Chapter 26: Pulmonary Arterial Hypertension in the ICU

Pulmonary arterial hypertension (PAH) is a chronic, progressive disease affecting small pulmonary arteries that results in increased pulmonary arterial pressures and eventual right ventricular failure (RVF). PAH can be caused by idiopathic or heritable sources, induced by drugs and toxins, has associations with connective tissue disease, HIV infection, portal hypertension, congenital heart disease, schistosomiasis, chronic hemolytic anemia, and can also result from persistent pulmonary hypertension (PHTN) of the newborn.¹ Clinically, PHTN is diagnosed with a right heart catheterization showing pulmonary arterial pressure greater than 25 mm Hg. As the disease progresses, chronic or acute increases in pulmonary arterial pressures result in RVF which is the most common cause of death in this patient population.² RVF is clinically defined as a reduced cardiac output and an increase in RV filling pressure.³ Due to their delicate hemodynamic states and advanced disease, PAH patients in the ICU have mortality rates reported as high as 41%.⁴

Chronic destruction of pulmonary vasculature as well as increases in pulmonary vascular resistance (PVR) and pulmonary arterial pressures cause RVF.⁵ The right ventricle responds to increased pulmonary pressures with compensatory structural changes that compromise the heart's ability to maintain sufficient cardiac output. As such, an understanding of the underlying physiology of PHTN and the right heart is required in order to treat this complex and dangerous disorder in the ICU.

The normal structure and function of the right ventricle reflects the low resistance and high compliance and capacitance of the pulmonary vasculature system to which it delivers blood. The thin-walled structure of the right ventricle implies the low resistance of the pulmonary vasculature. Functionally, the right ventricle spends little time in isovolumic contraction or relaxation and as a result is able to generate cardiac output with only a fifth of the energy demanded by the left ventricle (LV).⁶ The right ventricle receives a continuous flow of coronary blood via the RCA during both systole and diastole.⁶ This blood supply is possible given the thin-walled structure of the RV as well as its relatively small isovolumic activity. Given this physiology adapted specifically for the low resistance pulmonary vasculature, the right ventricle has difficulty responding to the increased resistance of PHTN.⁶ The adaptive changes that the RV undergoes cause structural changes that compromise its ability to maintain cardiac output.

In order to reduce wall tension caused by the increased afterload of PHTN, hypertrophy of the right ventricle occurs. As a result, coronary flow no longer occurs in diastole despite the increased demand of the hypertrophied right ventricle. Also, the right ventricle spends more time in isovolumic contraction and relaxation in order to overcome increased pulmonary pressures, which results in a reduction of right heart output and greater energy demand.⁶ RV hypertrophy also interferes with the normal motion of the tricuspid valve and together with increased pulmonary pressures results in tricuspid regurgitation.⁶ The growth of the right ventricle also impedes on the function of the LV as the interventricular septum bulges into the LV.⁶ These changes in the right ventricle all contribute to the reduction of cardiac output, which in turn decreases coronary flow to the RV and causes ischemic damage. Finally, this hypertrophy of the right ventricle accompanied by ischemic damage eventually leads to ventricular dilatation and total right heart failure.

Given the lack of physiologic reserve of patients with PHTN, any further physiologic imbalance can trigger hemodynamic collapse and result in an ICU admission. The differential diagnosis for patients with PHTN presenting with acute RVF should include the pathologies unique to PHTN discussed later. It is also important to note that advanced treatments for PHTN work to slow progress of the disease, and do not cure the disease. As such, RVF occurs when the compensatory mechanisms of the RV are overwhelmed by progressive destruction of the pulmonary vasculature even with use of advanced therapies.

Patients with PHTN are at risk for developing sepsis. Patients with low cardiac output may poorly perfuse the bowel, leading to a leaky endothelial barrier that allows bacteria and their toxins to invade, which can result in sepsis.⁷ Prostacyclin, one of the advanced medications for the treatment of PHTN has an immunosuppressive effect.⁸ Additionally, prostacyclin is delivered via an indwelling catheter, which has its own infection risk.⁸ As such, sepsis was found to be the most common identifiable trigger for ICU admission in a study of 46 patients with PAH or inoperable chronic thromboembolic pulmonary hypertension (CTEPH) admitted to the ICU.⁴

