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.
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 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 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.
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.