a b s t r a c t

Background: Pulmonary hypertension (PH) is characterized by increased pulmonary vascular resistance and pul- monary arterial pressure and is associated with significant morbidity and mortality.

Objective: This narrative review evaluates PH, outlines the complex pathophysiologic derangements, and ad- dresses the emergency department (ED) management of this patient population.

Discussion: Approximately 10-20% of individuals in the United States suffer from PH. Each year nearly 12,000 PH patients seek care in the ED for a variety of symptoms which may or may not be related to PH. There are 5 classes of PH, some of which respond to particular therapies outlined in this review. As Presenting complaints are fre- quently vague and non-specific, emergency physicians must recognize manifestations of PH and complications related to PH to deliver appropriate care. early imaging with chest radiograph, bedside echocardiogram, and computed tomography can assist in determining the Underlying etiology of PH exacerbation. Restarting oral or intravenous pH medications that may have been discontinued is crucial in initial management. Immense care should be taken to avoid hypoxia and hypercarbia as well as maintaining right ventricular preload support. In ad- dition to correction of underlying precipitants, judicious vasopressor and inotrope use can help to correct path- ophysiology and avoid further airway intervention.

Conclusions: An understanding of the pathophysiology of PH and available emergency treatments can assist emergency clinicians in reducing the immediate morbidity and mortality associated with this disease. Restarting maintenance PH medications and proper selection of vasopressors and inotropes will benefit decompensating patients with PH.

Introduction

Pulmonary hypertension (PH), characterized by increased pulmo- nary vascular resistance and pulmonary arterial pressure, is associated with significant morbidity and mortality. The disease is heterogenous, with varying demographics and underlying etiologies. PH affects 15-60 million individuals worldwide [1]. Although rare, with an esti- mated 5-15 cases per 1 million adults, recent studies identify PH- associated complaints as responsible for 64,000 ED visits over a 5 year period [2]. In the United States, the most common cause of PH is left sided heart failure [2,3]. In 1973, the World Health Organization (WHO) defined a classification system for PH to design and implement international health standards [4,5]. Published in 2013, the most recent revision defines Groups 1-5 [4,5]. A discussion of these groups begins

* Corresponding author at: 3841 Roger Brooke Dr, Fort Sam Houston, TX 78234, United States.

E-mail address: [email protected] (B. Long).

with an abbreviated review of pulmonary pathophysiology underlying PH, as an understanding of the errant physiology is crucial when ad- dressing PH and respective therapies in the ED.

Methods

This narrative review provides a focused evaluation of ED-based PH treatment. The authors searched PubMed and Google Scholar for articles containing the key words “Pulmonary hypertension.” The PubMed search was conducted from database inception to September 1, 2019. The first 200 articles in Google Scholar were also evaluated for inclusion. The literature search was restricted to studies published in English. Au- thors evaluated case reports and series, retrospective and prospective studies, systematic reviews and meta-analyses, and narrative reviews. Authors also reviewed guidelines and supporting citations of included articles. Articles with a focus on emergency medicine and critical care were chosen based upon author consensus. When available, systematic reviews and meta-analyses were preferentially selected. These were

https://doi.org/10.1016/j.ajem.2020.02.041 0735-6757/

followed sequentially by randomized controlled trials, prospective stud- ies, retrospective studies, case reports, and other narrative reviews, when alternate data were not available. Over 6000 resources were found on initial literature search. Many of the resources found on liter- ature search included in vivo studies, animal models, genetic studies, case reports or series, and studies focused on outpatient management of PH. Authors of this review focused on resources pertaining to emer- gency medicine and critical care, resulting in selection of 89 resources for this narrative review.

Discussion

Pulmonary pathophysiology

In the setting of PH, physiologic derangements represent changes in pulmonary and systemic circulation, altering the pressures in each sys- tem. The pulmonary circulation is normally a low-resistance, low- pressure system, composed of thin-walled vessels capable of accommo- dating vast alterations in preload. In patients with chronic PH, pulmo- nary vascular resistance gradually increases with vascular remodeling of the pulmonary arteries. This remodeling involves vascular smooth muscle and endothelial cell proliferation, inflammation, and fibrosis. If remodeling occurs over a prolonged period of time, the right ventricle (RV) is able compensate, however, in the setting of RV dilation, tricuspid regurgitation becomes common. Beyond a specific point of RV disten- sion, RV output decreases secondary to increased pulmonary pressure and impedance to RV outflow. This derangement sets in motion a vicious cascade of interventricular dependence in which bulging of the RV into the Left ventricle decreases LV filling, subsequently decreas- ing cardiac output (Fig. 1) [6-9]. As cardiac output falls, end organ perfusion suffers, further exacerbating the pathophysiology of the in- herent underlying disease [8].

