a b s t r a c t

Introduction: Inhaled epoprostenol is a selective pulmonary vasodilator that has shown a potentially broad num- ber of applications in the management of critically ill patients. To date, the vast majority of the literature with re- gard to efficacy, indications for use, and adverse effects of inhaled epoprostenol is focused on use of this agent in critical care settings, with relatively little literature describing use of inhaled epoprostenol in the Emergency De- partment. This retrospective review sought to examine instances in which inhaled epoprostenol was adminis- tered in the Emergency Department of a tertiary-care, Level I trauma center following implementation of a clinical pathway for administration of this medication for cases of refractory hypoxemia, RV dysfunction, and refractory hypoxemia. Primary outcomes were monitoring for adverse effects (i.e. hypotension), trend in FiO2 requirement over time, and clinical indication for initiation of inhaled epoprostenol.

Methods: An automated review was performed to query cases in which inhaled epoprostenol had been initiated in the Emergency Department following adoption of the inhaled epoprostenol clinical pathway. Cases were ex- cluded if the medication was initiated in the prehospital setting, ordered but not administered, or administered for a period of <1 h. Vital signs and co-administration of vasopressors were followed before and following epoprostenol administration to assess for change over time. Clinical indication of epoprostenol administration was assessed via manual chart review.

Results: Inhaled epoprostenol was administered in 20 instances, with 15 cases ultimately meeting inclusion criteria. There were no cases of clinically Significant hypotension (MAP <65) in any of the cases in which inhaled epoprostenol was administered in the Emergency Department, and mean Vasopressor requirement did not in- crease over time. A majority of patients saw a reduction in FiO2 requirement following administration of inhaled epoprostenol. The most common indication for initiation of inhaled epoprostenol based on manual chart review was pulmonary embolism.

Discussion: In this review of cases in which inhaled epoprostenol was administered following adoption of a clin- ical pathway for medication administration, there were no cases of hypotension or other adverse effects that ap- pear to be attributable to medication administration. Pulmonary embolism and refractory hypoxemia were the most common noted indications for administration of inhaled epoprostenol. Further research is warranted re- garding development of clinical protocols for administration of inhaled pulmonary vasodilators in the Emergency Department setting.

(C) 2022

1. Introduction

Inhaled epoprostenol (Flolan(R), Veletri(R)) is a prostaglandin used as a pulmonary vasodilator in the treatment of acute respiratory distress syndrome, pulmonary hypertension, and a range of conditions produc- ing right heart strain [1]. It improves oxygenation in patients with acute respiratory distress syndrome [2] with effects seen in minutes, and is at

* Corresponding author at: 55 Fruit Street, Boston, MA 02114, United States of America.

E-mail address: [email protected] (D. Toomey).

least as effective as alternative inhaled pulmonary vasodilators such as Nitrous oxide [3]. The most commonly observed adverse effect of in- haled epoprostenol is hypotension, which is reported in some studies as occurring at a rate as high as 18% [3]. Inhaled epoprostenol is used ex- tensively in the critical care setting and is typically employed in patients who are mechanically ventilated and sedated. As a result, much of the research focusing on the use of inhaled epoprostenol and other inhaled prostaglandins is found in the Critical care literature and is particularly focused on patients presenting with acute respiratory distress syndrome and refractory hypoxemia [4]. However, the potential applications for

https://doi.org/10.1016/j.ajem.2022.06.009

0735-6757/(C) 2022

inhaled epoprostenol and other inhaled prostaglandins are numerous, and include severe or refractory chronic obstructive pulmonary disease, decompensated right sided heart failure, pulmonary embolism, and pulmonary Arterial hypertension [5-8].

