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408 SECTION 7: Cardiovascular Disease TABLE 57-9 Common Adverse Effects of Antihypertensive Drugs Antihypertensive Class Recommended Ancillary Testing Before Therapy Most Common Adverse Effects Diuretic Chemistry panel: renal function and electrolytes Hypokalemia, hypomagnesemia, hyperglycemia, hypercalcemia, hyperuremia, hyponatremia Angiotensin-converting enzyme inhibitor Chemistry panel: renal function and electrolytes Pregnancy test Cough, hyperkalemia, acute renal failure, angioedema, myopathy, fetal abnormalities Angiotensin receptor blocker Chemistry panel: renal function and electrolytes Pregnancy test Hyperkalemia, acute renal failure, angioedema, myopathy, fetal abnormalities β-Blocker ECG Bronchospasm, bradycardia, depression, erectile dysfunction Calcium channel blocker ECG Bradycardia, constipation, lower extremity edema Aldosterone antagonist Chemistry panel: renal function and electrolytes Pregnancy test Hyperkalemia, gynecomastia, feminization of male fetuses TABLE 57-10 Agents for Severely Hypertensive Pediatric Patients With Life-Threatening Symptoms Agent Dosage Indications/Comments/Cautions Esmolol 100–500 micrograms/kg/min IV infusion Typically used in perioperative cardiac patients Risk of bradycardia Hydralazine 0.1–0.2 milligram/kg per dose IV or IM; up to 0.4 milligram/kg per dose Likely the most commonly used agent; caution with inadvertent overshooting of BP reduction Risk of tachycardia Give every 4 h if given as bolus Labetalol IV bolus: 0.2–1.0 milligrams/kg per dose; up to 40 milligrams per dose Infusion: 0.25–3.0 milligrams/kg/h Rapid onset if given IV (2–5 min) Avoid in asthma and heart failure Risk of hypotension in children <24 months and concomitant ischemic or traumatic brain injury Nicardipine IV bolus: 30 micrograms/kg up to 2 milligrams per dose Infusion: 0.5–4 micrograms/kg/min May need central access to avoid thrombophlebitis Risk of tachycardia; increases cyclosporine and tacrolimus levels Nitroprusside Starting: 0–3 micrograms/kg/min Maximum: 10 micrograms/kg per min Significant experience in pediatric population Risk of cyanide poisoning after >48 h or earlier in renal/liver dysfunction patients Oral Agents for Severely Hypertensive Pediatric Patients With Less Significant Symptoms and No Target Organ Damage Clonidine 2–5 milligrams/kg per dose up to 10 milligrams/kg per dose given every 6–8 h (PO) Often used in patients with chronic hypertension and those refractory to other agents Risk of dry mouth, drowsiness Fenoldopam 0.2–0.5 milligram/kg/min up to 0.8 milligram/kg/min IV infusion Higher doses may lead to tachycardia without much more BP reduction Hydralazine 0.25 milligram/kg per dose up to 25 milligrams per dose given every 6–8 h (PO) Half-life varies with genetically determined acetylation rates Isradipine 0.05–0.1 milligram/kg per dose up to 5 milligrams per dose given every 6–8 h (PO) Exaggerated BP decrease in patients receiving azole antifungal agents Minoxidil 0.1–0.2 milligram/kg per dose up to 10 milligrams per dose given every 8–12 h (PO) Most potent oral vasodilator; long acting Abbreviation: BP = blood pressure. Data adapted from: Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. 76-79 REFERENCES The complete reference list is available online at www.TintinalliEM.com. Pulmonary Hypertension John C.
