Air Care Series: Epoprostenol/VELETRI: a Skybridge to Somewhere?
/CLINICAL CASE:
History of Present Illness:
An elderly female initially presented to an outside hospital with a variety of respiratory symptoms and was subsequently diagnosed with COVID-19 pneumonia. During her hospitalization, her respiratory status gradually deteriorated and five days into her hospitalization, she unfortunately required endotracheal intubation. Despite mechanical ventilation, she developed refractory hypoxia. Initial attempts were made to increase the PEEP from 5 to 15cm H2O, to little avail. On the eighth day of admission, the decision was then made to paralyze and prone the patient. A follow-up chest x-ray at that time revealed pneumomediastinum, and she was started on broad-spectrum antibiotics. Ultimately, on the cusp of deterioration, the patient was deemed most appropriate for transfer to a medical intensive care unit (MICU) at a large academic hospital via helicopter emergency medical services (HEMS).
On arrival of the UC Air Care team, the patient was found to be intubated, sedated, and paralyzed in the prone position. Ventilator settings were ARVC with an FiO2 80%, RR 24bpm, Vt 450cc, and a PEEP 12cm H20.
While preparing for transport, the patient was placed in the supine position, leading to an acute desaturation event to 85%. The HEMS team did not feel that air transport in the prone position would be a safe option and needed other methods to improve the patient’s oxygenation. While still in the supine position, inhaled epoprostenol (aka VELETRI) was initiated and the set FiO2 was increased to 100%. Much to the relief of the team, these interventions rapidly improved her SpO2 readings to 94-96%. While preparing the patient and equipment for loading into the helicopter, she became hypotensive and required 10mcg of push-dose epinephrine.
In flight, a rapid blood gas analysis revealed a prominent respiratory acidosis with hypercapnia, prompting the set respiratory rate to be raised. Meanwhile, as the SpO2 remained above 90%, FiO2 was gradually weaned down. She was noted to be persistently hypotensive, with systolic blood pressures in the 90’s, and the norepinephrine drip rate was titrated to 20 mcg/min. She was successfully unloaded from the helicopter and her care was relinquished to the MICU team eagerly awaiting her arrival.
Hospital Course:
On arrival to the MICU, a chest x-ray was performed and revealed a moderate left-sided pneumothorax associated with pneumomediastinum and diffuse airspace disease. A chest tube was placed with improvement in her respiratory status, allowing ventilator settings to be gradually liberated. Additionally, epoprostenol was weaned and then discontinued 24 hours after her initial arrival. During the admission, she completed a course of broad-spectrum antibiotics and as the underlying shock state improved, she was also weaned off all vasopressor support. She was noted to have improvement in her underlying respiratory status as well and was extubated approximately three weeks later.
With time, the patient serially progressed down the various levels of medical care. On hospital day 38, she was successfully discharged to a skilled nursing facility, requiring just a nasal cannula for supplemental oxygen support, as well as a prescription for apixaban for new-onset atrial fibrillation.
DISCUSSION:
This case highlights changes that have been made in the arena of critical care transport, specifically UC Air Care transport, during the COVID-19 pandemic. Often, patients with refractory hypoxia or pulmonary artery hypertension previously have had epoprostenol started prior to initiating transportation. In the wake of the pandemic, we now carry epoprostenol on all flights for use on patients with severe refractory hypoxemia, right heart failure, and/or pulmonary hypertension. It is important to understand how this drug is delivered, its basic pharmacology, and ultimately how it can be leveraged to improve our patients’ care enroute to a definitive treatment facility.
INHALDED PULMONARY VASODILATORS: EPOPROSTENOL
Epoprostenol and Prostacyclin Analogs:
Epoprostenol is a prostacyclin analogue that acts at the prostaglandin I receptor, specifically the prostaglandin I2 receptor (PGI2). This is a G protein-coupled receptor (GPCR) found on platelets, smooth muscles, and immune cell membranes. Once bound, GPCR activation leads to increased release of cyclic AMP (cAMP). Elevation in cAMP leads to inhibition of platelet aggregation, smooth muscle relaxation, and decreased inflammatory cell proliferation (1,2). Smooth muscle relaxation occurs through the inhibition of endothelin release and increased production of nitric oxide (1). When epoprostenol is used via the inhaled route, it causes targeted effects to areas of the lung receiving sufficient ventilation. This targeted pulmonary vasodilation is thought to improve underlying ventilation-perfusion mismatch, leading to increased blood flow to already well-ventilated lung tissue (3). Oxygenation is further improved through decreased pulmonary vascular resistance (PVR) and pulmonary mean arterial pressure (PMAP) (4). Since epoprostenol is often administered in the critical care setting via inhalation, its systemic effects are thought to be limited. However, inhalational administration of epoprostenol requires certain equipment, namely a drug delivery device such as an Aerogen nebulizer (5).