To date, there is little research focusing on the use of inhaled prosta- glandins in the Emergency Department and prehospital setting. The paucity of research in this area may be due to the relatively novel appli- cation of inhaled epoprostenol in the emergency setting combined with the relatively small number of Emergency Departments with defined clinical pathways for the use of inhaled prostaglandins. Our Emergency Department at a tertiary-care, Level I trauma center with over 110,000 visits per year developed and implemented a clinical pathway for the use of inhaled epoprostenol in 2018. The purpose of this study is to re- view cases of inhaled epoprostenol administration in the Emergency Department and describe the demographics of patients who were ad- ministered inhaled epoprostenol. Specifically, we sought to define the safety profile of inhaled epoprostenol, quantifying adverse effects fol- lowing administration while assessing clinical improvement in oxygen- ation and vasopressor requirement following administration based on primary indication.

1. Methods

Approval for retrospective chart review of cases in which inhaled epoprostenol was ordered as well as corresponding patient data was obtained from the study site’s Institutional Review Board. We per- formed a retrospective review of cases in which inhaled epoprostenol was administered in the Emergency Department from July 1st, 2018 to November 30th, 2021. Due to the retrospective nature of the study, all decisions to administer inhaled epoprostenol were made by the clin- ical teams caring for the patients in question. Administration of inhaled epoprostenol was managed by physicians, nurses, pharmacists, and re- spiratory therapists who had undergone extensive training in manage- ment of severe hypoxemic respiratory failure and right ventricular failure through Clinical training and didactics. The indications for the use of inhaled epoprostenol outlined in the inhaled epoprostenol clini- cal pathway fell into three general categories: pulmonary hypertension, supportive therapy for right ventricular dysfunction or failure, and treatment of severe refractory hypoxemia in acute respiratory distress syndrome. Specific metrics were not assigned to define pulmonary hy- pertension or right ventricular dysfunction that would indicate the ini- tiation of inhaled epoprostenol, rather it was used at the clinical discretion of the clinical team. For example, epoprostenol was consid- ered in cases of right ventricular infarct, high risk pulmonary embolism, or in patients with known pulmonary hypertension or right ventricular failure. However, severe refractory hypoxemia in acute respiratory dis- tress syndrome was specifically defined as a partial pressure of oxygen (PaO2) to fraction of inspired oxygen (FiO2) ratio < 100, or an oxygen saturation (SpO2) <88% on FiO2 of 1.0 following patient specific optimi- zation of the ventilator (i.e. optimal positive end expiratory pressure) and Neuromuscular blockade.

Inclusion criteria were patients in which epoprostenol was ordered in the Emergency Department. Exclusion criteria were patients who were ordered epoprostenol in the Emergency Department but not started on epoprostenol until arrival in the Intensive Care Unit, and pa- tients who were administered epoprostenol for <1 h. The Electronic Medical Record database was queried for administration of epoprostenol in the Emergency Department to identify patients meeting the inclusion criteria. After the initial acquisition of charts, they were reviewed by study staff to verify that the epoprostenol was inhaled rather than given intravenously.

Patient medical records were electronically queried for demographic data, including predicted body weight, diagnosis, use of vasopressors, use of neuromuscular blockade, mode of ventilation, and mechanical Ventilator settings. Charts were reviewed by the authors (DT, MO) to determine the indication for inhaled epoprostenol. In cases of

disagreement, the charts would be reviewed by the senior author (SRW). There were no instances of disagreement. To focus on the immediate and Short-term effects of inhaled epoprostenol, data reviewed included all oxygen saturations and mean arterial pressures from time of administration until 2 h following administration of inhaled epoprostenol. When a patient had an Arterial line and non- invasive blood Pressure measurements, mean arterial pressure values from the arterial line were used preferentially. Vital signs were collected and documented in the patient medical record per Emergency Depart- ment protocol. The times were rounded to the nearest 5-min intervals. If two values were recorded in the same interval, the first was included. To facilitate direct comparison of vasopressor requirements, all vaso- pressors were converted into norepinephrine equivalent units using the following equation: Norepinephrine equivalents (mcg/min) = Total (mcg/min) = norepinephrine (mcg/min) + epinephrine (mcg/min) + phenylephrine/10 (mcg/min) + vasopressin*225 (u/min) [9,10].

