What is the evidence on the use of high-dose nitroglycerin for SCAPE?
Heart failure is a complex syndrome resulting from a number of causes, most commonly coronary artery disease, and is associated with increased morbidity and mortality.1 In the United States, heart failure accounts for 65,000 deaths and 1 million hospitalizations annually.2
Heart failure is characterized by the heart’s inability to move blood throughout the circulatory system, due to dysfunction in heart contractility and filling.1,3 Adaptive responses by the body can compensate for cardiac dysfunction seen in heart failure, making it a chronic condition.
However, even with adaptive responses, acute decompensation can occur. This acute phase of decompensation is known as acute heart failure syndrome (AHFS). Symptoms of AHFS, most commonly dyspnea, can develop rapidly and require immediate treatment, usually in the emergency department.3,4 One distinct subgroup of AHFS manifests with systolic hypertension and rapid onset (minutes to hours) pulmonary congestion and severe dyspnea, and is referred to by several names, including hypertensive acute heart failure (H-AHF), flash pulmonary edema, and sympathetic crashing acute pulmonary edema (SCAPE).5-8 Untreated, SCAPE can result in respiratory failure and death.
The sudden onset of pulmonary congestion and dyspnea in SCAPE is primarily a result of vascular redistribution, caused by sympathetic stimulation of splanchnic veins.3,5 This stimulation causes venoconstriction and mobilization of up to 800 mL of blood into the systemic circulation. With existing cardiac dysfunction, both preload and afterload are increased, with eventual movement of that volume into the pulmonary circulation precipitating rapid pulmonary congestion and severe dyspnea. Hypertension is also present in SCAPE, with systolic blood pressures exceeding 140 mm Hg.
Treatment of SCAPE
The initial focus on the treatment of any AHFS is stabilization in the emergency department, followed by in-hospital management and discharge planning.9 For SCAPE, rapid stabilization can reduce the need for mechanical ventilation and intensive care unit admission and prevent morbidity and mortality.3
Treatment options for AHFS include diuretics, morphine, nitroglycerin, and assisted ventilation. Although diuretics and morphine are commonly used for the treatment of pulmonary edema resulting from fluid overload in decompensated heart failure, the underlying mechanism of pulmonary edema in SCAPE differs, making use of these agents less beneficial. 4,5 Nitroglycerin can be effective for treatment of SCAPE by reducing both preload and afterload when dosed appropriately. For AHFS, nitroglycerin is typically given as intravenous infusion doses of 10 to 20 mcg/min. While venodilatation can be achieved, this low dose does not provide arteriodilatation for afterload reduction; therefore, higher doses of nitroglycerin are needed for SCAPE.
Efficacy of high-dose nitroglycerin in SCAPE
Literature is available describing the use of high-dose nitroglycerin for the treatment of SCAPE. Overall, when given at doses of up to 800 mcg/min by infusion or by repeated 2 mg intravenous bolus, nitroglycerin has been associated with reduced need for intubation and intensive care unit admission, and symptom stabilization in patients with SCAPE or hypertensive acute heart failure with dyspnea. These reports are summarized in the Table.
