should not be used for lowering PVR in patients without impaired systemic perfusion.59,60,84 The off-label use of PAH-specific therapies in PH-LHD has not been shown to improve clinical outcomes and remains investigational. For selected patients with PH-LHD, persistently elevated PVR despite normalized LV filling pressures, chronic off-label oral PDE-5 inhibitor therapy may improve hemodynamics and/or symptoms without improving outcomes, and other PAH-specific therapies such as prostanoids have been associated with increased mortality during chronic use in PH-LHD.13 Any drug selectively lowering PVR can raise LV filling pressures, precipitate acute pulmonary edema, and/ or induce chronic fluid overload in PH-LHD patients, so PAWP should be normalized before initiating any PAH-specific therapy.12,13 Heart transplantation (HT) is the gold standard treatment of end-stage heart failure, but markedly elevated PVR is a contraindication.13,112 Chronic treatment with milrinone and/or off-label PDE-5 inhibitors may improve PVR in HT candidates, but chronic LV unloading with an left ventricular assist device (LVAD) is generally more effective.13,116-118

Pulmonary Hypertension Due to Lung Disease Lung disease is the second most common cause of PH overall and an important cause of PH in the ICU, but PAH-specific therapy has not improved outcomes in PH-PLD.2,3,10,12,22,23 The PH-PLD is most common in lung transplant candidates and/or during acute lung disease exacerbations, but PH is usually mild to moderate and rarely produces severe low-output RVF.2,3,12,22 Significant PH and clinical RVF are more common in mechanically ventilated patients with severe ARDS and high airway pressures but rarely require PAH-specific therapy.2,23 Management of PH-PLD involves treatment of the underlying lung disease, correction of hypoxemia and hypercarbia, and minimization of potentially harmful mechanical ventilator settings.2,22,23 A suggested RV-sparing approach to ventilator management in patients with ARDS involves maintaining a plateau pressure