The primary outcome was development of hypotension (defined as a mean arterial pressure < 65 or initiation of a new vasopressor) in the 2 h period following administration of inhaled epoprostenol. Secondary outcomes included improvement in oxygenation, reason for adminis- tration of epoprostenol, and overall morbidity/mortality of patients in the study population. Data were analyzed in a descriptive manner.

1. Results

In total, this search yielded 20 instances in which inhaled epoprostenol was ordered by Emergency Department providers. On pri- mary review, 5 cases were excluded based on predefined exclusion criteria of administration of epoprostenol after Emergency Department course (n = 2), administration of epoprostenol <1 h (n = 1), improper documentation (n = 1), as well as a patient being made comfort mea- sures only within 30 min of initiation of inhaled epoprostenol (n = 1). Primary demographic data for cases reviewed can be found below in Table 1. The average patient age was 54 years old. Nine cases reviewed were female. The most common comorbidities prior to patient presen- tation were hypertension (40%), tobacco smoking (27%), prior Cancer diagnosis (27%), chronic obstructive pulmonary disease (20%), obesity (20%), and diabetes (20%). The most common Emergency Department chief complaint was hypoxia/respiratory failure (53%). Three patients had known pulmonary embolism at time of presentation to the Emer- gency Department. Only 4 of 15 patients had undergone comprehensive cardiac echocardiogram (either transthoracic or transesophageal) at any point prior to Emergency Department presentation and in all 4 cases the comprehensive echocardiogram had been performed within 6 months prior to arrival. In all cases left ventricular ejection fraction was >50%. Right ventricular systolic pressure ranged from 39 to

47 mmHg with either mild or no tricuspid regurgitation.

The primary outcome of development of clinically significant hypo- tension following administration of inhaled epoprostenol was assessed by monitoring for changes in vasopressor requirement over time and by observing for initiation of vasopressors in patients who had not been on vasopressors prior to initiation of inhaled epoprostenol. Of the 15 pa- tients ultimately selected for review, 10 were on vasopressor medica- tions prior to administration of inhaled epoprostenol, with norepinephrine being the most common vasopressor employed either alone or in combination with other vasoactive agents (9/10 cases). Only one patient was newly initiated on a vasopressor following the ad- dition of inhaled epoprostenol. The median vasopressor requirement did not increase following inhaled epoprostenol, with a median norepi- nephrine requirement of 29.5 ug/min when epoprostenol was started and 20.5 ug/min 2 h following initiation. Additional information regard- ing vasopressor requirements can be seen in Fig. 1.

Two patients who were on vasopressors prior to initiation of inhaled epoprostenol saw an increase in their vasopressor requirements. The first was a 27 year old patient who had concomitant acute respiratory distress syndrome and sepsis secondary to Aspiration pneumonia. This

Table 1

Patient features and medical comorbidities.

to the Emergency Department with significant hypoxemia on non- rebreather and was intubated with an FiO2 of 100% and started on in-

Patient features and medical comorbidities

N: Total 15

haled epoprostenol simultaneously. Of the patients who were adminis- tered inhaled epoprostenol, all survived their Emergency Department

Age (years): n(%) 0-18: 0

18-24: 1(7)

25-34: 3(20)

35-44: 1(7)

45-54: 4(37)

55-64: 1(7)

65+: 5(33)

Mean = 54

Standard Deviation = 21

Sex n(%) M 6(40)

F 9(60)

Location prior to ED n(%) Private Residence / SNF 7(47) Outside Hospital 8(53)

Comorbidities n(%) Chronic Obstructive Pulmonary Disease 3(20) Asthma 2(13)

Obesity 3(20)

Pregnancy 0

Cancer Diagnosis 4(27) Coronary Artery Disease 2(13) Hypertension 6(40)

smoking history 4(27) Congestive Heart Failure 1(7) Cirrhosis 0

Chronic Kidney Disease 0 Peripheral Vascular Disease 1(7) Cerebrovascular Accident 3(20)