Inhaled prostacyclin, and prostacyclin analogs, are commonly used in the management of acute respiratory distress syndrome (ARDS) or for combatting acute right-sided heart failure. Their actions likely stretch beyond just the vasodilatory properties mentioned above. For instance, agonism on the PGI2 receptors leads to reduced leukocyte adhesion, as well as platelet de-aggregation and antithrombotic effects (6). This likely tapers the large-scale inflammatory response of these disease processes, especially ARDS.
Despite the physiologic advantages associated with the use of prostacyclin, there is a theoretical risk of diffuse pulmonary vasodilation and worsening V/Q mismatching in patients with significant ARDS (7). Further, though aerosolized prostacyclin and their analogs have the advantage of acting primarily on the pulmonary vasculature, systemic absorption can occur as well, leading to systemic hypotension, bleeding, flushing, headache, nausea, vomiting and chest pain (4,8).
Pharmacokinetics:
Epoprostenol is rapidly hydrolyzed in the blood and therefore has a half-life between 2 and 5 minutes (9,10). It is most often delivered via a nebulizer directly into the ventilator circuit of an intubated patient, but it may also be administered via high flow nasal canula and/or CPAP/BiPAP (10). Though uncommon in the critical care setting, it can be administered intravenously as well. Inhalation doses typically range between 0-50 ng/kg/min; however, in the management of critically ill patients, treatment is often started at the maximum dose and then weaned as tolerated (10). Please see the associated image for epoprostenol dosing.
CLINICAL UTILITY OF EPOPROSTENOL:
Acute Respiratory Distress Syndrome
The patient presented in this case was diagnosed with COVID-19 pneumonia complicated by Acute Respiratory Distress Syndrome (ARDS). ARDS is caused by direct and indirect insult to the lungs, which leads to a cascade of inflammatory processes hindering the alveoli and results in various degrees of impaired oxygenation. It is graded from mild to severe, based on the PaO2 to FiO2 ratio (P/F ratio) and can also be formally graded using the Berlin Criteria (11). The cause of death in patients with ARDS is often multisystem organ failure and/or refractory hypoxemia.
ARDS also leads to inadequate ventilation to a high proportion of damaged parenchymal lung tissue. This occurs from the direct injury to the alveolar tissue by surrounding interstitial edema, making it difficult for effective gas exchange to occur despite ventilation. This impaired perfusion at the level of the alveoli is caused by hypoxia, microthrombi, and direct injury to the tissue. This cumulatively leads to pulmonary vasoconstriction and increases the afterload faced by the right side of the heart. ARDS contributes to two main issues, hypoxemia and increased pulmonary vascular resistance, both of which epoprostenol aims to address.
Through the inhaled route, epoprostenol will cause improved V/Q matching through vasodilation of well-ventilated areas of the lung. This will allow improved gas exchange, oxygenation, and in turn improve the P/F ratio.
For a more complete discussion on ARDS, please see this other Air Care Series post on the subject.
Right Ventricular Physiology:
The other prominent effect that epoprostenol has is decreased pulmonary vascular resistance, therefore improving right heart function through a reduction in the perceived RV afterload.
Right ventricular physiology is governed by four key components: 1) systemic venous return, or preload, 2) pulmonary arterial pressure, or right ventricular afterload, 3) right ventricular compliance, and 4) right ventricular free wall / interventricular septum contractility (12). Under normal physiologic circumstances, the right ventricle contracts against a highly compliant and low resistance pulmonary circulation. As a result, the right ventricle is well adapted to changes in volume (12,13). However, the RV experiences a greater change in end-systolic volume as compared to the left ventricle (LV) and is highly sensitive to changes in afterload (12,14,15). Unlike the left ventricle, which receives its blood supply from the coronary arteries during diastole, the right ventricle receives its blood flow during both systole and diastole (16).16 As such, the right ventricle is prone to decreased coronary blood flow and subendocardial ischemia in the setting of increased right ventricular end diastolic pressures, which may exacerbate RV dysfunction.
For a complete discussion of cardiogenic shock and right ventricular failure, please see this other Air Care Series post on the subject.