The effects of sepsis on the patient with PHTN can be devastating. Sepsis-induced drops in systemic vascular resistance (SVR) can severely compromise patients with reduced cardiac output from PHTN. Furthermore, sepsis has been shown to cause pulmonary vasoconstriction and dysfunction as well as produce cytokines that reduce right heart contractility.^9,10 Clinically, sepsis was found to be a leading cause of patient mortality in the ICU for patients with PHTN exacerbations.⁴

Iatrogenic causes can also trigger hemodynamic instability leading to an ICU admission in a patient with PHTN. Negative inotropes, such as beta-blockers and calcium channel blockers can depress the contractile ability of the right ventricle and cause an acute decrease in cardiac output. Abrupt cessation of pulmonary vasodilator medications can cause rebound pulmonary vasoconstriction.

PAH also provides a setting for pulmonary emboli to form. Patients with PAH often live sedentary lifestyles due to poor exercise capacity resulting in venous stasis.⁶ Also, pulmonary blood travels slowly through the pulmonary vasculature in PHTN with RVF. A PE with a resulting loss of oxygenation, shunting of blood, and increased pulmonary arterial pressures can severely destabilize the hemodynamics of a patient with PHTN.

As the heart remodels in response to PAH, patients become susceptible to atrial arrhythmias. The remodeling process predisposes patients with PAH to arrhythmias by modulating autonomic activity and delaying cardiac repolarization.¹¹ Also, ischemic myocardial damage to the RV itself can predispose patients to developing an arrhythmia.¹¹ One study of 231 patients with PAH or CTEPH showed a yearly incidence of 2.8% for new onset supraventricular tachycardia, most commonly atrial fibrillation or flutter.¹² Any loss of the ability of the LA to fill the LV can further reduce CO in addition to the already decreased RV CO. Also, the poorly compliant RV is dependent on the atrial kick of the RA to fill and produce adequate output. As such, onset of arrhythmias was related to clinical deterioration in patients with PHTN and patients with sustained atrial fibrillation had a cumulative mortality rate of 82%, emphasizing the need for conversion to sinus rhythm.¹²

Atrial arrhythmias are challenging to manage in the ICU given the potential negative inotropic effects of beta-blockers and high doses of calcium channel blockers on the right heart. Therefore, rhythm control may be a better management choice than rate control, with amiodarone, cardioversion, or ablation as potential therapies.¹¹

Careful monitoring of patients with PAH and RVF is necessary given their fragile hemodynamic state.

Hypoxia causes selective pulmonary vessel vasoconstriction as the body attempts to shunt blood to areas of the lung with better oxygenation. However, this process will increase pulmonary arterial pressures and exacerbate PHTN, so pulse oximetry or more invasive methods of monitoring can be valuable tools in the prevention of desaturation.

Troponins should be checked to identify if myocardial infarction was the trigger event for the ongoing PHTN/RVF episode. Trending troponins may also give insight into any ongoing ischemia occurring in the right ventricle due to the PHTN exacerbation.

BNP can be used to confirm dilation of the right ventricle and to trend the function of the right ventricle over time. High admission BNP levels in patients with PAH or inoperable CTEPH were found to be predictive of mortality.⁴

Hemoglobin levels should be monitored and maintained at a level above 10 mg to avoid compensatory cardiac reaction to anemia as per expert opinion.³

Due to the delicate hemodynamic state of the right heart in PAH, electrolyte disturbances have potential to be very harmful and should be carefully monitored. BUN and creatinine should be followed as measures of kidney function and cardiogenic shock. AST, ALT, and bilirubin should be monitored as markers for liver damage caused by cardiogenic shock. Finally, lactate is a useful marker for ischemia and RV insufficiency.

Echocardiography is a valuable noninvasive monitoring modality used to observe the function and structure of the right ventricle. Echocardiographic signs of right heart failure include RV dilatation and loss of the RV's normal, triangular shape.¹³ Systolic paradoxical motion of the interventricular septum is another sign of RVF as it represents RV systolic overload.¹³ An echocardiogram can also help identify possible causes of the PHTN associated right heart failure exacerbation such as left heart failure, RV ischemia, new valvular abnormalities, or pericardial effusions.¹³ Furthermore, right atrial enlargement, septal displacement, pericardial effusion, and low tricuspid annual plane systolic excursion are echocardiographic signs associated with poor outcomes in patients with chronic right heart failure.¹⁴ However, these associations were identified in chronic right heart failure patients only, and the value of these signs in an acutely ill patient is unclear. For patients with poor transthoracic echocardiographic imaging, a transesophageal echocardiogram is a valuable option, although it is more invasive and, therefore, carries greater risks.