potent oral vasodilator; long acting Abbreviation: BP = blood pressure. Data adapted from: Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. 76-79 REFERENCES The complete reference list is available online at www.TintinalliEM.com. Pulmonary Hypertension John C. Greenwood Michael Winters INTRODUCTION AND EPIDEMIOLOGY The pulmonary vascular system is normally a high-flow, low-resistance circuit, with a mean pulmonary arterial pressure that constitutes approximately 15% to 20% of the systemic circulation. 1 Normal pulmonary arterial systolic pressures range from 15 to 30 mm Hg, and diastolic CHAPTER pulmonary arterial pressures range from 4 to 12 mm Hg. 1 Pulmonary hypertension exists when a mean pulmonary arterial pressure is >25 mm Hg at rest or >30 mm Hg during exertion. 1,2 Pulmonary hypertension classification uses measurements of pulmonary arterial pressure, pulmonary vascular resistance, and pulmonary capillary wedge pressure (Table 58-1). 1,3 Although echocardiography estimates pulmonary arterial pressure in a patient with suspected pulmonary hypertension, definitive diagnosis requires right heart catheterization. Patients with group 1 pulmonary arterial hypertension have a mean pulmonary arterial pressure >25 mm Hg, a pulmonary vascular resistance >240 dynes/s/cm 5, and a pulmonary capillary wedge pressure <15 mm Hg. 2 Group 2 disease is caused by left heart disease and is the most common etiology. 2 Group 3 occurs with chronic hypoxemic lung disease. Chronic thromboembolic pulmonary hypertension, group 4, develops in up to 4% of patients with thromboembolic disease. 4-6 Regardless of the cause, pulmonary hypertension is associ ated with high rates of morbidity and mortality, 4,7 with a 5-year death rate for patients with idiopathic pulmonary arterial hypertension exceeding 30%. Tintinalli_Sec07_p0329-0424.indd 408 8/2/19 6:42 PM
in up to 4% of patients with thromboembolic disease. 4-6 Regardless of the cause, pulmonary hypertension is associ ated with high rates of morbidity and mortality, 4,7 with a 5-year death rate for patients with idiopathic pulmonary arterial hypertension exceeding 30%. Tintinalli_Sec07_p0329-0424.indd 408 8/2/19 6:42 PM CHAPTER 58: Pulmonary Hypertension 409 tension during systole, increased oxygen consumption, and eventually decreased contractility. With progressive RV dilation, the intraventricular septum displaces toward the left ventricle, which inhibits left ventricular filling and ultimately impairs cardiac output and systemic perfusion. Perfusion of the right coronary artery depends on the coronary perfusion pressure (systemic diastolic pressure – right atrial pressure), which normally occurs during both systole and diastole. In patients with advanced pulmonary hypertension, right coronary artery perfu sion occurs almost exclusively during diastole. 10,11 Decreased perfusion results in RV ischemia and further impairment of cardiac output. Eventually, this cycle results in RV failure and cardiovascular collapse. CLINICAL FEATURES The most common symptom of pulmonary hypertension is dyspnea, either at rest or with exertion, and is present in over 50% of patients. 1,12 Other symptoms include fatigue, chest pain, syncope, and exertional lightheadedness. 3,12,13 Delays in diagnosis are common, with a mean interval between symptom onset and diagnosis of 2 years. 14 As pul monary artery pressure increases, patients can develop symptoms of advanced heart failure such as early satiety, anorexia, orthopnea, paroxysmal nocturnal dyspnea, and peripheral edema. The physical examination is often normal in the early stages. 1 As the disorder worsens, findings of RV failure emerge (e.g., a holosystolic tri cuspid regurgitation murmur, jugular venous distention, hepatomegaly, ascites, increased intensity of the pulmonary component of the second heart sound [P 2], and lower extremity edema).1,4 DIAGNOSTIC TESTING ECG The most common ECG abnormality is right axis deviation. 13 Additional findings include signs of RV hypertrophy or RV failure, such as an R/S ratio >1 in lead V 1, an R/S ratio <1 in leads V 5 and V 6, a qR complex in lead V 1, an S 1Q3T3, right atrial enlargement in the infe rior leads, and an incomplete or complete right bundle branch block (Figure 58-1). 15 These findings are neither sensitive nor specific for pulmonary hypertension. The ECG may show signs of RV ischemia or dysrhythmia. The most common dysrhythmias in patients with pulmonary hypertension are atrial fibrillation, atrial flutter, and atrioventricular nodal reentrant tachycardia.