Alterations in Pulmonary system pressure and ventricular wall thickness additionally reduce coronary artery perfusion. In a normal physiologic setting, the coronary arteries of the RV are perfused in both systole and diastole due to low RV wall tension as compared to the LV [9]. In PH, as RV pressures increase, RV perfusion falls until pulmonary artery pressures exceed systemic pressure, generating RV is- chemia. In this under-perfused state, RV contractility declines, worsen- ing RV overload [7,10,11]. The emergency management of PH focuses on many of the aforementioned pathways to combat these physiologic

derangements in order to improve patient hemodynamic and respira- tory status.

WHO Groups

Most recently updated in 2013, the WHO organizes PH into 5 distinct groups based upon pathophysiology. Group 1 is defined by pulmonary Arterial hypertension (PAH), a resting mean pulmonary artery pres- sure >= 25 mmHg, and a pulmonary capillary wedge pressure <= 15 mmHg as measured during right heart catheterization [1,4,12]. More than half of all PAH cases are idiopathic [13,14]. The most common cause world- wide is schistosomiasis. Schistosomula migrate to the lungs, heart, and liver, causing (PAH) and portal hypertension [13,14]. While more than half of all PAH cases are idiopathic, mutations in bone morphogenetic protein receptor type 2 (BMPR2), a gene responsible for cell prolifera- tion, are responsible for the majority of heritable forms [15,16]. Addi- tional rare etiologies, such as drug associated PH, are outlined in Table 1 [17].

Group 2 PH represents pulmonary venous hypertension (PVH) due to left-sided heart disease, defined as mean pulmonary artery pres- sure >= 25 mmHg and a pulmonary capillary wedge pressure >= 15 mmHg [18]. PVH is the most common form of PH [18]. In this disease process, elevated left atrial pressure is transmitted to the pulmonary system, through the pulmonary capillaries, and to the pulmonary arteries - manifestations of left heart or valvular pathologies [4,18-20]. Morbidity and mortality in patients with PVH is related to RV dysfunction [18]. As pulmonary compliance decreases due to PH, the work of the RV in- creases, leading to Right heart failure (RHF) and ultimately death [18].

WHO Group 3 individuals develop PH secondary to lung diseases and/or hypoxia [4,19]. In these patients, PH occurs results from chronic alveolar hypoxemia [21-23]. Alveolar hypoxemia induces hypoxic pulmonary vasoconstriction, increasing pulmonary vascular resistance [21]. WHO Group 4 includes persons who display PH which persists for >=6 months following anticoagulation therapy for pulmonary emboli (PE) [24]. Chronic thromboembolic pulmonary hypertension (CTEPH) is estimated to occur in 4.8% of survivors of acute PE and 10% of patients with recurrent PE [25]. Surprisingly, the majority of cases of CTEPH arise from asymptomatic venous thromboemboli [26]. Finally, WHO Group 5 encompasses a heterog- enous collection of disease processes in which PH results from mul- tifactorial mechanisms (Table 1).

Fig. 1. Pathophysiology of PH.

Table 1

Classification of WHO Groups 1-5 with underlying disease mechanisms. PH-pulmonary hypertension, PVH - pulmonary venous hypertension, SSRI—Selective serotonin reuptake inhibitor, COPD-chronic obstructive pulmonary disease, ILD-interstitial lung disease, CTEPH-chronic thromboembolic pulmonary hypertension [17,27-31].

WHO classification Underlying disease state Additional notes or

associations

individuals frequently present with symptoms of RHF: ascites, periph- eral edema, and hemoptysis [39,40]. Emergency clinicians should eval- uate for underlying precipitants of RHF including sepsis, unplanned withdrawal of PH therapy, medication non-compliance, pregnancy, pneumonia, anemia, and arrhythmias [41].