Outcomes of invasive monitoring with pulmonary artery (PA) catheters have not been specifically studied in patients with PAH. Studies of PA catheterization (PAC) in the ICU patient population have shown no mortality benefit and possibly increased mortality with PAC.¹⁵ Furthermore, PAC involves risks including PA rupture and tachyarrhythmia and one study of patients with PHTN receiving nonacute PAC in an expert center showed an incident rate of 1.1% for adverse events.¹⁶ However, information on PA pressures and RVF can be directly obtained from PAC. As such, the decision to monitor patients with RVF/PAH should be made based on individual patient presentation and course, as hemodynamic information obtained from PAC may give valuable physiologic information only hinted at by indirect biomarkers such as lactate.

Treatment of patients in the ICU with evidence of right heart failure due to PHTN involves supportive care, correcting the underlying cause of the hemodynamic instability and supporting hemodynamic function of the right heart. Specifically, the goals of supportive cardiac care for PHTN in the ICU focus on maintaining aortic root pressure, systemic blood pressure, and cardiac output as well as reducing pulmonary arterial pressures. If these treatments are ineffective, invasive strategies, such as extracorporeal support and ultimately lung transplantation should be considered. Unfortunately, PAH in the ICU has not been studied extensively, and much of the following information is based on animal studies and studies of other classes of PHTN.

Supportive Care

As discussed earlier, hypoxia can exacerbate elevated pulmonary pressures, so supplemental oxygenation should be used to maintain hemoglobin oxygen saturation to at least 90% to prevent or reverse any hypoxia induced pulmonary vasoconstriction. Also, there is evidence showing the efficacy of oxygen as a selective pulmonary vasodilator in patients with PAH, as treatment with 100% O₂ for 5 minutes in patients undergoing PAC increased cardiac index and reduced PVR.¹⁷

PAH patients should be anticoagulated as they are at high risk for new DVT or PE given their limited mobility and altered pulmonary hemodynamics as discussed above.

Diuresis helps reduce the pressure of fluid overload on a failing right ventricle that is on the far right of the Frank Starling curve. Dialysis should be considered if the patient fails to respond to diuresis. Patients should be followed clinically with regards to fluid management, as over diuresis can reduce cardiac output. As such, input and outputs for the patient should be carefully monitored to ensure diuresis is proceeding appropriately. In the case of pure diastolic failure of the RV with signs of fluid overload and normal CO, diuresis alone would be the appropriate choice for management.

Intubation of patients with PHTN and RVF should be avoided as sedatives can depress cardiac function and lower SVR and increased transpulmonary pressures can further lower CO. If mechanical ventilation is necessary, pretreatment with catecholamines to avoid a drop in BP may be necessary. Etomidate is a preferred induction agent, as it has relatively fewer effects on vascular tone or cardiac contractility than propofol.⁶ In general, ventilator strategies should avoid high intrathoracic pressures in order to prevent PVR increases or RV preload decrease. Also, ventilation strategies should attempt to prevent compression of pulmonary vasculature by avoiding high lung volumes and should also avoid hypercapnia, hypoxia, and atelectasis, which can increase PVR.¹⁸

Pulmonary Vasodilators

Pulmonary vasodilators are used to reduce RV afterload by reducing pulmonary arterial pressures. Medications effective at reducing RV afterload cause improvements in CO and oxygenation.

Intravenous (IV) prostanoids are short acting pulmonary vasodilators and platelet aggregation inhibitors delivered by continuous IV infusion or implanted perfusion devices. IV prostanoids are potent pulmonary vasodilators and have been used in the treatment of acute RVF in patients after cardiac surgery where they significantly reduced PVR and increased RV function.^19,20 IV prostanoids should specifically be avoided in patients with PHTN due to left heart failure, as increased volume delivered to the LV can result in pulmonary edema. Hypotension is a significant adverse effect of IV prostanoids and must be watched for as prostanoids are up titrated. Also, IV prostanoids can cause nonselective pulmonary vasodilation resulting in V/Q mismatch and worsening of cardiac and pulmonary function. Other systemic side effects of IV prostanoids include nausea, diarrhea, flushing, and headache.