anch block (Figure 58-1). 15 These findings are neither sensitive nor specific for pulmonary hypertension. The ECG may show signs of RV ischemia or dysrhythmia. The most common dysrhythmias in patients with pulmonary hypertension are atrial fibrillation, atrial flutter, and atrioventricular nodal reentrant tachycardia. 16,17 TABLE 58-1 World Health Organization Classification of Pulmonary Hypertension Group 1: Pulmonary Arterial Hypertension • Idiopathic • Genetic/heritable abnormalities • Drug or toxin induced • Associated with known risk factors for pulmonary arterial hypertension (human immunodeficiency virus, portal hypertension, pulmonary veno-occlusive disease, collagen vascular disorders) Group 2: Pulmonary Venous Hypertension (left heart disease) • Left ventricular systolic or diastolic dysfunction • Mitral or aortic valve disease Group 3: Chronic Hypoxemic Lung Disease • Obstructive lung disorders (chronic obstructive pulmonary disease) • Interstitial lung disease • Idiopathic pulmonary fibrosis • Collagen vascular disorders • Sleep-disordered breathing (obstructive sleep apnea) • Chronic exposure to high altitude Group 4: Chronic Thromboembolic Pulmonary Hypertension Group 5: Miscellaneous • Lymphatic obstruction • Hematologic disorders: myeloproliferative disorders • Systemic disorders: sarcoidosis, neurofibromatosis • Metabolic disorders: glycogen storage disease, thyroid disorders PATHOPHYSIOLOGY Pulmonary arterial hypertension consists of vascular remodeling in all layers of small and mid-sized pulmonary arterioles, plus inflamma tion and in situ thrombosis formation. 9 Additional pathology includes alterations in microvascular permeability, hypoxic vasoconstriction, and plexiform lesion formation in arteriolar walls. The cumulative effect of these changes is sustained elevations of pulmonary vascular resistance and impaired pulmonary blood flow. With persistent elevations in pulmonary vascular resistance, the right ventricle (RV) dilates. RV dilation leads to increased ventricular wall III aVR aVL aVF V3 V2 V1 V6 V5 V4 FIGURE 58-1. ECG with atrial fibrillation and findings predictive of pulmonary hypertension: R/S ratio in V1 >1, right axis deviation, and ST depressions in V3 to V5 indicating possible right ventricular strain. Tintinalli_Sec07_p0329-0424.indd 409 8/2/19 6:42 PM
eased ventricular wall III aVR aVL aVF V3 V2 V1 V6 V5 V4 FIGURE 58-1. ECG with atrial fibrillation and findings predictive of pulmonary hypertension: R/S ratio in V1 >1, right axis deviation, and ST depressions in V3 to V5 indicating possible right ventricular strain. Tintinalli_Sec07_p0329-0424.indd 409 8/2/19 6:42 PM 410 SECTION 7: Cardiovascular Disease Right atrium Dilated hepatic vein Dilated IVC FIGURE 58-2. US of elevated right atrial pressures. Inferior vena cava (IVC) and hepatic vein dilation. FIGURE 58-3. Cardiac US, parasternal short-axis view (PSS), of right ventricle (RV) and left ventricle (LV). Notice the flattening of the interventricular septum occurring in systole, suggesting elevated right ventricular systolic pressures. This is also known as a D-shaped septum. Illustration of normal PSS view in top left corner. Flat septum Dilated right ventricle Left ventricle LABORATORY TESTING Routine laboratory testing (e.g., CBC, comprehensive metabolic panel) is nonspecific. Elevations in troponin from myocardial ischemia or a strain-induced leak of B-type natriuretic peptide are associated with more serious disease. 18-21 Elevated liver function tests, lactate, and coagulation panel can reflect liver congestion and are a poor prognostic finding. IMAGING Common chest radiographic abnormalities associated with pulmonary hypertension include enlargement of the right atrium, RV , and hilar pulmonary arteries. 