Pathophysiology of Right Sided Heart Failure:
Though complex and multifactorial, the pathophysiology of acute right-sided heart failure typically involves an abrupt increase in right ventricular afterload (16). Hypoxic vasoconstriction, such as in the setting of ARDS or a pulmonary embolism, is a common underlying and usually reversible cause of an abrupt increase in RV afterload. Furthermore, these rapid changes in pulmonary vascular resistance can lead to significant reduction in RV stroke volume and subsequent RV dilation & tricuspid regurgitation (16). As RV dilation progresses and right-sided filling pressures rise, there is a risk of coronary sinus venous congestion and subsequent RV ischemia, further worsening ventricular function (17,18).
Besides an acute increase in RV afterload, a reduction in RV contractility can also lead to acute right-sided heart failure. This is commonly seen in the setting of an acute myocardial ischemia and can be seen in up to 50% of inferior ST elevation myocardial infarctions (19). Furthermore, structural abnormalities to the myocardium, such as myocarditis, may also contribute to worsened right ventricular contractility. Since the RV does not exist in isolation, its failure goes on to propel hepatic and renal dysfunction via back-up of venous blood. This cumulates to self-enforce a cycle of worsening venous congestion and propagating RV failure (16).
Medical management of right sided heart failure is geared toward optimizing a patient’s preload and right ventricular afterload. Inhaled pulmonary vasodilators, such as epoprostenol, can play a direct role in this process. In patients with acute increases in RV afterload, commonly due to increased pulmonary vasoconstriction from hypoxia or thrombus, inhaled prostacyclin can help reduce RV afterload and ideally temporize RV function.
In the patient case discussed above, inhaled epoprostonel assisted with improved oxygenation and decreased stress on the RV.
Efficacy and Evidence
Epoprostenol is thought to have physiologic benefits in patients with acute right sided heart failure, elevated pulmonary vascular pressures, and ARDS. The use of epoprostenol is often debated, and evidence is lacking regarding the benefits on mortality (7,8). To date there are only a small number of observational studies, and even less randomized control trials.
A recent meta-analysis conducted by Fuller et al. in 2015 included 25 studies, two of which were randomized control trials. Researchers in this study found an increase in the PaO2 to FiO2 ratio in those treated with prostacyclin analogs, as well as a decrease in the mean pulmonary artery pressure in patients. However, in the setting of significant heterogeneity of data as well as reported side effects, the authors concluded that they were unable to reliably attest to the benefit or harm in the use of prostacyclin analogs in patients with ARDS (8).
In a recent Cochrane Review of available literature assessing the efficacy of prostacyclin analog use in the treatment of ARDS, Afshari et al. 2017 conducted a systematic review of two randomized control trials (7,20,21). One of the included studies evaluated the efficacy of inhaled prostacyclin in children (20). The authors found that overall oxygen index was improved significantly among those treated with prostacyclin analog compared to those treated with saline. The other study included those 18 years of age or older and found that there was a non-significant improvement in the PaO2 to FiO2 ratio among those treated with alprostadil compared to those treated with saline (21). Ultimately, the authors of the Cochrane Review concluded that both studies had “very low quality of evidence” and stated that there is insufficient evidence to support the routine use of aerosolized prostacyclin in people with acute respiratory distress syndrome” due to a lack of reliable data on its impact on overall mortality (7). Despite the unclear data on epoprostenol efficacy and its ambiguous effects on overall morbidity & mortality, a recent prospective study found that there may be a potential cost benefit when comparing it to nitric oxide (22).
SUMMARY:
The management of ARDS and right-sided heart failure can be daunting. Fortunately, we have multiple tools to combat refractory hypoxia, elevated pulmonary arterial pressures, and right ventricular failure. Of these, epoprostenol and other prostacyclin analogs have been utilized despite limited data on their actual efficacy. Though promising data has been published endorsing the use of prostacyclin analogs in the treatment of acute right sided heart failure, specifically in the setting of ARDS, there are very few randomized controlled trials providing evidence of its benefit on actual meaningful patient outcomes. Though there may be a cost benefit associated with its use, there is an urgent need for further randomized studies evaluating the use of these aerosolized pulmonary vasodilators and their impact on morbidity &mortality. Though further outcome data is certainly needed, inhaled epoprostenol is just another tool in our arsenal to help stabilize critically-ill patients several thousand feet in the sky, while transferring them to a definite center of care.
AUTHORED BY Josh ferreri, MD
Dr. Ferreri is a PGY-3 in Emergency Medicine at the University of Cincinnati
POSTED BY max kletsel, MD, MS and Christopher Zalesky, MD MSc
Dr. Kletsel is a PGY-3 in Emergency Medicine at the University of Cincinnati
Dr. Zalesky is a PGY-4 in Emergency Medicine at the University of Cincinnati
FACULTY EDITOR william knight, MD
Dr. Knight is a Professor of Emergency Medicine and Neurosurgery at the University of Cincinnati
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