In order to avoid hypotension V/Q mismatch from IV prostanoids, inhaled prostanoids, which are only approved for chronic treatment of PAH, should be strongly considered in the care of the acutely ill patient. One study of 35 patients with PAH undergoing right heart catheterization showed greater efficacy of inhaled iloprost versus NO as an inhaled pulmonary vasodilator.²¹ The ultrasonic nebulizer is being used as a delivery device for inhaled prostanoids in the postsurgical setting to treat RVF.⁶

Inhaled NO directly vasodilates the pulmonary vasculature and may be especially useful in patients who cannot tolerate IV prostanoids due to hypotension and v/q mismatch. NO has a short half-life given its rapid deactivation by hemoglobin in pulmonary capillaries. A study of 26 patients with acute RVF admitted to the ICU and treated with inhaled NO showed in half of all patients a significant decrease more than 20% in PVR and pressure.²² Additionally, in a study comparing NO to IV prostanoids in patients with RVF following cardiac surgery, NO was shown to increase CI and reduce PVR with similar efficacy to IV prostanoids.²⁰ However, prolonged use of high concentration inhaled NO can cause methemoglobinemia so cyanosis should be watched for and periodic methemoglobin levels should be drawn. Withdrawal of NO therapy should be carefully monitored as rebound increases in PA pressure can result from abrupt withdrawal.

Although unstudied in an acute setting, IV PDE5 inhibitors, such as Sildenafil may be a possible therapy for patients with PAH and acute RVF. IV sildenafil does have risks of systemic hypotension and V/Q mismatch from nonselective pulmonary vasodilation.

After patients are stabilized with IV or inhaled medications, endothelin receptor blockers and PDE5 antagonists can be added as oral medications for discharge. These oral medications should be bridged carefully over the ICU medication, as abrupt withdrawal of IV prostanoids, inhaled NO or inhaled prostanoids can cause rebound PHTN.

Inotropes

Inotropes are used to maintain cardiac output in the presence of cardiogenic shock from right heart failure due to PHTN.

Dobutamine is a beta-1 receptor agonist that augments cardiac contractility and reduces RV and LV afterload. Animal models of RVF and PHTN had increased CO and RV-PA coupling with little effects on the PA after dobutamine treatment.²³ Dobutamine significantly improved hemodynamics and cardiac function of patients with PH after RV infarction²⁴ as well as increasing RV contractility and decreasing afterload in patients with PH at liver transplantation.²⁵ However, dobutamine is a direct adrenergic agonist and also has an agonistic effect at beta-2 receptors, which can cause vasodilation resulting in hypotension and tachycardia. This vasodilation and tachycardia can be especially harmful as it reduces diastolic filling time on an already volume deprived LV. Dobutamine-induced hypotension should be anticipated at higher doses and may be treated with vasopressors should the need arise.

Another inotrope used in the ICU treatment of patients with PHTN is Milrinone, a PDE3 inhibitor. Milrinone directly increases cAMP which causes increased contractility and reduced afterload. Animal models of chronic PAH treated with Milrinone showed significant increases in RV function, pulmonary blood flow and LV filling.²⁶ One example of Milrinone's efficacy in human RVF can be seen in a study of patients with RVF after LVAD placement who received Milrinone and had a resulting significant reduction in PVR and an increase in LVAD flow.²⁷ As with any systemic inotrope, there is a risk of systemic hypotension with milrinone usage and vasopressors should be used as necessary to prevent hypotension.

Inhaled milrinone has been used as salvage therapy when other PAH therapies could not be increased due to hypotension.²⁸ Also, in a study of patients with PHTN undergoing mitral valve surgery inhaled milrinone decreased mean PA pressure and PVR in a similar range as IV milrinone.²⁹ As such, inhaled milrinone should be considered in the patient with hypotension and for any patient in which V/Q mismatching and shunting is a major concern.

Vasopressors

Pressure support medications should be used to maintain aortic root pressure and RCA perfusion of the RV. These medications are especially important given the loss of CO in RVF as well as the hypotensive side effects of advanced PAH therapies and inotropes. Also, by increasing the afterload, vasopressors have an additional benefit of normalizing the shape of the LV against an enlarged RV.