History

Group 1: Pulmonary arterial hypertension

Group 2: PVH with left heart disease

Group 3: PH due to underlying lung disease or hypoxia

• Schistosomiasis
• Idiopathic
• drug induced
• Portal hypertension
• congenital heart disease
• Connective tissue diseases
• Persistent pulmonary hypertension of the newborn
• LV systolic and diastolic disease
• Valvular disease (mitral and aortic)
• Congenital or acquired left heart inflow/outflow tract obstructions
• COPD
• ILD
• Hypoxemia
• Obesity Hypoventilation Syndrome
• Developmental lung disease
• Chronic high-altitude exposure
• Schistosomiasis most common cause globally.
• Associated drugs: [17]
  • Anorexigens - elevated serotonin levels stimulate smooth muscle growth, increasing pulmonary vascular resistance: [17] SSRIs, tyrosine kinase inhibitors, lithium, buprenorphine, cocaine, chemotherapy.
• In left heart disease, 69% of individuals will develop concomitant PVH [32].
• In aortic valve disease, development of PVH is correlated with left heart dysfunction, and is an indication for surgical intervention [33].
• Prevalence of PH in patients with ILD is 30-40% [34].

In individuals absent a previous diagnosis of PH, initial history should include PH risk factors including congenital heart disease, left- sided heart disease, valvular disease, pulmonary disease, connective tis- sue disease, liver disease, blood dyscrasias, thyroid disorders, dialysis- dependent renal disease, malignancy, stimulant use, and family history of PH [39,42]. In patients diagnosed with PH, questions regarding cur- rent therapy and medication compliance are essential to guide treat- ment and specialty consultation Therapeutic side effects (Table 2) should be considered diagnoses of exclusion. The possibility of preg- nancy and vaccination status should be discussed and documented.

Physical examination findings

Physical examination is unreliable for determining the presence of PH in early disease stages. In advanced PH, signs of RHF are commonly present: elevated jugular venous pressure, hepatojugular reflex, ascites, hepatomegaly, and peripheral edema [4,39,42]. On auscultation, an increased pulmonic component of the second heart sound (P2), an RV gallop, or the murmur of tricuspid regurgitation may be present. Ar- rhythmias including atrial fibrillation, atrial flutter, and atrioventricular node re-entry tachycardias are common in PH patients [40]. Palpation of the precordium may reveal an RV heave. In one systematic review, au- thors found that although a number of the aforementioned signs had high specificities (88% for an S4 on inspiration, 85% for a loud P2 on in- spiration, 84% for an RV lift on inspiration), their sensitivities were low (12%, 29%, and 21%, respectively) [55]. The physical examination finding

with the highest positive likelihood ratio was a loud P2 on inspiration

Group 4: PH following pulmonary embolism

- CTEPH - Risk of CTEPH is worsened by prothrombotic states, post splenectomy, or infection of cardiac shunt or pacemaker [35].

(LR+ 1.9, 95% Credible Interval 1.2-3.1) [55]. Patients with decompen- sated PH frequently present with hypotension, displaying signs of sys- temic hypoperfusion: diaphoresis, cool extremities, peripheral cyanosis, and tachycardia. Patients with a patent foramen ovale who suffer from

Group 5: PH secondary to multifactorial mechanism

ED evaluation

Hemolytic: Chronic hemolytic anemia, myeloproliferative disorders

Systemic Disorders: Pulmonary histiocytosis, Sarcoidosis

Metabolic: Thyroid disorders, Glycogen storage disease, Gaucher’s disease

Other: end stage renal disease requiring dialysis, Tumor obstruction, Fibrosing mediastinitis

20% of patients with untreated thyroid disease will develop PH [36].

PH occurs in 6-10% of Sickle cell disease and thalassemia patients and is a major risk factor for mortality [37,38].

PH may exhibit symptoms of right-to-left shunting, such as systemic hypoxemia and cyanosis [56,57].

Studies

An electrocardiogram (ECG) should be obtained. If PH is pro- nounced, ECG will reveal Right axis deviation and right ventricular hy- pertrophy (Fig. 2) [41,58]. In addition to a tachyarrhythmia, right Atrial enlargement, and ST segment depression and T wave inversion in the precordial leads (right heart strain) may be present [42].