Diabetes 3(20)

intravenous drug use 2(13) Body mass index, mean (SD) – kg/m2 24 (11)

Code Status at Presentation n(%) Full Code 13(87)

Do Not Resuscitate 2(13)

ED diagnosis/diagnoses n(%) Acute Respiratory Distress Syndrome 3(20)

Pneumonia 1(7)

Sepsis 3(20)

Pulmonary Embolism 7(47)

Cardiac Arrest 2(13)

Trauma 1(7)

Other 8(53) Vasopressors on presentation n(%) None 11(73)

Epinephrine 1(7)

Norepinephrine 4(27)

Vasopressin 2(13)

Phenylephrine 1(7) Intubated prior to arrival n(%) No 7(47)

Yes 8(53)

patient was on a combination of vasopressin, norepinephrine, and phenylephrine prior to initiation of inhaled epoprostenol, and epineph- rine was added as a fourth vasopressor approximately 1 h after initia- tion. The second was a 28 year old patient with acute respiratory distress syndrome, sepsis, and empyema. The patient was on both nor- epinephrine and vasopressin prior to initiation of inhaled epoprostenol, and required increasing doses of both medications following initiation. In both cases, inhaled epoprostenol was added for the purpose of treating refractory hypoxemia in acute respiratory distress syndrome.

With regard to mechanical ventilation, a majority of patients (8/15) had been placed on mechanical ventilation either with emergency med- ical services or at an outside facility prior to arrival to the Emergency De- partment. Among patients who were not intubated in the field or placed on mechanical ventilation prior to arrival in the Emergency Depart- ment, an additional 3/7 patients were intubated during their Emergency Department stay. Of these, a single case was noted to have been compli- cated by hypotension in the peri-intubation period. All but one of the 15 patients saw either a decrease in FiO2 requirement or stable FiO2 re- quirements between time of presentation and 30 min status post in- haled epoprostenol administration. One patient saw an increase in FiO2 requirement over this time period, though this patient had arrived

course and were ultimately admitted to a critical care setting.

Following workup and evaluation, the most common primary diag- nosis in the Emergency Department of cases reviewed was pulmonary embolism, which was either known or formally diagnosed in 7/15 (47%) of cases. Other prevalent diagnoses included acute respiratory distress syndrome (20%) and sepsis (20%). In total, only 2/15 cases could be clearly categorized into a World Health Organization pulmo- nary hypertension class [11]. One case was considered to be a case of group 3 pulmonary hypertension (pulmonary hypertension due to chronic hypoxia), and 1 was considered a case of group 2 pulmonary hy- pertension (pulmonary hypertension due to left heart disease). None of the 7 cases in which inhaled epoprostenol was administered for pulmo- nary embolism had clearly established pulmonary hypertension due to chronic pulmonary emboli, which would indicate inclusion into group 4 pulmonary hypertension. There were no cases in which in- haled epoprostenol was administered out of suspicion for group 1 or Pulmonary arterial hypertension. On review of clinician notes in the remaining cases, inhaled epoprostenol was administered as an adjunctive measure for refractory hypoxemia in patients undergoing mechanical ventilation.

1. Limitations

Charts underwent manual review for the indication for initiation of inhaled epoprostenol by the authors. While this may introduce bias, de- lineating the indication for medication administration was not a pri- mary objective of the study. In addition, during the COVID pandemic, our institution avoided inhaled epoprostenol for hypoxemic COVID pa- tients. Because epoprostenol is viscous and sticky, it mandates frequent ventilator tubing changes. Our institution, therefore, preferentially used inhaled nitric oxide in COVID patients to avoid the need to break the ventilator circuit and increase the risk of aerosolizing the virus. Finally, this study is limited by the small number of patients that were adminis- tered inhaled epoprostenol during the review period, which the authors feel is due to a combination of the relatively small number of patients for which inhaled epoprostenol was indicated as well as lack of comfort/ familiarity with the use of inhaled epoprostenol among Emergency Department providers.