13,23 Depending on the cause, additional radiographic findings might include pulmonary edema, hyperinflation, or interstitial lung disease. In most patients presenting with dyspnea, a chest radio graph may identify other causes of dyspnea, such as pneumonia or pneumothorax. Transthoracic echocardiography (TTE) is the best initial diagnostic test to assess pulmonary hypertension in the ED. Signs of disease severity include RV hypertrophy, decreased RV function, and tricus pid regurgitation. 1,4 Echocardiography detects precipitating factors for RV failure, including ventricular regional wall motion abnormalities and acute valvular abnormalities. 24 Additional findings in patients with severe disease include leftward deviation of the intraventricular septum and an RV-to-left ventricle end-diastolic diameter >1 in the four-chamber view. 1,25 Figures 58-2, 58-3, and 58-4 demonstrate typical echocardiographic findings in patients with pulmonary hypertension. CT pulmonary angiography is the imaging method of choice to evaluate for acute pulmonary embolism (PE). TTE should not be used to exclude acute venous thromboembolism (VTE). 26 Given the high risk for VTE in this patient population, obtain a CT angiogram early if an acute PE is suspected, which also allows RV assessment. 27,28 TREATMENT The mainstays of ED therapy are supplemental oxygen, optimizing intravascular volume, augmenting RV function, maintaining coronary artery perfusion, and decreasing RV afterload (Table 58-2). OXYGEN AND MECHANICAL VENTILATION Consensus opinion is to titrate supplemental oxygen to maintain a level >90% (rather than routinely targeting higher saturations). 29 Although intubation and mechanical ventilation are common ED therapies for the patient with acute respiratory failure, RV failure is often exacerbated by positive-pressure ventilation, with rapid cardiovascular collapse due to increased intrathoracic pressure and reduced coronary perfusion. Tintinalli_Sec07_p0329-0424.indd 410 8/2/19 6:43 PM
mechanical ventilation are common ED therapies for the patient with acute respiratory failure, RV failure is often exacerbated by positive-pressure ventilation, with rapid cardiovascular collapse due to increased intrathoracic pressure and reduced coronary perfusion. Tintinalli_Sec07_p0329-0424.indd 410 8/2/19 6:43 PM CHAPTER 58: Pulmonary Hypertension 411 TABLE 58-2 Pharmacotherapy for Acute Pulmonary Hypertension Condition Drug Comments RV failure Dobutamine 2–10 micrograms/kg/min or Milrinone 0.125–0.375 microgram/kg/min Avoid >10 micrograms/ kg/min Higher doses can cause hypotension RCA perfusion Norepinephrine 0.05–0.75 microgram/kg/min Avoid high doses of norepinephrine; avoid dopamine and phenylephrine afterload Inhaled epoprostenol: 50 nanograms/kg/min Inhaled nitric oxide: 20–80 ppm IV prostanoids Inhaled therapy limits vasodilatory effect to pulmonary circulation. Rarely initiated in ED; obtain consultation Abbreviations: RCA = right coronary artery; RV = right ventricle. FIGURE 58-4. Apical four-chamber (A4C) view of right ventricle (RV) and left ventricle (LV). The right atrium (RA) and RV are dilated, with RV is dilated with hypertrophy of the RV trabeculae, indicating chronic RV overload. The interventricular septum is shifted toward the LV in systole, suggesting RV pressure overload. Illustration of normal A4C view in top left corner. LV RV LA RA Dilated right atrium RV hypertrophy Underfilled left ventricle If ventilation is needed, set the ventilator to maintain low airway pressure, using lung-protective settings (i.e., a tidal volume of 6 to 8 mL/kg of ideal body weight and the lowest positive end-expiratory pressure to maintain the oxygen saturation >90%), 29 and target a plateau pressure of <30 cm H2O. Adjust the respiratory rate to avoid hypercapnia, which can increase pulmonary vascular resistance, pulmonary artery pressure, and RV strain. INTRAVASCULAR VOLUME Volume overload can cause RV dilation, impaired left ventricular out put, and ultimately compromise tissue perfusion. 