Given the numerous etiologies of PH, laboratory studies should be guided by the patient presentation, history, and examination findings. In patients with chronic PH, venous blood gas frequently demonstrates hypoxemia and respiratory alkalosis [39,42]. Brain Natriuretic Protein (BNP) measurement may be useful in narrowing the differential diagno- sis of a patient presenting with dyspnea [58]. BNP levels N400 pg/mL

Patient presentation

Accounting for approximately 5 to 15 cases per one million ED visits, PH and its associated symptoms are non-specific [3]. Dyspnea is the most common presenting complaint, though patients also report fa- tigue, weakness, chest pain, and syncope [4,39]. Symptomatology in un- diagnosed PH is insidious; many individuals experience dyspnea and fatigue, which typically worsens over a period of weeks to months, and becomes apparent when limitations in daily activities occur. Angina results from ischemic subendocardial injury from ventilation-perfusion mismatch or compression of the left main coronary artery by the pul- monary trunk [39]. Syncope, the result of decreased cerebral blood flow due to reduced cardiac output, is associated with a poor prognosis [39]. Hoarseness may occur due to compression of the recurrent laryn- geal nerve by an enlarged pulmonary artery [4,39]. In advanced disease,

suggest heart failure, but do not exclude other underlying conditions [59]. Normal plasma BNP levels increase with age and are higher in women than in men [60]. In the setting of renal failure, BNP should be interpreted with caution as reduced clearance may lead to chronic ele- vation [58]. Evaluation of myocardial perfusion and end-Organ function is critical in patients presenting with signs and symptoms consistent with heart failure [59]. In this setting, a troponin, renal function panel, liver function panel, and a lactate are advised [59]. An elevated troponin and abnormal liver function tests portend a poor prognosis. Elevations in AST, ALT, and total bilirubin signify a decreased cardiac index and in- creased central venous pressure, reflecting the degree of heart failure [60,61].

Imaging may narrow the differential diagnosis among etiologies of PH and guide resuscitation. ED imaging should include a chest radiograph

Table 2

Medical Management of PH, Side Effects, and Considerations [19,43-50]. It should be noted that not all of the WHO PH Groups are amenable to pharmaceutical management, as the main- stay of treatment focuses on improving the underlying physiology based upon PH etiology. iNO—inhaled nitric oxide, V/Q-ventilation perfusion, PDE-phosphodiesterase, PH-pulmonary hypertension, PVR-pulmonary vascular resistance, SVR—systemic vascular resistance, sGC-soluble Guanylate Cyclase, IV-intravenous, ppm-parts per million.

Medication class	Method of administration	Mechanism of action	Side effects	PH Group	Additional considerations
Calcium	Oral	Vasodilation through inhibition of	Hypotension; Worsening hypoxemia and pulmonary	1	- Affordable

channel blockers

• Nifedipine
• Diltiazem
• Amlodipine Prostacyclin Agonists
• Epoprostenol
• Iloprost
• Selexipag
• Treprostinil

Continuous infusion Inhalation Oral

Oral

Calcium channels

Smooth Muscle relaxation via direct arterial vasodilation [19]

vasoconstriction [45]

Worsens V/Q mismatch if IV, Hypotension, Dizziness, Flushing, Headache, Leg Pain, jaw pain

IV Epoprostenol or Treprostinil: Bacteremia, catheter thrombosis, Fetal loss/demise

1,5 - Sudden withdrawal causes rebound PH

• Inhalational only-decreases PVR
• Infusion decreases SVR and PVR
• Used in place of iNO in severe RV failure [9]

Endothelin Receptor Agonists

• Bosentan
• Macitentan
• Ambrisentan

Oral Inhibition of endothelin decreases vasoconstriction [51]

Bosentan and Ambrisentan: Peripheral edema 1,4 - Long term treatment:

minimal utility in emergency situations

PDE5

Inhibitors

• Sildenafil
• Tadalafil

Oral Inhibits degradation of cGMP, inducing smooth muscle relaxation [52]

Hypotension, Dizziness, Flushing, Headache, Leg pain, Back pain, Myalgias

1,5 - Do not administer nitrates

iNO Inhalation Vasodilation by decrease of intracellular calcium and increased cGMP [53]

Free radical oxidation [53], Respiratory tract hypersensitivity in chronic use [53], N5 ppm causes pulmonary toxicity [54]

• Improves V/Q without changing SVR [9]

and Bedside echocardiography (Fig. 3). Radiographic findings of PH in- clude dilated pulmonary arteries, peripheral pruning, and an enlarged right atria and RV [42]. In severe disease, Pleural effusions may be pres- ent. While chest radiography demonstrates high sensitivity (96.9%) and specificity (99.1%) for detecting severe PH, it lacks sufficient sensitivity for detecting mild PH (defined as 40-50 mmHg estimated pulmonary ar- tery systolic pressure [ePASP], though this information may not be avail- able in the ED) [62].