Norepinephrine causes vasoconstriction and improves SVR via alpha-1 receptor agonist activity as well as exerting inotropic effect by beta-1 receptor agonist activity. In a study comparing mortality and adverse event outcomes of norepinephrine versus dopamine treatment in patients with shock in the ICU, the subset of patients with cardiogenic shock treated with norepinephrine had a decreased rate of 28-days mortality and arrhythmias as compared to patients treated with dopamine.³⁰ However, in a small study of 10 patients with septic shock, PH and RVF treated with norepinephrine showed an increase in PVR and no improvement in RV EF.³¹ This increase in PVR was thought to be from a dose-dependent beta-1 effect of norepinephrine on the pulmonary vasculature.

Vasopressin acts at V1 receptors on vascular smooth muscle cells to cause vasoconstriction. Vasopressin also potentiates the vascular effects of catecholamines. Vasopressin has been shown to cause pulmonary vasodilation in animal models via endothelial NO production³² and a reduction in PVR and PVR/SVR ratio in humans,¹⁸ making it a theoretically better choice than norepinephrine for patients with PHTN. Vasopressin has been used effectively to treat sepsis induced hypotension, RVF and PHTN after cardiac surgery and chronic PHTN.¹⁸ However, vasopressin does have dose related toxicities such as coronary vasoconstriction and depressed myocardial function at higher doses and has not been studied as well as norepinephrine in the ICU setting.¹⁸ As such, for patients with pulmonary vascular dysfunction and vasodilatory shock, vasopressin can be used at low doses in those not responding to norepinephrine and other conventional treatments.

Atrial septostomy (AS) can be used to reduce RV pressures by shunting blood from the RA to LA. This shunting decompresses the dilated RV, improves LV function and RV contractility, and reduces deforming pressure on the LV from the enlarged RV. Paradoxically, this procedure does not result in decreased oxygenation as the increased cardiac function resulting from AS outweighs the loss of hemoglobin oxygenation from the atrial shunt. However, this procedure is not appropriate for the end stages of the disease or hemodynamically unstable patients, as patients with RA pressures greater than 20 mm Hg or O₂ sat less than 80% on room air or low CI who underwent this procedure had a significantly higher risk of fatal complications.^33,34

For patients with end stage PAH and RVF refractory to optimized medical treatment, lung transplantation with bridging via extracorporeal life support (ECLS) should be considered. ECLS unloads the RV, increases organ perfusion and can even remove the need for catecholamine medications. As such, ECLS as a bridge to transplantation is a good choice of therapy for patients with PAH refractory to treatment exhibited by persistent hypoperfusion and continuous end organ dysfunction.

Venoarterial ECMO draws blood from the RA via a femoral venous cannula, oxygenates the blood externally to the patient, and returns the newly oxygenated blood into the lower abdominal aorta. A series of 5 patients in Germany with PH and RVF showed rapid improvement in end organ function and reversal of cardiovascular failure with V/A ECMO treatment while awake and breathing spontaneously without intubation.³⁵ Of these 5 patients, 4 survived to transplantation and 3 of these patients survived for one additional year.³⁵ A follow-up retrospective study comparing awake V/A ECMO to patients receiving traditional intubated V/A ECMO showed a significant increase in 6 months survival after lung transplantation and shortened postoperative stay in patients receiving awake V/A ECMO.³⁶ As such, awake V/A ECMO seems to be a promising bridging strategy to lung transplant for patients with PHTN. However, bleeding complications are a risk given the anticoagulation required to use V/A ECMO and 2 weeks may be the maximum time patients can remain on ECMO before other complications such as hemolysis, organ failure, sepsis, renal failure, and cerebral vascular accidents begin to occur with greater frequency.³⁷

Pumpless lung assist devices have been used in hemodynamically unstable patients with PAH and veno-occlusive disease as a bridge to lung transplantation.³⁷ Pumpless lung assist devices are low-resistance membrane oxygenators, which are connected between the PA and the left atrium. This device effectively offloads the RV in the same way as BAS, but instead allows for oxygenation of the shunted blood over the membrane device.

If a patient does have cardiac arrest during their ICU stay, CPR has very little efficacy. One study of 132 patients with PAH who had CPR performed after circulatory arrest showed that only 8 patients survived for more than 90 days and 7 of these patients had identifiable causes of circulatory arrest.³⁸ Given the high PVR present in patients with PAH in the ICU, it is not surprising that chest compressions are unable to generate forward flow of blood from the RV through the constricted pulmonary vasculature. Timely discussions of goals of care and DNR orders are, therefore, appropriate for patients with PAH and RVF in the ICU.