3 For patients who are hypovolemic, fluid challenges with 100- to 250-mL of isotonic crystal loid is a good first step. 26 Dynamic measures of volume responsiveness may be unreliable due to baseline elevations in right-sided pressures. 31 Eventually, diuresis may be accomplished to remove any excess fluid. RV FUNCTION For RV failure without hypotension, inotropic therapy to augment contractility and RV afterload can improve cardiac output. Dobutamine (a β 1 agonist) is preferred, starting at 2 micrograms/kg/min and titrated to 10 micrograms/kg/min. 29,32,33 Higher doses of dobutamine can cause tachydysrhythmias and hypotension. 34,35 For patients unable to tolerate dobutamine, milrinone, a phosphodiesterase-3 inhibitor, is an option. 29 Initiate milrinone at 0.125 microgram/kg/min and titrate to a maximum of 0.75 microgram/kg/min. Higher doses of milrinone can cause hypotension and require cardiac output monitor ing for titration. RIGHT CORONARY ARTERY PERFUSION Adequate perfusion of the right coronary artery is necessary to main tain RV function. To maintain right coronary artery blood flow, arterial pressure at the aortic root must be higher than the pulmonary artery pressure. For the hypotensive pulmonary hypertension patient, initiate vasopressor therapy. Although there are limited data regarding a singular superior agent, most experts recommend norepinephrine, 29 aiming to improve cardiac output, initiated at a dose of 0.05 microgram/kg/min. Avoid high doses of norepinephrine, which may increase pulmonary vascular resistance and impair RV output. Avoid dopamine, which can cause tachydysrhythmias, and avoid phenylephrine, which may provide less benefit compared to norephinephrine.
ming to improve cardiac output, initiated at a dose of 0.05 microgram/kg/min. Avoid high doses of norepinephrine, which may increase pulmonary vascular resistance and impair RV output. Avoid dopamine, which can cause tachydysrhythmias, and avoid phenylephrine, which may provide less benefit compared to norephinephrine. RV AFTERLOAD Patients with chronic pulmonary hypertension may be prescribed pulmonary vasodilators as outpatients. Such agents are rarely initi ated in the ED. The most commonly prescribed outpatient pulmonary vasodilators are prostanoids, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors ( Table 58-3). For the acutely ill patient receiving outpatient IV prostanoid therapy, restart the home infusion quickly. The first step is to confirm patency of the home IV catheter and check for proper infusion pump function. If occlusion or malfunction is detected, immediately restart the homeadministered prostanoid through a peripheral IV . If initiating pulmonary vasodilator therapy for acute exacerbations of pulmonary hypertension with RV failure, inhaled therapy with epoprostenol or nitric oxide therapy can be administered by facemask, high-flow nasal cannula, or endotracheal tube to reduce RV afterload and improve patient hemodynamics. 50 Initiation of IV pulmonary vasodilators is not recommended in the acutely ill patient. DISPOSITION AND FOLLOW-UP When patients with pulmonary hypertension present to an ED, they are often critically ill and with evidence of acute right heart failure. Nearly all require admission, often to an intensive care or coronary care unit with expertise in pulmonary hypertension. On rare occa sions, a mildly symptomatic patient may be discharged home after consultation, care plan development, and close follow-up with the primary provider. Tintinalli_Sec07_p0329-0424.indd 411 8/2/19 6:43 PM