In the setting of PH, bedside echocardiography will demonstrate right-sided pressure overload: right atrial enlargement, RV dilation (RV: LV N 1:1; normal b 0.6), increased RV free wall thickness (N5-7 mm as measured at end-diastole by M-mode or 2D echocardiog- raphy from the Parasternal long axis or subxiphoid view), end-systolic flattening of the intraventricular septum, and interventricular interde- pendence visualized as a “D”-shaped left ventricle in diastole (Fig. 3) [63]. ultrasound assessment of the Inferior vena cava may be

Fig. 2. ECG with evidence of pulmonary hypertension.

Fig. 3. Ultrasound depicting RV dilatation. A. Apical 4 chamber echocardiography. B. Notice the end-systolic flattening of the intraventricular septum, and interventricular interdependence visualized as a “D”-shaped left ventricle in diastole (Red). A markedly thickened moderator band (blue), indicative of RV hypertrophy, is located in the right ventricular apex connecting the interventricular septum to the anterior papillary muscle. When looking within the RV, the moderator band appears similar to other trabecula except that it does not seem to be attached to one single side, but rather crosses the lower portion of the RV. RV: right ventricle; LV: left ventricle; RA: right atrium; LA: left atrium.

misleading in PH patients, especially those with Mitral regurgitation or aortic stenosis (Group 2 PH), revealing plethora that may not reflect in- travascular volume status [9,64].

Computed Tomography (CT) plays an essential role in identifying potential etiologies underlying PH (Fig. 4). A CT demonstrating right atrial enlargement, RV dilation, and main pulmonary artery/Ascending aorta diameter ratio >= 1 is suggestive of PH, with a positive predictive value of 96% (Fig. 3) [65]. On CT, the pulmonary trunk should be no larger than 2.8 cm at the level of its bifurcation. Measurements N2.8 cm suggest PH with a sensitivity of 69%-87% and a specificity of 89%-100% [66]. For individuals with CTEPH, CT angiography may reveal thrombi in the pulmonary vasculature and identify intra- and extra- cardiac shunts contributing to the patient’s presentation. In this patient population, non-enhanced CT may reveal a mosaic pattern of variable attenuation in the lung parenchyma with evidence of irregular pulmo- nary perfusion due to chronic thromboemboli.

LV dysfunction is suggested on CT by the presence ofa mosaic pulmo- nary perfusion pattern and pulmonary ground-glass opacities (indica- tive of chronic pulmonary edema). The use of high-resolution CT in patients with PAH, without co-existing lung disease, should demonstrate normal lung parenchyma. Interstitial pulmonary abnormalities revealed by CT may point to an intrinsic lung disease as the etiology of the PH.

ED management

The primary goal of the emergency clinician is the identification and treatment of the underlying etiologies of PH (e.g. alveolar hypoxia in

Fig. 4. CT of the chest demonstrating evidence of PH.

COPD, hyperthyroidism, etc.). For individuals presenting with RHF, trig- gering factors should be addressed: antibiotic therapy administered for infections, transfusions given as indicated for anemia to maintain a he- moglobin of N10 g/dL, and arrhythmias treated [60,67]. new-onset atrial fibrillation or flutter are common in PH patients. In the absence of ran- domized controlled trials, observational studies suggest improved sur- vival with a Rhythm control strategy [68]. Rate control with calcium channel blockers or ?-blockers is not advised, as these medications fur- ther impair RV function [60]. Although digoxin may slow the ventricular rate in patients with supraVentricular tachyarrhythmias associated with RV dysfunction, cardioversion is the preferred therapy for PH patients given this population’s propensity for digoxin toxicity [69]. electrical cardioversion is favored, as prolonged Atrial arrhythmias in patients with PH are associated with rapid decompensation. Pharmacologic car- dioversion with Class III agents, such as amiodarone and sotalol, have been reported [70-72]. While Class IC agents may theoretically be uti- lized, data in PH patients are lacking. In individuals with atrial arrhyth- mias lasting N48 h, anticoagulation is advised prior to cardioversion [68].