|Table. High-dose nitroglycerin for treatment of SCAPE.7, 10-14|
|Study design and duration||Subjects||Interventions||Results|
|Stemple et al 202010|
|4 patients with SCAPE (heart failure, hypertension, and dyspnea)||NTG infusion 400 mcg/min increased to 800 mcg/min after 8 or 30 min then tapered off, with or without BiPAP; 1 patient was initiated on 200 mcg/min and kept at >150 mg/min for 1 h 45 min||All patients achieved symptomatic improvement following prolonged NTG infusion with no need for mechanical ventilation|
|Paone et al 20187|
|87-year-old male with hypertension and severe dyspnea||NTG infusion started at 400 mcg/min and titrated down every 5 minutes by 50 mcg/min until symptom resolution (resolution of at least 2 of the following: tachypnea, dyspnea, hypoxia, hypertension)||Symptom resolution criteria were met at 6 minutes after initiation of NTG infusion; no additional interventions were needed and NTG was discontinued|
|Hsieh et al 201811|
|3 patients with hypertension and severe dyspnea||All 3 patients underwent BiPAP with NTG 1 mg IVP every 2 minutes;1 patient received NTG infusion at 40 mcg/min|
All 3 patients initially received 3 SL NTG doses without improvement
|3 to 6 doses of NTG IVP resulted in symptom stabilization with discontinuation of BiPAP|
|Wilson et al 201712|
|395 patients with AHF given NTG as a bolus, continuous infusion, or both during a 5-year period||Bolus NTG was prepared as 10 mg in 10 mL and given in increments of up to 2 mg every 3 to 5 minutes|
NTG infusions were titrated according to physician preference
For bolus only, the median NTG total bolus was 2 mg (79% of patients received one dose)
For infusion only, the median infusion rate was 20 mcg/min with a maximum rate of 35 mcg/min and a median duration of 16 hours
For combination therapy, the median starting infusion rate was 20 mcg/min, with a maximum of 60 mcg/min and a median duration of 16.5 hours; the median bolus dose was 2 mg (40.5% of patients received one dose)
|ICU admission occurred in 48.4%, 68.7%, and 83% in the bolus, infusion, and combination groups, respectively (p<0.0001)
Hospital length of stay was also lower in the bolus group (3.7 vs 4.7 vs 5.0 days; p=0.02)
|Mallick et al 201113|
Prospective cohort study
|41 patients with SCAPE expected to need emergent intubation||NPPV followed by repeated bolus doses of NTG|
Mean NTG bolus dose was 4 (mean 1588 mcg)
|No patient required intubation and all had improvement in respiratory parameters|
|Levy et al 200714|
Open-label, nonrandomized, single-arm
|29 adults with severe decompensated HF who did not respond to an initial treatment regimen||NTG infusion at 0.3 to 0.5 mcg/kg/min, titrated to a maximum of 400 mcg/min with concurrent 2 mg IV bolus repeated to a maximum of 20 mg over 30 minutes; along with standard of care||ET intubation within 6 hours, BiPAP ventilation, and ICU admission occurred in 13.8%, 6.9%, and 37.9% of treated patients vs 26.7%, 20.0%, 80% in noninterventional patients compared retrospectively|
|Abbreviations: AHF=acute heart failure; BiPAP=bi-level positive airway pressure; ET=endotracheal intubation; HF=heart failure; ICU=intensive care unit; IV=intravenous; IVP= intravenous push; NPPV=non-invasive positive pressure ventilation; NTG=nitroglycerin; SCAPE=sympathetic crashing acute pulmonary edema; SL=sublingual
Additionally, Agrawal et al have proposed an algorithm for nitroglycerin use for the treatment of SCAPE.4 The authors suggest a nitroglycerin bolus dose of 500 to 1000 mcg over 2 minutes, followed by a nitroglycerin infusion at 100 mcg/min, with rapid titration to 400 mcg/min, then a rapid reduction to 100 mcg/min and tapering with clinical improvement. This regimen includes concurrent use of non-invasive ventilation, close monitoring of blood pressure and oxygen saturation, and avoidance of diuretics.
Paone et al propose an initial infusion rate of nitroglycerin of 400 mcg/min (the maximum infusion rate), with titration down by 50 mcg/min every 5 minutes, with BiPAP as needed; endotracheal intubation may be performed after 20 minutes if no symptom resolution is seen.7 Criteria for resolution include improvements in at least 2 of the following: tachypnea, dyspnea, hypoxia, and systolic blood pressure or mean arterial pressure.