1. Discussion

With regard to the primary outcome, there were no cases of clini- cally significant hypotension (Mean Arterial Pressure < 65) in any of the cases in which inhaled epoprostenol was administered in the Emer- gency Department. We intentionally only followed this metric over 2 h in order to monitor the short term effects of inhaled epoprostenol in- duction, which would be a more relevant outcome with regard to initi- ation of inhaled prostaglandins in the Emergency Department. Only one patient required the initiation of a vasopressor following inhaled epoprostenol and their total vasopressor requirement remained <10 ug/min of norepinephrine equivalents throughout the study period. Two patients required increasing doses of vasopressor following initia- tion of inhaled epoprostenol. In both cases, the indication for initiation of inhaled epoprostenol was refractory hypoxemia in acute respiratory distress syndrome, though in both cases patients had also been diag- nosed with sepsis, the progression of which would be expected to drive hypotension outside of the effects of inhaled pulmonary vasodila- tors. Prior retrospective reviews of acute respiratory distress syndrome patients receiving inhaled epoprostenol also note sepsis to be an inde- pendent predictor of in-hospital mortality [12]. The median vasopressor requirement did not increase by a clinically significant amount at any point.

Fig. 1. Vasopressor requirements over time.

This figure includes all patients that required a vasopressor at any point during the study period and depicts their vasopressor requirement overtime following the initiation of inhaled epoprostenol. The black dashed line represents the median vasopressor requirement at each time point.

Based on review of the cases in which inhaled epoprostenol was given, two general trends arise. First, in the majority of cases the pri- mary documented indication was pulmonary embolism, which can broadly be put in the category of ‘right ventricular dysfunction or failure’ as outlined in the Emergency Department clinical guideline. Second, there were several cases in which inhaled epoprostenol was administered as an adjunctive measure for refractory hypox- emia in Mechanically ventilated patients. The first of these two trends is suggestive of a pattern of clinical practice in the manage- ment of acute, severe pulmonary embolism that is currently absent from existing pulmonary embolism management protocols within the Emergency Department under review, and suggests a possible role for initiation of inhaled prostaglandins into pulmonary embo- lism guidelines.

Inhaled epoprostenol has been used in the critical care setting for years. While inhaled epoprostenol has never been shown to improve mortality, it improves oxygenation in approximately 40-60% of patients with hypoxemic respiratory failure [13-15] and decreases pulmonary artery pressures in patients with pulmonary hypertension or right ven- tricular failure [16]. The risks of inhaled epoprostenol are minimal [13] with some reports of hypotension, but this has not been seen univer- sally [17]. As refractory hypoxemia and right ventricular failure are very challenging to manage in the Emergency Department, inhaled epoprostenol may benefit these challenging patient populations in emergency situations.

Ultimately, the above review demonstrates several cases in which inhaled epoprostenol was administered in the Emergency Department of a tertiary-care, Level I trauma center without associ- ated clinically significant adverse effects such as hypotension. All patients survived admission to a critical care setting. The indica- tions for administration of inhaled epoprostenol were relatively di- verse, and did not include any cases in which prostaglandins were given for primary pulmonary hypertension. While these results are from a small number of cases, they suggest that inhaled epoprostenol can be safely initiated in the Emergency Department setting.

Funding

Not applicable.

CRediT authorship contribution statement David Toomey: Writing – review & editing, Writing – original draft,

Project administration, Investigation, Data curation, Conceptualization. Michael O’Brien: Writing – review & editing, Writing – original draft, Methodology, Investigation, Formal analysis, Data curation. Bryan D. Hayes: Writing – review & editing, Supervision, Resources, Project administration, Formal analysis, Data curation, Conceptualization. Susan Wilcox: Writing – review & editing, Supervision, Conceptualiza- tion.

Declaration of Competing Interest

The authors noted in the attached title page have no conflicts of in- terest to disclose. There was no external funding to disclose in the devel- opment of this manuscript.

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