In PH patients who present due to an unexpected discontinuation in oral or IV PH therapy, every effort should be made to contact the patient’s PH specialist to initiate ED treatment and prevent acute de- compensation. While prostacyclins, endothelin receptor agonists, and phosphodiesterase inhibitors may not be immediately available in the ED, initiating these therapies early in the ED course may improve pa- tient hemodynamics, though optimizing oxygenation and circulation should take priority [19,43,45]. In individuals with PH, supplemental oxygen is indicated to maintain an oxygen saturation N 90% [51,60]. Hypercapnia should be avoided as it results in further pulmonary vaso- constriction [6,41,51,60]. Continuous non-invasive positive pressure ventilation may be considered, though fluid balance must be optimized prior to initiation to eliminate dangerous decreases in cardiac output [60]. Although data are limited in the setting of acute exacerbations, non-invasive positive pressure ventilation in Group 3 PH patients with no LV dysfunction is typically well tolerated and improves hypercapnia [73,74]. There are no current recommendations regarding the use of bilevel positive pressure ventilation in PH patients given the paucity of data [69,74]. high-flow nasal cannula is an alternative therapy that may improve hypoxemia, especially if patients are unable to toler- ate the mask utilized for NIPPV.

Intubation should be avoided if possible, as the effect of sedatives and positive intrathoracic pressure may reduce cardiac function and cause Peripheral vasoconstriction, resulting in hypotension and cardio- vascular collapse [9]. If intubation is required, etomidate is recom- mended for induction, given its limited effects on cardiac contractility and vascular tone. Hemodynamic optimization prior to intubation is recommended. If the patient is hemodynamically unstable, vasopres- sors should be initiated before attempts to establish a definitive airway

are made [59,75]. Awake intubation with Topical anesthetics is an alter- native that should be considered given the reduced risk of hemody- namic decompensation as compared to rapid sequence intubation. Medications administered during rapid sequence induction will likely result in profound Hemodynamic collapse, hypercarbia, hypoxemia, and acidosis [9]. Ventilator settings should target 6-8 mL/kg of ideal body weight and Plateau pressures b30 cm H₂O. Low positive end expi- ratory pressures should be utilized to minimize decreases in preload and increases in RV afterload [7,59]. Hypoxemia and hypercapnia should be avoided [9,42,51,58].

In the majority of cases, RV failure will be associated with fluid over- load [69]. IV diuretics should be used cautiously to obtain a negative fluid balance, optimizing Circulating blood volume and reducing RV preload, and thus improving cardiac output [76]. For patients not previ- ously receiving oral diuretics, an initial dose of 20-40 mg IV furosemide is recommended for hypervolemia [76]. In individuals utilizing home di- uretic therapy, the initial IV dose should be at least equivalent to the oral dose [75]. Consultation may be required for ultrafiltration in patients who are resistant to diuretic therapy [75]. In hypovolemic patients, vol- ume should be delivered conservatively, with boluses of 250 mL over 15-30 min [76].

In the setting of hemodynamic instability, vasopressors should be initiated. Vasopressors increase aortic root pressure, increasing RV perfusion [9]. Norepinephrine is an effective first-line vasopressor for patients with PH [76-78]. Although norepinephrine primarily tar- gets ?₁ receptors, with limited ?₁ stimulation to increase cardiac contractility, studies in heart failure patients have demonstrated im- proved RV myocardial oxygen delivery following administration (dose: 0.01-0.03 ug/kg/min IV) [77]. The addition of low dose vaso- pressin (0.01-0.03 U/min) may be considered if the aforementioned therapies fail to result in Hemodynamic improvement. Higher doses should be avoided, which result in pulmonary and coronary vaso- constriction [75,77].

Epinephrine may benefit PH patients given the combined alpha and beta stimulation which provides systemic vascular support with inotropy, though this may increase myocardial oxygen demand. To date, there have been no trials regarding epinephrine use in adult PH patients. In a pilot study of hemodynamically stable children, epi- nephrine demonstrated an increase in systemic vascular resistance, though it worsened the systolic pulmonary artery pressure: aortic pressure ratio [79]. Additionally, two patients experienced brief dysrhythmias, atrial bigeminy and ventricular bigeminy following administration of epinephrine [79]. Animal models suggests that epinephrine improves cardiac index through inotropy, with systemic vascular resistance increasing in a dose dependent fashion [79,80]. In contrast, sole ? stimulation from phenylephrine should not be used in the unstable PH patient as it increases pulmonary vascular resis- tance and may induce Reflex bradycardia [81]. Dopamine should be also avoided given ?₂-mediated decreases in systemic vascular resis- tance and possible arrhythmias [77].