Treatment of acute heart failure generally consists of diuretics for management of volume overload, with vasodilators used for patients resistant to this therapy.9 However, for patients with SCAPE, the underlying cause of decompensation is not volume overload but rather vascular redistribution of fluid, resulting in sudden onset of pulmonary edema and severe dyspnea in the presence of hypertension.4,5,7 For these patients, reduction in both preload and afterload is needed, requiring the use of vasodilators such as nitroglycerin. To achieve this effect, doses of nitroglycerin higher than those typically used in acute heart failure are needed. Although data are limited, nitroglycerin has been shown to be effective for the treatment of SCAPE when administered at initial infusion rates of 400 mcg/min, with rapid downward titration, or with intravenous bolus doses of 1 to 2 mg.4,7,10-12 This approach has resulted in symptom resolution and avoidance of mechanical ventilation in patients with SCAPE. However, more study is needed to determine the optimal dose of nitroglycerin in SCAPE.
- Gaggin HK, Dec G. Pathophysiology of heart failure. In: Fuster V, Harrington RA, Narula J, Eapen ZJ. eds. Hurst’s The Heart. 14th ed. McGraw-Hill; Accessed March 09, 2021. https://accessmedicine-mhmedical-com.proxy.cc.uic.edu/content.aspx?bookid=2046§ionid=176561634
- Gupta DK, Andersson C, Vasan RS, Wang TJ. The epidemiology of heart failure. In: Fuster V, Harrington RA, Narula J, Eapen ZJ. eds. Hurst’s The Heart. 14th ed. McGraw-Hill; Accessed March 09, 2021. https://accessmedicine-mhmedical-com.proxy.cc.uic.edu/content.aspx?bookid=2046§ionid=176561808
- Weintraub NL, Collins S, Pang PS, et al. Acute heart failure syndromes: emergency department presentation, treatment, and disposition: current approaches and future aims. Circulation. 2010;122(19):1975-1996.
- Agrawal N, Kumar A, Aggarwal P, Jamshed N. Sympathetic crashing acute pulmonary edema. Indian J Crit Care Med. 2016; 20(12): 719–723.
- Collins S, Martindale J. Optimizing hypertensive acute heart failure management with afterload reduction. Curr Hypertens Rep. 2018;20(1):9. doi: 10.1007/s11906-018-0809-7.
- Wang K, Samai K. Role of high-dose intravenous nitrates in hypertensive acute heart failure. Am J Emerg Med. 2020;39(1):132-137.
- Paone S, Clarkson L, Sin B. Punnapuzha S. Recognition of sympathetic crashing acute pulmonary edema (SCAPE) and use of high-dose nitroglycerin infusion. Am J Emerg Med. 2018;36(8):1526e5-1526e7.
- Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: Current state and framework for future research. Circulation. 2005;112(25):3958-3968.
- Bloom M, Cole RT, Butler J. Evaluation and management of acute heart failure. In: Fuster V, Harrington RA, Narula J, Eapen ZJ. eds. Hurst’s The Heart. 14th ed. McGraw-Hill; Accessed March 09, 2021. https://accessmedicine-mhmedical-com.proxy.cc.uic.edu/content.aspx?bookid=2046§ionid=176562062
- Stemple K, DeWitte K, Porter BA, et al. High-dose nitroglycerin infusion for the management of sympathetic crashing acute pulmonary edema (SCAPE): a case series. Am J Emerg Med. 2020;S0735-6757(20)30219-9.doi: 10.1016/j.ajem.2020.03.062.
- Hsieh Y, Lee T, Kao J, Hsu H, Chong C. Treating acute hypertensive cardiogenic pulmonary edema with high-dose nitroglycerin. Turk J Emerg Med. 2018;18(1):34-36.
- Wilson S, Kwiatkowski GM, Millis SR, et al. Use of nitroglycerin by bolus prevents intensive care unit admission in patients with acute hypertensive heart failure. Am J Emerg Med. 2017;35(1):126-131.
- Mallick P, Upadhyay S, Senthilnathan T, Waleed E, Weingart S. 258. A protocol of bolus-dose nitroglycerin and non-invasive ventilation to avert intubation in emergency department acute pulmonary edema. Crit Care Med. 2011;39(12):67.
- Levy P, Compton S, Welch R, et al High-dose intravenous nitroglycerin: a feasibility and outcome analysis. Ann Emerg Med. 2007;50(2):144-153.
Joan Stachnik, PharmD
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy
The information presented is current as March 6. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.