Inotropes increase the risk of tachyarrhythmias and should only be utilized in the setting of inadequate oxygen delivery, despite correction of abnormalities in RV preload, and conditions causing ischemia [77]. If inotrope support is required, dobutamine is the agent of choice [75,76]. At low doses (5-10 ug/kg/min), dobuta- mine improves RV contractility and increases cardiac output through ?₁ receptor stimulation [75,76]. Higher doses should be avoided, given increased stimulation of ?₂ receptors, causing vaso- dilation and hypotension [76]. Milrinone, a selective PDE-3 inhibitor, is recommended for PH resulting from biventricular failure (0.375- 0.75 ug/kg/min IV). Use in the ED may be limited given the requirement for pharmacy preparation and the drug’s slow onset of action [76]. Milrinone improves inotropy and pulmonary vasodilation, but similar to dobutamine, it may cause hypotension [75,76].

There are several other therapeutic options for patients with PH. Al- though sildenafil reduces RV afterload through pulmonary and systemic

vasodilation, its use in critically ill patients in the ED is limited given the risk of hypotension. Patients who fail to respond to inotrope and vaso- pressor therapy should be considered for venoarterial extracorporeal membrane oxygenation [76,81]. Patients with PH have a high risk of sudden cardiac death and poor outcomes. Cardiopulmonary resuscita- tion outcomes in PH patients with RV failure are poor: in a cohort of 3130 PH patients who required CPR, only 6% survived for N90 days [59,82-84].

Special population - prostacyclin agonist pump

A life-threatening emergency can occur if the patient has been pre- scribed IV epoprostenol or treprostinil and the IV catheter is removed or damaged, or the pump stops working [85,86]. A PH specialist should be consulted emergently, and if possible, the pump should not be turned off as this may result in sudden death. If there is a problem with the line, pump, or cassette, peripheral access should be obtained and the pump tubing connected directly to this access [43,85,86]. The line should not be primed or flushed, as a bolus of prostacyclin agonist may be delivered to the patient, resulting in fatal hypotension. The patient’s catheter should be inspected for drainage and surrounding cellulitis, which sug- gest infection. If administering medications or drawing laboratory stud- ies, a second peripheral IV is required. An alternative infusion pump should not be utilized unless advised by the PH specialist [85,86].

Inhaled therapies

Inhaled vasodilators such as nitric oxide and epoprostenol may re- duce pulmonary vascular resistance. These medications have low sys- temic absorption, minimal effect on blood pressure, and may improve cardiac output [87]. These can be administered via endotracheal tube, NIPPV, or HFNC [88]. However, inhaled vasodilators should only be ini- tiated with PH specialist consultation, and they are not recommended in patients with left ventricular failure [87].

Disposition

Admission and consultation are needed if new onset PH, worsening PH, or prostacyclin agonist pump malfunction is suspected or diagnosed during the ED course. Transthoracic echocardiography is required to as- sess RV size and function and measure pulmonary artery systolic pressure and tricuspid jet velocity [40,42]. In patients with PH, echocardiography determines the extent of deterioration. In individuals without a previous diagnosis of PH, tricuspid jet velocity N2.8 m/s estimates the likelihood of the disease, predicting the need for right heart catheterization and ancil- lary testing (pulmonary function tests, functional exercises tests, etc.) [4,42,89].

Conclusions

Patients with new onset PH or a history of PH may present with a myriad of chief complaints. ED evaluation and treatment center upon identifying underlying etiologies which may trigger acute decompensa- tion. The patient presenting with RHF is commonly critically ill. Point of Care Ultrasound may be utilized to guide acute resuscitation. For this pa- tient population, knowledge of recommendations regarding inotrope and vasopressor therapy is essential. In the majority of cases, admission will be warranted. The emergency medicine physician must be pre- pared to address this complex disease process.

Declaration of competing interest

None.

Acknowledgements

All authors conceived the idea for this manuscript and contributed substantially to the writing and editing of the review. This manuscript

did not utilize any grants, and it has not been presented in abstract form. This clinical review has not been published, it is not under consideration for publication elsewhere, its publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out, and that, if accepted, it will not be published elsewhere in the same form, in English or in any other language, including electroni- cally without the written consent of the copyright-holder. This review does not reflect the views or opinions of the U.S. government, Depart- ment of Defense, U.S. Army, U.S. Air Force, or SAUSHEC EM Residency Program.

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